Substituted pyrrolo[2,3-d]pyrimidines, their preparation and their 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] Disclosed herein are substituted pyrrolo[2,3-d]pyrimidine compounds, methods for their preparation, pharmaceutical compositions containing the compounds, and their therapeutic uses. [Background technology]

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

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

[0004] Immunofluorescence experiments in human brain showed colocalization of LRRK2 with neurofibrillary tangles (Non-Patent Document 12). Furthermore, LRRK2 has been reported to phosphorylate microtubule-associated tau (Non-Patent Document 13), and tau hyperphosphorylation has been observed in LRRK2 kinase-activated mutant transgenic mice (Non-Patent Document 14). These data indicate that LRRK2 kinase inhibitor treatment may be useful in treating tauopathy 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 Document 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 have utility in treating these pathologies.

[0006] Patent Document 1 discloses compounds having a pyrrolopyrimidine nucleus substituted with a (hetero)arylamine group and a cyano group. These compounds are capable of inhibiting 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-associated diseases.

[0008] Patent Document 3 discloses compounds having a pyrrolopyrimidine nucleus substituted with a (hetero)arylamino group and a cyano group, which can 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] EM Rocha 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] MS Moehle et al., J.Neurosci.2012 Summary of the Invention [Problem to be solved by the invention]

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

[0012] Summary of the Invention According to one embodiment, a compound of formula (I): [ka] [In formula: R1 is selected from the group consisting of aryl groups, ortho-fused bicyclic heteroaryl groups, and heteroaryl groups, wherein the ortho-fused bicyclic heteroaryl groups are unsubstituted or substituted with one or more -(C1-C3)-alkyl groups; and wherein the aryl and heteroaryl groups are unsubstituted or a) a fluorine atom, b) deuterium atoms, c) an alkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group; d) cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, -(C1-C3)-alkyl groups or hydroxy 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) alkyloxyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy groups and fluorine atoms; g) —O-cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, —(C1-C3)-alkyl groups or hydroxy groups; h) an —O-heterocycloalkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, a hydroxy group, and an alkylcarbonyl group; i) an -O-spirocyclic group, j) alkylsulfonylalkyl groups, and k) alkylsulfonyl group substituted with one or more substituents independently selected from the group consisting of: R2 is selected from the group consisting of alkyloxylalkyl groups and heterocycloalkyl groups, wherein the heterocycloalkyl groups represented by R2 are bonded through a carbon atom and are unsubstituted or substituted with an alkyl group, an alkyloxyl group, or one or more fluorine atoms; or a pharmaceutically acceptable salt thereof is 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 compounds of formula (I) above and their pharmaceutically acceptable salts exhibit inhibitory activity against wild-type and mutant LRRK2 and are useful in the treatment of neurodegenerative diseases. DETAILED DESCRIPTION OF THE INVENTION

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

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

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

[0018] As used herein, the term "alkylcarbonyl" means alkyl-C(=O)-, where alkyl is as defined herein. Exemplary alkylcarbonyls include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, and isobutylcarbonyl.

[0019] As used herein, the term "alkyloxyl" means alkyl-O-, where alkyl is as described herein. Examples of alkyl-O- are methoxyl, ethoxyl, n-propoxyl, isopropoxyl, n-butoxyl, isobutoxyl, sec-butoxyl, tert-butoxyl, and the like.

[0020] As used herein, the term "alkyloxylalkyl" means an alkyl-O-alkyl- group having two straight-chain or branched alkyl groups as defined herein that are independent of each other.

[0021] As used herein, the term "alkylsulfonyl" means alkyl-S(=O)2-, where alkyl is as defined herein. Exemplary alkylsulfonyl groups 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" means an aromatic monocyclic or bicyclic ring system of about 5 to about 10 carbon atoms. Exemplary 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 cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0025] As used herein, the term "heteroaryl," whether used alone or with other terms, such as "heteroaryl group," refers to a cyclic aromatic group containing 2 to 10 carbon atoms and between 1 and 4 heteroatoms, such as nitrogen, oxygen, or sulfur. The heteroaryl group can be monocyclic or bicyclic. As used herein, the term "monocyclic heteroaryl" refers to a cyclic aromatic group containing 2 to 5 carbon atoms and between 1 and 3 heteroatoms, such as nitrogen, oxygen, or sulfur. Examples of monocyclic heteroaryl groups may 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, thiophene, and the like.

[0026] As used herein, the term "heterocycloalkyl" means a 4-, 5-, 6-, or 7-membered non-aromatic monocyclic ring system having at least one carbon atom and at least one non-carbon heteroatom, such as nitrogen, oxygen, or sulfur. Examples of heterocycloalkyl include azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dioxepanyl, dithiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, hexahydro-1,3,5-triazinyl, trioxanyl, trithianyl, azepanyl, oxepanyl, thiepanyl, and diazepanyl.

[0027] As used herein, the term "ortho-fused" refers to a ring system in which two adjacent rings share two adjacent atoms and the second ring is alpha to the branched carbon atom. The term "ortho-fused heteroaryl" refers to 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 rings in which both rings are monocyclic heteroaryl, are included within the definition of an ortho-fused heteroaryl group. Examples include indolyl and benzimidazolyl.

[0028] As used herein, the term "spirocycle" or "spirocyclic" refers to a carbogenic bicyclic ring system in which both rings are connected through a single atom. The rings may be different in size and nature or may be the same in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both rings in a spirocycle may be fused to another carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more of the carbon atoms in the spirocycle may be replaced with a heteroatom (e.g., O, N, S, or P). C5-C 12 A spirocycle is a spirocycle containing between 5 and 12 carbon atoms. One or more of the carbon atoms may be replaced by a heteroatom.

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

[0030] As used herein, the term "one or more substituents" refers to a number of substituents equal to one to the maximum number of possible substituents based on the number of available bonding sites, provided that the above conditions of stability and chemical feasibility are met. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position 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 instances of a given variable in a single compound.

[0032] As used herein, the term "unsubstituted" indicates that the respective group does not bear any specified substituents.

[0033] As used herein, the term "pharmaceutically acceptable salts" refers to the relatively non-toxic, inorganic and organic acid addition salts, and base addition salts, of compounds of Formula (I), which may be prepared in situ during the final isolation and purification of the compounds.

[0034] When a compound of formula (I) contains one or more acidic or basic groups, such as a basic heterocyclic group, the present disclosure also includes corresponding physiologically or toxicologically acceptable salts, particularly pharmaceutically acceptable salts. Thus, compounds of formula (I) can be deprotonated at the acidic group and used, for example, as alkali metal or ammonium salts. Compounds of formula (I) containing at least one basic group can be prepared and used in the form of their acid addition salts, for example, in the form of pharmaceutically acceptable salts with inorganic and organic acids. 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 conventional procedures. When a compound of formula (I) contains both an acidic and a basic group in the molecule, the present disclosure also includes internal salts (betaines, zwitterions) in addition to the above-mentioned salt forms. The present disclosure also includes all salts of compounds of formula (I) which, because of their poor physiological tolerability, are not directly suitable for pharmaceutical use, but are suitable as intermediates for chemical reactions or for the preparation of physiologically acceptable salts, for example using anion or cation exchange.

[0035] As used herein, the term "pharmaceutically acceptable excipient" refers to a non-toxic solvent, dispersant, excipient, adjuvant, or other material that is mixed with the compounds of the present disclosure to allow the formation of a pharmaceutical composition, i.e., a dosage 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 term "pharmaceutically effective amount" or "therapeutically effective amount" means an amount of a compound / composition according to the present disclosure effective in producing the desired therapeutic effect.

[0037] As used herein, the term "treating" or "treatment" means to halt, slow, or reduce the progression of a disease; to cause regression of its biological signs and / or clinical symptoms; i.e., to inhibit 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 human suffering from a disease.

[0039] As used herein, the term "compounds of formula (I)", and equivalent expressions, where the context allows, are intended to include racemic compounds of formula (I), as well as their enantiomers, epimers, diastereomers, geometric isomers, tautomers and mixtures thereof.

[0040] As used herein, the term "isomers" refers to compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space. The terms "isomer 1" and "isomer 2" can be assigned to isomers of known absolute configuration or can be used to describe stereoisomers of unknown absolute configuration. Thus, use of the terms "isomer 1" and "isomer 2" should not be construed as indicating that the absolute configuration of both isomers is known. The term "isomeric 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 non-superimposable mirror images of each other. 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 plane of polarized light of the molecule and are designated as dextrorotatory or levorotatory (i.e., (+)- or (-)-isomer, respectively). Chiral compounds can exist as either individual enantiomers, individual diastereomers, or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture." A mixture containing any proportion of diastereomers is called a "diastereomeric 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. "Racemic trans" refers to equal proportions of two trans enantiomers, and "racemic cis" refers to equal proportions of two cis enantiomers. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, chromatography and / or fractional crystallization. Enantiomers can also be separated directly using chiral chromatographic techniques or indirectly using enzymatic methods. It is understood that all such isomers and mixtures thereof, in any proportion, are encompassed within the scope of the present disclosure.

[0042] Formula (I): [ka] [In formula: R1 is selected from the group consisting of aryl groups, ortho-fused bicyclic heteroaryl groups, and heteroaryl groups, wherein the ortho-fused bicyclic heteroaryl groups are unsubstituted or substituted with one or more -(C1-C3)-alkyl groups; and wherein the aryl and heteroaryl groups are unsubstituted or a) a fluorine atom, b) deuterium atoms, c) an alkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group; d) cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, -(C1-C3)-alkyl groups or hydroxy 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) alkyloxyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy groups and fluorine atoms; g) —O-cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, —(C1-C3)-alkyl groups or hydroxy groups; h) an —O-heterocycloalkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, a hydroxy group, and an alkylcarbonyl group; i) an -O-spirocyclic group, j) alkylsulfonylalkyl groups, and k) alkylsulfonyl group substituted with one or more substituents independently selected from the group consisting of: R2 is selected from the group consisting of alkyloxylalkyl groups and heterocycloalkyl groups, wherein the heterocycloalkyl groups represented by R2 are bonded via a carbon atom and are unsubstituted or substituted with an alkyl group, an alkyloxyl group, or one or more fluorine atoms; or a pharmaceutically acceptable salt thereof.

[0043] Formula (I): [ka] [In formula: R1 is selected from the group consisting of aryl groups, ortho-fused bicyclic heteroaryl groups, and heteroaryl groups, wherein the ortho-fused bicyclic heteroaryl groups are unsubstituted or substituted with one or more -(C1-C3)-alkyl groups; and wherein the aryl and heteroaryl groups are unsubstituted or a) a fluorine atom, b) deuterium atoms, c) an alkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group; d) cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms or by -(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) alkyloxyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy groups and fluorine atoms; g) —O-cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms or by —(C1-C3)-alkyl groups; h) an —O-heterocycloalkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, and alkylcarbonyl groups; i) an -O-spirocyclic group, j) alkylsulfonylalkyl groups, and k) alkylsulfonyl group substituted with one or more substituents independently selected from the group consisting of: R2 is selected from the group consisting of alkyloxylalkyl groups and heterocycloalkyl groups, wherein the heterocycloalkyl groups represented by R2 are bonded via a carbon atom and are unsubstituted or substituted with an alkyl group, an alkyloxyl group, or one or more fluorine atoms; or a pharmaceutically acceptable salt thereof.

[0044] One embodiment is a compound of formula (I), wherein R1 is selected from the group consisting of phenyl and heteroaryl groups, wherein the aryl and heteroaryl groups are unsubstituted or a) a fluorine atom, b) an alkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group; c) cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, -(C1-C3)-alkyl groups or hydroxy 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 which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy groups and fluorine atoms; f) -O-cycloalkyl groups which are unsubstituted or substituted with one or more fluorine atoms, -(C1-C3)-alkyl groups or hydroxy 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, hydroxy groups, and alkylcarbonyl groups; h) an -O-spirocyclic group, i) alkylsulfonylalkyl groups, and j) Alkylsulfonyl group substituted with one or more substituents independently selected from the group consisting of: R2 is selected from the group consisting of alkyloxylalkyl groups and heterocycloalkyl groups, where the heterocycloalkyl groups represented by R2 are bonded through a carbon atom and are unsubstituted or substituted with an alkyl group, an alkyloxyl group, or one or more fluorine atoms; or a pharmaceutically acceptable salt thereof.

[0045] One embodiment is a compound of formula (I), wherein: R1 is a substituted or unsubstituted phenyl group, an ortho-fused bicyclic heteroaryl group, and [ka] selected from the group consisting of: wherein the ortho-fused bicyclic heteroaryl group is unsubstituted or substituted with one or more -(C1-C3)-alkyl groups; R2 is selected from the group consisting of alkyloxylalkyl groups and heterocycloalkyl groups, where the heterocycloalkyl groups are bonded via a carbon atom and are 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 hydroxy groups and fluorine atoms; b) -O-cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, -(C1-C3)-alkyl groups or hydroxy 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 hydroxy groups; and d) -O-spirocyclic group selected from the group consisting of: R5 is a) a hydrogen atom, b) an alkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group; c) cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, -(C1-C3)-alkyl groups or hydroxy 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 a hydrogen atom and a deuterium atom; or a pharmaceutically acceptable salt thereof.

[0046] One embodiment is a compound of formula (I), wherein: R1 is [ka] It is a base;

[0047] R2 is an alkyloxylalkyl group, and [ka] selected from the group consisting of: where 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 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 hydroxy groups and fluorine atoms; b) -O-cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, -(C1-C3)-alkyl groups or hydroxy 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, hydroxy groups, and alkylcarbonyl groups; and d) -O-spirocyclic group selected from the group consisting of: R5 is a) a hydrogen atom, b) an alkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group; c) cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, -(C1-C3)-alkyl groups or hydroxy 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 a hydrogen atom and a deuterium atom; or a pharmaceutically acceptable salt thereof.

[0048] One embodiment is a compound of formula (I), wherein: R1 is selected from the group consisting of phenyl and heteroaryl groups, wherein the phenyl and heteroaryl groups are unsubstituted or a) a fluorine atom, b) deuterium atoms, c) an alkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group; d) cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, -(C1-C3)-alkyl groups or hydroxy 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) alkyloxyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy groups and fluorine atoms; g) -O-cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, -(C1-C3)-alkyl groups or hydroxy groups; h) an —O-heterocycloalkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, a hydroxy group, and an alkylcarbonyl group; i) an -O-spirocyclic group, j) alkylsulfonylalkyl groups, and k) alkylsulfonyl group substituted with one or more substituents independently selected from the group consisting of: R2 is bonded via a carbon atom and is unsubstituted or is an alkyl group, an alkyloxyl group or a heterocycloalkyl group substituted with one or more fluorine atoms; or a pharmaceutically acceptable salt thereof.

[0049] One embodiment is a compound of formula (I), wherein: R1 is [ka] It is a base; R2 is bonded via a carbon atom and is unsubstituted or is an alkyl group, an alkyloxyl group or a heterocycloalkyl group substituted with 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 hydroxy groups and fluorine atoms; b) -O-cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, -(C1-C3)-alkyl groups or hydroxy 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 hydroxy groups; and d) -O-spirocyclic group selected from the group consisting of: R5 is a) a hydrogen atom, b) an alkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group; c) cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, -(C1-C3)-alkyl groups or hydroxy 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 a hydrogen atom and a deuterium atom; or a pharmaceutically acceptable salt thereof.

[0050] One embodiment is a compound of formula (Ia) [ka] [In formula: R1 is selected from the group consisting of aryl groups, ortho-fused bicyclic heteroaryl groups, and heteroaryl groups, wherein the ortho-fused bicyclic heteroaryl groups are unsubstituted or substituted with one or more -(C1-C3)-alkyl groups; and the aryl and heteroaryl groups are unsubstituted or a) deuterium atoms, b) a fluorine atom, c) an alkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group; d) cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, hydroxy groups or -(C1-C3)-alkyl groups; e) heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from alkyl, alkyloxyl, or alkylcarbonyl groups; f) alkyloxyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy groups and fluorine atoms; g) -O-cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, -(C1-C3)-alkyl groups or hydroxy groups; h) an —O-heterocycloalkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, an alkylcarbonyl group, and a hydroxy group; i) an -O-spirocyclic group, j) alkylsulfonylalkyl groups, and k) alkylsulfonyl 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 0 or 1]; or a pharmaceutically acceptable salt thereof.

[0051] One embodiment is a compound of formula (Ia) [ka] [In formula: R1 is selected from the group consisting of aryl groups, ortho-fused bicyclic heteroaryl groups, and heteroaryl groups, wherein the ortho-fused bicyclic heteroaryl groups are unsubstituted or substituted with one or more -(C1-C3)-alkyl groups; and the aryl and heteroaryl groups are unsubstituted or a) deuterium atoms, b) a fluorine atom, c) an alkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group; d) cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms or by -(C1-C3)-alkyl groups; e) heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from alkyl, alkyloxyl, or alkylcarbonyl groups; f) alkyloxyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy groups and fluorine atoms; g) —O-cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms or by —(C1-C3)-alkyl groups; h) an —O-heterocycloalkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, and alkylcarbonyl groups; i) an -O-spirocyclic group, j) alkylsulfonylalkyl groups, and k) alkylsulfonyl 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 0 or 1]; or a pharmaceutically acceptable salt thereof.

[0052] One embodiment is a compound of formula (Ia), wherein: R1 is selected from the group consisting of phenyl and heteroaryl groups, wherein the phenyl and heteroaryl groups are unsubstituted or a) a fluorine atom, b) an alkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group; c) cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, hydroxy 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 which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy groups and fluorine atoms; f) -O-cycloalkyl groups which are unsubstituted or substituted with one or more fluorine atoms, -(C1-C3)-alkyl groups or hydroxy 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 hydroxy groups; h) an -O-spirocyclic group, i) alkylsulfonylalkyl groups, and j) Alkylsulfonyl 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]; or a pharmaceutically acceptable salt thereof.

[0053] One embodiment is a compound of 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 hydroxy groups and fluorine atoms; b) -O-cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, -(C1-C3)-alkyl groups or hydroxy 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 hydroxy groups; and d) -O-spirocyclic group selected from the group consisting of: m represents 1, 2 or 3; n represents 0 or 1; R5 is a) a hydrogen atom, b) an alkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group; c) cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, hydroxy 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: R6 is selected from the group consisting of a hydrogen atom and a deuterium atom; or a pharmaceutically acceptable salt thereof.

[0054] One embodiment is a compound of 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 hydroxy groups and fluorine atoms; b) -O-cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms or by -(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-spirocyclic group selected from the group consisting of: m represents 1, 2 or 3; n represents 0 or 1; R5 is a) a hydrogen atom, b) an alkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group; c) cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms or by -(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 a hydrogen atom and a deuterium atom; or a pharmaceutically acceptable salt thereof.

[0055] One embodiment is a compound of 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 hydroxy groups and fluorine atoms; b) -O-cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, -(C1-C3)-alkyl groups or hydroxy 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 hydroxy groups; and d) -O-spirocyclic group selected from the group consisting of: m represents 1 or 2; n represents 0 or 1; R5 is a) a hydrogen atom, b) an alkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group; c) cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, -(C1-C3)-alkyl groups or hydroxy 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 a hydrogen atom]; or a pharmaceutically acceptable salt thereof.

[0056] One embodiment is a compound of 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 hydroxy groups and fluorine atoms; b) -O-cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, -(C1-C3)-alkyl groups or hydroxy groups, and c) an —O-heterocycloalkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, an alkylcarbonyl group, and a hydroxy group; 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 hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group; b) cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, hydroxy 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: R6 is a hydrogen atom]; or a pharmaceutically acceptable salt thereof.

[0057] One embodiment is a compound of formula (Ib) [ka] [In formula: R3 is a -(C1-C3)-alkyl group; R4 is a) -O-cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, -(C1-C3)-alkyl groups or hydroxy groups; b) an —O-heterocycloalkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, an alkylcarbonyl group, and a hydroxy group; and m represents 1; n represents 1; R5 is an alkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy 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]; or a pharmaceutically acceptable salt thereof.

[0058] One embodiment is a compound of 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 hydroxy groups and fluorine atoms; b) -O-cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, -(C1-C3)-alkyl groups or hydroxy 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 hydroxy groups; and d) -O-spirocyclic group selected from the group consisting of: R5 is a) a hydrogen atom, b) an alkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group; c) cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, -(C1-C3)-alkyl groups or hydroxy 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]; or a pharmaceutically acceptable salt thereof.

[0059] One embodiment is a compound of 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 hydroxy groups and fluorine atoms; b) -O-cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms or by -(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-spirocyclic group selected from the group consisting of: R5 is a) a hydrogen atom, b) an alkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group; c) cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms or by -(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]; or a pharmaceutically acceptable salt thereof.

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

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

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

[0063] In one embodiment, R1 is selected from the following list: [ka] and wherein R represents an ortho-fused bicyclic heteroaryl group selected from:

[0064] One embodiment is a compound of formula (I) wherein 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 hydroxy groups and fluorine atoms; b) -O-cycloalkyl groups which are unsubstituted or substituted by one or more fluorine atoms, -(C1-C3)-alkyl or hydroxy 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 hydroxy groups; and d) -O-spirocyclic group selected from the group consisting of: R5 is a) a hydrogen atom, b) an alkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group; c) unsubstituted or hydroxy-substituted cycloalkyl groups; d) heterocycloalkyl groups; e) alkylsulfonylalkyl groups, and f) alkylsulfonyl group selected from the group consisting of: R6 is selected from the group consisting of a hydrogen atom and a deuterium atom; or a pharmaceutically acceptable salt thereof.

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

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

[0068] In one embodiment, R2 is [ka] represents a group, in compounds of formula (I).

[0069] In one embodiment, R2 is selected from the following list: [ka] and wherein R represents a heterocycloalkyl group selected from the group consisting of:

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

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

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

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

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

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

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

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

[0078] One embodiment is a compound of formula (Ib) wherein R4 represents an alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy groups and fluorine atoms.

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

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

[0081] One embodiment is a compound of formula (Ib) wherein R4 represents an -O-spirocyclic group.

[0082] In one embodiment, R4 is selected from the following list: [ka] is a compound of formula (Ib), wherein

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

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

[0085] One embodiment is a compound of formula (Ib) wherein R5 represents a cycloalkyl group that is unsubstituted or substituted with a hydroxy group.

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

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

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

[0089] In one embodiment, R5 is selected from the following list: [ka] is a compound of formula (Ib), wherein

[0090] In one embodiment, the compound of formula (I) is: 2-[[3-(1-acetylazetidin-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-methyl-3-[(3S,4R)-4-methyltetrahydrofuran-3-yl]oxy-1H-pyrazol-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-[[1-methyl-3-[(3R,4S)-4-methyltetrahydrofuran-3-yl]oxy-1H-pyrazol-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-[[1-methyl-3-[(trans)-4-methyltetrahydrofuran-3-yl]oxy-1H-pyrazol-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-[[1-[(1R)-2,2-difluoro-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; 2-[[1-[(1S)-2,2-difluoro-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; 2-[[1-(2,2-difluoro-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; 2-((1-methyl-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-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-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-[[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-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-((1-(methyl-d3)-3-(oxetan-3-yloxy)-1H-pyrazol-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-(oxetan-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-trifluoropropan-2-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-3-(((S)-1,1,1-trifluoropropan-2-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-3-((1,1,1-trifluoropropan-2-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-(((2R,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-(((2S,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-(((cis)-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-isopropoxy-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-isopropoxy-1-methyl-1H-pyrazol-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-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-cyclopropoxy-1-(methyl-d3)-1H-pyrazol-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-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-cyclopropoxy-1-(oxetan-3-yl)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-isopropoxy-1-(oxetan-3-yl)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(methoxymethyl)-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(methylsulfonyl)-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-cyclopropoxy-1-(methoxymethyl)-1H-pyrazol-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-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-cyclopropyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-ethyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-[[1-(methoxymethyl)-3-[(trans)-2-methyloxetan-3-yl]oxy-pyrazol-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-[[1-methyl-3-[(2-oxaspiro[3.3]heptan-7-yl)oxy]pyrazol-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 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-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-cyclopropoxy-1-(1,1-difluoropropan-2-yl)-1H-pyrazol-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)-1H-pyrazol-4-yl)amino)-7-((3S,4S)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((3S,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((3R,4S)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((cis)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-isopropoxy-1-methyl-1H-pyrazol-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-pyrazol-4-yl)amino)-7-((3S,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(1-cyanoethyl)-3-isopropoxy-1H-pyrazol-4-yl)amino)-7-((cis)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-((S)-1-cyanoethyl)-3-isopropoxy-1H-pyrazol-4-yl)amino)-7-((3S,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-((R)-1-cyanoethyl)-3-isopropoxy-1H-pyrazol-4-yl)amino)-7-((3R,4S)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-((S)-1-cyanoethyl)-3-isopropoxy-1H-pyrazol-4-yl)amino)-7-((3R,4S)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; (R)-2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; (S)-2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-2-((1-(oxetan-3-yl)-3-((1,1,1-trifluoropropan-2-yl)oxy)-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((4-(2-hydroxypropan-2-yl)-2-(oxetan-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-pyrazol-4-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-((R)-1-cyanoethyl)-3-isopropoxy-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(1-cyanoethyl)-3-isopropoxy-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(1-cyanoethyl)-3-cyclopropoxy-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(2-cyanopropan-2-yl)-3-cyclopropoxy-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(2-cyanopropan-2-yl)-3-isopropoxy-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-cyclopropoxy-1-isopropyl-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-isopropoxy-1-methyl-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-isopropoxy-1-(oxetan-3-yl)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-cyclopropoxy-1-(oxetan-3-yl)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(3,3-difluorocyclobutoxy)-1-methyl-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-((R)-sec-butoxy)-1-methyl-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-((S)-sec-butoxy)-1-methyl-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((2,2-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-8-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-2-(((R)-2-methyl-3,4-dihydro-2H-[1,4]dioxepino[2,3-b]pyridin-9-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-((trans)-4-methoxytetrahydrofuran-3-yl)-2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((4-(2-hydroxypropan-2-yl)-2-(oxetan-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-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-((trans)-4-ethyltetrahydrofuran-3-yl)-2-((3-isopropoxy-1-methyl-1H-pyrazol-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-pyrazol-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-pyrazol-4-yl)amino)-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((trans)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((3S,4S)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; ((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((cis)-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]oxy-pyrazol-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]oxy-pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-Methoxy-1-methyl-ethyl]-2-[[1-methyl-3-[(trans)-2-methyloxetan-3-yl]oxy-pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-Methoxy-1-methyl-ethyl]-2-[[3-[(2S,3R)-2-methyloxetan-3-yl]oxy-1-(methyl-d3)pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-Methoxy-1-methyl-ethyl]-2-[[3-[(2R,3S)-2-methyloxetan-3-yl]oxy-1-(methyl-d3)pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-Methoxy-1-methyl-ethyl]-2-[[3-[(trans)-2-methyloxetan-3-yl]oxy-1-(methyl-d3)pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(2S)-1-Methoxypropan-2-yl]-2-[[3-(oxetan-3-yloxy)-1-(methyl-d3)pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-[[3-(cyclopropoxy)-1-(methoxymethyl)pyrazol-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-(oxetan-3-yloxy)pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-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-pyrazol-4-yl-5-d)amino)-7-(1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-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-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl-5-d)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(methyl-d3)-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl-5-d)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(((R)-2,2-dimethyloxetan-3-yl)oxy)-1-(methyl-d3)-1H-pyrazol-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(((S)-2,2-dimethyloxetan-3-yl)oxy)-1-(methyl-d3)-1H-pyrazol-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-((2,2-dimethyloxetan-3-yl)oxy)-1-(methyl-d3)-1H-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; (S)-2-((3-cyclopropoxy-1-(2-methoxyethyl)-1H-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(((R)-5,5-dimethyltetrahydrofuran-3-yl)oxy)-1-(methyl-d3)-1H-pyrazol-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-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(methyl-d3)-3-(((S)-tetrahydrofuran-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-(((R)-tetrahydrofuran-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-((tetrahydrofuran-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-cyclopropoxy-1-(2-methoxyethyl)-1H-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(((S)-2,2-dimethyloxetan-3-yl)oxy)-1-(methyl-d3)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(((R)-2,2-dimethyloxetan-3-yl)oxy)-1-(methyl-d3)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-((2,2-dimethyloxetan-3-yl)oxy)-1-(methyl-d3)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; (S)-2-((3-((2,2-dimethyloxetan-3-yl)oxy)-1-(methyl-d3)-1H-pyrazol-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; (R)-2-((3-((2,2-dimethyloxetan-3-yl)oxy)-1-(methyl-d3)-1H-pyrazol-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-((2,2-dimethyloxetan-3-yl)oxy)-1-(methyl-d3)-1H-pyrazol-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-cyclopropoxy-1-(2-methoxyethyl)-1H-pyrazol-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(methyl-d3)-3-(oxetan-3-yloxy)-1H-pyrazol-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-methyloxetan-3-yl)oxy)-1H-pyrazol-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-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)amino)-7-(tetrahydro-2H-pyran-4-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-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; (R)-2-((3-cyclopropoxy-1-(1-methoxypropan-2-yl)-1H-pyrazol-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-pyrazol-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-pyrazol-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(1-methoxypropan-2-yl)-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-((S)-1-methoxypropan-2-yl)-2-((1-((S)-1-methoxypropan-2-yl)-3-(oxetan-3-yloxy)-1H-pyrazol-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-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-((S)-1-methoxypropan-2-yl)-2-((1-(1-methoxypropan-2-yl)-3-(oxetan-3-yloxy)-1H-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-4-yl)amino)-7-(1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; (S)-2-((1-(2-hydroxyethyl)-3-(oxetan-3-yloxy)-1H-pyrazol-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-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-((1R,2S)-2-hydroxy-2-methylcyclobutoxy)-1-(methyl-d3)-1H-pyrazol-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-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-((trans-2-hydroxy-2-methylcyclobutoxy)-1-(methyl-d3)-1H-pyrazol-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-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-((1R,2R)-2-hydroxy-2-methylcyclobutoxy)-1-(methyl-d3)-1H-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-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-(oxetan-3-yloxy)-1H-pyrazol-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-(oxetan-3-yloxy)-1H-pyrazol-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-(oxetan-3-yloxy)-1H-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-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-(oxetan-3-yloxy)-1H-pyrazol-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-(oxetan-3-yloxy)-1H-pyrazol-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-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-(trans-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0091] In one embodiment, the compound of formula (I) is: 2-((1-methyl-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-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-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-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-isopropoxy-1-methyl-1H-pyrazol-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)-1H-pyrazol-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-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]oxy-pyrazol-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]oxy-pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-Methoxy-1-methyl-ethyl]-2-[[3-[(2S,3R)-2-methyloxetan-3-yl]oxy-1-(methyl-d3)pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-Methoxy-1-methyl-ethyl]-2-[[3-[(2R,3S)-2-methyloxetan-3-yl]oxy-1-(methyl-d3)pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; (S)-2-((1-(2-hydroxyethyl)-3-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(((R)-5,5-dimethyltetrahydrofuran-3-yl)oxy)-1-(methyl-d3)-1H-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-((1R,2R)-2-hydroxy-2-methylcyclobutoxy)-1-(methyl-d3)-1H-pyrazol-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-pyrazol-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-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(((S)-2,2-dimethyloxetan-3-yl)oxy)-1-(methyl-d3)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(((R)-2,2-dimethyloxetan-3-yl)oxy)-1-(methyl-d3)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(2-hydroxyethyl)-3-(oxetan-3-yloxy)-1H-pyrazol-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-(oxetan-3-yloxy)-1H-pyrazol-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)pyrazol-4-yl]amino]-7-[(1S)-2-methoxy-1-methyl-ethyl]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0092] In one embodiment, the compound of formula (I) is: 2-((1-methyl-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-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-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-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-isopropoxy-1-methyl-1H-pyrazol-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)-1H-pyrazol-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-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]oxy-pyrazol-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]oxy-pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-Methoxy-1-methyl-ethyl]-2-[[3-[(2S,3R)-2-methyloxetan-3-yl]oxy-1-(methyl-d3)pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-Methoxy-1-methyl-ethyl]-2-[[3-[(2R,3S)-2-methyloxetan-3-yl]oxy-1-(methyl-d3)pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; and 2-[[3-(cyclopropoxy)-1-(methoxymethyl)pyrazol-4-yl]amino]-7-[(1S)-2-methoxy-1-methyl-ethyl]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0093] In one embodiment, the compound of Formula (I) is 2-((1-methyl-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; or a pharmaceutically acceptable salt thereof.

[0094] In one embodiment, the compound of Formula (I) is 2-((1-methyl-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; or a pharmaceutically acceptable salt thereof.

[0095] In one embodiment, the compound of Formula (I) is 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; or a pharmaceutically acceptable salt thereof.

[0096] In one embodiment, the compound of Formula (I) is 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; or a pharmaceutically acceptable salt thereof.

[0097] In one embodiment, the compound of formula (I) is 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; or a pharmaceutically acceptable salt thereof.

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

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

[0100] In one embodiment, the compound of formula (I) is 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; or a pharmaceutically acceptable salt thereof.

[0101] In one embodiment, the compound of formula (I) is 2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-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-(oxetan-3-yloxy)-1H-pyrazol-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-pyrazol-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-pyrazol-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-methyloxetan-3-yl]oxy-1-(methyl-d3)pyrazol-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-methyloxetan-3-yl]oxy-1-(methyl-d3)pyrazol-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)pyrazol-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-pyrazol-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-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 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-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 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-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 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-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 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-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-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-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 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-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 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-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 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-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.

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

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

[0124] In one embodiment, the compound of formula (I) is 2-((1-(2-hydroxyethyl)-3-(oxetan-3-yloxy)-1H-pyrazol-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-(oxetan-3-yloxy)-1H-pyrazol-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] The compounds of formula (I) may contain one or more asymmetric carbon atoms. They may therefore 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 compounds of formula (I) can exist in the form of bases or in the form of acid addition salts. Such addition salts form part of the present disclosure. These salts are advantageously prepared with pharmaceutically acceptable acids, although salts of other acids useful, for example, for the purification or isolation of compounds of formula (I), also form part of the present disclosure.

[0128] Another embodiment is a method for making a compound of formula (I), the method comprising reacting a compound of formula (11X) with a compound of formula (15X): [ka] wherein R1 and R2 are as defined herein for compounds 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 a compound of formula (I), or a pharmaceutically acceptable salt thereof, as the active ingredient, 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-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile.

[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-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile.

[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-(oxetan-3-yloxy)pyrazol-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitrile.

[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-methyloxetan-3-yl)oxy)-1H-pyrazol-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-methyloxetan-3-yl)oxy)-1H-pyrazol-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-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile.

[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-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile.

[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-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile.

[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-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile.

[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-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile.

[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-pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile.

[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-pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile.

[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-methyloxetan-3-yl]oxy-1-(methyl-d3)pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile.

[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-methyloxetan-3-yl]oxy-1-(methyl-d3)pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile.

[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)pyrazol-4-yl]amino]-7-[(1S)-2-methoxy-1-methyl-ethyl]pyrrolo[2,3-d]pyrimidine-6-carbonitrile.

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

[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, dementia with Lewy bodies, Pick's disease, progressive supranuclear palsy, and frontotemporal dementia, the method comprising administering to a patient in need of such 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 dementia with Lewy bodies, the method comprising administering to a patient in need of said 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 tauopathy 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 such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0150] One embodiment is a method of 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 thereof.

[0151] One embodiment is a medicament comprising 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 a neurodegenerative disease selected from the group consisting of Parkinson's disease, multiple sclerosis, HIV-induced dementia, amyotrophic lateral sclerosis, dementia with Lewy bodies, 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 a neurodegenerative disease selected from the group consisting of Parkinson's disease, multiple sclerosis, HIV-induced dementia, amyotrophic lateral sclerosis, and dementia with Lewy bodies.

[0155] One embodiment is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a tauopathy disorder 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 steps: Starting materials and solvents used in the synthesis were obtained from chemical suppliers such as ABCR, Aldrich, Acros, Apollo, Fluka, Netchem, Lancaster, and others.

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

[0159] Compounds of formula (I) herein may be prepared by the methods outlined in the following reaction schemes and examples.

[0160] The preparation of compounds of formula (11X) can be carried out according to Scheme 1.

[0161] Scheme 1 [ka]

[0162] Commercially available 4-chloro-2-(methylthio)pyrimidine-5-carbaldehyde (1X) can be converted to derivative (3X) by reaction with protected glycine methyl ester (2X) in a polar aprotic solvent such as DCM or THF in the presence of a base such as triethylamine. Derivative (3X) undergoes a cyclization reaction 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 give compound (4X). Derivative (5X) can be obtained by removing the protecting group according to methods known to those skilled in the art.

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

[0164] Compounds 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) [wherein R2 is as defined above] by reaction with a substituted glycine methyl ester of formula (12X) in the presence of a base such as triethylamine in a polar aprotic solvent such as DCM or THF. Cyclization of compound (13X) in the presence of an organic base such as DBU or an inorganic base such as sodium hydride in a polar aprotic solvent such as acetonitrile, DMF, or THF provides compound (7X).

[0167] The preparation of compounds of formula (15X) can be carried out according to Scheme 3.

[0168] Scheme 3 [ka]

[0169] Compounds of formula (15X), where R1 is as defined above, can be prepared from compound (14X) by reaction with formic acid, optionally in the presence of acetic anhydride, at a temperature between 0° C. and ambient temperature. Most of the 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 preparing compounds of formula (14X) where R1 is a substituted pyrazole.

[0171] Scheme 4 [ka]

[0172] Pyrazoles of general formula (14X), where R is an alkyloxyl group and R is as defined herein above 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) with a halide R X (where X is Cl, Br, or I) or a sulfonate R OSO R', such as mesylate (R' = CH), tosylate (R' = PhMe), triflate (R' = CF), or nonaflate (R' = CFCFCFCF), in the presence of a base such as potassium carbonate or cesium carbonate or sodium hydride in a polar aprotic solvent such as DMF, NMP, or DMSO at a temperature between ambient temperature and 80 °C. Alternatively, 3,4-dinitro-1H-pyrazole (16X) can be converted to pyrazole (21X) via a Chan-Lam coupling by reaction with boronic acid R5B(OH)2 in the presence of Cu(OAc)2 and a base such as pyridine or 4'-di-tert-butyl-2,2'-bipyridine at reflux in an aprotic solvent such as dichloromethane or 1,2-dichloroethane. When R5 is an alkylsulfonyl group, pyrazole (16X) can be sulfonylated with sulfonyl chloride in the presence of a base such as triethylamine in an aprotic solvent such as dichloromethane at temperatures between 0 °C and ambient temperature.

[0173] Dinitro-pyrazole (21X) can be treated with an alcohol R4H in the presence of a base such as potassium carbonate, cesium carbonate, or sodium hydride in a polar aprotic solvent such as DMF, NMP, or DMSO at a temperature between ambient and 80° C. to give compound (20X).

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

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

[0176] The preparation of compounds of general formula (I) can be carried out according to Scheme 5.

[0177] Scheme 5 [ka]

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

[0179] The embodiments provided herein are more specifically described 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 stated in the examples below: AcOH acetic acid BTTP tert-butylimino-tri(pyrrolidino)phosphorane HCl Hydrogen chloride CDI 1,1'-carbonyldiimidazole DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane DIAD Diisopropyl azodiformate DEAD Diethoxycarbonyldiazene DMF N,N-dimethylformamide DMSO dimethyl sulfoxide eq. equivalent amount Et Ethyl EtOH ethanol Et2O diethyl ether EtOAc 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 anhydride

[0181] LC / MS analysis was performed using the following method. Method A: UPLC Waters and Mass Spectrometer SQD2 Waters Purity is measured by 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, 2.1x50mm, 1.7μm

[0182] Method B: Waters UPLC-SQD2 Eluent A: H2O (+ 0.1%HCO2H) Eluent B: CH3CN (+ 0.1%HCO2H) Gradient (2.5 min): 3% to 100% B in 2.1 min; 100% B in 2.45 min; 3% B in 2.5 min 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): 5% B 0–0.3 min; 5% to 100% B in 4 min; 100% B 4–4.6 min; 5.3 min: 5% B 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, 2.1x50mm, 1.6μm

[0188] Method H: UPLC Waters and Mass Spectrometer SQD Waters The purity is measured by 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, 2.1x50mm, 1.7μm

[0189] Method I: LCMS Waters and Mass Spectrometer SQD Waters Eluent A: H2O (+ 0.1%HCO2H) Eluent B: CH3CN (+ 0.1%HCO2H) Gradient: t = 0 min: 5% B, t = 1.5 min: 99% B, t = 1.9 min: 99% B Flow rate: 1mL / min Column: Cortecs UPLC C18, 2.1x50mm, 1.6μm.

[0190] Intermediates Intermediate 1: 2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate methyl ester 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 (35 min) to a solution of 71 mL (1 eq.) of (4-methoxyphenyl)methanamine and 116 mL of triethylamine (1.5 eq.) in 750 mL of tetrahydrofuran at 0 °C (ice-water / methanol bath) under argon. After completion of the reaction at room temperature for 5 h, the mixture was filtered. The filtrate was taken up in 975 mL of ethyl acetate and 375 mL of water was added. After drying the organic layer over magnesium sulfate and concentrating under vacuum, the residue was purified on silica gel eluting with 100% dichloromethane, then dichloromethane / ethyl acetate (90 / 10), then dichloromethane / ethyl acetate (70 / 30) to give 60.9 g of (4-methoxybenzyl)glycine methyl ester.

[0191] Step 2: Preparation of N-(5-formyl-2-(methylthio)pyrimidin-4-yl)-N-(4-methoxybenzyl)glycine methyl ester [ka] 52.5 mL (1.5 eq.) of triethylamine was added 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 at 0°C. 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 and washed twice with 1000 mL of water, followed by 1000 mL of 0.5 N aqueous HCl. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was stirred in 500 mL of heptane for 12 hours. The resulting precipitate was filtered and dried under vacuum to give 90 g of N-(5-formyl-2-(methylthio)pyrimidin-4-yl)-N-(4-methoxybenzyl)glycine methyl ester. MS (Method B) m / z362[M+1]+;t=1.53 min.

[0192] Step 3: Preparation of methyl 7-(4-methoxybenzyl)-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate [ka] 167 mL (4 eq.) of 1,8-diazabicyclo[5.4.0]undec-7-ene was added dropwise to a solution of 99 g (1 eq.) of N-(5-formyl-2-(methylthio)pyrimidin-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 taken up in 800 mL of ethyl acetate and 500 mL of water. The organic layer was washed with 300 mL of 1N aqueous HCl, 300 mL of saturated aqueous sodium bicarbonate, 500 mL of water, then 300 mL of brine, and concentrated under reduced pressure to give 82.4 g of methyl 7-(4-methoxybenzyl)-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate. 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 methyl 7-(4-methoxybenzyl)-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate 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, maintaining the temperature below 5°C. A precipitate formed when a pH of 6 was reached. The precipitate was filtered, washed with water (2 x 250 mL) and 250 mL of heptane, and then dried under vacuum to give 37.72 g of methyl 2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate. 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 (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 (1 eq.) (commercially available) in 100 mL of anhydrous tetrahydrofuran was added over 30 minutes to a solution of 68 g (1.06 eq.) of (+)-B-chlorodiisopinocampheylborane [(+)-DIP chloride] in 270 mL of anhydrous tetrahydrofuran cooled to −25° C. under argon. The mixture was stirred for 2 hours at −25° C. Then, a suspension of 46 g (2.16 eq.) of diethanolamine in tetrahydrofuran was added in portions. The mixture was stirred for 18 hours at room temperature, 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 a reduced pressure of 120 mbar. The residue was dissolved in 50 mL of dichloromethane and 50 mL of cyclohexane, filtered, and purified on silica gel eluting with 10%, 30%, 50%, and 100% diethyl ether in cyclohexane. Pure fractions were concentrated under reduced pressure of 120 mbar at 40° C. to give 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 (3S,4S)-4-methyltetrahydrofuran-3-yl acetate (precursor to intermediate 2) and enantiopure (3R,4R)-4-methyltetrahydrofuran-3-ol - intermediate 3 [ka] To a solution of 14.7 g (1 eq.) of the 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 Pseudomonas fluorescens 20.000 U / g; catalog number: 534730-50G) was added, and the suspension was stirred for 16 hours at 22°C and then filtered through a pad of decalite. The filter cake was rinsed twice with 50 mL of diethyl ether, and the filtrate was carefully concentrated under a reduced pressure of 180 mbar at 40°C. The residue was purified on silica eluting with 0-50% ether in cyclohexane to give 9.15 g of (3S,4S)-4-methyltetrahydrofuran-3-yl acetate (precursor to intermediate 2) and 5.64 g of enantiopure (3R,4R)-4-methyltetrahydrofuran-3-ol (intermediate 3) consecutively.

[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: 1H NMR (400 MHz, 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] A precooled (0°C) 94 mL (1.09 eq.) of a 1N methanolic solution of sodium methoxide was added 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 at 0°C. 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 solution of hydrogen chloride in diethyl ether. After adding an additional 100 mL of diethyl ether, the suspension was filtered through a pad of decalite, and the filter cake was rinsed with 50 mL of diethyl ether. The filtrate was concentrated under reduced pressure at 120 mbar at 40°C, and the residue was dissolved in 50 mL of dichloromethane and 50 mL of cyclohexane, filtered, and purified on silica gel eluting with 10%, 30%, 50%, and 100% diethyl ether in cyclohexane to give (after concentration under reduced pressure at 120 mbar at 40°C) 7.2 g of enantiopure (3S,4S)-4-methyltetrahydrofuran-3-ol (Intermediate 2). 1H NMR (400 MHz, 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-(oxetan-3-yloxy)-1H-pyrazol-4-yl)formamide Step 1: Preparation of 1-methyl-4-nitro-3-(oxetan-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 (commercially available) in 12 mL of acetonitrile. The mixture was heated at 50°C for 2 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 in vacuo. The residue was suspended in 15 mL of diethyl ether, filtered, concentrated in vacuo, and purified on silica gel eluting with a gradient of 0 to 50% ethyl acetate in heptane to give 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-(oxetan-3-yloxy)-1H-pyrazol-4-yl)formamide [ka] A solution of 3.5 g (1 eq.) of 1-methyl-4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole in 170 mL of methanol was treated with 0.1 g of palladium on carbon (10%) under 2.5 bar of hydrogen for 2 hours. The mixture was filtered, washed with dichloromethane, and concentrated under reduced pressure. The residue was taken up in dichloromethane and concentrated under reduced pressure twice. A solution of 6.63 mL of acetic anhydride in 12.13 mL of formic acid, premixed for 30 minutes, was added dropwise to a solution of the residue in 12 mL of tetrahydrofuran at 0°C. The reaction mixture was stirred for 2 hours and allowed to warm to room temperature. It was then poured into 10% aqueous sodium bicarbonate solution, 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 purified on silica gel eluting with a gradient of 0 to 100% ethyl acetate in heptane to give 2.02 g of N-(1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-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-pyrazol-4-yl)formamide and N-(1-methyl-3-(((3R,4S)-4-methyltetrahydrofuran-3-yl)oxy)-1H-pyrazol-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 (commercially available) 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 (commercially available) in 40 mL of acetonitrile. The 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 in vacuo. The residue was purified on silica gel eluting with a gradient of 10 to 50% ethyl acetate in heptane to give 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-pyrazol-4-amine and 1-methyl-3-(((3R,4S)-4-methyltetrahydrofuran-3-yl)oxy)-1H-pyrazol-4-amine [ka] In a microwave vial, a solution of 1.09 g (1 eq.) of the 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 palladium on carbon (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 taken up in dichloromethane and filtered, and the filtrate was concentrated under reduced pressure to give 904 mg of a racemic mixture of 1-methyl-3-(((3S,4R)-4-methyltetrahydrofuran-3-yl)oxy)-1H-pyrazol-4-amine and 1-methyl-3-(((3R,4S)-4-methyltetrahydrofuran-3-yl)oxy)-1H-pyrazol-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-pyrazol-4-yl)formamide and N-(1-methyl-3-(((3R,4S)-4-methyltetrahydrofuran-3-yl)oxy)-1H-pyrazol-4-yl)formamide [ka] A solution of 904 mg (1 eq.) of the racemic mixture of 1-methyl-3-(((3S,4R)-4-methyltetrahydrofuran-3-yl)oxy)-1H-pyrazol-4-amine and 1-methyl-3-(((3R,4S)-4-methyltetrahydrofuran-3-yl)oxy)-1H-pyrazol-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. The reaction mixture was stirred at 5°C for 5 minutes and at room temperature for 1.5 hours, then concentrated in vacuo. The residue was purified on silica gel eluting with a gradient of 0 to 40% acetone in dichloromethane to give 810 mg of a racemic mixture of N-(1-methyl-3-(((3S,4R)-4-methyltetrahydrofuran-3-yl)oxy)-1H-pyrazol-4-yl)formamide and N-(1-methyl-3-(((3R,4S)-4-methyltetrahydrofuran-3-yl)oxy)-1H-pyrazol-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-pyrazol-4-yl)formamide Step 1: Preparation of 2-methyl-1-((1-methyl-4-nitro-1H-pyrazol-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. The mixture was heated at 80° C. for 2 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 in vacuo. The residue was purified on silica gel eluting with 50% ethyl acetate in heptane to give 358 mg of 2-methyl-1-((1-methyl-4-nitro-1H-pyrazol-3-yl)oxy)propan-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-pyrazol-4-yl)formamide [ka] In a microwave vial, a solution of 115 mg (1 eq.) of 2-methyl-1-((1-methyl-4-nitro-1H-pyrazol-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 palladium on carbon (10%). The reaction mixture was heated at 70° C. for 10 min. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The crude material 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 min. The reaction mixture was stirred at 5° C. for 1 h 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-pyrazol-4-yl)formamide Step 1: Preparation of 1-methyl-4-nitro-3-((1,1,1-trifluoropropan-2-yl)oxy)-1H-pyrazole (racemic) [ka] Racemic 1,1,1-trifluoropropan-2-ol (819 mg, 1.3 eq.) and cesium carbonate (3.67 g, 2 eq.) were added to a solution of 1 g (1 eq.) of 1-methyl-3,4-dinitro-1H-pyrazole (commercially available) in 20 mL of acetonitrile. The mixture was heated at 65°C for 2 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 in vacuo. The residue was purified on silica gel eluting with a gradient of 20 to 50% ethyl acetate in heptane to give 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-pyrazol-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 palladium on carbon (10%). The reaction mixture was heated at 70° C. for 10 min. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The crude material was taken on to the next step without further purification.

[0209] Step 3: Preparation of N-(1-methyl-3-((1,1,1-trifluoropropan-2-yl)oxy)-1H-pyrazol-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-pyrazol-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. The reaction mixture was stirred at 5° C. for 5 minutes and at room temperature for 1.5 hours, and then concentrated in vacuo to give 895 mg of racemic N-(1-methyl-3-((1,1,1-trifluoropropan-2-yl)oxy)-1H-pyrazol-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-pyrazol-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-sulfonate and 2.45 g (3 eq.) of potassium carbonate were added to a solution of 1 g (1 eq.) of 3-isopropoxy-4-nitro-1H-pyrazole (commercially available) in 16 mL of dimethylformamide. The mixture was heated at 80°C for 1.5 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 in vacuo. The residue was purified on silica gel eluting with a gradient of 20 to 50% ethyl acetate in heptane to give 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-pyrazol-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 palladium on carbon (10%). The reaction mixture was heated at 70° C. for 10 min. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The crude material was taken on to the next step without further purification.

[0212] Step 3: Preparation of N-(3-isopropoxy-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)formamide [ka] A solution of 780 mg (1 eq.) of 3-isopropoxy-1-(2,2,2-trifluoroethyl)-1H-pyrazol-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 min. The reaction mixture was stirred at 5 °C for 5 min and at room temperature for 1 h, then concentrated in vacuo. The residue was purified on silica gel, eluting with 18% ethyl acetate / 2% 7N NH3 in MeOH / 80% heptane to 45% ethyl acetate / 5% 7N NH3 in MeOH / 50% heptane, to give 730 mg of N-(3-isopropoxy-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)formamide. MS (Method A) m / z 252 [M+1]; t = 1.94 min.

[0213] Intermediate 9: N-(3-((1-acetylazetidin-3-yl)oxy)-1-methyl-1H-pyrazol-4-yl)formamide Step 1: Preparation of tert-butyl 3-((1-methyl-4-nitro-1H-pyrazol-3-yl)oxy)azetidine-1-carboxylate [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-pyrazol-3-ol (commercially available) in 125 mL of dimethylformamide. The mixture was heated at 90°C for 30 hours, then at room temperature for 70 hours, and then poured onto 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 in vacuo. The residue was purified on silica gel eluting with a gradient of 10 to 60% ethyl acetate in heptane to give 8 g of tert-butyl 3-((1-methyl-4-nitro-1H-pyrazol-3-yl)oxy)azetidine-1-carboxylate. MS (Method A) m / z243[M-tBu]+;t=1.87 min.

[0214] Step 2: Preparation of 3-(azetidin-3-yloxy)-1-methyl-4-nitro-1H-pyrazole (TFA salt) [ka] 32 mL of trifluoroacetic acid was added to a solution of 8 g (1 eq.) of tert-butyl 3-((1-methyl-4-nitro-1H-pyrazol-3-yl)oxy)azetidine-1-carboxylate in 160 mL of dichloromethane at 0° C. The mixture was stirred at room temperature for 1.5 hours and cooled to 0° C. 10 mL of MeOH, followed by 150 mL of 7N NH3 in MeOH, was slowly added to the reaction mixture. The mixture was concentrated in vacuo. The residue was purified on silica gel eluting with a mixture of dichloromethane / MeOH / 7N methanolic ammonia solution in ratios from (95 / 4.5 / 0.5) to (80 / 18 / 2) to give 9.9 g of 3-(azetidin-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: Preparation of 1-(3-((1-methyl-4-nitro-1H-pyrazol-3-yl)oxy)azetidin-1-yl)ethan-1-one [ka] 13.4 mL (10 eq.) of triethylamine was added to a solution of 3 g (1 eq.) of 3-(azetidin-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 and then at room temperature for 1 hour, then poured onto 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 in vacuo. The residue was purified on silica gel eluting with a gradient of 10 to 50% acetone in dichloromethane to give 1.34 g of 1-(3-((1-methyl-4-nitro-1H-pyrazol-3-yl)oxy)azetidin-1-yl)ethan-1-one. MS (Method A) m / z241[M+1]+;t=1.22 min.

[0216] Step 4: Preparation of 1-(3-((4-amino-1-methyl-1H-pyrazol-3-yl)oxy)azetidin-1-yl)ethan-1-one [ka] In a microwave vial, a solution of 1.34 g (1 eq.) of 1-(3-((1-methyl-4-nitro-1H-pyrazol-3-yl)oxy)azetidin-1-yl)ethan-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 palladium on carbon (10%). The reaction mixture was heated at 70° C. for 10 min. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The crude material was taken on to the next step without further purification.

[0217] Step 5: Preparation of N-(3-((1-acetylazetidin-3-yl)oxy)-1-methyl-1H-pyrazol-4-yl)formamide [ka] A solution of 1.29 g (1 eq.) of 1-(3-((4-amino-1-methyl-1H-pyrazol-3-yl)oxy)azetidin-1-yl)ethan-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. 15 mL of tetrahydrofuran was added, and the reaction mixture was stirred at room temperature for 35 minutes. The residue was concentrated in vacuo, 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 give 1.08 g of N-(3-((1-acetylazetidin-3-yl)oxy)-1-methyl-1H-pyrazol-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-dimethylmethanamine [ka] A solution of 1 g (1 eq.) of 3-cyclopropoxy-4-nitrobenzaldehyde, 4.6 mL of acetic acid, and 2.41 mL of a 2N solution of dimethylamine in tetrahydrofuran in 23 mL of dichloromethane was 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 aqueous sodium bicarbonate solution were added. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified on silica gel, eluting with a mixture of dichloromethane / ethyl acetate / 7N NH3 in MeOH (80 / 18 / 2), to give 471 mg of 1-(3-cyclopropoxy-4-nitrophenyl)-N,N-dimethylmethanamine. MS (Method A) m / z 237 [M+1]+; t = 0.72 min.

[0219] Step 2: Preparation 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-dimethylmethanamine in 12 mL of methanol was treated with 363 mg (2.8 eq.) of ammonium formate and 212 mg (0.1 eq.) of 10% palladium on carbon. The reaction mixture was heated at 80° C. for 15 min. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The crude material was triturated in diisopropyl ether, and the filtrate was evaporated to give 337 mg of 2-cyclopropoxy-4-((dimethylamino)methyl)aniline. The crude material was taken on to 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 min. The reaction mixture was stirred at room temperature for 1 h. The residue was concentrated in vacuo to give 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-pyrazol-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. The mixture was heated at 80 °C for 24 h, 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 in vacuo. The residue was purified on silica gel eluting with a gradient of 20 to 50% ethyl acetate in heptane to give 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-pyrazol-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 palladium on carbon (10%). The reaction mixture was heated at 70° C. for 10 min. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The crude material was taken on to the next step without further purification.

[0223] Step 3: Preparation of N-(3-cyclopropoxy-1-(oxetan-3-yl)-1H-pyrazol-4-yl)formamide [ka] A solution of 250 mg (1 eq.) of 3-cyclopropoxy-1-(oxetan-3-yl)-1H-pyrazol-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 min. The reaction mixture was stirred at 0 °C for 1 h. The residue was concentrated in vacuo to give 200 mg of N-(3-cyclopropoxy-1-(oxetan-3-yl)-1H-pyrazol-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-pyrazol-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-pyrrolidinone. The mixture was heated at 80°C for 24 h, 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 in vacuo. The residue was purified on silica gel eluting with a gradient of 20 to 50% ethyl acetate in heptane to give 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-pyrazol-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 10% palladium on carbon. The reaction mixture was heated at 70° C. for 10 min. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The crude material was taken on to the next step without further purification.

[0226] Step 3: Preparation of N-(3-isopropoxy-1-(oxetan-3-yl)-1H-pyrazol-4-yl)formamide [ka] A solution of 130 mg (1 eq.) of 3-isopropoxy-1-(oxetan-3-yl)-1H-pyrazol-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. The reaction mixture was stirred at 0 °C for 1 hour. The residue was concentrated in vacuo to give 200 mg of N-(3-isopropoxy-1-(oxetan-3-yl)-1H-pyrazol-4-yl)formamide. MS (Method A) m / z 226 [M+1] +; t = 1.36 min.

[0227] Intermediate 13: N-(1-((methylsulfonyl)methyl)-3-(oxetan-3-yloxy)-1H-pyrazol-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 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 in vacuo. The residue was purified on silica gel eluting with a gradient of 10 to 50% ethyl acetate in heptane to give 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-(oxetan-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. The mixture was heated at 80° C. for 3 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 in vacuo. The residue was triturated in diisopropyl ether to give 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: Preparation of 4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole [ka] 32.33 g (2.5 eq.) of ceric ammonium nitrate was added to a solution of 7.1 g (1 eq.) of 1-(4-methoxybenzyl)-4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole in 170 mL of acetonitrile and 170 mL of water. The mixture was stirred at room temperature for 16 hours. An additional 4.5 g of ceric ammonium nitrate was added, and the reaction mixture was stirred for 30 minutes at room temperature and poured into 85 mL of ethyl acetate and 85 mL of saturated aqueous 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 in vacuo. The residue was triturated with diethyl ether, and the precipitate was filtered to give 2.38 g of 4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole. MS (Method A) m / z 186 [M+1]; t = 0.90 min.

[0230] Step 4: Preparation of 1-((methylthio)methyl)-4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole [ka] 937 μL (1.4 eq.) of (chloromethyl)(methyl)sulfane and 2.24 g (2 eq.) of potassium carbonate were added to a solution of 1.5 g (1 eq.) of 4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole in 50 mL of dimethylformamide. The mixture was heated at 80°C for 2.5 h, 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 in vacuo. The residue was purified on silica gel eluting with a gradient of 20 to 50% ethyl acetate in heptane to give 935 mg of 1-((methylthio)methyl)-4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole. MS (Method A) m / z 246 [M+1]; t = 1.15 min.

[0231] Step 5: Preparation of 1-((methylsulfonyl)methyl)-4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole [ka] 2.55 g (77% purity - 3 eq.) of 3-chloroperbenzoic acid was added to a solution of 931 mg (1 eq.) of 1-((methylthio)methyl)-4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole in 40 mL of dichloromethane at 0 °C. The mixture was allowed to warm 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 min. The organic layer was washed successively with 50 mL of saturated aqueous sodium carbonate, 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 give 255 mg of 1-((methylsulfonyl)methyl)-4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole. The residue from evaporation of the organic layer was purified on silica eluting with heptane / ethyl acetate / 7N NH in MeOH (80 / 18 / 2) to give 291 mg of 1-((methylsulfonyl)methyl)-4-nitro-3-(oxetan-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-(oxetan-3-yloxy)-1H-pyrazol-4-amine [ka] A solution of 546 mg (1 eq.) of 1-((methylsulfonyl)methyl)-4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole in 50 mL of methanol was treated with 0.42 g of palladium on carbon (10%) under 4 bar of hydrogen for 1 h. The mixture was filtered, washed with methanol, and concentrated under reduced pressure to give 450 mg of 1-((methylsulfonyl)methyl)-3-(oxetan-3-yloxy)-1H-pyrazol-4-amine. MS (Method A) m / z 248 [M+1]; t=0.24 min.

[0233] Step 7: Preparation of N-(1-((methylsulfonyl)methyl)-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)formamide [ka] A solution of 486 mg (1 eq.) of 1-((methylsulfonyl)methyl)-3-(oxetan-3-yloxy)-1H-pyrazol-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 min. The reaction mixture was stirred at room temperature for 1 h. The residue was concentrated in vacuo and purified on silica eluting with heptane / ethyl acetate / 7N NH in MeOH (50 / 45 / 5) to give 450 mg of N-(1-((methylsulfonyl)methyl)-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)formamide. MS (Method A) m / z 276 [M+1]; t = 0.52 min.

[0234] Intermediate 14: N-(1-(methoxymethyl)-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)formamide Step 1: Preparation of 1-(methoxymethyl)-4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole [ka] 121 mg (1.4 eq.) of sodium hydride (60% purity) was added to a solution of 400 mg (1 eq.) of 4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole (Intermediate 13, Step 3) in 12 mL of tetrahydrofuran at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and at room temperature for 15 min. 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 min and slowly 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 in vacuo. The residue was purified on silica gel eluting with a gradient of 20 to 50% ethyl acetate in heptane to give 373 mg of 1-(methoxymethyl)-4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole. MS (Method A) m / z230[M+1]+;t=1.34 min.

[0235] Step 2: Preparation of 1-(methoxymethyl)-3-(oxetan-3-yloxy)-1H-pyrazol-4-amine [ka] In a microwave vial, a solution of 453 mg (1 eq.) of 1-(methoxymethyl)-4-nitro-3-(oxetan-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 10% palladium on carbon. The reaction mixture was heated at 70° C. for 10 min. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The crude material was taken on to the next step without further purification.

[0236] Step 3: Preparation of N-(1-(methoxymethyl)-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)formamide [ka] A solution of 393 mg (1 eq.) of 1-(methoxymethyl)-3-(oxetan-3-yloxy)-1H-pyrazol-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 min. The reaction mixture was stirred at 0 °C for 1 h. The residue was concentrated in vacuo and purified on silica eluting with heptane / ethyl acetate / 7N NH in MeOH (50 / 45 / 5) to give 312 mg of N-(1-(methoxymethyl)-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)formamide. MS (Method A) m / z 228 [M+1]; t = 0.74 min.

[0237] Intermediate 15: N-(3-cyclopropoxy-1-(methoxymethyl)-1H-pyrazol-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 h, 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 in vacuo. The residue was purified on silica gel eluting with a gradient of 20 to 50% ethyl acetate in heptane to give 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. An additional 4 g of cerium ammonium nitrate was added, and the reaction mixture was stirred at room temperature for 30 minutes and poured onto 85 mL of ethyl acetate and 85 mL of saturated aqueous 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 in vacuo. The residue was purified on silica gel, eluting with 5% methanol in dichloromethane, to give 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] 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 was added 667 mg (1.4 eq.) of chloro(methoxy)methane at 0°C. The mixture was warmed to room temperature, stirred for 1.5 h, 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 in vacuo. The residue was purified on silica gel eluting with a gradient of 20 to 50% ethyl acetate in heptane to give 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-pyrazol-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 10% palladium on carbon. The reaction mixture was heated at 100° C. for 10 min. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The crude material was taken on to the next step without further purification.

[0241] Step 5: Preparation of N-(3-cyclopropoxy-1-(methoxymethyl)-1H-pyrazol-4-yl)formamide [ka] A solution of 700 mg (1 eq.) of 3-cyclopropoxy-1-(methoxymethyl)-1H-pyrazol-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 in vacuo and purified on silica gel, eluting with dichloromethane and then 2% methanol in dichloromethane, to give 620 mg of N-(3-cyclopropoxy-1-(methoxymethyl)-1H-pyrazol-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-pyrazol-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)sulfane 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 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 in vacuo. The residue was purified on silica gel eluting with 20% ethyl acetate in heptane to give 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 (70% purity - 3 eq.) of 3-chloroperbenzoic acid 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% aqueous sodium thiosulfate sodium carbonate solution. The mixture was stirred for 15 minutes. The organic layer was washed successively 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 residue was triturated in diisopropyl ether, and the solid was filtered and dried under vacuum to give 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-pyrazol-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 palladium on carbon (10%) under 4 bar of hydrogen for 1 h. The mixture was filtered, washed with methanol, and concentrated under reduced pressure to give 680 mg of 3-cyclopropoxy-1-((methylsulfonyl)methyl)-1H-pyrazol-4-amine. The crude material was taken on to the next step without further purification.

[0245] Step 4: Preparation of N-(3-cyclopropoxy-1-((methylsulfonyl)methyl)-1H-pyrazol-4-yl)formamide [ka] A solution of 680 mg (1 eq.) of 3-cyclopropoxy-1-((methylsulfonyl)methyl)-1H-pyrazol-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 at room temperature for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour. The residue was concentrated in vacuo and purified on silica, eluting with dichloromethane and then 2% methanol in dichloromethane, to give 490 mg of N-(3-cyclopropoxy-1-((methylsulfonyl)methyl)-1H-pyrazol-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-pyrazol-4-yl)formamide and N-(3-(((3S,4S)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-1H-pyrazol-4-yl)formamide Step 1: Preparation 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 sodium bicarbonate solution 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 in vacuo to give 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 in vacuo to give an additional 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 taken onto the next step 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 and 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. The mixture was heated at 80° C. for 6 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 in vacuo. The residue was purified on silica gel eluting with a gradient of 10-20% ethyl acetate in dichloromethane to give 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-pyrazol-4-amine and 3-(((3S,4S)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-1H-pyrazol-4-amine [ka] A solution of 1 g (1 eq.) of the 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 in 32 mL of ethanol and 6.6 mL of water was 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. The 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 sodium bicarbonate solution. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give 0.9 g of a racemic mixture of 3-(((3R,4R)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-1H-pyrazol-4-amine and 3-(((3S,4S)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-1H-pyrazol-4-amine. MS (Method A) m / z 214 [M+1]+.

[0249] Step 4: Preparation of N-(3-(((3R,4R)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-1H-pyrazol-4-yl)formamide and N-(3-(((3S,4S)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-1H-pyrazol-4-yl)formamide [ka] A solution of 1.3 g (1 eq.) of the racemic mixture of 3-(((3R,4R)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-1H-pyrazol-4-amine and 3-(((3S,4S)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-1H-pyrazol-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 in vacuo and purified on silica eluting with 5% methanol in dichloromethane to give 300 mg of a racemic mixture of N-(3-(((3R,4R)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-1H-pyrazol-4-yl)formamide and N-(3-(((3S,4S)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-1H-pyrazol-4-yl)formamide. MS (Method B) m / z 242 [M+1]; t=0.87 min.

[0250] Intermediate 18: N-(1-(methylsulfonyl)-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)formamide Step 1: Preparation of 1-(methylsulfonyl)-4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole [ka] 502 μL (1.5 eq.) of methanesulfonyl chloride was added to a solution of 0.8 g (1 eq.) of 4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole (Intermediate 13, Step 3) in 40 mL of dichloromethane and 1.21 mL (2 eq.) of triethylamine at 0° C. The mixture was stirred at room temperature for 2 hours and poured onto 20 mL of a 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 in vacuo. The residue was purified on silica gel eluting with 5% ethyl acetate in dichloromethane to give 600 mg of 1-(methylsulfonyl)-4-nitro-3-(oxetan-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-(oxetan-3-yloxy)-1H-pyrazol-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-(oxetan-3-yloxy)-1H-pyrazole in 18 mL of ethanol and 2 mL of water. The reaction mixture was heated at 80° C. under vigorous stirring for 10 minutes, 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 magnesium sulfate and concentrated under vacuum.

[0252] A solution of the residue 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 in vacuo. The residue was purified on silica, eluting with 5% methanol in dichloromethane, to give 250 mg of N-(1-(methylsulfonyl)-3-(oxetan-3-yloxy)-1H-pyrazol-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-pyrazol-4-yl)formamide and N-(1-methyl-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-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. The mixture was heated at 65°C for 3 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 in vacuo. The residue was purified on silica gel eluting with a gradient of 10 to 50% ethyl acetate in heptane to give 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 cis 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 cis).

[0257] Step 2: Preparation of N-(1-methyl-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)formamide and N-(1-methyl-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)formamide (racemic trans) [ka] A solution of 535 mg (1 eq.) of a 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 (racemic trans) in 170 mL of methanol was treated with 0.26 g of palladium on carbon (10%) under 2.5 bar of hydrogen for 1.5 hours. The mixture was filtered, washed with methanol, and concentrated under reduced pressure. A solution of 943 μL (4 eq.) of acetic anhydride in 1.73 mL (18 eq.) of formic acid, which had been mixed for 30 minutes, was added dropwise to a solution of the residue in 12 mL of tetrahydrofuran at 0° C. The reaction mixture was stirred for 1 hour, allowed to warm to room temperature, and then concentrated under vacuum. The residue was purified on silica gel eluting with a gradient of 0 to 100% ethyl acetate in heptane to give 410 mg of a mixture of N-(1-methyl-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)formamide and N-(1-methyl-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)formamide (racemic trans). 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-pyrazol-4-yl)formamide and N-(1-methyl-3-(((2R,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)formamide (racemic cis) [ka] A solution of 350 mg (1 eq.) of a mixture of 1-methyl-3-(((2S,3S)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole (racemic cis) prepared in Step 1 of Intermediate 19 and 1-methyl-3-(((2R,3R)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole in 40 mL of methanol was treated with 0.1 g of palladium on carbon (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 in 1.13 mL (18 eq.) of formic acid, which had been premixed for 30 minutes, was added dropwise to a solution of the residue in 10 mL of tetrahydrofuran at 0° C. The reaction mixture was stirred for 1 hour, allowed to warm to room temperature, and concentrated in vacuo. The residue was purified on silica gel eluting with a gradient of 0 to 100% ethyl acetate in heptane to give 143 mg of a mixture (racemic cis) of N-(1-methyl-3-(((2R,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)formamide and N-(1-methyl-3-(((2S,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-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-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)formamide and N-(1-(methyl-d3)-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)formamide (racemic trans) Step 1: Preparation of 1-(methyl-d3)-3,4-dinitro-1H-pyrazole [ka] Iodomethane-d3 (6.42 g, 1.4 eq.) and potassium carbonate (8.83 g, 2 eq.) were added to a solution of 5 g (1 eq.) of 3,4-dinitro-1H-pyrazole (commercially available) in 150 mL of acetonitrile at 0°C. 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 in vacuo. The residue was purified on silica gel eluting with a gradient of 20 to 50% ethyl acetate in heptane to give 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. The mixture was heated at 65° C. for 7 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 in vacuo. The residue was purified on silica gel eluting with 20% ethyl acetate in heptane to give 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 cis 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-methyloxetan-3-yl)oxy)-1H-pyrazol-4-amine and 1-(methyl-d3)-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-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 palladium on carbon (10%). The reaction mixture was heated at 85° C. for 30 min. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure to give 1.9 g of 1-(methyl-d3)-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-amine and 1-(methyl-d3)-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-amine (racemic trans). The crude material was taken on to the next step without further purification.

[0264] Step 4: Preparation of N-(1-(methyl-d3)-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)formamide and N-(1-(methyl-d3)-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)formamide (racemic trans) [ka] A solution of 1.9 g (1 eq.) of 1-(methyl-d3)-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-amine and 1-(methyl-d3)-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-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 in vacuo. The residue was purified on silica gel eluting with 2% methanol in dichloromethane to give 1.7 g of N-(1-(methyl-d3)-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)formamide and N-(1-(methyl-d3)-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)formamide (racemic trans). 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-pyrazol-4-amine and 1-(methyl-d3)-3-(((2R,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-amine (racemic cis) Step 1: Preparation of 1-(methyl-d3)-3-(((2S,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-amine and 1-(methyl-d3)-3-(((2R,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-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 palladium on carbon. The reaction mixture was heated at 85° C. for 30 min. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure to give 1 g of 1-(methyl-d3)-3-(((2S,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-amine and 1-(methyl-d3)-3-(((2R,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-amine (racemic cis). The crude material was taken on to the next step without further purification.

[0266] Step 2: Preparation of N-(1-(methyl-d3)-3-(((2S,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)formamide and N-(1-(methyl-d3)-3-(((2R,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)formamide (racemic cis) [ka] A solution of 1.08 g (1 eq.) of 1-(methyl-d3)-3-(((2S,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-amine and 1-(methyl-d3)-3-(((2R,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-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 in vacuo. The residue was purified on silica gel eluting with 2% methanol in dichloromethane to give 0.95 g of N-(1-(methyl-d3)-3-(((2S,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)formamide and N-(1-(methyl-d3)-3-(((2R,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)formamide (racemic cis) as a beige solid. 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-methyl-ethoxy]pyrazol-4-yl]formamide (racemic) Step 1: Preparation of 1-[(4-methoxyphenyl)methyl]-4-nitro-3-[2,2,2-trifluoro-1-methyl-ethoxy]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 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 in vacuo. The residue was triturated in 10 mL of isopropyl ether, and the precipitate was filtered and dried in vacuo to give 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-methyl-ethoxy]-1H-pyrazole (racemic) [ka] 8.1 g (2.5 eq.) of ammonium cerium(IV) 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 onto 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 in vacuo. The residue was triturated in 40 mL of diethyl ether, and the solid was filtered and dried in vacuo to give 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-methyl-ethoxy]pyrazole [ka] 588 μL (1.3 eq.) of 3-iodo-oxetane 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-methyl-ethoxy]-1H-pyrazole in 16 mL of N,N-dimethylformamide. The mixture was heated at 80°C for 24 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 washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified on silica gel eluting with a gradient of 0 to 5% ethyl acetate in dichloromethane to give 700 mg of racemic 4-nitro-1-(oxetan-3-yl)-3-[2,2,2-trifluoro-1-methyl-ethoxy]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-methyl-ethoxy]pyrazol-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-methyl-ethoxy]pyrazole in 15 mL of methanol was treated with 620 mg (6 eq.) of ammonium formate and 170 mg of palladium on carbon (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 taken up in dichloromethane, the solid was filtered, and the filtrate was concentrated under reduced pressure to give 500 mg of racemic 1-(oxetan-3-yl)-3-[2,2,2-trifluoro-1-methyl-ethoxy]pyrazol-4-amine. The crude material was taken to the next step without further purification.

[0271] Step 5: Preparation of racemic N-[1-(oxetan-3-yl)-3-[2,2,2-trifluoro-1-methyl-ethoxy]pyrazol-4-yl]formamide [ka] A solution of 500 mg (1 eq.) of racemic 1-(oxetan-3-yl)-3-[2,2,2-trifluoro-1-methyl-ethoxy]pyrazol-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 at room temperature for 1 hour, and then concentrated in vacuo. The residue was diluted with ethyl acetate and poured onto 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 concentrated in vacuo. The residue was purified on silica gel eluting with a gradient of 0 to 5% methanol in dichloromethane to give 530 mg of racemic N-[1-(oxetan-3-yl)-3-[2,2,2-trifluoro-1-methyl-ethoxy]pyrazol-4-yl]formamide. MS (Method B) m / z 280 [M+1]; t=1.20 min.

[0272] Intermediate 24: N-(1-cyclopropyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)formamide Step 1: Preparation of 1-cyclopropyl-4-nitro-3-(oxetan-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-(oxetan-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 onto dichloromethane and water, and filtered through a pad of Celite. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified on silica gel eluting with 10% to 50% ethyl acetate in cyclohexane to give 0.6 g of 1-cyclopropyl-4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole. MS (Method A) m / z 226 [M+1]+; t=1.69 min.

[0273] Step 2: Preparation of 1-cyclopropyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-amine [ka] A solution of 0.6 g (1 eq.) of 1-cyclopropyl-4-nitro-3-(oxetan-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 10% palladium on carbon. The reaction mixture was heated at 70° C. for 15 min. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure to give 1-cyclopropyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-amine, which was used in the next step without further purification.

[0274] Step 3: Preparation of N-(1-cyclopropyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)formamide [ka] A solution of 478 mg (1 eq.) of 1-cyclopropyl-3-(oxetan-3-yloxy)-1H-pyrazol-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 in vacuo. The residue was purified on silica gel, eluting with heptane / ethyl acetate / 7N NH in MeOH (50 / 45 / 5), to give 390 mg of N-(1-cyclopropyl-3-(oxetan-3-yloxy)-1H-pyrazol-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-(oxetan-3-yloxy)pyrazol-4-yl]formamide Step 1: Preparation of 1,1-difluoropropan-2-yl methanesulfonate (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 allowed to warm 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 in vacuo to give 1.5 g of racemic 1,1-difluoropropan-2-yl methanesulfonate. 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-(oxetan-3-yloxy)-1H-pyrazole (racemic) [ka] 282 mg (1.5 eq.) of racemic 1,1-difluoropropan-2-yl methanesulfonate 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 h. The mixture was filtered through decalite, washed twice with 5 mL of acetonitrile, and concentrated under reduced pressure. The residue was purified on silica gel eluting with a gradient of 0 to 40% ethyl acetate in cyclohexane to give 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-(oxetan-3-yloxy)pyrazol-4-yl]formamide (racemic) [ka] 101 mg of ammonium chloride (5 eq.) and 106 mg (5 eq.) of iron were added to a solution of 100 mg of racemic 1-[2,2-difluoro-1-methyl-ethyl]-4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole in 8 mL of ethanol and 1.2 mL of water. The reaction mixture was stirred at 80 °C under vigorous stirring 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. A 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 purified on silica eluting with 5% methanol in dichloromethane to give 60 mg of racemic N-[1-[2,2-difluoro-1-methyl-ethyl]-3-(oxetan-3-yloxy)pyrazol-4-yl]formamide as a brown oil. MS (Method E) m / z 262 [M+1]; t=0.92 min.

[0278] Intermediate 26: N-(1-(methyl-d3)-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)formamide Step 1: Preparation of 1-(methyl-d3)-4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole [ka] 126 μL (1.5 eq.) of iodomethane-d3 (commercially available) and 880 mg of cesium carbonate were added to a solution of 250 mg (1 eq.) of 4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole (Intermediate 13, Step 3) in 10 mL of N,N-dimethylformamide. The mixture was stirred at room temperature for 1 h and 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 in vacuo. The residue was purified on silica gel eluting with a gradient of 0 to 80% ethyl acetate in cyclohexane to give 215 mg of 1-(methyl-d3)-4-nitro-3-(oxetan-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-(oxetan-3-yloxy)-1H-pyrazol-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-(oxetan-3-yloxy)-1H-pyrazole in 8 mL of ethanol and 1.2 mL of water. The reaction mixture was heated at 80°C under vigorous stirring for 10 minutes, 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 in vacuo.

[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 in vacuo. The residue was purified on silica, eluting with 5% methanol in dichloromethane, to give 150 mg of N-(1-(methyl-d3)-3-(oxetan-3-yloxy)-1H-pyrazol-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-(oxetan-3-yloxy)-1H-pyrazol-4-yl)formamide Step 1: Preparation of methyl 2-(3,4-dinitro-1H-pyrazol-1-yl)-2-methylpropanoate [ka] Methyl 2-bromo-2-methylpropanoate (1.6 mL, 1 eq.) and cesium carbonate (8.2 g, 2 eq.) 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. The 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 in vacuo. The residue was purified on silica gel, eluting with a gradient of 0 to 40% ethyl acetate in cyclohexane, to give 1 g of methyl 2-(3,4-dinitro-1H-pyrazol-1-yl)-2-methylpropanoate. MS (Method E) m / z 257 [M+1]+; t = 1.23 min.

[0282] Step 2: Preparation of methyl 2-methyl-2-(4-nitro-3-(oxetan-3-yloxy)-1H-pyrazol-1-yl)propanoate [ka] 574 mg (2 eq.) of oxetan-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-pyrazol-1-yl)-2-methylpropanoate in 50 mL of acetonitrile. The mixture was heated at 130 °C for 1 h, 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 in vacuo. The residue was purified on silica gel eluting with a gradient of 0 to 40% ethyl acetate in cyclohexane to give 602 mg of methyl 2-methyl-2-(4-nitro-3-(oxetan-3-yloxy)-1H-pyrazol-1-yl)propanoate. MS (Method E) m / z 286 [M+1]+; t = 1.12 min.

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

[0284] Step 4: Preparation of 2-methyl-2-(4-nitro-3-(oxetan-3-yloxy)-1H-pyrazol-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-(oxetan-3-yloxy)-1H-pyrazol-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 allowed to warm to room temperature, stirred for 1 h, and then poured onto 50 mL of diethyl ether and 20 mL of water. The organic layer was dried over sodium sulfate and concentrated in vacuo to give 1 g of 2-methyl-2-(4-nitro-3-(oxetan-3-yloxy)-1H-pyrazol-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-(oxetan-3-yloxy)-1H-pyrazol-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-(oxetan-3-yloxy)-1H-pyrazol-1-yl)propanenitrile in 16 mL of ethanol and 4 mL of water. The reaction mixture was heated at 80° C. under vigorous stirring for 10 minutes, 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 in vacuo.

[0286] A solution of the residue 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 in vacuo. The residue was purified on silica, eluting with 5% methanol in dichloromethane, to give 750 mg of N-(1-(2-cyanopropan-2-yl)-3-(oxetan-3-yloxy)-1H-pyrazol-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-pyrazol-4-yl)formamide Step 1: Preparation of 3-cyclopropoxy-1-(1,1-difluoropropan-2-yl)-4-nitro-1H-pyrazole (racemic) [ka] 200 mg of racemic 3-cyclopropoxy-1-(1,1-difluoropropan-2-yl)-4-nitro-1H-pyrazole was prepared starting with 300 mg of 3-cyclopropoxy-4-nitro-1H-pyrazole according to the general 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-pyrazol-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. under vigorous stirring for 10 minutes, 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.

[0289] A solution of the residue 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. The reaction mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was purified on silica, eluting with 5% methanol in dichloromethane, to give 45 mg of racemic N-(3-cyclopropoxy-1-(1,1-difluoropropan-2-yl)-1H-pyrazol-4-yl)formamide. MS (Method E) m / z 246 [M+1]+; t=1.01 min.

[0290] Intermediate 29: N-[3-(cyclopropoxy)-1-(methyl-d3)pyrazol-4-yl]formamide Step 1: Preparation of trimethyl-[2-[(4-nitropyrazol-1-yl)methoxy]ethyl]silane [ka] 10 g (1 eq.) of 4-nitro-1H-pyrazole (commercially available) 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 portionwise. 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 quenched by adding ice and diethyl ether. The organic layer was separated and washed twice with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified on silica gel eluting with 20% ethyl acetate in heptane to give 21.34 g of trimethyl-[2-[(4-nitropyrazol-1-yl)methoxy]ethyl]silane. MS (Method E) m / z242[MH];t=1.95 min.

[0291] Step 2: Preparation of 2-[(3-chloro-4-nitro-pyrazol-1-yl)methoxy]ethyl-trimethyl-silane [ka] 53 mL (1.2 eq.) of 1N lithium bis(trimethylsilyl)amide in tetrahydrofuran was added dropwise to a solution of 10.8 g (1 eq.) of trimethyl-[2-[(4-nitropyrazol-1-yl)methoxy]ethyl]silane in 80 mL of dry tetrahydrofuran at −78° C. The mixture was stirred at −50° C. for 30 minutes, then cooled back 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 and diethyl ether. The organic layer was separated and washed with 10% aqueous citric acid, water, and brine, dried over sodium sulfate and sodium bicarbonate, and concentrated in vacuo. The residue was purified on silica gel eluting with 5% ethyl acetate in cyclohexane to give 10 g of 2-[(3-chloro-4-nitro-pyrazol-1-yl)methoxy]ethyl-trimethyl-silane. MS (Method E), no ionization, t=1.60 min.

[0292] Step 3: Preparation of 2-[[3-(cyclopropoxy)-4-nitro-pyrazol-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-pyrazol-1-yl)methoxy]ethyl-trimethyl-silane in 10 mL of anhydrous tetrahydrofuran was added. The mixture was stirred at 5° C. for 30 minutes and quenched with 10% aqueous citric acid and diethyl ether. The organic layer was separated and washed twice with water, dried over magnesium sulfate, and concentrated in vacuo to give 2.1 g of 2-[[3-(cyclopropoxy)-4-nitro-pyrazol-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: Preparation of [3-(cyclopropoxy)-4-nitro-pyrazol-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-nitro-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane in 200 mL of dry acetonitrile. After heating at 40 °C for 3 h, 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 purified on silica gel eluting with a gradient of 0 to 50% ethyl acetate in cyclohexane to give 4.72 g of [3-(cyclopropoxy)-4-nitro-pyrazol-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-nitro-pyrazol-1-yl]methanol in 20 mL of methanol and 100 mL of 7N NH3 in MeOH was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give 2.5 g of 3-(cyclopropoxy)-4-nitro-1H-pyrazole. MS m / 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 (commercially available) 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. The mixture was heated at 80°C for 1 h. After cooling to room temperature, the mixture was filtered, washed with acetonitrile, and the solvent was concentrated. The residue was purified on silica gel eluting with a gradient of 0 to 40% ethyl acetate in cyclohexane to give 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)pyrazol-4-yl]formamide [ka] Iron powder (112.5 mg, 5.0 eq.) and ammonium chloride (108.0 mg, 5.0 eq.) were added to a solution of 3-(cyclopropoxy)-4-nitro-1-(methyl-d3)pyrazole (75 mg, 1 eq.) in a mixture of ethanol (8 mL) and water (2 mL). The mixture was heated at 80°C for 30 minutes and then allowed to cool to room temperature. The reaction mixture was filtered through Celite, washed with ethanol, and the filtrate was concentrated under reduced pressure. The residue in dry tetrahydrofuran (10 mL) was added dropwise to a solution of acetic anhydride (190 μL, 5 eq.) in formic acid (273 μL, 18 eq.) that 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 purified on silica gel eluting with a gradient of 0 to 10% methanol in dichloromethane to give 25 mg of N-[3-(cyclopropoxy)-1-(methyl-d3)pyrazol-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)pyrazol-4-yl]formamide Step 1: Preparation of methyl 2-[3-(cyclopropoxy)-4-nitro-pyrazol-1-yl]-2-methyl-propanoate [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-nitro-pyrazol-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 h, 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 an additional 3 h, after which the reaction was quenched by the addition of water. The aqueous layer was extracted with ethyl acetate / diethyl ether. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified on silica gel eluting with a gradient of 0 to 10% ethyl acetate in cyclohexane to give 1.78 g of methyl 2-[3-(cyclopropoxy)-4-nitro-pyrazol-1-yl]-2-methylpropanoate as a colorless oil. MS (Method E) m / z270[M+1]+;t=1.63 min.

[0298] Step 2: Preparation of 2-[3-(cyclopropoxy)-4-nitro-pyrazol-1-yl]-2-methyl-propanenitrile [ka] A solution of 1.78 g (1 eq.) of methyl 2-[3-(cyclopropoxy)-4-nitro-pyrazol-1-yl]-2-methyl-propanoate in 360 mL of 7N NH3 in MeOH was stirred at room temperature for 2 days, and then the reaction mixture was concentrated in vacuo. The residue was taken up 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. The reaction mixture was stirred for 1 hour, and then quenched by the addition of water and diethyl ether. The aqueous layer was separated and extracted with diethyl ether. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give 1.35 g of 2-[3-(cyclopropoxy)-4-nitro-pyrazol-1-yl]-2-methyl-propanenitrile. 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)pyrazol-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-nitro-pyrazol-1-yl]-2-methyl-propanenitrile in 4 mL of ethanol and 2 mL of water. The mixture was heated at 80°C for 30 minutes and then allowed to cool to room temperature. The reaction mixture was filtered through Celite, washed with ethanol, and the filtrate was concentrated under reduced pressure. The residue was taken up 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 in vacuo. The residue was purified on silica gel eluting with a gradient of 0 to 10% methanol in dichloromethane to give 46 mg of N-[1-(1-cyano-1-methyl-ethyl)-3-(cyclopropoxy)pyrazol-4-yl]formamide. MS m / z 235 [M+1]; t=1.03 min.

[0300] Intermediate 31: N-[1-(1-cyano-1-methyl-ethyl)-3-isopropoxy-pyrazol-4-yl]formamide Step 1: Preparation of methyl 2-(3-isopropoxy-4-nitro-pyrazol-1-yl)-2-methyl-propanoate [ka] 3-Isopropoxy-4-nitro-1H-pyrazole (commercially available) (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 portionwise. The reaction mixture was stirred at 0°C for 30 minutes, followed by the addition of 3.04 mL (1.35 eq.) of methyl 2-bromo-2-methylpropanoate. The resulting mixture was stirred for 2 days, after which the reaction was quenched by the addition of 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 in vacuo. The residue was purified on silica gel eluting with a gradient of 0-60% ethyl acetate in cyclohexane to give 3.3 g of methyl 2-(3-isopropoxy-4-nitro-pyrazol-1-yl)-2-methyl-propanoate. MS (Method E) m / z 272 [M+1]+; t=1.76 min.

[0301] Step 2: Preparation of 2-(3-isopropoxy-4-nitro-pyrazol-1-yl)-2-methyl-propanenitrile [ka] A solution of 3 g (1 eq.) of methyl 2-(3-isopropoxy-4-nitro-pyrazol-1-yl)-2-methyl-propanoate in 100 mL of 7N NH3 in MeOH was heated at 100 °C for 18 hours, then the reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was taken up in 50 mL of anhydrous tetrahydrofuran and cooled to 0 °C, and 2.06 mL (1.2 eq.) of trifluoroacetic anhydride and 4.24 mL (2.5 eq.) of triethylamine were added. The reaction mixture was stirred at room temperature for 1 hour, after which the reaction was quenched by the addition of 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 in vacuo. The residue was purified on silica gel eluting with 10-15% ethyl acetate in cyclohexane to give, after concentration in vacuo, 2.6 g of 2-(3-isopropoxy-4-nitro-pyrazol-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-isopropoxy-pyrazol-4-yl]formamide [ka] 3.05 g (5 eq.) of iron was added to a solution of 2.6 g of 2-(3-isopropoxy-4-nitro-pyrazol-1-yl)-2-methyl-propanenitrile in 90 mL of ethanol, 10 mL of water, and 5 mL of acetic acid at 80° C. The reaction mixture was vigorously stirred at 80° C. for 20 minutes, and the mixture was cooled and 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 chloride solution. The organic layer was dried over sodium sulfate and concentrated in vacuo.

[0303] A solution of the residue 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 with vigorous stirring for 30 minutes. The organic layer was separated and washed twice with 50 mL of 10% aqueous sodium carbonate solution, then concentrated in vacuo. The residue was taken up in 100 mL of toluene and concentrated in vacuo. The residue was triturated in 100 mL of a 70 / 30 pentane / ether mixture, and the solid was filtered to give 2.06 g of N-[1-(1-cyano-1-methyl-ethyl)-3-isopropoxy-pyrazol-4-yl]formamide. MS (Method F): m / z 237 [M+1]+; t = 1.37 min.

[0304] Intermediate 32: N-(3-((1-acetyl-2,2-dimethylazetidin-3-yl)oxy)-1-methyl-1H-pyrazol-4-yl)formamide (racemic) Step 1: tert-butyl 2,2-dimethyl-3-((1-methyl-4-nitro-1H-pyrazol-3-yl)oxy)azetidine-1-carboxylate (racemic) Manufacturing [ka] Racemic tert-butyl 3-hydroxy-2,2-dimethylazetidine-1-carboxylate (482 mg, 1.3 eq.) and cesium carbonate (1.5 g, 2 eq.) were added to a solution of 1-methyl-3,4-dinitro-1H-pyrazole (400 mg, 1 eq.) (commercially available) in 8 mL of acetonitrile. The 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 in vacuo. The residue was purified on silica gel eluting with a gradient of 0 to 20% ethyl acetate in dichloromethane to give 460 mg of racemic tert-butyl 2,2-dimethyl-3-((1-methyl-4-nitro-1H-pyrazol-3-yl)oxy)azetidine-1-carboxylate. MS (Method B) m / z237[M+1]+;t=1.69 min.

[0305] Step 2: Preparation of 3-((2,2-dimethylazetidin-3-yl)oxy)-1-methyl-4-nitro-1H-pyrazole (racemic) [ka] Trifluoroacetic acid (5.5 mL, 19 eq.) was added to a solution of 1.2 g (1 eq.) of racemic tert-butyl 2,2-dimethyl-3-((1-methyl-4-nitro-1H-pyrazol-3-yl)oxy)azetidine-1-carboxylate in 30 mL of dichloromethane. The mixture was stirred for 2 hours at room temperature. The mixture was concentrated in vacuo, then dissolved in 10 mL of methanol, treated with 30 mL of 7 M methanolic ammonia solution for 1 hour, and concentrated in vacuo. The residue was purified on silica gel, eluting with a gradient of 0 to 5% 7 M methanolic ammonia solution in dichloromethane, to give 460 mg of racemic 3-((2,2-dimethylazetidin-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: Preparation of 1-(2,2-dimethyl-3-((1-methyl-4-nitro-1H-pyrazol-3-yl)oxy)azetidin-1-yl)ethan-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-dimethylazetidin-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 and 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 in vacuo. The residue was purified on silica gel eluting with a gradient of 0 to 5% methanol in dichloromethane to give 360 ​​mg of racemic 1-(2,2-dimethyl-3-((1-methyl-4-nitro-1H-pyrazol-3-yl)oxy)azetidin-1-yl)ethan-1-one. MS (Method B) m / z 269 [M+1]; t=1.13 min.

[0307] Step 4: Preparation of 1-(3-((4-amino-1-methyl-1H-pyrazol-3-yl)oxy)-2,2-dimethylazetidin-1-yl)ethan-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-pyrazol-3-yl)oxy)azetidin-1-yl)ethan-1-one in 12 mL of methanol was treated with 515 mg (7 eq.) of ammonium formate and 86 mg of palladium on carbon (10%). The reaction mixture was heated at 70° C. for 10 min. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The residue was filtered into dichloromethane, and the filtrate was concentrated under reduced pressure to give 260 mg of racemic 1-(3-((4-amino-1-methyl-1H-pyrazol-3-yl)oxy)-2,2-dimethylazetidin-1-yl)ethan-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-dimethylazetidin-3-yl)oxy)-1-methyl-1H-pyrazol-4-yl)formamide (racemic) [ka] A solution of 264 mg (1 eq.) of racemic 1-(3-((4-amino-1-methyl-1H-pyrazol-3-yl)oxy)-2,2-dimethylazetidin-1-yl)ethan-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 min. The reaction mixture was stirred at 5 °C for 30 min and then concentrated in vacuo. The residue was taken up in toluene and concentrated in vacuo. The residue was purified on silica gel eluting with a gradient of 0 to 5% methanol in dichloromethane to give 250 mg of racemic N-(3-((1-acetyl-2,2-dimethylazetidin-3-yl)oxy)-1-methyl-1H-pyrazol-4-yl)formamide. MS (Method B) m / z267[M+1]+;t=0.92 min.

[0309] Intermediate 33: Methyl 2-(4-formamido-3-(oxetan-3-yloxy)-1H-pyrazol-1-yl)propanoate (racemic) Step 1: Preparation of methyl 2-(4-nitro-3-(oxetan-3-yloxy)-1H-pyrazol-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-(oxetan-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 h 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 in vacuo. The residue was purified on silica gel eluting with a gradient of 10 to 50% ethyl acetate in heptane to give 594 mg of racemic methyl 2-(4-nitro-3-(oxetan-3-yloxy)-1H-pyrazol-1-yl)propanoate. MS method B: m / z272[M+1]+;t=1.19 min.

[0310] Step 2: Preparation of methyl 2-(4-amino-3-(oxetan-3-yloxy)-1H-pyrazol-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 methyl 2-(4-nitro-3-(oxetan-3-yloxy)-1H-pyrazol-1-yl)propanoate in 20 mL of ethanol and 5 mL of water. The reaction mixture was vigorously stirred at 90° C. for 2.5 hours, and the mixture was 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 chloride solution. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give 454 mg of racemic methyl 2-(4-amino-3-(oxetan-3-yloxy)-1H-pyrazol-1-yl)propanoate, which was used in the next step without further purification.

[0311] Step 3: Preparation of methyl 2-(4-formamido-3-(oxetan-3-yloxy)-1H-pyrazol-1-yl)propanoate (racemic) [ka] A solution of 454 mg (1 eq.) of racemic methyl 2-(4-amino-3-(oxetan-3-yloxy)-1H-pyrazol-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 min. The reaction mixture was stirred at 5° C. for 5 min and at room temperature for 1.5 h, then concentrated in vacuo. The residue was purified on silica gel eluting with a gradient of 10-30% acetone in dichloromethane to give 366 mg of racemic methyl 2-(4-formamido-3-(oxetan-3-yloxy)-1H-pyrazol-1-yl)propanoate. MS Method A: m / z 270 [M+1]; t=1.26 min.

[0312] Intermediate 34: 3-(cyclopropoxy)-4-formamidobenzoic acid methyl ester Step 1: Preparation of methyl 3-(cyclopropoxy)-4-nitro-benzoate [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, and quenched with 50 mL of a saturated solution of ammonium chloride and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and purified on silica gel eluting with 20% ethyl acetate in heptane to give 380 mg of methyl 3-(cyclopropoxy)-4-nitrobenzoate. MS (Method H): m / z238[M+1]+;t=1.53 min.

[0313] Step 2: Preparation 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 h. The mixture was filtered through Celite, washed with ethanol, and concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and purified on silica gel eluting with a gradient of 2 to 5% methanol in dichloromethane to give 280 mg of 4-amino-3-(cyclopropoxy)benzoate. MS (Method H) m / z 208 [M+1]; t = 1.69 min.

[0314] Step 3: Preparation of methyl 3-(cyclopropoxy)-4-formamidobenzoate [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. The reaction mixture was stirred at room temperature for 2 hours and 30 minutes and then concentrated under vacuum. The residue was taken up 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 give 250 mg of methyl 3-(cyclopropoxy)-4-formamidobenzoate. MS (Method A) m / z 236 [M+1]+; t = 1.99 min.

[0315] Intermediate 35: 4-Formamido-3-(oxetan-3-yloxy)benzoic acid methyl ester Step 1: Preparation of methyl 4-nitro-3-(oxetan-3-yloxy)benzoate and 4-nitro-3-(oxetan-3-yloxy)benzoic acid [ka] Sodium (1.4 g, 1.9 eq., 60% oil dispersion) was added portionwise to a solution of 2.23 g (2 eq.) of oxetan-3-ol in 50 mL of anhydrous tetrahydrofuran cooled to 0°C. The reaction mixture was stirred at 0°C for 1 hour, followed by the addition of a solution of 3 g (1 eq.) of methyl 3-fluoro-4-nitrobenzoate in 15 mL of anhydrous tetrahydrofuran. The mixture was allowed to warm 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 in vacuo. The residue was purified on silica gel, eluting with a gradient of 20% to 50% ethyl acetate in heptane, to give 900 mg of methyl 4-nitro-3-(oxetan-3-yloxy)benzoate. MS (Method A) m / z 254 [M+1]+; t = 1.97 min. The aqueous layer was acidified to pH = 5 with 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 in vacuo. The residue was purified on silica gel, eluting with a gradient of 5 to 10% methanol in dichloromethane, to give 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: Preparation of methyl 4-amino-3-(oxetan-3-yloxy)benzoate [ka] In a microwave vial, a solution of 500 mg (1 eq.) of methyl 4-nitro-3-(oxetan-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 10% palladium on carbon. The reaction mixture was heated at 85° C. for 15 min. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure to give 440 mg of methyl 4-amino-3-(oxetan-3-yloxy)benzoate. MS (Method A) m / z 254 [M+1]; t = 1.55 min.

[0317] Step 3: Preparation of methyl 4-formamido-3-(oxetan-3-yloxy)benzoate [ka] A solution of 440 mg (1 eq.) of methyl 4-amino-3-(oxetan-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. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated in vacuo to give 435 mg of methyl 4-formamido-3-(oxetan-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-pyrazol-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 (commercially available) 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 (commercially available) in 25 mL of acetonitrile. The mixture was heated at 70 °C overnight, 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 in vacuo. The residue was purified on silica gel eluting with 50% ethyl acetate in heptane to give 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-pyrazol-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 palladium on carbon (10%). The reaction mixture was heated at 70° C. for 10 min. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The residue was dissolved in 2 mL of tetrahydrofuran, and the 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 min. The reaction mixture was stirred at 5° C. for 5 min and at room temperature for 1 h, then concentrated under vacuum. The residue was taken up in 50 mL of toluene and concentrated in vacuo to give 395 mg of N-(3-((2-oxaspiro[3.3]heptan-5-yl)oxy)-1-methyl-1H-pyrazol-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-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)formamide and N-(1-(methoxymethyl)-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-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. The mixture was stirred at room temperature for 2 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 in vacuo. The residue was purified on silica gel eluting with 20-50% ethyl acetate in heptane to give 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. The 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 in vacuo. The residue was purified on silica gel eluting with 10% to 50% ethyl acetate in heptane to give 501 mg (MS (Method A) m / z 24.4) of a 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, characterized as racemic trans by NMR. 4 [M+1] +; t = 1.13 min), and 940 mg of 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, characterized as racemic cis by NMR (MS (Method A) m / z 244 [M+1] +; t = 1.17 min).

[0322] Step 3: Preparation of 1-(methoxymethyl)-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-amine and 1-(methoxymethyl)-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-amine (racemic trans) [ka] In a microwave vial, a solution of 501 mg (1 eq.) of the 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 palladium on carbon (10%). The reaction mixture was heated at 70° C. for 15 min. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The crude material was taken on to the next step without further purification.

[0323] Step 4: Preparation of N-(1-(methoxymethyl)-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)formamide and N-(1-(methoxymethyl)-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)formamide (racemic trans) [ka] A solution of 439 mg (1 eq.) of the racemic mixture of 1-(methoxymethyl)-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-amine and 1-(methoxymethyl)-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-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 that had been mixed at room temperature for 30 minutes. The reaction mixture was stirred for 1 hour at 0°C. The residue was concentrated in vacuo and purified on silica gel eluting with heptane / AcOEt / 7NNH in MeOH (50 / 45 / 5) to give 387 mg of a mixture of N-(1-(methoxymethyl)-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)formamide and N-(1-(methoxymethyl)-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)formamide (racemic trans). MS (Method B) m / z 242 [M+1]; t=0.85 min (racemic trans).

[0324] Intermediate 38: N-(3-isopropoxy-1-methyl-1H-pyrazol-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. The mixture was heated at 70° C. for 1 h 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 100 mL of water, then dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica gel eluting with an 85 / 15 mixture of cyclohexane / ethyl acetate to give 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-pyrazol-4-amine [ka] 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 was added 1.51 g (5 eq.) of iron at 80° C. The reaction mixture was vigorously stirred at 80° C. for 20 minutes, and the mixture was 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. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel eluting with 5% methanol in dichloromethane to give 650 mg of 3-isopropoxy-1-methyl-1H-pyrazol-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-pyrazol-4-yl)formamide [ka] A solution of 3 g of 3-isopropoxy-1-methyl-1H-pyrazol-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. 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 with vigorous stirring for 30 minutes. The organic layer was separated and washed twice with 50 mL of 10% aqueous sodium carbonate solution, then concentrated in vacuo. The residue was purified on silica gel, eluting with a 70 / 30 cyclohexane / ethyl acetate mixture, to give 2.18 g of N-(3-isopropoxy-1-methyl-1H-pyrazol-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-pyrazol-4-yl)formamide and (S)-N-(1-(1-cyanoethyl)-3-isopropoxy-1H-pyrazol-4-yl)formamide Step 1: Preparation of (R)-2-(3-isopropoxy-4-nitro-1H-pyrazol-1-yl)propanenitrile and (S)-2-(3-isopropoxy-4-nitro-1H-pyrazol-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 (commercially available) in 20 mL of 1-methyl-2-pyrrolidinone (NMP). The mixture was stirred at room temperature for 1 hour 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 reduced pressure. The residue was purified on silica gel eluting with 50% ethyl acetate in heptane to give 2.2 g of a racemic mixture of (R)-2-(3-isopropoxy-4-nitro-1H-pyrazol-1-yl)propanenitrile and (S)-2-(3-isopropoxy-4-nitro-1H-pyrazol-1-yl)propanenitrile. MS (Method B) m / z225[M+1]+;t=1.34 min.

[0328] Step 2: Preparation of (R)-2-(4-amino-3-isopropoxy-1H-pyrazol-1-yl)propanenitrile and (S)-2-(4-amino-3-isopropoxy-1H-pyrazol-1-yl)propanenitrile [ka] Ammonium chloride (680 mg, 3 eq.) and iron (710 mg, 3 eq.) were added to a solution of a racemic mixture of (R)-2-(3-isopropoxy-4-nitro-1H-pyrazol-1-yl)propanenitrile (950 mg, 1 eq.) and (S)-2-(3-isopropoxy-4-nitro-1H-pyrazol-1-yl)propanenitrile (950 mg, 1 eq.)) in ethanol (25 mL) and water (7 mL). 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 taken up in ethyl acetate, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The crude material was purified on silica gel eluting with 5% methanol in dichloromethane to give 850 mg of a racemic mixture of (R)-2-(4-amino-3-isopropoxy-1H-pyrazol-1-yl)propanenitrile and (S)-2-(4-amino-3-isopropoxy-1H-pyrazol-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-pyrazol-4-yl)formamide and (S)—N-(1-(1-cyanoethyl)-3-isopropoxy-1H-pyrazol-4-yl)formamide [ka] A solution of 1.4 g (1 eq.) of the racemic mixture of (R)-2-(4-amino-3-isopropoxy-1H-pyrazol-1-yl)propanenitrile and (S)-2-(4-amino-3-isopropoxy-1H-pyrazol-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 taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated under reduced pressure. The crude material was purified on silica gel, eluting with 2% methanol in dichloromethane. The resulting oil was triturated in diisopropyl ether and the precipitate was filtered to give 1.1 g of a racemic mixture of (R)—N-(1-(1-cyanoethyl)-3-isopropoxy-1H-pyrazol-4-yl)formamide and (S)—N-(1-(1-cyanoethyl)-3-isopropoxy-1H-pyrazol-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 the racemic mixture, yielding 488 mg of the first-eluting isomer and 503 mg of the second-eluting isomer (conditions: column Chiralpak AY, 20 μm, 230 × 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-pyrazol-4-yl)formamide Step 1: Preparation of (R)-2-(3-cyclopropoxy-4-nitro-1H-pyrazol-1-yl)propanenitrile and (S)-2-(3-cyclopropoxy-4-nitro-1H-pyrazol-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 purified on silica gel eluting with 50% ethyl acetate in heptane to give 755 mg of a racemic mixture of (R)-2-(3-cyclopropoxy-4-nitro-1H-pyrazol-1-yl)propanenitrile and (S)-2-(3-cyclopropoxy-4-nitro-1H-pyrazol-1-yl)propanenitrile. MS (Method A) m / z223[M+1]+;t=1.96 min.

[0332] Step 2: Preparation of (R)-2-(4-amino-3-cyclopropoxy-1H-pyrazol-1-yl)propanenitrile and (S)-2-(4-amino-3-cyclopropoxy-1H-pyrazol-1-yl)propanenitrile [ka] 545 mg of ammonium chloride (3 eq.) and 570 mg (3 eq.) of iron were added to a solution of 755 mg (1 eq.) of the racemic mixture of (R)-2-(3-cyclopropoxy-4-nitro-1H-pyrazol-1-yl)propanenitrile and (S)-2-(3-cyclopropoxy-4-nitro-1H-pyrazol-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 taken up in ethyl acetate, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The crude material was taken to the next step without further purification.

[0333] Step 3: Preparation of (R)—N-(1-(1-cyanoethyl)-3-cyclopropoxy-1H-pyrazol-4-yl)formamide and (S)—N-(1-(1-cyanoethyl)-3-cyclopropoxy-1H-pyrazol-4-yl)formamide [ka] A solution of 0.65 g (1 eq.) of (R)-2-(4-amino-3-cyclopropoxy-1H-pyrazol-1-yl)propanenitrile and (S)-2-(4-amino-3-cyclopropoxy-1H-pyrazol-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. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure to give 620 mg of a racemic mixture of (R)-N-(1-(1-cyanoethyl)-3-cyclopropoxy-1H-pyrazol-4-yl)formamide and (S)-N-(1-(1-cyanoethyl)-3-cyclopropoxy-1H-pyrazol-4-yl)formamide. MS (Method A) m / z221[M+1]+;t=1.42 min.

[0334] Intermediate 41: N-(3-cyclopropoxy-1-isopropyl-1H-pyrazol-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). The mixture was heated at 80 °C for 1 h 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 100 mL of water, dried over sodium sulfate, and concentrated in vacuo. The residue was purified on silica gel eluting with an 80 / 20 heptane / ethyl acetate mixture to give 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-pyrazol-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 10% palladium on carbon. The reaction mixture was heated at 70° C. for 10 min. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The crude material was taken on to the next step without further purification.

[0336] Step 3: Preparation of N-(3-cyclopropoxy-1-isopropyl-1H-pyrazol-4-yl)formamide [ka] A solution of 234 mg of 3-cyclopropoxy-1-isopropyl-1H-pyrazol-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 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 purified on silica gel, eluting with a 50 / 50 heptane / ethyl acetate mixture, to give 155 mg of N-(3-cyclopropoxy-1-isopropyl-1H-pyrazol-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-pyrazol-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-nitro-pyrazol-1-yl)methoxy]ethyl-trimethyl-silane (Intermediate 29, Step 2) in 5 mL of dry tetrahydrofuran was added. The mixture was stirred at 5° C. for 30 minutes and quenched with 10% aqueous citric acid and diethyl ether. The organic layer was separated and washed twice with water, dried over magnesium sulfate, and concentrated in vacuo to give 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 a 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 a 1N aqueous solution of sodium hydroxide. The reaction mixture was extracted twice with 50 mL of ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give 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 the solution. The mixture was heated at 80°C for 2 hours and 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 in vacuo. The residue was purified on silica gel, eluting with an 80 / 20 to 50 / 50 heptane / ethyl acetate mixture, to give 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-pyrazol-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 taken up in ethyl acetate, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give 579 mg of 3-(3,3-difluorocyclobutoxy)-1-methyl-1H-pyrazol-4-amine as an orange gum. The crude material was taken to the next step without further purification.

[0340] Step 4: Preparation of N-(3-(3,3-difluorocyclobutoxy)-1-methyl-1H-pyrazol-4-yl)formamide [ka] A solution of 579 mg of 3-(3,3-difluorocyclobutoxy)-1-methyl-1H-pyrazol-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, premixed for 30 minutes, cooled to 0 °C. The reaction mixture was stirred at 0 °C for 10 minutes, then at room temperature for 30 minutes, and concentrated in vacuo. The residue was purified on silica gel, eluting with a 50 / 50 heptane / ethyl acetate mixture, to give 374 mg of N-(3-(3,3-difluorocyclobutoxy)-1-methyl-1H-pyrazol-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 methyl 2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (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 material was filtered and dried under vacuum to give 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] Trifluoroacetic anhydride (4.25 mL, 3.6 eq.) and triethylamine (5.31 mL, 4.5 eq.) were added 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 at 0° C. under argon. The mixture was stirred for 1 hour from 0° C. to room temperature and then poured into 200 mL of water. The precipitate was vacuum filtered and triturated with diethyl ether to give 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-(oxetan-3-yloxy)-1H-pyrazol-4-yl)formamide Step 1: Preparation of 1-ethyl-4-nitro-3-(oxetan-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-(oxetan-3-yloxy)-1H-pyrazole (Intermediate 13, Step 3) in 10 mL of N,N-dimethylformamide. The mixture was stirred at room temperature for 1 h 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, dried over sodium sulfate, and concentrated in vacuo. The residue was purified on silica gel eluting with a gradient of 0 to 80% ethyl acetate in cyclohexane to give 374 mg of 1-ethyl-4-nitro-3-(oxetan-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-pyrazol-4-yl)formamide [ka] 200 mg of N-(1-ethyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)formamide was prepared starting from 373 mg of 1-ethyl-4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole according to the general 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)pyrazol-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 according to the general procedure described in Intermediate 26, Step 1. MS (Method E) m / z 189 [M+1]+; t=1.11 min.

[0346] Step 2: Preparation of N-[3-isopropoxy-1-(methyl-d3)pyrazol-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. The organic layer was dried over sodium sulfate and concentrated under vacuum to form a residue.

[0347] A solution of the residue 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. The reaction mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was purified on silica gel, eluting with 5% methanol in dichloromethane, to give 95 mg of N-[3-isopropoxy-1-(methyl-d3)pyrazol-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-pyrazol-4-yl)formamide Step 1: Preparation of (S)-5-(2-butoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole [ka] 785 mg of (S)-5-(2-butoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole was prepared starting from 1 g of 5-chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole according to the general procedure described in Step 3 of Intermediate 29. MS (Method F) m / z no ionization; t=2.14 min.

[0349] Step 2: Preparation of (S)-(5-(2-butoxy)-4-nitro-1H-pyrazol-1-yl)methanol [ka] Following the general 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-pyrazol-1-yl)methanol. The crude material was taken on to 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-pyrazol-1-yl)methanol in 30 mL of N,N-dimethylformamide. The mixture was stirred at 60° C. for 2 h, 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 in vacuo. The residue was purified on silica gel eluting with a gradient of 0 to 60% ethyl acetate in cyclohexane to give 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-pyrazol-4-yl)formamide [ka] Following the general 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-pyrazol-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-pyrazol-4-yl)formamide Step 1: Preparation of (R)-5-(2-butoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole [ka] Following the general 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 no ionization; t=2.14 min.

[0353] Step 2: Preparation of (R)-(5-(2-butoxy)-4-nitro-1H-pyrazol-1-yl)methanol [ka] Following the general procedure described in Step 4 of Intermediate 29, 890 mg of (R)-5-(2-butoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole was converted to 607 mg of (R)-(5-(2-butoxy)-4-nitro-1H-pyrazol-1-yl)methanol. 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] Following the general procedure described in Step 3 of Intermediate 46, 620 mg of (R)-(5-(2-butoxy)-4-nitro-1H-pyrazol-1-yl)methanol was converted to 440 mg of (R)-3-(2-butoxy)-1-methyl-4-nitro-1H-pyrazole. 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-pyrazol-4-yl)formamide [ka] Following the general procedure described in Step 4 of Intermediate 46, 440 mg of (R)-3-(2-butoxy)-1-methyl-4-nitro-1H-pyrazole was converted to 175 mg of (R)—N-(3-(2-butoxy)-1-methyl-1H-pyrazol-4-yl)formamide. 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]pyridin-8-yl)formamide Step 1: Preparation of 2,2-dimethyl-2,3-dihydro-4H-pyrano[3,2-b]pyridin-4-one [ka] In a sealed vessel, 4.52 mL of pyrrolidine (1.5 eq.) was added to a solution of 5 g (1 eq.) of 1-(3-hydroxypyridin-2-yl)ethan-1-one in 100 mL of toluene. The mixture was stirred for 15 minutes at room temperature. Then, 5.4 mL (2 eq.) of acetone was added, and the reaction mixture was stirred at 40°C for 24 hours. An additional 4 mL (1.5 eq.) of acetone was added, and the mixture was again stirred for 15 hours at room temperature, then filtered through a pad of silica gel eluting with a gradient of 0 to 100% ethyl acetate in cyclohexane to give 3.29 g of 2,2-dimethyl-2,3-dihydro-4H-pyrano[3,2-b]pyridin-4-one. MS (Method F) m / z 178 [M+1]+; t = 1.63 min.

[0357] Step 2: Preparation of 2,2-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-ol [ka] A solution of 1 g (1 eq.) of 2,2-dimethyl-2,3-dihydro-4H-pyrano[3,2-b]pyridin-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 with stirring. The reaction mixture was stirred at reflux for 2 hours, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in 200 mL of ethyl acetate and washed with 150 mL of saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate and then concentrated in vacuo, and the residue was purified on silica gel eluting with a gradient of 0 to 5% methanol in dichloromethane to give 820 mg of 2,2-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-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]pyridin-4-ol and 87 mg (0.1 eq.) of para-toluenesulfonic acid hydrate in 50 mL of toluene was refluxed for 5 h with constant removal of water. After cooling to room temperature and concentration in vacuo, the residue was purified on silica gel eluting with a gradient of 0–5% methanol in dichloromethane to give 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: Preparation 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 weight palladium on carbon in a Parr apparatus under 2.5 bar of hydrogen for 1.5 h. After filtration through decalite, rinsing with 30 mL of methanol, and concentration under vacuum, the residue was purified on silica gel eluting with a gradient of 0 to 70% ethyl acetate in cyclohexane to give 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% wt. purity) was added 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 at 0 °C. The reaction mixture was stirred at room temperature for 18 h, then washed with 100 mL of saturated aqueous sodium carbonate, and the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica gel eluting with a gradient of 0 to 5% methanol in dichloromethane to give 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: Preparation 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] Two 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 12 N aqueous sodium hydroxide. 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 and concentrated in vacuo to give 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]pyridin-8-yl)formamide [ka] Following the general 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 give 150 mg of N-(2,2-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-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-pyrazol-4-yl)formamide and N-(3-isopropoxy-1-[(1S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazol-4-yl)formamide Step 1: Preparation of 3-isopropoxy-4-nitro-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole (racemic) [ka] 1.74 g (1.5 eq.) of racemic 1,1,1-trifluoropropan-2-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (commercially available) and 1.22 g (3 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 2 mL of dimethylformamide. The 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 in vacuo. The residue was taken up in diethyl ether and water. The organic layer was separated, washed with water, dried over magnesium sulfate, and concentrated in vacuo to give 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-pyrazol-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 h under 2.5 bar of hydrogen in the presence of 100 mg (0.05 eq.) of palladium on carbon (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 min. The reaction mixture was stirred at 0 °C for 1 h, allowed to warm to room temperature, and then poured into 10% aqueous sodium carbonate solution and stirred for 15 min. 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 purified on silica gel eluting with a gradient of 0 to 20% ethyl acetate in heptane to give 510 mg of racemic N-(3-isopropoxy-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazol-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 from Pseudomonas fluorescens 20.000 U / g; Catalog No.: 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 17, Step 1) and 150 mL of vinyl acetate in 300 mL of heptane. The suspension was stirred for 5 days at 22 °C 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 on silica gel eluting with 30 to 90% ethyl acetate in heptane to give 11.72 g of (3S,4S)-4-methoxytetrahydrofuran-3-ol. 1 H 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 [ka] To a solution of 5 g (1 eq.) of (S)-butane-1,3-diol in 50 mL of N,N-dimethylformamide under argon, 4.07 g (1.1 eq.) of imidazole was added. The mixture was cooled to 0°C, and 9.2 g (1.1 eq.) of tert-butyl dimethylsilyl chloride was added. The reaction mixture was stirred for 24 h at room temperature and then diluted with 150 mL of diethyl ether and 100 mL of water. The organic layer was washed three times with 50 mL of water, dried over sodium sulfate, and concentrated in vacuo. The residue was purified on silica gel eluting with a gradient of 0 to 10% ethyl acetate in cyclohexane to give 9 g of (S)-4-((tert-butyldimethylsilyl)oxy)butan-2-ol. 1 H NMR (400MHz, CDCl3) δ ppm:0,1 (s, 6 H);0,89 (s, 9 H);1,19 (d, J=6.3 Hz, 3 H);1,64 (m, 2 H);3.30 (wide s, 1 H);3,81 (m, 1 H);3,88 (m, 1 H);4,02 (m, 1 H).

[0367] Step 2: Preparation of (R)-3-((2-chloropyridin-3-yl)oxy)butan-1-ol [ka] 9.11 g (1.1 eq.) of triphenylphosphine and 6.45 mL (1.05 eq.) of diisopropyl azodicarboxylate were added dropwise successively 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-chloropyridin-3-ol in 80 mL of tetrahydrofuran at 0 °C. The reaction mixture was stirred for 1 h from 0 °C to room temperature 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 in vacuo. The residue was purified on silica gel eluting with a gradient of 0 to 10% ethyl acetate in cyclohexane to give 8.24 g of the silylated intermediate. The resulting compound was dissolved in 250 mL of acetonitrile and 50 mL of 1N aqueous hydrogen chloride solution, and the reaction mixture was stirred for 1 hour, then carefully poured into 200 mL of saturated aqueous sodium bicarbonate and 400 mL of dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica gel, eluting with a gradient of 0 to 70% ethyl acetate in cyclohexane, to give 4.4 g of (R)-3-((2-chloropyridin-3-yl)oxy)butan-1-ol. MS (Method F) m / z 202 [M+1]; t = 1.17 min.

[0368] Step 3: Preparation 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-chloropyridin-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 weight in mineral oil) in 50 mL of 1-methyl-2-pyrrolidinone at 95°C under argon over 30 min. The reaction mixture was stirred at 90-100°C for 2 h, 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 combined organic layers were washed four times with 50 mL of water, then dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica gel eluting with a gradient of 0 to 50% ethyl acetate in cyclohexane to give (R)-2-methyl-3,4-dihydro-2H-[1,4]dioxepino[2,3-b]pyridine 1g. 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 a 1.6 N 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, maintaining the temperature below −55°C. The reaction mixture was stirred for 1 hour and 30 minutes at −60°C. The temperature was allowed to slowly rise to room temperature with 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% aqueous citric acid. After five extractions with a 75 / 25 mixture of dichloromethane / isopropanol, the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was triturated in 10 mL of a 60 / 40 mixture of pentane / diethyl ether to give 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 tert-butyl (R)-(2-methyl-3,4-dihydro-2H-[1,4]dioxepino[2,3-b]pyridin-9-yl)carbamate [ka] 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 under argon, 316 μL (1.2 eq.) of triethylamine and 503 μL (1.2 eq.) of diphenylphosphoryl azide were added. 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 another 10 mL of tert-butanol were added, and the mixture was stirred at 110°C for 1 hour and 30 minutes. It was 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 in vacuo. The residue was purified on silica gel eluting with a gradient of 0 to 30% ethyl acetate in cyclohexane to give 450 mg of tert-butyl (R)-(2-methyl-3,4-dihydro-2H-[1,4]dioxepino[2,3-b]pyridin-9-yl)carbamate. 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]pyridin-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 in 10 mL of dichloromethane and 10 mL of trifluoroacetic acid was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was azeotroped three times with a 50 / 50 mixture of toluene and tetrahydrofuran, then taken up in 5 mL of tetrahydrofuran and added to a premixed solution of 492 μL (8 eq.) of formic acid and 606 μL (4 eq.) of 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 biphasic mixture was vigorously stirred for 10 minutes, and the aqueous layer was extracted with an additional 20 mL of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was triturated in 10 mL of a 50 / 50 mixture of pentane / diethyl ether to give 238 mg of (R)-N-(2-methyl-3,4-dihydro-2H-[1,4]dioxepino[2,3-b]pyridin-9-yl)formamide. MS (Method F) m / z 209 [M+1]; t=0.84 min.

[0372] Intermediate 52: N-(3-((2,2-dimethyloxetan-3-yl)oxy)-1-(methyl-d3)-1H-pyrazol-4-yl)formamide (racemic) Step 1: Preparation of 3-((2,2-dimethyloxetan-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. The 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 in vacuo. The residue was purified on silica gel eluting with 20% ethyl acetate in heptane to give 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-dimethyloxetan-3-yl)oxy)-1-(methyl-d3)-1H-pyrazol-4-yl)formamide (racemic) [ka] In a microwave vial, a solution of 0.66 g (1 eq.) of 3-((2,2-dimethyloxetan-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 palladium on carbon (10%). The reaction mixture was heated at 70° C. for 15 min. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure to give 0.62 g of 3-((2,2-dimethyloxetan-3-yl)oxy)-1-(methyl-d3)-1H-pyrazol-4-amine (racemic). The crude material was taken on to 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-pyrazol-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 min. The reaction mixture was stirred at room temperature for 3 h and then concentrated in vacuo. The residue was purified on silica gel eluting with 5% methanol in dichloromethane to give 0.51 g of N-(3-((2,2-dimethyloxetan-3-yl)oxy)-1-(methyl-d3)-1H-pyrazol-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-pyrazol-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 in vacuo. The residue was purified on silica gel, eluting with dichloromethane and then 1% methanol in dichloromethane, to give 1.0 g of 1-(2-methoxyethyl)-3,4-dinitro-1H-pyrazole. MS (Method B) t = 1.19 min; no mass detected.

[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. The 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 in vacuo. The residue was purified on silica gel eluting with 10% ethyl acetate in dichloromethane to give 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-pyrazol-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 palladium on carbon (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 to give 715 mg of 3-cyclopropoxy-1-(2-methoxyethyl)-1H-pyrazol-4-amine. The crude material was taken on to the next step without further purification.

[0378] A solution of 0.71 g (1 eq.) of 3-cyclopropoxy-1-(2-methoxyethyl)-1H-pyrazol-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. The reaction mixture was stirred at room temperature for 20 minutes and then concentrated under vacuum. The residue was purified on silica gel, eluting with 5% methanol in dichloromethane, to give 455 mg of N-(3-cyclopropoxy-1-(2-methoxyethyl)-1H-pyrazol-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-pyrazol-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. The mixture was heated at 80° C. overnight, 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 in vacuo. The residue was purified on silica gel eluting with 10% ethyl acetate in dichloromethane to give 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-pyrazol-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 palladium on carbon (10%). The reaction mixture was heated at 100° C. for 10 min. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure to give 1-(methyl-d3)-3-((tetrahydrofuran-3-yl)oxy)-1H-pyrazol-4-amine. The crude material was taken on to 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-pyrazol-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. The reaction mixture was stirred at room temperature for 90 minutes and then concentrated in vacuo. The residue was taken up 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 in vacuo. The residue was purified on silica gel, eluting with 5% methanol in dichloromethane, to give 140 mg of N-(1-(methyl-d3)-3-((tetrahydrofuran-3-yl)oxy)-1H-pyrazol-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-pyrazol-4-yl)formamide and trans N-(1-((4-hydroxy-4-methylcyclohexyl)-3-isopropoxy-1H-pyrazol-4-yl)formamide Step 1: Preparation of 3-isopropoxy-4-nitro-1-(1,4-dioxaspiro[4.5]decan-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]decan-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 in vacuo, and purified on silica eluting with 10% ethyl acetate in dichloromethane to give 1.45 g of 3-isopropoxy-4-nitro-1-(1,4-dioxaspiro[4.5]decan-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-pyrazol-1-yl)cyclohexan-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]decan-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-paratoluenesulfonic acid (PPTS). The reaction mixture was heated at 120 °C for 30 min. The mixture was concentrated under reduced pressure and taken up 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 in vacuo, and purified on silica eluting with 10% ethyl acetate in dichloromethane to give 500 mg of 4-(3-isopropoxy-4-nitro-1H-pyrazol-1-yl)cyclohexan-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-pyrazol-4-yl)formamide [ka] 800 mg of ammonium chloride (5 eq.) and 836 mg (5 eq.) of iron were added to a solution of 800 mg of 4-(3-isopropoxy-4-nitro-1H-pyrazol-1-yl)cyclohexan-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] A solution of the residue 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. The reaction mixture was stirred at room temperature for 50 minutes and then concentrated in vacuo. The residue was purified on silica gel, eluting with 5% methanol in dichloromethane, to give 170 mg of N-(3-isopropoxy-1-(4-oxocyclohexyl)-1H-pyrazol-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-pyrazol-4-yl)formamide and trans N-(1-((4-hydroxy-4-methylcyclohexyl)-3-isopropoxy-1H-pyrazol-4-yl)formamide [ka] 311 μL (1.5 eq.) of methylmagnesium bromide (3 M in tetrahydrofuran) was added to a solution of 165 mg of N-(3-isopropoxy-1-(4-oxocyclohexyl)-1H-pyrazol-4-yl)formamide in 8 mL of tetrahydrofuran at −78° C. The reaction mixture was stirred at −78° C. for 10 minutes, then 104 μL (0.5 eq.) of methylmagnesium bromide (3 M in tetrahydrofuran) was added, and the mixture was stirred at −78° C. for 1 hour. The reaction was quenched with 3 mL of a saturated aqueous solution of ammonium chloride and extracted with 20 mL of ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified on silica eluting with 3% methanol in dichloromethane to give 50 mg (cis) of N-(1-((4-hydroxy-4-methylcyclohexyl)-3-isopropoxy-1H-pyrazol-4-yl)formamide = Intermediate 55, MS (Method B) m / z 282 [M+1] +; t = 1.19 min, and 30 mg (trans) of N-(1-((4-hydroxy-4-methylcyclohexyl)-3-isopropoxy-1H-pyrazol-4-yl)formamide = 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-pyrazol-4-yl)formamide and trans N-(3-cyclopropoxy-1-(hydroxy-4-methylcyclohexyl)-1H-pyrazol-4-yl)formamide Step 1: Preparation of 3,4-dinitro-1-(1,4-dioxaspiro[4.5]decan-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]decan-8-ol in 60 mL of tetrahydrofuran. The mixture was cooled to 0° C., and 7.68 g (1.5 eq.) of diisopropyl azodicarboxylate (DIAD) was added. The mixture was stirred at room temperature for 72 hours and then diluted with 200 mL of ethyl acetate and 100 mL of water. The organic layer was washed with water, brine, dried over magnesium sulfate, concentrated under reduced pressure, and purified on silica eluting with 10% ethyl acetate in dichloromethane to give 1.6 g of 3,4-dinitro-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazole. MS (Method A) t = 1.47 min - mass not available.

[0388] Step 2: Preparation of 3-cyclopropoxy-4-nitro-1-(1,4-dioxaspiro[4.5]decan-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]decan-8-yl)-1H-pyrazole in 20 mL of acetonitrile. The mixture was heated at 80° C. for 5 hours, allowed to cool to room temperature, and diluted with ethyl acetate and water. The organic layer was washed with water, brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified on silica gel eluting with 10% ethyl acetate in dichloromethane to give 700 mg of 3-cyclopropoxy-4-nitro-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazole. MS (Method B) m / z 310 [M+1]; t = 1.51 min.

[0389] Step 3: Preparation of 4-(3-cyclopropoxy-4-nitro-1H-pyrazol-1-yl)cyclohexan-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]decan-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 paratoluenesulfonate (PPTS). The reaction mixture was heated at 120 °C for 30 min. The mixture was concentrated under reduced pressure, and the residue was then taken up in 50 mL of ethyl acetate and 20 mL of water. The organic layer was dried over magnesium sulfate, concentrated in vacuo, and purified on silica eluting with 10% ethyl acetate in dichloromethane to give 500 mg of 4-(3-cyclopropoxy-4-nitro-1H-pyrazol-1-yl)cyclohexan-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-pyrazol-4-yl)formamide [ka] 363 mg of ammonium chloride (5 eq.) and 380 mg (5 eq.) of iron were added to a solution of 360 mg of 4-(3-cyclopropoxy-4-nitro-1H-pyrazol-1-yl)cyclohexan-1-one in 12 mL of ethanol and 2 mL of water. The reaction mixture was heated at 80° C. with vigorous stirring for 90 minutes, and the mixture was filtered through Celite, washed with ethanol, and concentrated under reduced pressure.

[0391] A solution of the residue 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. The reaction mixture was stirred at room temperature for 4 hours and then concentrated in vacuo. The residue was purified on silica gel, eluting with 5% methanol in dichloromethane, to give 80 mg of N-(3-cyclopropoxy-1-(4-oxocyclohexyl)-1H-pyrazol-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-pyrazol-4-yl)formamide and trans N-(3-cyclopropoxy-1-(hydroxy-4-methylcyclohexyl)-1H-pyrazol-4-yl)formamide [ka] 380 μL (2.5 eq.) of methylmagnesium bromide (3 M in tetrahydrofuran) was added to a solution of 120 mg of N-(3-cyclopropoxy-1-(4-oxocyclohexyl)-1H-pyrazol-4-yl)formamide in 6 mL of tetrahydrofuran at −78° C. The reaction mixture was stirred at −78° C. for 1 hour. 3 mL of saturated aqueous ammonium chloride solution and 20 mL of ethyl acetate were added. The two phases were separated. The organic layer was dried over magnesium sulfate, concentrated in vacuo, and purified on silica eluting with 5% methanol in dichloromethane to give 35 mg (cis) of N-(3-cyclopropoxy-1-(hydroxy-4-methylcyclohexyl)-1H-pyrazol-4-yl)formamide = Intermediate 57, MS (Method A) m / z 280 [M+1] +; t = 1.53 min, and 25 mg (trans) of N-(3-cyclopropoxy-1-(hydroxy-4-methylcyclohexyl)-1H-pyrazol-4-yl)formamide = 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-pyrazol-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. The mixture was heated at 80° C. overnight, 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 dissolved in 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. The mixture was heated at 80° C. overnight, allowed to cool to room temperature, and diluted with ethyl acetate and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in heptane

number

[0395] Step 3: Preparation of N-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrazol-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 palladium on carbon (10%). The reaction mixture was heated at 70° C. for 15 min. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure to give 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrazol-4-amine. The crude material was taken on to the next step without further purification.

[0396] A solution of (2-((tert-butyldimethylsilyl)oxy)ethyl)-3-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrazol-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. The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was purified on silica gel, eluting with 5% methanol in dichloromethane, to give 324 mg of N-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrazol-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-(oxetan-3-yloxy)-1H-pyrazol-4-yl)formamide Step 1: Preparation of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitro-3-(oxetan-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 at 80° C. overnight, 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 in vacuo. The residue was purified on silica gel eluting with 20% ethyl acetate in heptane, then 50% ethyl acetate in heptane to give 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-(oxetan-3-yloxy)-1H-pyrazol-4-yl)formamide [ka] In a microwave vial, a solution of 0.48 g (1 eq.) of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole in 10 mL of methanol was treated with 612 mg (7 eq.) of ammonium formate and 150 mg of palladium on carbon (10%). The reaction mixture was heated at 70° C. for 15 min. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure to give 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(oxetan-3-yloxy)-1H-pyrazol-4-amine.

[0399] Crude 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(oxetan-3-yloxy)-1H-pyrazol-4-amine in 10 mL of tetrahydrofuran was added dropwise to a cooled (0° C.) solution of 592 mg (4 eq.) of acetic anhydride in 1.2 g (18 eq.) of formic acid, which had been mixed at room temperature for 30 min. The reaction mixture was stirred at room temperature for 2 h and then concentrated in vacuo. The residue was purified on silica gel, eluting with 5% methanol in dichloromethane, to give 308 mg of N-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)formamide. MS (Method A) m / z 342 [M+1]; t=2.35 min

[0400] Intermediate 61: N-(3-(3-hydroxy-2,2-dimethylcyclobutoxy)-1-(methyl-d3)-1H-pyrazol-4-yl)formamide Step 1: Preparation of 2,2-dimethyl-3-((1-(methyl-d3)-4-nitro-1H-pyrazol-3-yl)oxy)cyclobutan-1-ol (racemic) [ka] 690 mg of 2,2-dimethylcyclobutane-1,3-diol (1.6 eq.) and 2.4 g (2 eq.) of cesium carbonate were added to a solution of 650 mg (1 eq.) of 1-(methyl-d3)-3,4-dinitro-1H-pyrazole (Intermediate 21, Step 1) in 15 mL of acetonitrile. The mixture was heated to 80° C. overnight, 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 in vacuo. The residue was dissolved in heptane

number

[0401] Step 2: Preparation of N-(3-(3-hydroxy-2,2-dimethylcyclobutoxy)-1-(methyl-d3)-1H-pyrazol-4-yl)formamide (racemic) [ka] In a microwave vial, a solution of 0.43 g (1 eq.) of 2,2-dimethyl-3-((1-(methyl-d3)-4-nitro-1H-pyrazol-3-yl)oxy)cyclobutan-1-ol in 13 mL of methanol was treated with 768 mg (7 eq.) of ammonium formate and 60 mg of palladium on carbon (10%). The reaction ...

Claims

1. Formula (I) 【Chemical 1】 [wherein: R1 is selected from the group consisting of an aryl group, an ortho-fused bicyclic heteroaryl group, and a heteroaryl group, where the ortho-fused bicyclic heteroaryl group is unsubstituted or substituted with one or more -(C １ -C ３ )-alkyl groups; and where the aryl group and the heteroaryl group are unsubstituted or a) a deuterium atom, b) a fluorine atom, c) an alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group, d) a cycloalkyl group that is unsubstituted or substituted with one or more fluorine atoms, hydroxy groups or -(C １ -C ３ )-alkyl groups, e) a heterocycloalkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, and an alkylcarbonyl group, f) an alkyloxyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group and a fluorine atom, g) is non-substituted or is an -O-cycloalkyl group substituted with one or more fluorine atoms, hydroxy groups or -(C １ -C ３ )-alkyl groups, h) an -O-heterocycloalkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, a hydroxy group, and an alkylcarbonyl group, i) an -O-spiro ring group, j) an alkylsulfonylalkyl group, and k) an alkylsulfonyl group is substituted with one or more substituents independently selected from the group consisting of; and R2 is selected from the group consisting of an alkyloxylalkyl group and a heterocycloalkyl group, wherein the heterocycloalkyl group represented by R2 is bonded via a carbon atom and is unsubstituted or substituted with an alkyl group, an alkyloxyl group, or one or more fluorines]] or a pharmaceutically acceptable salt thereof.

2. R1 is selected from the group consisting of an aryl group, an ortho-fused bicyclic heteroaryl group, and a heteroaryl group, where the ortho-fused bicyclic heteroaryl group is unsubstituted or substituted with one or more -(C １ -C ３ )-alkyl groups; and where the aryl group and the heteroaryl group are unsubstituted or a) a deuterium atom, b) a fluorine atom, c) an alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group, d) a cycloalkyl group which is unsubstituted or substituted with one or more fluorine atoms or a -(C １ -C ３ )-alkyl group e) a heterocycloalkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, and an alkylcarbonyl group, f) an alkyloxyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group and a fluorine atom, g) unsubstituted or substituted with one or more fluorine atoms or a —(C １ —C ３ )—alkyl group, an —O—cycloalkyl group h) a -O -heterocycloalkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, and an alkylcarbonyl group; i) a -O -spiro ring group; j) an alkylsulfonylalkyl group; and k) an alkylsulfonyl group is 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, wherein the phenyl group and the heteroaryl group are unsubstituted or a) a fluorine atom; b) an alkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group; c) a cycloalkyl group which is unsubstituted or substituted by one or more fluorine atoms, hydroxy groups or -(C １ -C ３ )-alkyl groups, d) a heterocycloalkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, and an alkylcarbonyl group; e) an alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group and a fluorine atom; f) unsubstituted or substituted with one or more fluorine atoms, hydroxy groups or —(C １ —C ３ )—alkyl-substituted —O—cycloalkyl group, g) a -O -heterocycloalkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, a hydroxy group, and an alkylcarbonyl group; h) a -O -spiro ring group; i) an alkylsulfonylalkyl group; and j) an alkylsulfonyl group is 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. Formula (Ia) 【Chemical Formula 2】 [wherein: R3 is selected from the group consisting of a hydrogen atom, -(C １ -C ３ )-alkyl group and -(C １ -C ３ )-alkyloxyl group; m represents 1, 2, or 3; and n represents 0 or 1]; The compound according to claim 1 or a pharmaceutically acceptable salt thereof having the same.

5. Formula (Ia) 【Chemical Formula 3】 [wherein, R1 is selected from the group consisting of a phenyl group and a heteroaryl group, wherein the phenyl group and the heteroaryl group are unsubstituted or a) a fluorine atom; b) an alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group, c) a cycloalkyl group which is unsubstituted or substituted with one or more fluorine atoms, hydroxy groups or -(C １ -C ３ )-alkyl groups, d) a heterocycloalkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, and an alkylcarbonyl group, e) an alkyloxyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group and a fluorine atom, f) is non-replaceable or is an -O-cycloalkyl group substituted with one or more fluorine atoms, hydroxy groups or -(C １ -C ３ )-alkyl group, g) an -O-heterocycloalkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, a hydroxy group, and an alkylcarbonyl group, h) an -O-spiro ring group, i) an alkylsulfonylalkyl group, and j) an alkylsulfonyl group is substituted with one or more substituents independently selected from the group consisting of; m represents 1 or 2; and n represents 0 or 1]; The compound according to claim 1 or a pharmaceutically acceptable salt thereof having the same.

6. Formula (Ib) [Chemical Formula 4] [Wherein: R3 is selected from the group consisting of a hydrogen atom, -(C １ -C ３ )-alkyl group and -(C １ -C ３ )-alkyloxyl group; R4 is a) an alkyloxyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group and a fluorine atom b) unsubstituted or substituted with one or more fluorine atoms, hydroxy groups or —O—cycloalkyl groups substituted with a —(C １ —C ３ )—alkyl group c) an -O-heterocycloalkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, a hydroxy group, and an alkylcarbonyl group, and d) an -O-spiro ring group is selected from the group consisting of; R5 is a) a hydrogen atom, b) an alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group, c) a cycloalkyl group which is unsubstituted or substituted by one or more fluorine atoms, hydroxy groups or -(C １ -C ３ )-alkyl groups, d) a heterocycloalkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, and an alkylcarbonyl group, e) an alkylsulfonylalkyl group, and f) an alkylsulfonyl group is selected from the group consisting of; R6 is selected from the group consisting of a hydrogen atom and a deuterium atom; m represents 1, 2, or 3; and n represents 0 or 1] The compound according to claim 1, or a pharmaceutically acceptable salt thereof, having

7. R3 is -(C １ -C ３ )-alkyl group and -(C １ -C ３ )-alkyloxyl group selected from the group consisting of; 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 selected from the group consisting of -(C １ -C ３ )-alkyl group and -(C １ -C ３ )-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 hydroxy group and a fluorine atom, b) is non-replaceable or is a -O-cycloalkyl group substituted with one or more fluorine atoms, hydroxy groups or -(C １ -C ３ )-alkyl group, and c) an -O-heterocycloalkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, a hydroxy group, and an alkylcarbonyl group selected from the group consisting of; R5 is a) an alkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group, b) a cycloalkyl group that is unsubstituted or substituted with one or more fluorine atoms, hydroxy groups or -(C １ -C ３ )-alkyl groups, and c) a heterocycloalkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, and an alkylcarbonyl group 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 )-alkyl group; R4 is a) unsubstituted or substituted with one or more fluorine atoms, hydroxy groups or —(C １ —C ３ )—alkyl groups, and b) an -O-heterocycloalkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, a hydroxy group, and an alkylcarbonyl group selected from the group consisting of, R5 is an alkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy 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) [Chemical Formula 5] [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 hydroxy group and a fluorine atom, b) unsubstituted or substituted with one or more fluorine atoms, hydroxy groups or —O—cycloalkyl groups substituted with a —(C １ —C ３ )—alkyl group c) an unsubstituted or substituted -O - heterocycloalkyl group, which is substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, a hydroxy group, and an alkylcarbonyl group, and d) an -O - spiro ring group selected from the group consisting of; R5 is a) a hydrogen atom, b) an unsubstituted or substituted alkyl group, which is substituted with one or more substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group, c) a cycloalkyl group which is unsubstituted or substituted by one or more fluorine atoms, hydroxy groups or -(C １ -C ３ )-alkyl groups, d) an unsubstituted or substituted heterocycloalkyl group, which is substituted with one or more substituents independently selected from the group consisting of an alkyl group, an alkyloxyl group, and an alkylcarbonyl group, e) an alkylsulfonylalkyl group, and f) an alkylsulfonyl group selected from the group consisting of; R6 is selected from the group consisting of a hydrogen atom and a deuterium atom; R7 is -(C １ -C ３ )-alkyl group; and R8 is -(C １ -C ３ )-alkyl group]; The compound according to claim 1 or a pharmaceutically acceptable salt thereof, having

11. 2 - ((1 - methyl - 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 - 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 - 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-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-(((3-isopropoxy-1-methyl-1H-pyrazol-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)-1H-pyrazol-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-(((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-(((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazol-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]oxy-pyrazol-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]oxy-pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[3-[(2S,3R)-2-methyloxetan-3-yl]oxy-1-(methyl-d3)pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[3-[(2R,3S)-2-methyloxetan-3-yl]oxy-1-(methyl-d3)pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; and 2-[[3-(cyclopropoxy)-1-(methoxymethyl)pyrazol-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, or a pharmaceutically acceptable salt thereof.

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

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. An agent for treating a neurodegenerative disease, comprising a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

15. 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, The agent according to claim 14.

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

17. An agent characterized by comprising a compound of formula (I) according to 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, A compound of formula (I) according to claim 18, or a pharmaceutically acceptable salt thereof, for the use described.

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

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