CN117881681A - Substituted pyrrolo [2,3-d ] pyrimidines, their preparation and their therapeutic use - Google Patents

Substituted pyrrolo [2,3-d ] pyrimidines, their preparation and their therapeutic use Download PDF

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CN117881681A
CN117881681A CN202280055079.0A CN202280055079A CN117881681A CN 117881681 A CN117881681 A CN 117881681A CN 202280055079 A CN202280055079 A CN 202280055079A CN 117881681 A CN117881681 A CN 117881681A
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group
methyl
pyrazol
substituted
alkyl
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P·伯纳德利
S·德普雷茨
L·杜波依斯
J·马科尔
F·佩蒂特
C·泰瑞
M·比安西奥托
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Sanofi Aventis France
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Sanofi Aventis France
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Priority claimed from PCT/EP2022/066231 external-priority patent/WO2022263472A1/en
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Abstract

Disclosed are compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are as defined herein. The use of such a chemical is also disclosedMethods of using the compounds as LRRK2 inhibitors, and pharmaceutical compositions comprising such compounds. These compounds are useful in the treatment of neurodegenerative diseases such as parkinson's disease.

Description

Substituted pyrrolo [2,3-d ] pyrimidines, their preparation and their therapeutic use
Disclosed herein are substituted pyrrolo [2,3-d ] pyrimidine compounds, methods for the preparation thereof, pharmaceutical compositions containing the compounds, and therapeutic uses thereof.
Background
Parkinson's Disease (PD) is an age-dependent neurodegenerative disorder with high unmet medical needs in the context of aging population. Mutations in several genes isolate PD in the family. Among them, seven leucine-rich repeat kinase 2 (LRRK 2) mutations are associated with autosomal dominant forms of PD. In the whole genome association study (Genome Wide Association Studies), the LRRK2 polymorph was identified as a risk factor for sporadic PD (j.h.kluss, biochemical Society Transactions 2019). LRRK2 carriers have similar clinical symptoms, onset and progression of disease as sporadic patients (H.Tomiyama, hum.Mov.Disord.2006), suggesting that the LRRK2 signaling pathway may be central to the underlying processes of both LRRK2 familial and sporadic late-onset PD. All pathogenic LRRK2 mutations as well as VPS 35D 620N mutations, another target genetically related to PD, induced increased LRRK2 kinase activity (M.Steger et al, eLife 2016; R, mir et al, biochem J.2018). In addition to familial PD, increased LRRK2 activity or levels are reported in human brains from idiopathic PD patients (r.di Maio et al, sci.Transl. Med.2018). These results support the hypothesis that dysregulated LRRK2 kinase activity may contribute to pathogenesis, suggesting that LRRK2 kinase inhibitors block the therapeutic potential of aberrant LRRK 2-dependent signaling in both LRRK2 and idiopathic forms of PD (a.b. west exp. Neurol. 2017). Accumulation of synuclein aggregates and loss of dopaminergic neurons are major markers of PD. Blocking of these phenotypes following LRRK2 kinase inhibitor treatment is demonstrated in many reports (e.m. rocha et al, neurobiol. Of Disease 2019). These results support the hypothesis that potent brain penetrating LRRK2 kinase inhibitors have therapeutic potential for treating PD.
There is growing evidence for a role for LRRK2 in regulating lysosomal activity (j.schapansky et al, neurobiol. Of Disease 2018). Elevated levels of bis (monoacylglycerols) phosphate, which are markers of lysosomal storage diseases such as pick's disease, were observed in fluid from carriers of LRRK2 function-acquired mutations (r.n. alcalay, movement Disorders, 2020). Lysosomal Glucocerebrosidase (GBA) mutations are the largest risk factor for PD development (GBA-PD). Reduced glucocerebrosidase activity was reported in neurons from GBA and LRRK2 mutant carriers (d.ysselstein, nature com.2019). In contrast, normalization of glucocerebrosidase activity and levels was achieved both in vitro and in vivo following treatment with LRRK2 kinase inhibitors, suggesting that patients with lysosomal storage diseases such as GBA-PD potentially benefit (a.sanyal et al, mov. Disorders 2020).
Immunofluorescence experiments in human brain showed co-localization of LRRK2 with neurofibrillary tangles (J.Miklossy, JNeuropathol.Exp.Neurol.2006). Furthermore, LRRK2 has been reported to phosphorylate tubulin-related tau (f.kawakami et al, ploS One 2012), and tau hyperphosphorylation was observed in LRRK2 kinase-activated mutant transgenic mice (y.li et al, nat. Neurosci.2009). These data indicate that LRRK2 kinase inhibitor treatment can be used to treat tauopathic disorders (such as pick's disease, progressive supranuclear palsy, and frontotemporal dementia).
LRRK2 is expressed in brain glial cells and reduced neuroinflammation is achieved following treatment with LRRK2 kinase inhibitors in various in vivo models (m.s. moehle et al, j. Neurosci.2012). Neuroinflammation is commonly observed in neurodegenerative diseases such as parkinson's disease, alzheimer's disease, multiple sclerosis, HIV-induced dementia and amyotrophic lateral sclerosis; LRRK2 kinase inhibitors are therefore useful in the treatment of these pathologies.
WO 2017106771 discloses compounds having a pyrrolopyrimidine core substituted with (hetero) arylamino and cyano groups. These compounds are capable of inhibiting certain protein kinases and in particular leucine rich repeat kinase 2 (LRRK 2) proteins and may be used in the treatment of disorders including neurodegenerative diseases such as parkinson's disease.
US2020239474 discloses novel pyrrolo-pyrimidine derivative compounds useful for the prevention or treatment of protein kinase related diseases.
WO 2020149715 discloses compounds having a pyrrolopyrimidine core substituted with (hetero) arylamino and cyano groups, which may be advantageously used for the treatment or prevention of protein kinase related diseases, cancer and degenerative brain diseases.
There is a need to provide LRRK2 kinase inhibitors with good efficacy.
Disclosure of Invention
According to one aspect, disclosed herein are compounds of formula (I):
wherein:
r1 is selected from aryl, ortho-fused bicyclic heteroaryl, and heteroaryl, wherein the ortho-fused bicyclic heteroaryl is unsubstituted or substituted with one or more- (C) 1 -C 3 ) -alkyl substitution; and wherein the aryl and heteroaryl groups are unsubstituted or substituted with one or more substituents independently selected from the group consisting of:
a) A fluorine atom is used as a carrier,
b) The deuterium atom is present in the form of a ring,
c) Alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl group, fluorine atom, deuterium atom, cyano group, alkoxy group, alkylamino group and dialkylamino group,
d) Cycloalkyl which is unsubstituted or substituted by one or more fluorine atoms, - (C) 1 -C 3 ) -an alkyl group or a hydroxyl group for substitution,
e) Heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl,
f) Alkoxy, said alkoxy being unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy and fluorine atoms,
g) -O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, - (C) 1 -C 3 ) -an alkyl group or a hydroxyl group for substitution,
h) An O-heterocycloalkyl group, said O-heterocycloalkyl group being unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy, hydroxy and alkylcarbonyl,
i) -an O-spiro group and a group,
j) Alkyl sulfonyl alkyl, and
k) An alkylsulfonyl group; and is also provided with
R2 is selected from alkoxyalkyl and heterocycloalkyl, wherein the heterocycloalkyl represented by R2 is attached via a carbon atom and is unsubstituted or substituted with alkyl, alkoxy, or one or more fluorine atoms;
or a pharmaceutically acceptable salt thereof.
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.
The compounds of formula (I) above and pharmaceutically acceptable salts thereof exhibit inhibitory activity against wild-type and mutant LRRK2 and are useful in the treatment of neurodegenerative diseases.
Detailed Description
As used herein, the following abbreviations are understood to have the following meanings, unless otherwise indicated:
as used herein, the term "alkyl" means a straight or branched aliphatic hydrocarbon group having 1 to 6 carbon atoms in the chain. In another aspect In one aspect, the alkyl groups have 1 to 4 carbon atoms in the chain. "lower alkyl" means an alkyl group having from 1 to about 3 carbon atoms in the alkyl chain, which may be straight or branched. Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a straight alkyl chain. Furthermore, the term "(C) 1 -C 4 ) -alkyl "means a straight or branched alkyl group having one to four carbon atoms. The term "(C) 1 -C 3 ) -alkyl "means a straight or branched alkyl group having one to three carbon atoms. Exemplary alkyl groups include methyl, ethyl, isopropyl, t-butyl, and the like.
As used herein, the term "alkylamino" means alkyl-N (H) -, wherein alkyl is as defined herein.
As used herein, the term "dialkylamino" means an amino group having two straight or branched chain alkyl groups as defined herein, independent of each other. The term "dialkylamino" includes, for example: dimethylamino, diethylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, N-isopropyl-N-propylamino, N-tert-butyl-N-methylamino.
As used herein, the term "alkylcarbonyl" means alkyl-C (=o) -, wherein alkyl is as defined herein. Exemplary alkylcarbonyl groups include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutylcarbonyl.
As used herein, the term "alkoxy" means alkyl-O-, wherein alkyl is as described herein. Examples of alkyl-O-are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
As used herein, the term "alkoxyalkyl" means an alkyl-O-alkyl-having two straight or branched chain alkyl groups as defined herein, independent of each other.
As used herein, the term "alkylsulfonyl" means alkyl-S (=o) 2-, wherein alkyl is as defined herein. Exemplary alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl and isobutylsulfonyl.
As used herein, the term "alkylsulfonylalkyl" means alkyl-S (=o) 2-alkyl-, wherein alkyl is as defined herein.
As used herein, the term "aryl" refers to an aromatic monocyclic or bicyclic ring system of about 5 to about 10 carbon atoms. Exemplary aryl groups include phenyl and naphthyl.
As used herein, the term "cycloalkyl" means a non-aromatic monocyclic system of 3 to 6 carbon atoms. (C) 3 -C 6 ) Cycloalkyl is cycloalkyl having 3, 4, 5 or 6 ring carbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
As used herein, the term "heteroaryl", whether used alone or with other terms (such as "heteroaryl"), means a cyclic aromatic group containing 2 to 10 carbon atoms and containing between 1 and 4 heteroatoms (such as nitrogen, oxygen, or sulfur). The heteroaryl group may be monocyclic or bicyclic. As used herein, the term "monocyclic heteroaryl" means a cyclic aromatic group containing 2 to 5 carbon atoms and containing between 1 and 3 heteroatoms (such as nitrogen, oxygen or sulfur). As examples of monocyclic heteroaryl groups, mention may be made of, but 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.
As used herein, the term "heterocycloalkyl" means a 4, 5, 6, or 7 membered non-aromatic monocyclic system having at least one carbon atom and at least one heteroatom other than carbon (e.g., nitrogen, oxygen, or sulfur). Examples of heterocycloalkyl groups include azetidinyl, oxetanyl, thietanyl, diazepine, dioxetanyl, dithianyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dioxepanyl, dithiolanyl, piperidinyl, tetrahydropyranyl, thiahexyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, hexahydro-1, 3, 5-triazinyl, trioxane, trithianyl, azepanyl, oxepinyl, thiepanyl and diazepinyl.
As used herein, the term "ortho-fused" means a ring system in which two adjacent rings have two common adjacent atoms and in which the second ring system is alpha to the branched carbon atom. The term "ortho-fused heteroaryl" means a bicyclic ring system comprising 7 to 10 carbon atoms and comprising 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. Included within the definition of ortho-fused heteroaryl are bicyclic systems in which one ring is a monocyclic heteroaryl and the other ring is an aryl or heterocycloalkyl ring, or both rings are monocyclic heteroaryl. Examples include indolyl and benzimidazolyl.
As used herein, the term "spiro" or "spirocyclic" means a carbobicyclo ring system in which two rings are connected by a single atom. The size and nature of the rings may be different or the size and nature of the rings may be the same. Examples include spiro pentane, spiro hexane, spiro heptane, spiro octane, spiro nonane or spiro decane. One or both rings in the spiro ring may be fused to another carbocyclic, heterocyclic, aromatic or heteroaromatic ring. One or more carbon atoms in the spiro ring may be substituted with heteroatoms (e.g., O, N, S or P). C (C) 5 -C 12 A spiro ring is a spiro ring containing between 5 and 12 carbon atoms. One or more carbon atoms may be substituted with heteroatoms.
As used herein, the term "substituted" means that a specified portion of a hydrogen group is replaced with a specified substituent group, provided that the substitution results in a stable or chemically feasible compound. Unless otherwise indicated, substituents may be in any position provided that the corresponding compounds are sufficiently stable and suitable as pharmaceutically active compounds. The definition of all groups in the compounds of the formula (I) applies generally to the preconditions that the particular groups and compounds of the formula I are sufficiently stable and suitable as pharmaceutically active compounds.
As used herein, the term "one or more substituents" refers to a number of substituents equal to one to the maximum number of substituents possible based on the number of available bonding sites, provided that the above-described conditions of stability and chemical feasibility are met. An optionally substituted group may have a substituent at each substitutable position of the group, and the substituents may be the same or different, unless otherwise indicated.
As used herein, the term "independently" or "independently selected" means that the same or different values may be selected for multiple instances of a given variable in a single compound.
As used herein, the term "unsubstituted" indicates that the corresponding group does not bear any specified substituents.
As used herein, the term "pharmaceutically acceptable salts" refers to relatively non-toxic inorganic and organic acid addition salts and base addition salts of the compounds of formula (I). These salts can be prepared in situ during the final isolation and purification of the compounds.
If the compound of formula (I) comprises one or more acidic or basic groups (e.g. basic heterocyclic groups), the corresponding physiologically or toxicologically acceptable salts, in particular pharmaceutically acceptable salts, are also included in the present disclosure. Thus, the compounds of the formula (I) can be deprotonated on acidic groups and used, for example, as alkali metal salts or as ammonium salts. Compounds of formula (I) comprising at least one basic group in the form of acid addition salts (e.g., in the form of pharmaceutically acceptable salts with inorganic and organic acids) may also be prepared and used. Salts can be prepared from acidic and basic compounds of formula (I) generally by reaction with an acid or base in a solvent or diluent according to conventional procedures. If the compounds of formula (I) contain both acidic and basic groups in the molecule, the present disclosure includes, in addition to the salt forms mentioned, also internal salts (betaines, zwitterionic). The present disclosure also includes all salts of the compounds of formula (I) which are not directly suitable for use as medicaments due to low physiological tolerance, but are suitable as intermediates for chemical reactions or for the preparation of physiologically acceptable salts, for example by means of anion exchange or cation exchange.
As used herein, the term "pharmaceutically acceptable excipient" refers to a non-toxic solvent, dispersant, excipient, adjuvant, or other material that is mixed with a compound of the present disclosure to allow for the formation of a pharmaceutical composition (i.e., a dosage form capable of administration to a patient). The excipients are selected from the conventional excipients known to those skilled in the art, depending on the desired pharmaceutical form and method of administration.
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 to produce the desired therapeutic effect.
As used herein, the term "treatment" or "treatment" means to prevent, slow or reduce the progression of a disease; causing regression of its biological manifestations and/or clinical symptoms; inhibiting further progression or worsening of at least one symptom (i.e., by reducing the severity or frequency of at least one symptom).
As used herein, the term "patient" refers to a person suffering from a disease.
As used herein, the term "compounds of formula (I)" and equivalent expressions are intended to include racemic compounds of formula (I) and their enantiomers, epimers, diastereomers, geometric isomers, tautomers, and mixtures thereof, as the context permits.
As used herein, the term "isomer" refers to compounds having the same formula but differing in the nature or order of the bonding of their atoms or the spatial arrangement of their atoms. The terms "isomer 1" and "isomer 2" may be designated as isomers of known absolute configuration or may be used to describe stereoisomers of unknown absolute configuration. Thus, the use of the terms "isomer 1" and "isomer 2" should not be construed to indicate that the absolute configuration of both isomers is known. The term "isomer mixture" refers to a mixture of isomers.
As used herein, the term "stereoisomer" is a generic term for all isomers of an individual molecule that differ only in the orientation of their atoms in space. The term "diastereoisomer" refers to stereoisomers that are not mirror images of each other, and the term "enantiomer" refers to stereoisomers that are mirror images that are not superimposable to each other. Enantiomers can be characterized by the absolute configuration of their asymmetric centers and are described by the R-and S-order rules of kane, engle and plaalog (Cahn, ingold and Prelog), or by the manner in which the molecules rotate the plane of polarized light and are designated as either the right-or left-handed (i.e., (+) or (-) -isomers, respectively). The chiral compounds may exist as individual enantiomers, individual diastereomers, or as mixtures thereof. Mixtures containing equal proportions of enantiomers are referred to as "racemic mixtures". Mixtures containing diastereomers in any proportion are referred to as "diastereomeric mixtures". For compounds having two chiral centers in the ring system, "trans" means that the substituents of the chiral centers (except hydrogen) are on opposite sides of the ring; "cis" means that the substituents at the chiral center are 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 by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization, based on their physicochemical differences. The enantiomers may 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.
Provided herein are compounds of formula (I):
wherein:
r1 is selected from aryl, ortho-fused bicyclic heteroaryl, and heteroaryl, wherein the ortho-fused bicyclic heteroaryl is unsubstituted or substituted with one or more- (C) 1 -C 3 ) -alkyl extractionSubstitution; and wherein the aryl and heteroaryl groups are unsubstituted or substituted with one or more substituents independently selected from the group consisting of:
a) A fluorine atom is used as a carrier,
b) The deuterium atom is present in the form of a ring,
c) Alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl group, fluorine atom, deuterium atom, cyano group, alkoxy group, alkylamino group and dialkylamino group,
d) Cycloalkyl which is unsubstituted or substituted by one or more fluorine atoms, - (C) 1 -C 3 ) -an alkyl group or a hydroxyl group for substitution,
e) Heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl,
f) Alkoxy, said alkoxy being unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy and fluorine atoms,
g) -O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, - (C) 1 -C 3 ) -an alkyl group or a hydroxyl group for substitution,
h) An O-heterocycloalkyl group, said O-heterocycloalkyl group being unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy, hydroxy and alkylcarbonyl,
i) -an O-spiro group and a group,
j) Alkyl sulfonyl alkyl, and
k) An alkylsulfonyl group; and is also provided with
R2 is selected from alkoxyalkyl and heterocycloalkyl, wherein the heterocycloalkyl represented by R2 is attached via a carbon atom and is unsubstituted or substituted with alkyl, alkoxy, or one or more fluorine atoms;
or a pharmaceutically acceptable salt thereof.
Provided herein are compounds of formula (I):
wherein:
r1 is selected from aryl, ortho-fused bicyclic heteroaryl, and heteroaryl, wherein the ortho-fused bicyclic heteroaryl is unsubstituted or substituted with one or more- (C) 1 -C 3 ) -alkyl substitution; and wherein the aryl and heteroaryl groups are unsubstituted or substituted with one or more substituents independently selected from the group consisting of:
a) A fluorine atom is used as a carrier,
b) The deuterium atom is present in the form of a ring,
c) Alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl group, fluorine atom, deuterium atom, cyano group, alkoxy group, alkylamino group and dialkylamino group,
d) Cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms or- (C) 1 -C 3 ) -an alkyl group substituted with a hydroxyl group,
e) Heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl,
f) Alkoxy, said alkoxy being unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy and fluorine atoms,
g) -O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms or- (C) 1 -C 3 ) -an alkyl group substituted with a hydroxyl group,
h) An O-heterocycloalkyl group, said O-heterocycloalkyl group being unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl,
i) -an O-spiro group and a group,
j) Alkyl sulfonyl alkyl, and
k) An alkylsulfonyl group; and is also provided with
R2 is selected from alkoxyalkyl and heterocycloalkyl, wherein the heterocycloalkyl represented by R2 is attached via a carbon atom and is unsubstituted or substituted with alkyl, alkoxy, or one or more fluorine atoms;
or a pharmaceutically acceptable salt thereof.
One embodiment is a compound of formula (I), wherein
R1 is selected from phenyl and heteroaryl, wherein the aryl and heteroaryl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of:
a) A fluorine atom is used as a carrier,
b) Alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl group, fluorine atom, deuterium atom, cyano group, alkoxy group, alkylamino group and dialkylamino group,
c) Cycloalkyl which is unsubstituted or substituted by one or more fluorine atoms, - (C) 1 -C 3 ) -an alkyl group or a hydroxyl group for substitution,
d) Heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl,
e) Alkoxy, said alkoxy being unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy and fluorine atoms,
f) -O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, - (C) 1 -C 3 ) -an alkyl group or a hydroxyl group for substitution,
g) An O-heterocycloalkyl group, said O-heterocycloalkyl group being unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy, hydroxy and alkylcarbonyl,
h) -an O-spiro group and a group,
i) Alkyl sulfonyl alkyl, and
j) An alkylsulfonyl group; and is also provided with
R2 is selected from alkoxyalkyl and heterocycloalkyl, wherein the heterocycloalkyl represented by R2 is attached via a carbon atom and is unsubstituted or substituted with alkyl, alkoxy, or one or more fluorine atoms; or a pharmaceutically acceptable salt thereof.
One embodiment is a compound of formula (I), wherein
R1 is selected from substituted or unsubstituted phenyl, ortho-fused bicyclic heteroaryl, and
a group;
wherein the ortho-fused bicyclic heteroaryl is unsubstituted or substituted with one or more- (C) 1 -C 3 ) -alkyl substitution;
r2 is selected from alkoxyalkyl and heterocycloalkyl, wherein the heterocycloalkyl is attached via a carbon atom and is unsubstituted or substituted with alkyl, alkoxy, or one or more fluorine atoms;
r4 is selected from:
a) Alkoxy, said alkoxy being unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy and fluorine atoms,
b) -O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, - (C) 1 -C 3 ) -an alkyl group or a hydroxyl group for substitution,
c) -O-heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy, alkylcarbonyl and hydroxy, and
d) -O-spiro group;
r5 is selected from:
a) The hydrogen atom is contained in the mixture,
b) Alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl group, fluorine atom, deuterium atom, cyano group, alkoxy group, alkylamino group and dialkylamino group,
c) Cycloalkyl which is unsubstituted or substituted by one or more fluorine atoms, - (C) 1 -C 3 ) -an alkyl group or a hydroxyl group for substitution,
d) Heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl,
e) Alkyl sulfonyl alkyl, and
f) An alkylsulfonyl group; and is also provided with
R6 is selected from the group consisting of a hydrogen atom and a deuterium atom;
or a pharmaceutically acceptable salt thereof.
One embodiment is a compound of formula (I), wherein
R1 is
A group;
r2 is selected from alkoxyalkyl and
a group;
wherein R3 is selected from the group consisting of hydrogen atom, - (C) 1 -C 3 ) -alkyl and- (C) 1 -C 3 ) -an alkoxy group;
m represents 1, 2 or 3;
n represents 0 or 1;
r4 is selected from:
a) Alkoxy, said alkoxy being unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy and fluorine atoms,
b) -O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, - (C) 1 -C 3 ) -an alkyl group or a hydroxyl group for substitution,
c) -O-heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy, hydroxy and alkylcarbonyl, and
d) -O-spiro group;
r5 is selected from:
a) The hydrogen atom is contained in the mixture,
b) Alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl group, fluorine atom, deuterium atom, cyano group, alkoxy group, alkylamino group and dialkylamino group,
c) Cycloalkyl which is unsubstituted or substituted by one or more fluorine atoms, - (C) 1 -C 3 ) -an alkyl group or a hydroxyl group for substitution,
d) Heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl,
e) Alkyl sulfonyl alkyl, and
f) An alkylsulfonyl group; and is also provided with
R6 is selected from the group consisting of a hydrogen atom and a deuterium atom;
or a pharmaceutically acceptable salt thereof.
One embodiment is a compound of formula (I), wherein
R1 is selected from phenyl and heteroaryl, wherein the phenyl and heteroaryl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of:
a) A fluorine atom is used as a carrier,
b) The deuterium atom is present in the form of a ring,
c) Alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl group, fluorine atom, deuterium atom, cyano group, alkoxy group, alkylamino group and dialkylamino group,
d) Cycloalkyl which is unsubstituted or substituted by one or more fluorine atoms, - (C) 1 -C 3 ) -an alkyl group or a hydroxyl group for substitution,
e) Heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl,
f) Alkoxy, said alkoxy being unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy and fluorine atoms,
g) -O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, - (C) 1 -C 3 ) -an alkyl group or a hydroxyl group for substitution,
h) An O-heterocycloalkyl group, said O-heterocycloalkyl group being unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy, hydroxy and alkylcarbonyl,
i) -an O-spiro group and a group,
j) Alkyl sulfonyl alkyl, and
k) An alkylsulfonyl group; and is also provided with
R2 is heterocycloalkyl attached via a carbon atom and is unsubstituted or substituted with an alkyl, alkoxy or one or more fluorine atoms;
or a pharmaceutically acceptable salt thereof.
One embodiment is a compound of formula (I), wherein
R1 is
A group;
r2 is heterocycloalkyl attached via a carbon atom and is unsubstituted or substituted with an alkyl, alkoxy or one or more fluorine atoms;
R4 is selected from:
a) Alkoxy, said alkoxy being unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy and fluorine atoms,
b) -O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, - (C) 1 -C 3 ) -an alkyl group or a hydroxyl group for substitution,
c) -O-heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy, alkylcarbonyl and hydroxy, and
d) -O-spiro group;
r5 is selected from:
a) The hydrogen atom is contained in the mixture,
b) Alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl group, fluorine atom, deuterium atom, cyano group, alkoxy group, alkylamino group and dialkylamino group,
c) Cycloalkyl which is unsubstituted or substituted by one or more fluorine atoms, - (C) 1 -C 3 ) -an alkyl group or a hydroxyl group for substitution,
d) Heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl,
e) Alkyl sulfonyl alkyl, and
f) An alkylsulfonyl group; and is also provided with
R6 is selected from the group consisting of a hydrogen atom and a deuterium atom;
or a pharmaceutically acceptable salt thereof.
One embodiment is a compound of formula (Ia)
Wherein:
r1 is selected from aryl, ortho-fused bicyclic heteroaryl, and heteroaryl, wherein the ortho-fused bicyclic heteroaryl is unsubstituted or substituted with one or more- (C) 1 -C 3 ) -alkyl substitution; the aryl and heteroaryl groups are unsubstituted or substituted with one or more substituents independently selected from the group consisting of:
a) The deuterium atom is present in the form of a ring,
b) A fluorine atom is used as a carrier,
c) Alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl group, fluorine atom, deuterium atom, cyano group, alkoxy group, alkylamino group and dialkylamino group,
d) Cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, hydroxy or- (C) 1 -C 3 ) -an alkyl group substituted with a hydroxyl group,
e) Heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy or alkylcarbonyl,
f) Alkoxy, said alkoxy being unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy and fluorine atoms,
g) -O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, - (C) 1 -C 3 ) -an alkyl group or a hydroxyl group for substitution,
h) An O-heterocycloalkyl group, said O-heterocycloalkyl group being unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy, alkylcarbonyl and hydroxy,
i) -an O-spiro group and a group,
j) Alkyl sulfonyl alkyl, and
k) An alkylsulfonyl group;
r3 is selected from hydrogen atom, - (C) 1 -C 3 ) -alkyl and- (C) 1 -C 3 ) -an alkoxy group;
m represents 1, 2 or 3; and is also provided with
n represents 0 or 1;
or a pharmaceutically acceptable salt thereof.
One embodiment is a compound of formula (Ia)
Wherein:
r1 is selected from aryl, ortho-fused bicyclic heteroaryl, and heteroaryl, wherein the ortho-fused bicyclic heteroaryl is unsubstituted or substituted with one or more- (C) 1 -C 3 ) -alkyl substitution; the aryl and heteroaryl groups are unsubstituted or substituted with one or more substituents independently selected from the group consisting of:
a) The deuterium atom is present in the form of a ring,
b) A fluorine atom is used as a carrier,
c) Alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl group, fluorine atom, deuterium atom, cyano group, alkoxy group, alkylamino group and dialkylamino group,
d) Cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms or- (C) 1 -C 3 ) -an alkyl group substituted with a hydroxyl group,
e) Heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy or alkylcarbonyl,
f) Alkoxy, said alkoxy being unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy and fluorine atoms,
g) -O-cycloalkyl, which is unsubstituted or substituted by one or moreMultiple fluorine atoms or- (C) 1 -C 3 ) -an alkyl group substituted with a hydroxyl group,
h) An O-heterocycloalkyl group, said O-heterocycloalkyl group being unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl,
i) -an O-spiro group and a group,
j) Alkyl sulfonyl alkyl, and
k) An alkylsulfonyl group;
r3 is selected from hydrogen atom, - (C) 1 -C 3 ) -alkyl and- (C) 1 -C 3 ) -an alkoxy group;
m represents 1, 2 or 3; and is also provided with
n represents 0 or 1;
or a pharmaceutically acceptable salt thereof.
One embodiment is a compound of formula (Ia), wherein
R1 is selected from phenyl and heteroaryl, wherein the phenyl and heteroaryl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of:
a) A fluorine atom is used as a carrier,
b) Alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl group, fluorine atom, deuterium atom, cyano group, alkoxy group, alkylamino group and dialkylamino group,
c) Cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, hydroxy or- (C) 1 -C 3 ) -an alkyl group substituted with a hydroxyl group,
d) Heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl,
e) Alkoxy, said alkoxy being unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy and fluorine atoms,
f) -O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, - (C) 1 -C 3 ) -an alkyl group or a hydroxyl group for substitution,
g) An O-heterocycloalkyl group, said O-heterocycloalkyl group being unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy, alkylcarbonyl and hydroxy,
h) -an O-spiro group and a group,
i) Alkyl sulfonyl alkyl, and
j) An alkylsulfonyl group;
m represents 1 or 2; and is also provided with
n represents 0 or 1;
or a pharmaceutically acceptable salt thereof.
One embodiment is a compound of formula (Ib)
Wherein:
r3 is selected from hydrogen atom, - (C) 1 -C 3 ) -alkyl and- (C) 1 -C 3 ) -an alkoxy group;
r4 is selected from:
a) Alkoxy, said alkoxy being unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy and fluorine atoms,
b) -O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, - (C) 1 -C 3 ) -an alkyl group or a hydroxyl group for substitution,
c) -O-heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy, alkylcarbonyl and hydroxy, and
d) -O-spiro group;
m represents 1, 2 or 3;
n represents 0 or 1;
r5 is selected from:
a) The hydrogen atom is contained in the mixture,
b) Alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl group, fluorine atom, deuterium atom, cyano group, alkoxy group, alkylamino group and dialkylamino group,
c) Cycloalkyl groups, which are unsubstitutedOr by one or more fluorine atoms, hydroxyl groups or- (C) 1 -C 3 ) -an alkyl group substituted with a hydroxyl group,
d) Heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl,
e) Alkyl sulfonyl alkyl, and
f) An alkylsulfonyl group; and is also provided with
R6 is selected from the group consisting of a hydrogen atom and a deuterium atom;
or a pharmaceutically acceptable salt thereof.
One embodiment is a compound of formula (Ib)
Wherein:
r3 is selected from hydrogen atom, - (C) 1 -C 3 ) -alkyl and- (C) 1 -C 3 ) -an alkoxy group;
r4 is selected from:
a) Alkoxy, said alkoxy being unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy and fluorine atoms,
b) -O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms or- (C) 1 -C 3 ) -an alkyl group substituted with a hydroxyl group,
c) -O-heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl, and
d) -O-spiro group;
m represents 1, 2 or 3;
n represents 0 or 1;
r5 is selected from:
a) The hydrogen atom is contained in the mixture,
b) Alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl group, fluorine atom, deuterium atom, cyano group, alkoxy group, alkylamino group and dialkylamino group,
c) Cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms or- (C) 1 -C 3 ) -an alkyl group substituted with a hydroxyl group,
d) Heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl,
e) Alkyl sulfonyl alkyl, and
f) An alkylsulfonyl group; and is also provided with
R6 is selected from the group consisting of a hydrogen atom and a deuterium atom;
or a pharmaceutically acceptable salt thereof.
One embodiment is a compound of formula (Ib)
Wherein:
r3 is selected from- (C) 1 -C 3 ) -alkyl and- (C) 1 -C 3 ) -an alkoxy group;
r4 is selected from:
a) Alkoxy, said alkoxy being unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy and fluorine atoms,
b) -O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, - (C) 1 -C 3 ) -an alkyl group or a hydroxyl group for substitution,
c) -O-heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy, alkylcarbonyl and hydroxy, and
d) -O-spiro group;
m represents 1 or 2;
n represents 0 or 1;
r5 is selected from:
a) The hydrogen atom is contained in the mixture,
b) Alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl group, fluorine atom, deuterium atom, cyano group, alkoxy group, alkylamino group and dialkylamino group,
c) Cycloalkyl which is unsubstituted or substituted by one or more fluorine atoms, - (C) 1 -C 3 ) -an alkyl group or a hydroxyl group for substitution,
d) Heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl,
e) Alkyl sulfonyl alkyl, and
f) An alkylsulfonyl group; and is also provided with
R6 is a hydrogen atom;
or a pharmaceutically acceptable salt thereof.
One embodiment is a compound of formula (Ib)
Wherein:
r3 is selected from- (C) 1 -C 3 ) -alkyl and- (C) 1 -C 3 ) -an alkoxy group;
r4 is selected from:
a) Alkoxy, said alkoxy being unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy and fluorine atoms,
b) -O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, - (C) 1 -C 3 ) -alkyl or hydroxy substitution, and
c) -O-heterocycloalkyl, which is unsubstituted or is one or more independently selected from alkanes
Substituents for groups, alkoxy, alkylcarbonyl and hydroxy;
m represents 1;
n represents 1;
r5 is selected from:
a) Alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl group, fluorine atom, deuterium atom, cyano group, alkoxy group, alkylamino group and dialkylamino group,
b) Cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, hydroxy or- (C) 1 -C 3 ) -an alkyl group substituted with a hydroxyl group,
c) A heterocycloalkyl group, said heterocycloalkyl group being unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl; and is also provided with
R6 is a hydrogen atom;
or a pharmaceutically acceptable salt thereof.
One embodiment is a compound of formula (Ib)
Wherein:
r3 is- (C) 1 -C 3 ) -an alkyl group;
r4 is selected from:
a) -O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, - (C) 1 -C 3 ) -an alkyl group or a hydroxyl group for substitution,
b) -O-heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy, alkylcarbonyl and hydroxy, and
m represents 1;
n represents 1;
r5 is alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy, fluoro, deuterium, cyano, alkoxy, alkylamino and dialkylamino, and
R6 is a hydrogen atom;
or a pharmaceutically acceptable salt thereof.
One embodiment is a compound of formula (Ic)
Wherein:
r4 is selected from:
a) Alkoxy, said alkoxy being unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy and fluorine atoms,
b) -O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, - (C) 1 -C 3 ) -an alkyl group or a hydroxyl group for substitution,
c) -O-heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy, alkylcarbonyl and hydroxy, and
d) -O-spiro group;
r5 is selected from:
a) The hydrogen atom is contained in the mixture,
b) Alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl group, fluorine atom, deuterium atom, cyano group, alkoxy group, alkylamino group and dialkylamino group,
c) Cycloalkyl which is unsubstituted or substituted by one or more fluorine atoms, - (C) 1 -C 3 ) -an alkyl group or a hydroxyl group for substitution,
d) Heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl,
e) Alkyl sulfonyl alkyl, and
f) An alkylsulfonyl group;
r6 is selected from the group consisting of a hydrogen atom and a deuterium atom;
r7 is- (C) 1 -C 3 ) -an alkyl group; and is also provided with
R8 is- (C) 1 -C 3 ) -an alkyl group;
or a pharmaceutically acceptable salt thereof.
One embodiment is a compound of formula (Ic)
Wherein:
r4 is selected from:
a) Alkoxy, said alkoxy being unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy and fluorine atoms,
b) -O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms or- (C) 1 -C 3 ) -an alkyl group substituted with a hydroxyl group,
c) -O-heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl, and
d) -O-spiro group;
r5 is selected from:
a) The hydrogen atom is contained in the mixture,
b) Alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl group, fluorine atom, deuterium atom, cyano group, alkoxy group, alkylamino group and dialkylamino group,
c) Cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms or- (C) 1 -C 3 ) -an alkyl group substituted with a hydroxyl group,
d) Heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl,
e) Alkyl sulfonyl alkyl, and
f) An alkylsulfonyl group;
r6 is selected from the group consisting of a hydrogen atom and a deuterium atom;
r7 is- (C) 1 -C 3 ) -an alkyl group; and is also provided with
R8 is- (C) 1 -C 3 ) -an alkyl group;
or a pharmaceutically acceptable salt thereof.
One embodiment are compounds of formula (I) wherein R1 represents substituted or unsubstituted aryl.
One embodiment are compounds of formula (I) wherein R1 represents substituted or unsubstituted phenyl.
One embodiment is a compound of formula (I) wherein R1 represents an ortho-fused bicyclic heteroarylWhich are unsubstituted or substituted by one or more- (C) 1 -C 3 ) -alkyl substitution.
One embodiment is a compound of formula (I) wherein R1 represents an ortho-fused bicyclic heteroaryl selected from the list:
one embodiment are compounds of formula (I) wherein R1 represents substituted or unsubstituted heteroaryl.
One embodiment is a compound of formula (I), wherein R1 representsA group.
Wherein:
r4 is selected from:
a) Alkoxy, said alkoxy being unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy and fluorine atoms,
b) -O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, - (C) 1 -C 3 ) -an alkyl group or a hydroxyl group for substitution,
c) -O-heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy, alkylcarbonyl and hydroxy, and
d) -O-spiro group;
r5 is selected from:
a) The hydrogen atom is contained in the mixture,
b) Alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl group, fluorine atom, deuterium atom, cyano group, alkoxy group, alkylamino group and dialkylamino group,
c) Cycloalkyl which is unsubstituted or substituted by hydroxy,
d) A heterocycloalkyl group, a heterocyclic ring-like group,
e) Alkyl sulfonyl alkyl, and
f) An alkylsulfonyl group; and is also provided with
R6 is selected from the group consisting of a hydrogen atom and a deuterium atom;
or a pharmaceutically acceptable salt thereof.
One embodiment is a compound of formula (I), wherein R2 represents alkoxyalkyl.
One embodiment is a compound of formula (I), wherein R2 represents heterocycloalkyl.
One embodiment is a compound of formula (I) wherein R2 represents
A group.
One embodiment is a compound of formula (I) wherein R2 represents a heterocycloalkyl selected from the list:
one embodiment is a compound of formula (Ia), wherein R3 represents a hydrogen atom.
One embodiment is a compound of formula (Ia), wherein R3 represents- (C) 1 -C 3 ) -an alkyl group.
One embodiment is a compound of formula (Ia), wherein R3 represents- (C) 1 -C 3 ) -an alkoxy group.
One embodiment is a compound of formula (Ia), wherein m represents 1.
One embodiment is a compound of formula (Ia), wherein m represents 2.
One embodiment is a compound of formula (Ia), wherein m represents 3.
One embodiment is a compound of formula (Ia), wherein n represents 0.
One embodiment is a compound of formula (Ib), wherein n represents 1.
An embodiment is a compound of formula (Ib) wherein R4 represents alkoxy, which is unsubstituted or substituted with one or more substituents independently selected from hydroxy and fluoro.
An embodiment are compounds of formula (Ib) wherein R4 represents-O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms or lower alkyl, hydroxy.
An embodiment is a compound of formula (Ib) wherein R4 represents-O-heterocycloalkyl, unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy, and alkylcarbonyl, hydroxy.
One embodiment is a compound of formula (Ib) wherein R4 represents an-O-spiro group.
One embodiment is a compound of formula (Ib) wherein R4 represents a group selected from the list:
One embodiment is a compound of formula (Ib) wherein R5 represents a hydrogen atom.
An embodiment is a compound of formula (Ib) wherein R5 represents alkyl, which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy, fluoro, deuterium, cyano, alkoxy, alkylamino and dialkylamino.
One embodiment is a compound of formula (Ib) wherein R5 represents unsubstituted or hydroxy-substituted cycloalkyl.
One embodiment is a compound of formula (Ib) wherein R5 represents heterocycloalkyl.
One embodiment is a compound of formula (Ib) wherein R5 represents alkylsulfonylalkyl.
One embodiment is a compound of formula (Ib) wherein R5 represents alkylsulfonyl.
One embodiment is a compound of formula (Ib) wherein R5 represents a group selected from the list:
in one embodiment, the compound of formula (I) is selected from the following:
2- [ [3- (1-acetylazetidin-3-yl) oxy-1-methyl-pyrazol-4-yl ] amino ] -7- [ (3 r,4 r) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- [ [ 1-methyl-3- [ (3 s,4 r) -4-methyltetrahydrofuran-3-yl ] oxy-1H-pyrazol-4-yl ] amino ] -7- [ (3 r,4 r) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- [ [ 1-methyl-3- [ (3 r,4 s) -4-methyltetrahydrofuran-3-yl ] oxy-1H-pyrazol-4-yl ] amino ] -7- [ (3 r,4 r) -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- [ (3 r,4 r) -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- [ (3 r,4 r) -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- [ (3 r,4 r) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1-methyl-3- (((2 r,3 s) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1-methyl-3- (((2 s,3 r) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -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- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- [ [ 1-methyl-3- (oxetan-3-yloxy) pyrazol-4-yl ] amino ] -7- [ (3 r,4 r) -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- [ (3 r,4 r) -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-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-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-trifluoro-1-methyl-ethoxy) pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- [ [3- [ (3 s,4 s) -4-methoxytetrahydrofuran-3-yl ] oxy-1-methyl-pyrazol-4-yl ] amino ] -7- [ (3 r,4 r) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- [ [3- [ (3 r,4 r) -4-methoxytetrahydrofuran-3-yl ] oxy-1-methyl-pyrazol-4-yl ] amino ] -7- [ (3 r,4 r) -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- [ (3 r,4 r) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- [ [1- (methylsulfonylmethyl) -3- (oxetan-3-yloxy) pyrazol-4-yl ] amino ] -7- [ (3 r,4 r) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1- (methyl-d 3) -3- (((2 r,3 s) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1- (methyl-d 3) -3- (((2 s,3 r) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1- (methyl-d 3) -3- (((trans) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -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- ((3 r,4 r) -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- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1- (methyl-d 3) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -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- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1-methyl-3- (((R) -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-trifluoropropan-2-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1-methyl-3- ((1, 1-trifluoropropan-2-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1- (methyl-d 3) -3- (((2 r,3 r) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1- (methyl-d 3) -3- (((2 s,3 s) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1- (methyl-d 3) -3- (((cis) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3-isopropoxy-1- (2, 2-trifluoroethyl) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3-isopropoxy-1-methyl-1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -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- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3-cyclopropoxy-1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -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- ((3 r,4 r) -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- ((3 r,4 r) -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- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (2-hydroxy-2-methylpropyloxy) -1-methyl-1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -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- ((3 r,4 r) -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- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3-cyclopropoxy-1- (methoxymethyl) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3-cyclopropoxy-1- ((methylsulfonyl) methyl) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -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- ((3 r,4 r) -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- ((3 r,4 r) -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- [ (3 r,4 r) -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- [ (3 r,4 r) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((2-cyclopropoxy-4- ((dimethylamino) methyl) phenyl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3-isopropoxy-1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -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- ((3 r,4 r) -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- ((3 s,4 s) -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- ((3 s,4 r) -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- ((3 s, 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, 4 r) -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- ((3 r,4 r) -4-methoxytetrahydrofuran-3-yl) -2- ((1- (oxetan-3-yl) -3- ((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- ((3 r,4 r) -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- ((3 r,4 r) -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- ((3 r,4 r) -4-methoxytetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1- (1-cyanoethyl) -3-cyclopropoxy-1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -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- ((3 r,4 r) -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- ((3 r,4 r) -4-methoxytetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3-cyclopropoxy-1-isopropyl-1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methoxytetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3-isopropoxy-1-methyl-1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -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- ((3 r,4 r) -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- ((3 r,4 r) -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- ((3 r,4 r) -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- ((3 r,4 r) -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- ((3 r,4 r) -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- [ (2 s,3 r) -2-methyl-oxetan-3-yl ] -2- [ [ 1-methyl-3- (oxetan-3-yloxy) pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
7- [ (2 r,3 s) -2-methyl-oxetan-3-yl ] -2- [ [ 1-methyl-3- (oxetan-3-yloxy) pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
7- [ (trans) -2-methyl-oxetan-3-yl ] -2- [ [ 1-methyl-3- (oxetan-3-yloxy) pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
7- [ (2 r,3 s) -2-methyl-oxetan-3-yl ] -2- [ (1-methyl-3-propan-2-yloxy pyrazol-4-yl) amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
7- [ (2 s,3 r) -2-methyl-oxetan-3-yl ] -2- [ (1-methyl-3-propan-2-yloxy pyrazol-4-yl) amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
7- [ (trans) -2-methyl-oxetan-3-yl ] -2- [ (1-methyl-3-propan-2-yloxy pyrazol-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- ((3 r,4 s) -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- ((3 s,4 r) -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- ((3 r,4 r) -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- ((3 s,4 s) -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, 3 r) -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- [ (2 r, 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, 3 r) -2-methyl-oxetan-3-yl ] oxy-1- (methyl-d 3) pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
7- [ (1S) -2-methoxy-1-methyl-ethyl ] -2- [ [3- [ (2 r, 3S) -2-methyl-oxetan-3-yl ] oxy-1- (methyl-d 3) pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
7- [ (1S) -2-methoxy-1-methyl-ethyl ] -2- [ [3- [ (trans) -2-methyl-oxetan-3-yl ] oxy-1- (methyl-d 3) pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
7- [ (2S) -1-methoxypropane-2-yl ] -2- [ [3- (oxetan-3-yloxy) -1- (methyl-d 3) pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- [ [3- (cyclopropyloxy) -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- ((3 r,4 r) -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-methoxypropane-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- ((3 s,4 r) -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- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1- (methyl-d 3) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl-5-d) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (((R) -2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (((S) -2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- ((2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
7- ((S) -1-methoxypropane-2-yl) -2- ((1- (methyl-d 3) -3- (((R) -tetrahydrofuranl-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
7- ((S) -1-methoxypropane-2-yl) -2- ((1- (methyl-d 3) -3- (((S) -tetrahydrofurane-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
7- ((S) -1-methoxypropane-2-yl) -2- ((1- (methyl-d 3) -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-methoxypropane-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-methoxypropane-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-methoxypropane-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-methoxypropane-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-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (3-hydroxy-2, 2-dimethylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (((S) -5, 5-dimethyltetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (((R) -5, 5-dimethyltetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -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-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1- (methyl-d 3) -3- (((S) -tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1- (methyl-d 3) -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-d 3) -3- ((tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3-cyclopropoxy-1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (((3 s,4 s) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (((3 r,4 r) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- ((trans-4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (((3S, 4S) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (((3 r,4 r) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- ((trans-4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (((S) -2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (((R) -2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -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-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
(S) -2- ((3- ((2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -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-d 3) -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-d 3) -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-d 3) -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-d 3) -3- (((2 s,3 r) -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-d 3) -3- (((2 r,3 s) -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-d 3) -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-methoxypropane-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-methoxypropane-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-methoxypropane-2-yl) -1H-pyrazol-4-yl) amino) -7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1- (1-methoxypropane-2-yl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
7- ((S) -1-methoxypropane-2-yl) -2- ((1- ((S) -1-methoxypropane-2-yl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
7- ((S) -1-methoxypropane-2-yl) -2- ((1- ((R) -1-methoxypropane-2-yl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
7- ((S) -1-methoxypropane-2-yl) -2- ((1- (1-methoxypropane-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-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (cis-3-hydroxy-2, 4-tetramethylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (trans-3-hydroxy-2, 4-tetramethylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (3-hydroxy-2, 4-tetramethylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (3-hydroxy-2, 2-dimethylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (isomer 1);
2- ((3- (3-hydroxy-2, 2-dimethylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (isomer 2);
2- ((3- (3-hydroxy-2, 2-dimethylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (((3S, 4 r) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (((3 r, 4S) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- ((cis-4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-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-methoxypropane-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-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- ((1 s,2 r) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- ((1 r,2 s) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (cis-2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- ((trans-2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- ((1 s,2 s) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- ((1 r,2 r) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (cis-2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- ((1S, 2 r) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- ((1 r, 2S) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (trans-2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- ((1S, 2S) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- ((1 r,2 r) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-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-methoxypropane-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-methoxypropane-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-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
(S) -2- ((2-cyclopropoxy-4- (2-hydroxypropan-2-yl) phenyl) amino) -7- (1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1- (methyl-d 3) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 s) -3-methyltetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1- (methyl-d 3) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- ((3 s,4 r) -3-methyltetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1- (methyl-d 3) -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- ((3 s,4 r) -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- ((3 s,4 r) -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.
In one embodiment, the compound of formula (I) is selected from the following:
2- ((1-methyl-3- (((2 r,3 s) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1-methyl-3- (((2 s,3 r) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- [ [ 1-methyl-3- (oxetan-3-yloxy) pyrazol-4-yl ] amino ] -7- [ (3 r,4 r) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1- (methyl-d 3) -3- (((2 r,3 s) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1- (methyl-d 3) -3- (((2 s,3 r) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1- (methyl-d 3) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3-isopropoxy-1-methyl-1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -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- ((3 r,4 s) -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- ((3 s,4 r) -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, 3 r) -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- [ (2 r, 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, 3 r) -2-methyl-oxetan-3-yl ] oxy-1- (methyl-d 3) pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
7- [ (1S) -2-methoxy-1-methyl-ethyl ] -2- [ [3- [ (2 r, 3S) -2-methyl-oxetan-3-yl ] oxy-1- (methyl-d 3) 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-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1- (methyl-d 3) -3- (((S) -tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1- (methyl-d 3) -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-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (((S) -5, 5-dimethyltetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (((R) -5, 5-dimethyltetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -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-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- ((1 r,2 r) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (cis-3-hydroxy-2, 4-tetramethylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (trans-3-hydroxy-2, 4-tetramethylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- ((1 s,2 s) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- ((1 r,2 r) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (((3 s,4 s) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (((3 r,4 r) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (((S) -2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3- (((R) -2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -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- ((3 s,4 r) -3-methyltetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; and
2- [ [3- (cyclopropyloxy) -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.
In one embodiment, the compound of formula (I) is selected from the following:
2- ((1-methyl-3- (((2 r,3 s) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1-methyl-3- (((2 s,3 r) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- [ [ 1-methyl-3- (oxetan-3-yloxy) pyrazol-4-yl ] amino ] -7- [ (3 r,4 r) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1- (methyl-d 3) -3- (((2 r,3 s) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1- (methyl-d 3) -3- (((2 s,3 r) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1- (methyl-d 3) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3-isopropoxy-1-methyl-1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -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- ((3 r,4 s) -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- ((3 s,4 r) -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, 3 r) -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- [ (2 r, 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, 3 r) -2-methyl-oxetan-3-yl ] oxy-1- (methyl-d 3) pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
7- [ (1S) -2-methoxy-1-methyl-ethyl ] -2- [ [3- [ (2 r, 3S) -2-methyl-oxetan-3-yl ] oxy-1- (methyl-d 3) pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; and
2- [ [3- (cyclopropyloxy) -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.
In one embodiment, the compound of formula (I) is 2- ((1-methyl-3- (((2 r,3 s) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound of formula (I) is 2- ((1-methyl-3- (((2 s,3 r) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
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.
In one embodiment, the compound of formula (I) is 2- ((1- (methyl-d 3) -3- (((2 r,3 s) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound of formula (I) is 2- ((1- (methyl-d 3) -3- (((2 s,3 r) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound of formula (I) is 2- ((1- (methyl-d 3) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound of formula (I) is 2- ((3-isopropoxy-1-methyl-1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
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.
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.
In one embodiment, the compound of formula (I) is 2- ((1-methyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- ((3 s,4 r) -3-methyltetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound of formula (I) is 7- [ (1S) -2-methoxy-1-methyl-ethyl ] -2- [ [ 1-methyl-3- [ (2S, 3 r) -2-methyloxetan-3-yl ] oxy-pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound of formula (I) is 7- [ (1S) -2-methoxy-1-methyl-ethyl ] -2- [ [ 1-methyl-3- [ (2 r, 3S) -2-methyl oxetan-3-yl ] oxy-pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound of formula (I) is 7- [ (1S) -2-methoxy-1-methyl-ethyl ] -2- [ [3- [ (2S, 3 r) -2-methyl-oxetan-3-yl ] oxy-1- (methyl-d 3) pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound of formula (I) is 7- [ (1S) -2-methoxy-1-methyl-ethyl ] -2- [ [3- [ (2 r, 3S) -2-methyloxetan-3-yl ] oxy-1- (methyl-d 3) pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound of formula (I) is 2- [ [3- (cyclopropyloxy) -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.
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-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound of formula (I) is 2- ((1- (methyl-d 3) -3- (((S) -tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound of formula (I) is 2- ((1- (methyl-d 3) -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.
In one embodiment, the compound of formula (I) is (S) -2- ((2-cyclopropoxy-4- (2-hydroxypropan-2-yl) phenyl) amino) -7- (1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound of formula (I) is 2- ((3- (((S) -5, 5-dimethyltetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound of formula (I) is 2- ((3- (((R) -5, 5-dimethyltetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -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.
In one embodiment, the compound of formula (I) is 2- ((3- ((1S, 2S) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound of formula (I) is 2- ((3- ((1 r,2 r) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound of formula (I) is 2- ((3- (cis-3-hydroxy-2, 4-tetramethylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound of formula (I) is 2- ((3- (trans-3-hydroxy-2, 4-tetramethylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound of formula (I) is 2- ((3- ((1 s,2 s) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound of formula (I) is 2- ((3- ((1 r,2 r) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound of formula (I) is 2- ((3- (((3 s,4 s) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound of formula (I) is 2- ((3- (((3 r,4 r) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound of formula (I) is 2- ((3- (((S) -2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound of formula (I) is 2- ((3- (((R) -2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -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.
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.
In one embodiment, the compound of formula (I) is 2- ((1- (2-hydroxyethyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- ((3 s,4 r) -3-methyltetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.
The compounds of formula (I) may contain one or more asymmetric carbon atoms. Thus, they may exist in enantiomeric or diastereoisomeric forms. Provided herein are these enantiomers and diastereomers, as well as mixtures thereof, including racemic mixtures.
Some of the compounds of formula (I) may exist as base or acid addition salts. Such addition salts form part of the present disclosure. These salts are advantageously prepared with pharmaceutically acceptable acids, but salts of other acids which may be used, for example, for purification or isolation of compounds of formula (I) also form part of the present disclosure.
Another embodiment is a process for preparing a compound of formula (I), comprising reacting a compound of formula (11X) with a compound of formula (15X):
wherein R1 and R2 are as defined herein for the compound of formula (I).
Another embodiment is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.
Another embodiment is a pharmaceutical composition comprising as an active ingredient an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
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- (((2 r,3 s) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
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- (((2 s,3 r) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
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- [ (3 r,4 r) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
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-d 3) -3- (((2 r,3 s) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
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-d 3) -3- (((2 s,3 r) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
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-d 3) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
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- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
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.
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- ((3 r,4 s) -3-methyltetra-hydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
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- ((3 s,4 r) -3-methyltetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
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, 3 r) -2-methyl oxetan-3-yl ] oxy-pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
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- [ (2 r, 3S) -2-methyloxetan-3-yl ] oxy-pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
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, 3 r) -2-methyl oxetan-3-yl ] oxy-1- (methyl-d 3) pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
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- [ (2 r, 3S) -2-methyl oxetan-3-yl ] oxy-1- (methyl-d 3) pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
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- (cyclopropyloxy) -1- (methoxymethyl) pyrazol-4-yl ] amino ] -7- [ (1S) -2-methoxy-1-methyl-ethyl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
One embodiment is a method for treating a disease or disorder selected from neurodegenerative diseases, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
One embodiment is a method for treating a neurodegenerative disease selected from parkinson's disease, multiple sclerosis, HIV-induced dementia, amyotrophic lateral sclerosis, dementia with lewy bodies, pick's disease, progressive supranuclear palsy and frontotemporal dementia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
One embodiment is a method for treating a neurodegenerative disease selected from parkinson's disease, multiple sclerosis, HIV-induced dementia, amyotrophic lateral sclerosis, and dementia with lewy bodies, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
One embodiment is a method for treating a tauopathy disorder selected from pick's disease, progressive supranuclear palsy, and frontotemporal dementia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
One embodiment is a method of treating parkinson's disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
One embodiment is a medicament, characterized in that the medicament comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof.
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 neurodegenerative diseases.
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 parkinson's disease, multiple sclerosis, HIV-induced dementia, amyotrophic lateral sclerosis, dementia with lewy bodies, pick's disease, progressive supranuclear palsy and frontotemporal dementia.
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 parkinson's disease, multiple sclerosis, HIV-induced dementia, amyotrophic lateral sclerosis and dementia with lewy bodies.
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 pick's disease, progressive supranuclear palsy and frontotemporal dementia.
One embodiment is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of parkinson's disease.
General procedure:
the starting materials and solvents used in the synthesis are obtained from chemical suppliers such as ABCR, aldrich, acros, apollo, fluka, netchem, lancaster and the like.
Typically, the crude product is purified by column chromatography or flash chromatography.
The compounds of formula (I) herein may be prepared by the methods outlined in the following reaction schemes and examples.
The preparation of the compound of formula (11X) may be performed according to scheme 1.
Scheme 1
Commercially available 4-chloro-2- (methylthio) pyrimidine-5-carbaldehyde (1X) may be converted to derivative (3X) by reaction with protected methylglycinate (2X) in the presence of a base such as triethylamine in a polar aprotic solvent such as DCM or THF. The derivative (3X) is subjected to 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). The protecting group may be removed according to methods known to those skilled in the art to give derivative (5X).
The compound (5X) is photolatent with an alcohol R2-OH of formula (6X) in the presence of diazodicarboxylate (DIAD or DEAD) and triphenylphosphine in a polar aprotic solvent such as THF at a temperature between ambient and 60 ℃ Mitsunobu reaction, followed by hydrolysis of the ester (7X) with a hydroxide source such as NaOH or LiOH to give formic acid (8X), wherein R2 is as defined above. Formic acid (8X) and NH in the presence of a coupling agent such as CDI, HATU, HBTU in a solvent such as DMF 4 OH reaction gave amide (9X). The nitrile derivative (10X) can be obtained by dehydrating formamide (9X) in the presence of DBU using phosphorus oxychloride or ethyl dichlorophosphate in a solvent such as DCM or in the presence of triethylamine using trifluoroacetic anhydride or using propane phosphoric anhydride such as T3P in a solvent such as THF. Finally, the sulfur is oxidized with an oxidizing agent such as 3-chloroperbenzoic acid, aqueous hydrogen peroxide, sodium perborate tetrahydrate or sodium bromate or oxone to give derivative (11X).
The preparation of compounds of formula (7X) wherein R2 is as defined above can also be carried out according to scheme 2.
Scheme 2
Commercially available 4-chloro-2- (methylthio) pyrimidine-5-carbaldehyde (11X) may be converted to compound (13X) by reaction with a substituted methylglycinate of formula (12X) in the presence of a base such as triethylamine in a polar aprotic solvent such as DCM or THF, wherein R2 is as defined above. 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 gives compound (7X).
The preparation of the compound of formula (15X) may be carried out according to scheme 3.
Scheme 3
Compounds of formula (15X) may be prepared from compound (14X) by reaction with formic acid, optionally in the presence of acetic anhydride, at a temperature between 0 ℃ and ambient temperature, wherein R1 is as defined above. Most of the compounds of formula (14X) can be prepared according to methods known to those skilled in the art.
The following scheme (scheme 4) provides a method for preparing a compound of formula (14X), wherein R1 is a substituted pyrazole.
Scheme 4
Pyrazole of the general formula (14X) wherein R4 is alkoxy and R5 is as defined in the compound of formula (Ib) above can be synthesized from commercially available 3, 4-dinitro-1H-pyrazole (16X). Pyrazole (16X) may be reacted with a halide R5X (wherein X is Cl, br or I) or with a sulfonate R5OSO 2 R '(such as mesylate (R' =ch) 3 ) Tosylate (R '=phme), triflate (R' =cf) 3 ) Or perfluorobutyl sulfonate (R' =cf) 2 CF 2 CF 2 CF 3 ) Alkylation of compound (21X) 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 and 80 ℃. Alternatively, 3, 4-dinitro-1H-pyrazole (16X) may be reacted with boric acid R5B (OH) 2 In Cu (OAc) 2 And a base such as pyridine or 4 '-di-tert-butyl-2, 2' -bipyridine in an aprotic solvent such as dichloromethane or 1, 2-dichloroethane at refluxThe lower reaction was converted to pyrazole (21X) via Chan Lam coupling. When R5 is alkylsulfonyl, pyrazole (16X) may be sulfonylated with sulfonyl chloride in the presence of a base such as triethylamine in an aprotic solvent such as dichloromethane at a temperature between 0 ℃ and ambient temperature.
Dinitro-pyrazole (21X) may 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 ℃ to provide compound (20X).
Alternatively, 4-dinitro-1H-pyrazole (16X) can be protected with p-methoxybenzyl under alkylation conditions to afford compound (17X). The resulting protected pyrazole (17X) may be treated with an alcohol of formula R4H to afford compound (18X), similar to the conversion of (21X) to (20X). Deprotection of compound (18X) to pyrazole (19X) may be achieved under conditions known to those skilled in the art (e.g., by reaction with ceric ammonium nitrate). The resulting deprotected pyrazole (19X) may be alkylated to compound (20X) using similar conditions as in the steps from compounds (16X) to (21X).
The nitro-substituted pyrazoles (20X) can be reduced to the corresponding amino-pyrazoles (14X) in aprotic or protic solvents, for example under hydrogen pressure in the presence of palladium on carbon.
The preparation of the compounds of the general formula (I) can be carried out according to scheme 5.
Scheme 5
Reacting compound (15X) with pyrrolopyrimidine (11X) in the presence of an organic base such as DBU or BTTP or an inorganic base such as cesium carbonate, potassium tert-butoxide or sodium hydride in a polar aprotic solvent such as DMF or DMSO at a temperature between ambient and 60 ℃ to give a compound of formula (I).
The embodiments provided herein will be more specifically explained with reference to the following examples, however, the scope of the embodiments provided herein is not limited to these examples.
Abbreviations (abbreviations)
The following abbreviations have the meanings set forth in the examples below, unless otherwise indicated:
AcOH acetic acid
BTTP t-butylimino-tris (pyrrolidinyl) phosphane
HCl hydrogen chloride
CDI 1,1' -carbonyl diimidazole
DBU 1, 8-diazabicyclo [5.4.0] undec-7-ene
DCM dichloromethane
DIAD diisopropyl azodicarboxylate
DEAD diethoxycarbonyl diazene
DMF N, N-dimethylformamide
DMSO dimethyl sulfoxide
eq. Equivalent weight
Et ethyl group
EtOH ethanol
Et 2 O-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
NH 4 OH ammonium hydroxide
NMP 1-methyl-2-pyrrolidone
Me methyl group
MeOH methanol
nM nanomole of
NMR nuclear magnetic spectrometry
r.t. room temperature
THF tetrahydrofuran
T 3 P1-propane phosphonic acid anhydride
LC/MS analysis was performed using the following method
Method A:
UPLC Waters and Mass spectrometer SQD2 Waters
Measurement of purity by UV diode array detector (192-400 nm)
Eluent a: h 2 O (+0.1% HCO) 2 H)
Eluent B: CH (CH) 3 CN (+0.1% HCO) 2 H)
Gradient:
time (min) A％ B％
0.00 95 5
0.20 95 5
3.60 2 98
4.10 2 98
5.00 95 5
Flow rate: 0.8mL/min
Column: acquity UPLC CSH Waters C18, 2.1X10 mm,1.7 μm
Method B:
Waters UPLC-SQD2
eluent a: h 2 O (+0.1% HCO) 2 H)
Eluent B: CH (CH) 3 CN (+0.1% HCO) 2 H)
Gradient (2.5 min): 3% to 100% B in 2.1 minutes; 2.45 minutes: 100% of B;2.5 minutes: 3% of B
Flow rate: 1mL/min
Column: ACQUITY CSH C18,1.7 μm, 2.1X50 mm
Method C:
HPLC Waters XeVo-QTof
eluent a: h 2 O (+0.1% HCO) 2 H)
Eluent B: CH (CH) 3 CN (+0.1% HCO) 2 H)
Gradient (5.3 min): 0 to 0.3min 5% B; 5% to 100% B in 4 minutes; from 4 to 4.6min 100% B;5.3 minutes: 5% of B
Flow rate: 0.5mL/min
Column: ACQUITY CSH C18,1.7 μm, 2.1X100 mm
Method D:
UPLC Waters and Mass spectrometer SQD Waters
Eluent a: h 2 O (+0.1% HCO) 2 H)
Eluent B: CH (CH) 3 CN (+0.1% HCO) 2 H)
Gradient:
time (min) A％ B％
0 98 2
2 0 100
2.6 0 100
2.7 98 2
3 98 2
Flow rate: 1mL/min
Column: acquity CORTECS C18, 2.1X10 mm,1.6 μm
Method E:
UPLC HCLASS and Mass spectrometer SQD2 Waters
Eluent a: h 2 O (+0.1% HCO) 2 H)
Eluent B: CH (CH) 3 CN (+0.1% HCO) 2 H)
Gradient:
time (min) A％ B％
0 95 5
1.00 50 50
1.30 0 100
1.45 0 100
1.75 98 2
2.00 98 2
Flow rate: 0.8mL/min
Column: cortecs UPLC C18, 2.1X50 mm,1.6 μm
Method F:
UPLC HCLASS and Mass spectrometer SQD2 Waters
Eluent a: h 2 O (+0.1% HCO) 2 H)
Eluent B: CH (CH) 3 CN (+0.1% HCO) 2 H)
Gradient:
time (min) A％ B％
0 98 2
2.50 0 100
2.90 0 100
2.95 98 2
3.00 98 2
Flow rate: 0.8mL/min
Column: cortecs UPLC C18, 2.1X50 mm,1.6 μm
Method G:
UPLC HCLASS and Mass spectrometer SQD2 Waters
Eluent a: h 2 O (+0.1% HCO) 2 H)
Eluent B: CH (CH) 3 CN (+0.1% HCO) 2 H)
Gradient:
time (min) ％A ％B
0 98 2
0.5 98 2
3.0 0 100
3.30 0 100
3.40 98 2
4.00 98 2
Flow rate: 0.8mL/min
Column: cortecs UPLC C18, 2.1X50 mm,1.6 μm
Method H:
UPLC Waters and Mass spectrometer SQD Waters
Measurement of purity by UV diode array detector (192-400 nm)
Eluent a: h 2 O (+0.1% HCO) 2 H)
Eluent B: CH (CH) 3 CN (+0.1% HCO) 2 H)
Gradient:
time (min) A％ B％
0.00 95 5
0.20 95 5
3.60 2 98
4.10 2 98
5.00 95 5
Flow rate: 0.8mL/min
Column: acquity UPLC CSH Waters C18, 2.1X10 mm,1.7 μm
Method I:
LCMS Waters and mass spectrometer SQD Waters
Eluent a: h 2 O (+0.1% HCO) 2 H)
Eluent B: CH (CH) 3 CN (+0.1% HCO) 2 H)
Gradient: t=0 min:5% B, t=1.5 min,99% B, t=1.9 min:99% of B
Flow rate: 1mL/min
Column: cortecs UPLC C18, 2.1X50 mm,1.6 μm
Intermediate products
Intermediate 1:2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid methyl ester
Step 1: preparation of methyl (4-methoxybenzyl) glycinate
53mL (1 eq.) of methyl 2-bromoacetate in 225mL tetrahydrofuran was slowly added (35 min) to a solution of 71mL (1 eq.) (4-methoxyphenyl) methylamine and 116mL triethylamine (1.5 eq.) in 750mL tetrahydrofuran under argon at 0deg.C (ice water/methanol bath). After 5 hours at room temperature and the reaction was complete, the mixture was filtered. The filtrate was taken up in 975mL of ethyl acetate and 375mL of water was added. After drying the organic layer over magnesium sulfate and concentrating in vacuo, the residue was purified on silica gel eluting with dichloromethane 100%, then dichloromethane/ethyl acetate (90/10), then dichloromethane/ethyl acetate (70/30) to give 60.9g of methyl (4-methoxybenzyl) glycine.
Step 2: preparation of N- (5-formyl-2- (methylthio) pyrimidin-4-yl) -N- (4-methoxybenzyl) glycine methyl ester
52.5mL of triethylamine (1.5 eq) was added to a solution of 49g of 4-chloro-2- (methylthio) pyrimidine-5-carbaldehyde (1 eq) in 500mL of tetrahydrofuran and 50mL of dichloromethane at 0deg.C. 63g of methyl (4-methoxybenzyl) glycinate (1.1 eq.) were added dropwise. The mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with 500mL of ethyl acetate and water. The organic layer was separated, washed twice with 1000mL of water, and then with 1000mL of 0.5n aqueous HCl. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was taken up in 500mL of heptane and stirred for 12 hours. The resulting precipitate was filtered and dried in vacuo to give 90g N- (5-formyl-2- (methylthio) pyrimidin-4-yl) -N- (4-methoxybenzyl) glycine methyl ester. MS (method B) m/z 362[ M+1] +; t=1.53 min.
Step 3: preparation of methyl 7- (4-methoxybenzyl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylate
167mL (4 eq.) of 1, 8-diazabicyclo [5.4.0] undec 7-ene was added dropwise to a solution of 99g N- (5-formyl-2- (methylthio) pyrimidin-4-yl) -N- (4-methoxybenzyl) glycine methyl ester (1 eq.) in 1000mL acetonitrile. The reaction mixture was heated at 85 ℃ for 40 minutes. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was taken up in 800mL of ethyl acetate and 500mL of water. The organic layer was washed with 300mL of 1n aqueous HCl, 300mL of saturated aqueous sodium bicarbonate, 500mL of water and then 300mL of brine, and concentrated under reduced pressure to give 82.4g 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.
Step 4: preparation of methyl 2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylate
169mL of trifluoromethanesulfonic acid (10 eq) was added dropwise to a solution of 62.8g of methyl 7- (4-methoxybenzyl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylate (1 eq) in 604mL of trifluoroacetic acid (44 eq). The reaction mixture was heated at 75 ℃ for 90 minutes. After cooling to room temperature, trifluoroacetic acid was concentrated under reduced pressure. The reaction mixture was diluted with 500mL of dichloromethane and cooled to-15 ℃. 360mL of 5M sodium hydroxide solution were added dropwise while maintaining the temperature below 5 ℃. When pH 6 was reached, a precipitate formed. The precipitate was filtered, then washed with water (250 mL twice) and 250mL heptane, then dried in vacuo to give 37.72g of methyl 2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylate. MS (method B) m/z 224[ M+1] +; t=1.18 min.
Intermediates 2 and 3: (3S, 4S) -4-methyltetrahydrofuran-3-ol (intermediate 2) and (3R, 4R) -4-methyltetrahydrofuran-3-ol (intermediate 3)
Step 1: preparation of cis-4-methyltetrahydrofuran-3-ol ((3S, 4S) -4-methyltetrahydrofuran-3-ol and racemic mixture of (3R, 4R) -4-methyltetrahydrofuran-3-ol)
A solution of 20g (1 eq.) of 4-methyldihydrofuran-3 (2H) -one (1 eq.) in 100mL of anhydrous tetrahydrofuran (commercially available) was added over 30min to a solution of 68g (1.06 eq.) of (+) -B-chlorodiisopinosylborane [ (+) -DIP chloride ] in 270mL of anhydrous tetrahydrofuran cooled at-25℃under argon. The mixture was stirred at-25℃for 2 hours. Then, 46g (2.16 eq) of diethanolamine suspended in tetrahydrofuran was added in portions. The mixture was stirred at room temperature for 18 hours, then diluted with 200mL pentane and filtered. The filter cake was washed twice with 50mL of diethyl ether and the filtrate was concentrated carefully at 40 ℃ and under reduced pressure of 120 mbar. The residue was dissolved in 50mL dichloromethane and 50mL cyclohexane, filtered and purified on silica gel (eluting with 10%, 30%, 50% and 100% diethyl ether in cyclohexane). The pure fractions were concentrated at 40℃and 120 mbar under reduced pressure to give 17g of a racemic mixture of (3S, 4S) -4-methyltetrahydrofuran-3-ol and (3R, 4R) -4-methyltetrahydrofuran-3-ol.
1 H NMR(400MHz,CDCl 3 ) Delta, 1.05 (d, j=7hz, 3 h) in ppm; 2.21 (m, 1H); 2.24 (s, 1H); 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, 1H).
Step 2: preparation of (3S, 4S) -4-methyltetrahydrofuran-3-yl acetate (precursor to intermediate 2) and enantiomerically pure (3R, 4R) -4-methyltetrahydrofuran-3-ol-intermediate 3
To a solution of 14.7G (1 eq) (3S, 4S) -4-methyltetrahydrofuran-3-ol in (3R, 4R) -4-methyltetrahydrofuran-3-ol in 130mL of vinyl acetate and 130mL of pentane was added 1.5G of lipase AMANO AK (cf. ALDRICH: 20.000U/G of Amano lipase from Pseudomonas fluorescens (Pseudomonas fluorescens; catalog No. 534730-50G) and the suspension was stirred at 22℃for 16 hours and then filtered through a pad of celite. The filter cake was rinsed twice with 50mL of diethyl ether and the filtrate was concentrated carefully at 40 ℃ and under reduced pressure of 180 mbar. The residue was purified on silica (eluted with 0-50% ether in cyclohexane) to give 9.15g of (3 s,4 s) -4-methyltetrahydrofuran-3-yl acetate (precursor to intermediate 2) and 5.64g of enantiomerically pure (3 r,4 r) -4-methyltetrahydrofuran-3-ol (intermediate 3) successively.
(3S, 4S) -4-methyltetrahydrofuran-3-yl acetate:
1 H NMR(400MHz,CDCl 3 ) Delta, 1.01 (d, j=7hz, 3 h) in ppm; 2.09 (s, 3H); 2.39 (m, 1H); 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=4Hz and j=10 Hz,1 h); 5.25 (m, 1H).
(3R, 4R) -4-methyltetrahydrofuran-3-ol-intermediate 3:
1 H NMR(400MHz,CDCl 3 ) Delta, 1.05 (d, j=7hz, 3 h) in ppm; 2.21 (m, 1H); 2.24 (s, 1H); 3.44 (dd, j=8 Hz and j=11 Hz,1 h); 3.74 (dd, j=1.4 Hz and 10Hz,1 h); 3.90 (t, j=8 hz,1 h); 3.93 (dd, j=4 Hz and 10Hz,1 h); 4.19 (m, 1H).
Step 3: preparation of (3S, 4S) -4-methyltetrahydrofuran-3-ol-intermediate 2
94mL (1.09 eq.) of a pre-cooled (0 ℃) 1N solution of sodium methoxide in methanol are added to 12.4g (86 mmol; 1 eq.) of (3S, 4S) -4-methyltetrahydrofuran-3-yl acetate (precursor of intermediate 2) in 20mL of methanol at 0 ℃. The mixture was stirred at 0 ℃ for 1 hour 30 minutes and then quenched with 47mL (1.09 eq) of a 2N hydrogen chloride solution in diethyl ether. After addition of an additional 100mL of diethyl ether, the suspension was filtered through a pad of celite and the filter cake was rinsed twice with 50mL of diethyl ether. The filtrate was concentrated at 40 ℃ and reduced pressure of 120 mbar, and the residue was dissolved in 50mL dichloromethane and 50mL cyclohexane, filtered and purified on silica gel (eluting with 10%, 30%, 50% and 100% diethyl ether in cyclohexane) to give (after concentration at 40 ℃ and reduced pressure of 120 mbar) 7.2g of enantiomerically pure (3 s,4 s) -4-methyltetrahydrofuran-3-ol (intermediate 2).
1 H NMR(400MHz,CDCl 3 ) Delta, 1.05 (d, j=7hz, 3 h) in ppm; 2.21 (m, 1H); 2.24 (s, 1H); 3.44 (dd, j=8 Hz and j=11 Hz,1 h); 3.74 (dd, j=1.4 Hz and 10Hz,1 h); 3.90 (t, j=8 hz,1 h); 3.93 (dd, j=4 Hz and 10Hz,1 h); 4.19 (m, 1H).
Intermediate 4: n- (1-methyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide
Step 1: preparation of 1-methyl-4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole
2.03g (1.3 eq) of oxetan-3-ol and 13.74g (2 eq) of cesium carbonate are added to a solution of 3.63g (1 eq) of 1-methyl-3, 4-dinitro-1H-pyrazole (commercially available) in 12mL of acetonitrile. The mixture was heated at 50 ℃ 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 suspended in 15mL of diethyl ether and filtered, concentrated in vacuo and purified on silica gel (elution with a gradient of 0 to 50% ethyl acetate in heptane) to give 3.7g of 1-methyl-4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole. MS (method B) m/z 200[ M+1] +; t=0.98 min.
Step 2: preparation of N- (1-methyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide
A solution of 3.5g (1 eq) of 1-methyl-4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole in 170mL of methanol was treated with 0.1g of palladium on carbon (10%) under 2.5 bar of hydrogen for 2 hours. The mixture was filtered by washing with dichloromethane and concentrated under reduced pressure. The residue was taken up in dichloromethane and concentrated twice under reduced pressure. A solution of 6.63mL of acetic anhydride in 12.13mL of formic acid, which had been premixed for 30 minutes, was added dropwise to a solution of the residue in 12mL of tetrahydrofuran at 0 ℃. The reaction mixture was allowed to stir for 2 hours and the temperature was allowed to warm to room temperature. Then it was poured into 10% aqueous sodium bicarbonate, stirred for 15 minutes, and extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified on silica gel (gradient elution with 0 to 100% ethyl acetate in heptane) to give 2.02g N- (1-methyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide. MS (method B) m/z 198[ M+1] +; t=0.62 min.
Intermediate 5: n- (1-methyl-3- (((3S, 4R) -4-methyltetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide and N- (1-methyl-3- (((3R, 4S) -4-methyltetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (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
1.54g (1.3 eq) of trans-4-methyltetrahydrofuran-3-ol (commercially available) and 7.34g (2 eq) of cesium carbonate are added to a solution of 2g (1 eq) of 1-methyl-3, 4-dinitro-1H-pyrazole (commercially available) in 40mL of acetonitrile. The mixture was heated at 80 ℃ 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 (gradient elution with 10% to 50% ethyl acetate in heptane) to give 1.1g of a racemic mixture of 1-methyl-3- (((3 s,4 r) -4-methyltetrahydrofuran-3-yl) oxy) -4-nitro-1H-pyrazole and 1-methyl-3- (((3 r,4 s) -4-methyltetrahydrofuran-3-yl) oxy) -4-nitro-1H-pyrazole. MS (method A) m/z 228[ M+1] +; t=1.68 min.
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
In a microwave vial, a solution of 1.09g (1 eq) of a racemic mixture of 1-methyl-3- (((3 s,4 r) -4-methyltetrahydrofuran-3-yl) oxy) -4-nitro-1H-pyrazole and 1-methyl-3- (((3 r,4 s) -4-methyltetrahydrofuran-3-yl) oxy) -4-nitro-1H-pyrazole in 32mL of methanol was treated with 1.15g of ammonium formate (7 eq) and 0.326g of palladium on carbon (10%). The reaction mixture was heated at 70℃for 10 minutes. The mixture was filtered by washing with methanol over celite and concentrated under reduced pressure. The residue was taken up in dichloromethane and filtered, and the filtrate was concentrated under reduced pressure to give 284 mg of a racemic mixture of 1-methyl-3- (((3 s,4 r) -4-methyltetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-amine and 1-methyl-3- (((3 r,4 s) -4-methyltetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-amine. MS (method A) m/z 198[ M+1] +; t=0.26 min.
Step 3: preparation of racemic mixture of N- (1-methyl-3- (((3S, 4R) -4-methyltetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide and N- (1-methyl-3- (((3R, 4S) -4-methyltetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide
A solution of 904mg (1 eq) 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 in 34mL of tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 1.29mL of acetic anhydride (3 eq) in 1.07mL of formic acid (6 eq) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at 5 ℃ for 5 minutes, at room temperature for 1.5 hours, and then concentrated in vacuo. The residue was purified on silica gel (elution with a gradient of 0 to 40% acetone in dichloromethane) to give 810mg of a racemic mixture of N- (1-methyl-3- (((3 s,4 r) -4-methyltetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide and N- (1-methyl-3- (((3 r,4 s) -4-methyltetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide. MS (method B) m/z 226[ M+1] +; t=0.94 min.
Intermediate 6: n- (3- (2-hydroxy-2-methylpropyloxy) -1-methyl-1H-pyrazol-4-yl) carboxamide
Step 1: preparation of 2-methyl-1- ((1-methyl-4-nitro-1H-pyrazol-3-yl) oxy) propan-2-ol
409mg (1.3 eq) of 2-methylpropane-1, 2-diol and 3.44g (3 eq) of cesium carbonate are added to a solution of 600mg (1 eq) of 1-methyl-3, 4-dinitro-1H-pyrazole (commercially available) in 30mL of acetonitrile. The mixture was heated at 80 ℃ 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 50% ethyl acetate in heptane) to give 356 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.
Step 2: preparation of N- (3- (2-hydroxy-2-methylpropyloxy) -1-methyl-1H-pyrazol-4-yl) carboxamide
In a microwave vial, a solution of 115mg (1 eq) 2-methyl-1- ((1-methyl-4-nitro-1H-pyrazol-3-yl) oxy) propan-2-ol in 4mL methanol was treated with 98mg ammonium formate (2.8 eq) and 57mg (0.1 eq) palladium on carbon (10%). The reaction mixture was heated at 70℃for 10 minutes. The mixture was filtered by washing with methanol over celite and concentrated under reduced pressure. The crude material dissolved in 2mL of tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 204 μl of acetic anhydride (4 equivalents) in 373 μl of formic acid (18 equivalents) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at 5 ℃ for 1 hour, then concentrated in vacuo. The residue was used in the next step without further purification. MS (method A) m/z 214[ M+1] +; t=1.1 min.
Intermediate 7: n- (1-methyl-3- ((1, 1-trifluoropropan-2-yl) oxy) -1H-pyrazol-4-yl) carboxamide
Step 1: preparation of 1-methyl-4-nitro-3- ((1, 1-trifluoropropan-2-yl) oxy) -1H-pyrazole (racemic)
819mg (1.3 eq) of racemic 1, 1-trifluoropropan-2-ol and 3.67g (2 eq) of cesium carbonate are added to a solution of 1g (1 eq) of 1-methyl-3, 4-dinitro-1H-pyrazole (commercially available) in 20mL of acetonitrile. The mixture was heated at 65 ℃ 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 (gradient elution with 20% to 50% ethyl acetate in heptane) to give 1.25g of rac 1-methyl-4-nitro-3- ((1, 1-trifluoropropan-2-yl) oxy) -1H-pyrazole. MS (method A) m/z 240[ M+1] +; t=1.48 min.
Step 2: preparation of 1-methyl-3- ((1, 1-trifluoropropan-2-yl) oxy) -1H-pyrazol-4-amine (rac)
In a microwave vial, a solution of 1.2g (1 eq) 1-methyl-4-nitro-3- ((1, 1-trifluoropropan-2-yl) oxy) -1H-pyrazole in 15mL of methanol was treated with 904mg ammonium formate (2.8 eq) and 0.267g (0.05 eq) palladium on carbon (10%). The reaction mixture was heated at 70℃for 10 minutes. The mixture was filtered by washing with methanol over celite and concentrated under reduced pressure. The crude material was taken to the next step without further purification.
Step 3: preparation of N- (1-methyl-3- ((1, 1-trifluoropropan-2-yl) oxy) -1H-pyrazol-4-yl) carboxamide (rac)
A solution of 1050mg (1 eq) of rac-1-methyl-3- ((1, 1-trifluoropropan-2-yl) oxy) -1H-pyrazol-4-amine in 7mL of tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 1.9mL of acetic anhydride (4 eq) in 3.87mL of formic acid (18 eq) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at 5 ℃ for 5 minutes, at room temperature for 1.5 hours, then concentrated in vacuo to give 895mg of racemic N- (1-methyl-3- ((1, 1-trifluoropropan-2-yl) oxy) -1H-pyrazol-4-yl) carboxamide. MS (method A) m/z 238[ M+1] +; t=1.61 min.
Intermediate 8: n- (3-isopropoxy-1- (2, 2-trifluoroethyl) -1H-pyrazol-4-yl) carboxamide
Step 1: preparation of 3-isopropoxy-4-nitro-1- (2, 2-trifluoroethyl) -1H-pyrazole
3.35g (1.5 eq) of 2, 2-trifluoroethyl group 1,2, 3, 4-nonafluorobutane-1-sulfonate and 2.45g (3 eq) Potassium carbonate were added to a solution of 1g (1 eq) 3-isopropoxy-4-nitro-1H-pyrazole (commercially available) in 16mL dimethylformamide. The mixture was heated at 80 ℃ 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 purified on silica gel (gradient elution with 20% to 50% ethyl acetate in heptane) to give 1.22g of 3-isopropoxy-4-nitro-1- (2, 2-trifluoroethyl) -1H-pyrazole. MS (method B) m/z 254[ M+1] +; t=1.59 min.
Step 2: preparation of 3-isopropoxy-1- (2, 2-trifluoroethyl) -1H-pyrazol-4-amine
In a microwave vial, a solution of 885mg (1 eq.) of 3-isopropoxy-4-nitro-1- (2, 2-trifluoroethyl) -1H-pyrazole in 17mL of methanol was treated with 630mg of ammonium formate (2.8 eq.) and 186mg (0.05 eq.) of palladium on carbon (10%). The reaction mixture was heated at 70℃for 10 minutes. The mixture was filtered by washing with methanol over celite and concentrated under reduced pressure. The crude material was taken to the next step without further purification.
Step 3: preparation of N- (3-isopropoxy-1- (2, 2-trifluoroethyl) -1H-pyrazol-4-yl) carboxamide
A solution of 780mg (1 eq) 3-isopropoxy-1- (2, 2-trifluoroethyl) -1H-pyrazol-4-amine in 5mL tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 1.33mL acetic anhydride (4 eq) in 2.7mL formic acid (18 eq) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at 5 ℃ for 5 minutes, at room temperature for 1 hour, and then concentrated in vacuo. The residue was taken up on silica gel (by 18% ethyl acetate/2% 7nnh in MeOH 3 80% heptane to 45% ethyl acetate/5% 7N NH in MeOH 3 50% heptane elution) to yield 730mg of N- (3-isopropoxy-1- (2, 2-trifluoroethyl) -1H-pyrazol-4-yl) carboxamide. MS (method A) m/z 252[ M+1 ] ]+；t＝1.94min。
Intermediate 9: n- (3- ((1-acetylazetidin-3-yl) oxy) -1-methyl-1H-pyrazol-4-yl) carboxamide
Step 1: preparation of 3- ((1-methyl-4-nitro-1H-pyrazol-3-yl) oxy) azetidine-1-carboxylic acid tert-butyl ester
13.71g (1.1 eq) of tert-butyl 3-iodoazetidine-1-carboxylate and 12.17g (2 eq) of potassium carbonate are added to a solution of 6.3g (1 eq) of 1-methyl-4-nitro-1H-pyrazol-3-ol (commercially available) in 125mL of dimethylformamide. The mixture was heated at 90 ℃ for 30 hours, then at room temperature for 70 hours, and then poured into 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 (elution with a gradient of 10% to 60% ethyl acetate in heptane) to give 8g of tert-butyl 3- ((1-methyl-4-nitro-1H-pyrazol-3-yl) oxy) azetidine-1-carboxylate. MS (method A) m/z 243[ M-tBu ] +; t=1.87 min.
Step 2: preparation of 3- (azetidin-3-yloxy) -1-methyl-4-nitro-1H-pyrazole (TFA salt)
32mL of trifluoroacetic acid was added to a solution of 8g (1 eq) of tert-butyl 3- ((1-methyl-4-nitro-1H-pyrazol-3-yl) oxy) azetidine-1-carboxylate in 160mL of dichloromethane at 0deg.C. The mixture was stirred at room temperature for 1.5 hours and cooled to 0 ℃. 10mL MeOH followed by 150mL 7N NH in MeOH 3 Slowly add 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 (ratio (95/4.5/0.5) to (80/18/2)) to give 9.9g of 3- (azetidin-3-yloxy) -1-methyl-4-nitro-1H-pyrazole (TFA salt). MS (method A) m/z 199[ M+1]]+；t＝0.26min。
Step 3: preparation of 1- (3- ((1-methyl-4-nitro-1H-pyrazol-3-yl) oxy) azetidin-1-yl) ethanol-1-one
13.4mL (10 eq.) of triethylamine are added to a solution of 3g (1 eq.) of 3- (azetidin-3-yloxy) -1-methyl-4-nitro-1H-pyrazole (TFA salt) in 100mL of tetrahydrofuran. The mixture was cooled to 0 ℃ and 1.4mL (2 eq.) of acetyl chloride was added dropwise. The reaction mixture was stirred at 0 ℃ for 5 min, then at room temperature for 1 hr, and then poured into 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 (eluted with a gradient of 10% to 50% acetone in dichloromethane) to give 1.34g of 1- (3- ((1-methyl-4-nitro-1H-pyrazol-3-yl) oxy) azetidin-1-yl) ethanol-1-one. MS (method A) m/z 241[ M+1] +; t=1.22 min.
Step 4: preparation of 1- (3- ((4-amino-1-methyl-1H-pyrazol-3-yl) oxy) azetidin-1-yl) ethanol-1-one
In a microwave vial, a solution of 1.34g (1 eq) 1- (3- ((1-methyl-4-nitro-1H-pyrazol-3-yl) oxy) azetidin-1-yl) ethanol-1-one in 32mL methanol was treated with 2.18g ammonium formate (6 eq) and 403mg (0.07 eq) palladium on carbon (10%). The reaction mixture was heated at 70℃for 10 minutes. The mixture was filtered by washing with methanol over celite and concentrated under reduced pressure. The crude material was taken to the next step without further purification.
Step 5: preparation of N- (3- ((1-acetylazetidin-3-yl) oxy) -1-methyl-1H-pyrazol-4-yl) carboxamide
A solution of 1.29g (1 eq) 1- (3- ((4-amino-1-methyl-1H-pyrazol-3-yl) oxy) azetidin-1-yl) ethanol-1-one in 20mL tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 2.32mL acetic anhydride (4 eq) in 1.88mL formic acid (8 eq) that had been premixed for 30 minutes at room temperature. 15mL 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 evaporated under reduced pressure to give 1.08g N- (3- ((1-acetylazetidin-3-yl) oxy) -1-methyl-1H-pyrazol-4-yl) carboxamide. MS (method A) m/z 239[ M+1] +; t=0.87 min.
Intermediate 10: n- (2-Cyclopropoxy-4- ((dimethylamino) methyl) phenyl) carboxamide
Step 1: preparation of 1- (3-cyclopropoxy-4-nitrophenyl) -N, N-dimethylamine
A solution of 1g (1 eq) 3-cyclopropoxy-4-nitrobenzaldehyde, 4.6mL acetic acid and 2.41mL 2N dimethylamine in tetrahydrofuran in 23mL dichloromethane was stirred at room temperature for 15 minutes. 2.05g (2 eq) sodium triacetoxyborohydride was added and the reaction mixture was stirred at room temperature for 70 hours. 40mL of methylene chloride and 40mL of saturated aqueous sodium bicarbonate were added. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was taken up on silica gel (dichloromethane/ethyl acetate/7N NH 3 The mixture in MeOH (80/18/2) was eluted to give 471mg of 1- (3-cyclopropoxy-4-nitrophenyl) -N, N-dimethylamine. MS (method A) m/z 237[ M+1 ]]+；t＝0.72min。
Step 2: preparation of 2-cyclopropoxy-4- ((dimethylamino) methyl) aniline
In a microwave vial, a solution of 471mg (1 eq.) of 1- (3-cyclopropoxy-4-nitrophenyl) -N, N-dimethylamine in 12mL of methanol was treated with 363mg of ammonium formate (2.8 eq.) and 212mg (0.1 eq.) of palladium on carbon (10%). The reaction mixture was heated at 80℃for 15 minutes. The mixture was filtered by washing with methanol over celite and concentrated under reduced pressure. The crude material was triturated in diisopropyl ether and the filtrate evaporated to give 337mg of 2-cyclopropoxy-4- ((dimethylamino) methyl) aniline. The crude material was taken to the next step without further purification.
Step 3: preparation of N- (2-cyclopropoxy-4- ((dimethylamino) methyl) phenyl) carboxamide
A solution of 337mg (1 eq) of 2-cyclopropoxy-4- ((dimethylamino) methyl) aniline in 10mL of tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 468. Mu.L of acetic anhydride (3 eq) in 779. Mu.L of formic acid (12 eq) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The residue was concentrated in vacuo to give 337mg of N- (2-cyclopropoxy-4- ((dimethylamino) methyl) phenyl) carboxamide. MS (method A) m/z 235[ M+1] +; t=0.36 min.
Intermediate 11: n- (3-cyclopropoxy-1- (oxetan-3-yl) -1H-pyrazol-4-yl) carboxamide
Step 1: preparation of 3-cyclopropoxy-4-nitro-1- (oxetan-3-yl) -1H-pyrazole
653mg (1.2 eq) of 3-iodooxetane and 817mg (2 eq) of potassium carbonate are added to a solution of 0.5g (1 eq) of 3-cyclopropoxy-4-nitro-1H-pyrazole (intermediate 15, step 2) in 20mL of 1-methyl-2-pyrrolidone. The mixture was heated at 80 ℃ for 24 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 (gradient elution with 20% to 50% ethyl acetate in heptane) to give 292 mg of 3-cyclopropoxy-4-nitro-1- (oxetan-3-yl) -1H-pyrazole. MS (method A) m/z 226[ M+1] +; t=1.68 min.
Step 2: preparation of 3-cyclopropoxy-1- (oxetan-3-yl) -1H-pyrazol-4-amine
In a microwave vial, a solution of 296mg (1 eq.) of 3-cyclopropoxy-4-nitro-1- (oxetan-3-yl) -1H-pyrazole in 9mL of methanol was treated with 240mg ammonium formate (2.8 eq.) and 140mg (0.1 eq.) of palladium on carbon (10%). The reaction mixture was heated at 70℃for 10 minutes. The mixture was filtered by washing with methanol over celite and concentrated under reduced pressure. The crude material was taken to the next step without further purification.
Step 3: preparation of N- (3-cyclopropoxy-1- (oxetan-3-yl) -1H-pyrazol-4-yl) carboxamide
A solution of 250mg (1 eq) 3-cyclopropoxy-1- (oxetan-3-yl) -1H-pyrazol-4-amine in 5mL tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 484. Mu.L acetic anhydride (4 eq) in 884. Mu.L formic acid (18 eq) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at 0 ℃ for 1 hour. The residue was concentrated in vacuo to give 200mg of N- (3-cyclopropoxy-1- (oxetan-3-yl) -1H-pyrazol-4-yl) carboxamide. MS (method A) m/z 224[ M+1] +; t=1.17 min.
Intermediate 12: n- (3-isopropoxy-1- (oxetan-3-yl) -1H-pyrazol-4-yl) carboxamide
Step 1: preparation of 3-isopropoxy-4-nitro-1- (oxetan-3-yl) -1H-pyrazole
653mg (1.2 eq) of 3-iodooxetane and 817mg (2 eq) of potassium carbonate are added to a solution of 0.5g (1 eq) of 3-isopropoxy-4-nitro-1H-pyrazole (commercially available) in 20mL of 1-methyl-2-pyrrolidone. The mixture was heated at 80 ℃ for 24 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 (gradient elution with 20% to 50% ethyl acetate in heptane) to give 564mg of 3-isopropoxy-4-nitro-1- (oxetan-3-yl) -1H-pyrazole. MS (method A) m/z 228[ M+1] +; t=1.86 min.
Step 2: preparation of 3-isopropoxy-1- (oxetan-3-yl) -1H-pyrazol-4-amine
In a microwave vial, a solution of 150mg (1 eq) of 3-isopropoxy-4-nitro-1- (oxetan-3-yl) -1H-pyrazole in 4mL of methanol was treated with 120mg of ammonium formate (2.8 eq) and 71mg (0.1 eq) of palladium on carbon (10%). The reaction mixture was heated at 70℃for 10 minutes. The mixture was filtered by washing with methanol over celite and concentrated under reduced pressure. The crude material was taken to the next step without further purification.
Step 3: preparation of N- (3-isopropoxy-1- (oxetan-3-yl) -1H-pyrazol-4-yl) carboxamide
A solution of 130mg (1 eq) 3-isopropoxy-1- (oxetan-3-yl) -1H-pyrazol-4-amine in 3mL tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 249. Mu.L acetic anhydride (4 eq) in 455. Mu.L formic acid (18 eq) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at 0 ℃ for 1 hour. The residue was concentrated in vacuo to give 200mg of N- (3-isopropoxy-1- (oxetan-3-yl) -1H-pyrazol-4-yl) carboxamide. MS (method A) m/z 226[ M+1] +; t=1.36 min.
Intermediate 13: n- (1- ((methylsulfonyl) methyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide
Step 1: preparation of 1- (4-methoxybenzyl) -3, 4-dinitro-1H-pyrazole
11.77g (1.2 eq.) of 4-methoxybenzyl chloride, 27.15g of tetrabutylammonium iodide and 36.02g (1.8 eq.) of cesium carbonate are added to a solution of 10g (1 eq.) of 3, 4-dinitro-1H-pyrazole in 50mL of dimethylformamide. The mixture was stirred at room temperature for 50 minutes 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 is purified on silica gel (gradient elution with 10% to 50% ethyl acetate in heptane) to give 15.25g of 1- (4-methoxybenzyl) -3, 4-dinitro-1H-pyrazole. MS (method A) m/z 277[ M-1]; t=1.61 min.
Step 2: preparation of 1- (4-methoxybenzyl) -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole
2.16g (1.25 eq) of oxetan-3-ol and 15.24g (2 eq) of cesium carbonate are added to a solution of 6.5g (1 eq) of 1- (4-methoxybenzyl) -3, 4-dinitro-1H-pyrazole in 80mL of acetonitrile. The mixture was heated at 80 ℃ for 3 hours, then allowed to cool to room temperature, 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 triturated in diisopropyl ether to give 7.1g of 1- (4-methoxybenzyl) -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole. MS (method A) m/z 306[ M+1] +; t=2.16 min.
Step 3: preparation of 4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole
32.33g (2.5 eq) of ceric ammonium nitrate are added to a solution of 7.1g (1 eq) of 1- (4-methoxybenzyl) -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole in 170mL of acetonitrile and 170mL of water. The mixture was stirred at room temperature for 16 hours. 4.5g of ceric ammonium nitrate was added and the reaction mixture was stirred at room temperature for 30 minutes and poured into 85mL of ethyl acetate and 85mL of saturated aqueous solution of sodium thiosulfate. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was triturated in ether and the precipitate filtered to give 2.38g of 4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole. MS (method A) m/z 186[ M+1] +; t=0.90 min.
Step 4: preparation of 1- ((methylthio) methyl) -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole
937. Mu.L (1.4 eq) (chloromethyl) (methyl) sulfane and 2.24g (2 eq) potassium carbonate were added to a solution of 1.5g (1 eq) 4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole in 50mL dimethylformamide. The mixture was heated at 80 ℃ for 2.5 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 (gradient elution with 20% to 50% ethyl acetate in heptane) to give 935mg of 1- ((methylthio) methyl) -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole. MS (method A) m/z 246[ M+1] +; t=1.15 min.
Step 5: preparation of 1- ((methylsulfonyl) methyl) -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole
2.55g (purity 77% -3 eq) of 3-chloroperoxybenzoic acid are added to a solution of 931mg (1 eq) of 1- ((methylthio) methyl) -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole in 40mL of dichloromethane at 0deg.C. The mixture was allowed to warm to room temperature and then quenched with 50mL DCM and 20mL of 10% aqueous sodium thiosulfate. Stirring the mixture Mix for 15 minutes. The organic layer was washed successively with 50mL of saturated aqueous sodium carbonate solution, 50mL of water and 50mL of brine, then dried over magnesium sulfate and concentrated under reduced pressure. The precipitate formed in the interface of the aqueous layer and the organic layer was filtered and dried in vacuo to give 255mg of 1- ((methylsulfonyl) methyl) -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole. The residue from evaporation of the organic layer was taken up on silica (7N NH in heptane/ethyl acetate/in MeOH 3 (80/18/2) elution) to yield 2911 mg of 1- ((methylsulfonyl) methyl) -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole. MS (method B) m/z 278[ M+1]]+；t＝0.85min。
Step 6: preparation of 1- ((methylsulfonyl) methyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-amine
A solution of 546mg (1 eq) of 1- ((methylsulfonyl) methyl) -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole in 50mL of methanol was treated with 0.42g of palladium on carbon (10%) under 4 bar of hydrogen for 1 hour. The mixture was filtered by washing with methanol and concentrated under reduced pressure to give 450mg of 1- ((methylsulfonyl) methyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-amine. MS (method A) m/z 248[ M+1] +; t=0.24 min.
Step 7: preparation of N- (1- ((methylsulfonyl) methyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide
A solution of 486mg (1 eq) of 1- ((methylsulfonyl) methyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-amine in 3mL of tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 742. Mu.L acetic anhydride (4 eq) in 1.36mL formic acid (18 eq) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The residue was concentrated in vacuo and purified on silica (withHeptane/ethyl acetate/7N NH in MeOH 3 (50/45/5) elution) to give 450mg of N- (1- ((methylsulfonyl) methyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide. MS (method A) m/z 276[ M+1]]+；t＝0.52min。
Intermediate 14: n- (1- (methoxymethyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide
Step 1: preparation of 1- (methoxymethyl) -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole
121mg (1.4 eq.) of sodium hydride (60% purity) are added to a solution of 400mg (1 eq.) of 4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole (intermediate 13, step 3) in 12mL of tetrahydrofuran at 0 ℃. The reaction mixture was stirred at 0 ℃ for 30 minutes and at room temperature for 15 minutes. The mixture was cooled to 0 ℃ and 244mg (1.4 eq) of chloro (methoxy) methane was added. The mixture was stirred at 0 ℃ for 30 minutes and slowly 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 (gradient elution with 20% to 50% ethyl acetate in heptane) to give 373mg of 1- (methoxymethyl) -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole. MS (method A) m/z 230[ M+1] +; t=1.34 min.
Step 2: preparation of 1- (methoxymethyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-amine
In a microwave vial, a solution of 453mg (1 eq) of 1- (methoxymethyl) -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole in 15mL of methanol was treated with 356mg of ammonium formate (2.8 eq) and 210mg (0.05 eq) of palladium on carbon (10%). The reaction mixture was heated at 70℃for 10 minutes. The mixture was filtered by washing with methanol over celite and concentrated under reduced pressure. The crude material was taken to the next step without further purification.
Step 3: preparation of N- (1- (methoxymethyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide
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A solution of 393mg (1 eq) of 1- (methoxymethyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-amine in 3mL of tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 745. Mu.L of acetic anhydride (4 eq) in 1.36mL of formic acid (18 eq) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at 0 ℃ for 1 hour. The residue was concentrated in vacuo and taken up on silica (7N NH in heptane/ethyl acetate/MeOH 3 (50/45/5) elution) to give 312mg of N- (1- (methoxymethyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide. MS (method A) m/z 228[ M+1 ] ]+；t＝0.74min。
Intermediate 15: n- (3-cyclopropoxy-1- (methoxymethyl) -1H-pyrazol-4-yl)
Step 1: preparation of 4-cyclopropoxy-1- (4-methoxybenzyl) -3-nitro-1H-pyrazole
2.51g (1.5 eq) of cyclopropyl alcohol and 19.2g (2 eq) of cesium carbonate are added to a solution of 8g (1 eq) of 1- (4-methoxybenzyl) -3, 4-dinitro-1H-pyrazole (intermediate 13, step 1) in 100mL of acetonitrile. The mixture was heated at 50 ℃ for 3 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 (gradient elution with 20% to 50% ethyl acetate in heptane) to give 5.1g 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.
Step 2: preparation of 3-cyclopropoxy-4-nitro-1H-pyrazole
18.35g (2.5 eq) of ammonium cerium nitrate are added to a solution of 5.1g (1 eq) of 4-cyclopropoxy-1- (4-methoxybenzyl) -3-nitro-1H-pyrazole in 100mL of acetonitrile and 100mL of water. The mixture was stirred at room temperature for 16 hours. 4g of ceric ammonium nitrate was added and the reaction mixture was stirred at room temperature for 30 minutes and poured into 85mL of ethyl acetate and 85mL 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 2.5g of 3-cyclopropoxy-4-nitro-1H-pyrazole. MS (method A) m/z 170[ M+1] +; t=1.3 min.
Step 3: preparation of 3-cyclopropoxy-1- (methoxymethyl) -4-nitro-1H-pyrazole
667mg (1.4 eq) of chloro (methoxy) methane was added to a solution of 1g (1 eq) 3-cyclopropoxy-4-nitro-1H-pyrazole in 30mL acetonitrile and 1.65g (2 eq) potassium carbonate at 0 ℃. The mixture was warmed to room temperature, stirred for 1.5 hours, 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 (gradient elution with 20% to 50% ethyl acetate in heptane) to give 815mg of 3-cyclopropoxy-1- (methoxymethyl) -4-nitro-1H-pyrazole. MS (method B), m/z 170[ M+1] +; t=1.18 min.
Step 4: preparation of 3-cyclopropoxy-1- (methoxymethyl) -1H-pyrazol-4-amine
In a microwave vial, a solution of 815mg (1 eq.) of 3-cyclopropoxy-1- (methoxymethyl) -4-nitro-1H-pyrazole in 10mL of methanol was treated with 689mg of ammonium formate (2.8 eq.) and 204mg (0.05 eq.) of palladium on carbon (10%). The reaction mixture was heated at 100℃for 10 minutes. The mixture was filtered by washing with methanol over celite and concentrated under reduced pressure. The crude material was taken to the next step without further purification.
Step 5: preparation of N- (3-cyclopropoxy-1- (methoxymethyl) -1H-pyrazol-4-yl) carboxamide
A solution of 700mg (1 eq) 3-cyclopropoxy-1- (methoxymethyl) -1H-pyrazol-4-amine in 7mL tetrahydrofuran was added dropwise to a solution of 1.45mL acetic anhydride (4 eq) in 1.31mL formic acid (18 eq) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred for 1 hour. The residue was concentrated in vacuo and purified on silica gel (eluting with dichloromethane, then 2% methanol in dichloromethane) to give 620mg of N- (3-cyclopropoxy-1- (methoxymethyl) -1H-pyrazol-4-yl) carboxamide. MS (method B) m/z 212[ M+1] +; t=0.86 min.
Intermediate 16: n- (3-cyclopropoxy-1- ((methylsulfonyl) methyl) -1H-pyrazol-4-yl) carboxamide
Step 1: preparation of 3-cyclopropoxy-1- ((methylthio) methyl) -4-nitro-1H-pyrazole
820. Mu.L (1.4 eq) (chloromethyl) (methyl) sulfane and 1.96g (2 eq) potassium carbonate are added to a solution of 1.2g (1 eq) 3-cyclopropoxy-4-nitro-1H-pyrazole (intermediate 15, step 2) in 45mL dimethylformamide. The mixture was heated at 50 ℃ 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 20% ethyl acetate in heptane) to give 800mg of 3-cyclopropoxy-1- ((methylthio) methyl) -4-nitro-1H-pyrazole.
Step 2: preparation of 3-cyclopropoxy-1- ((methylsulfonyl) methyl) -4-nitro-1H-pyrazole
2.50g (purity 70% -3 eq) of 3-chloroperoxybenzoic acid are added to a solution of 800mg (1 eq) 3-cyclopropoxy-1- ((methylthio) methyl) -4-nitro-1H-pyrazole in 10mL of dichloromethane. The mixture was stirred for 3 hours and then quenched with 50mL of dichloromethane and 20mL of 10% aqueous sodium thiosulfate sodium carbonate solution. The mixture was stirred for 15 minutes. The organic layer was washed successively with 50mL of saturated aqueous sodium carbonate solution, 50mL of water and 50mL of brine, then dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated in diisopropyl ether and the solid filtered and dried in vacuo to give 830mg of 3-cyclopropoxy-1- ((methylsulfonyl) methyl) -4-nitro-1H-pyrazole. MS (method A) m/z 263[ M+1] +; t=2.36 min.
Step 3: preparation of 3-cyclopropoxy-1- ((methylsulfonyl) methyl) -1H-pyrazol-4-amine
A solution of 730mg (1 eq) of 3-cyclopropoxy-1- ((methylsulfonyl) methyl) -4-nitro-1H-pyrazole in 70mL of methanol was treated with 595mg of palladium on carbon (10%) under 4 bar of hydrogen for 1 hour. The mixture was washed with methanol, filtered and concentrated under reduced pressure to give 680mg of 3-cyclopropoxy-1- ((methylsulfonyl) methyl) -1H-pyrazol-4-amine. The crude material was taken to the next step without further purification.
Step 4: preparation of N- (3-cyclopropoxy-1- ((methylsulfonyl) methyl) -1H-pyrazol-4-yl) carboxamide
A solution of 680mg (1 eq) 3-cyclopropoxy-1- ((methylsulfonyl) methyl) -1H-pyrazol-4-amine in 7mL tetrahydrofuran was added dropwise to a solution of 1.12mL acetic anhydride (4 eq) in 1.01mL formic acid (8 eq) that had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The residue was concentrated in vacuo and purified on silica (eluting with dichloromethane, then 2% methanol in dichloromethane) to give 490mg of N- (3-cyclopropoxy-1- ((methylsulfonyl) methyl) -1H-pyrazol-4-yl) carboxamide. MS (method B) m/z 260[ M+1] +; t=0.79 min.
Intermediate 17: n- (3- (((3R, 4R) -4-methoxytetrahydrofuran-3-yl) oxy) -1-methyl-1H-pyrazol-4-yl) carboxamide and N- (3- (((3S, 4S) -4-methoxytetrahydrofuran-3-yl) oxy) -1-methyl-1H-pyrazol-4-yl) carboxamide
Step 1: preparation of (3S, 4S) -4-methoxytetrahydrofuran-3-ol and (3R, 4R) -4-methoxytetrahydrofuran-3-ol
929 μl sulfuric acid (0.05 eq) was added dropwise to a solution of 30g (1 eq) 3, 4-epoxytetrahydrofuran in 450mL methanol. The reaction mixture was stirred at room temperature for 48 hours. 60mL of saturated aqueous sodium bicarbonate was added and the reaction mixture was stirred for 30 minutes. 150mL of ethyl acetate and 60mL 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 31.47g of a racemic mixture of (3 s,4 s) -4-methoxytetrahydrofuran-3-ol and (3 r,4 r) -4-methoxytetrahydrofuran-3-ol. The aqueous layer was further extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give an additional 4.88g of a racemic mixture of (3 s,4 s) -4-methoxytetrahydrofuran-3-ol and (3 r,4 r) -4-methoxytetrahydrofuran-3-ol. The crude material was taken to the next step without further purification.
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
1.37g (1.3 eq.) of a racemic mixture of (3S, 4S) -4-methoxytetrahydrofuran-3-ol and (3R, 4R) -4-methoxytetrahydrofuran-3-ol and 7.58g (2 eq.) of cesium carbonate are added to a solution of 2g (1 eq.) of 1-methyl-3, 4-dinitro-1H-pyrazole (commercially available) in 40mL of acetonitrile. The mixture was heated at 80 ℃ for 6h, 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 (elution with a gradient of 10% to 20% ethyl acetate in dichloromethane) to give 1.4g of a racemic mixture of 3- (((3 r,4 r) -4-methoxytetrahydrofuran-3-yl) oxy) -1-methyl-4-nitro-1H-pyrazole and 3- (((3 s,4 s) -4-methoxytetrahydrofuran-3-yl) oxy) -1-methyl-4-nitro-1H-pyrazole. MS (method B) m/z 244[ M+1] +; t=1.08 min.
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
A solution of 1g (1 eq) 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 in 32mL of ethanol and 6.6mL of water was treated with 1.11g of ammonium chloride (5 eq). The reaction mixture was heated at 80 ℃ and 1.15g (5 eq.) iron was added. The reaction mixture was heated at 80 ℃ for 2 hours, 10mL of ethanol was added, and the mixture was filtered by washing with ethanol over celite. The filtrate was concentrated under reduced pressure. The crude material was diluted with 20mL ethyl acetate and 10mL saturated aqueous 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 to give 0.9g of a racemic mixture of 3- (((3 r,4 r) -4-methoxytetrahydrofuran-3-yl) oxy) -1-methyl-1H-pyrazol-4-amine and 3- (((3 s,4 s) -4-methoxytetrahydrofuran-3-yl) oxy) -1-methyl-1H-pyrazol-4-amine. MS (method A) m/z 214[ M+1] + with a base station
Step 4: preparation of N- (3- (((3R, 4R) -4-methoxytetrahydrofuran-3-yl) oxy) -1-methyl-1H-pyrazol-4-yl) carboxamide and N- (3- (((3S, 4S) -4-methoxytetrahydrofuran-3-yl) oxy) -1-methyl-1H-pyrazol-4-yl) carboxamide
A solution of 1.3g (1 eq) 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 in 8mL of tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 2.33mL of acetic anhydride (4 eq) in 2.09mL of formic acid (8 eq) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at 0 ℃ for 15 minutes. The residue was concentrated in vacuo and purified on silica (eluting with 5% methanol in dichloromethane) to give 300mg of a racemic mixture of N- (3- (((3 r,4 r) -4-methoxytetrahydrofuran-3-yl) oxy) -1-methyl-1H-pyrazol-4-yl) carboxamide and N- (3- (((3 s,4 s) -4-methoxytetrahydrofuran-3-yl) oxy) -1-methyl-1H-pyrazol-4-yl) carboxamide. MS (method B) m/z 242[ M+1] +; t=0.87 min.
Intermediate 18: n- (1- (methylsulfonyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide
Step 1: preparation of 1- (methylsulfonyl) -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole
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502. Mu.L (1.5 eq.) of methanesulfonyl chloride was added to a solution of 0.8g (1 eq.) of 4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole (intermediate 13, step 3) in 40mL of dichloromethane and 1.21mL of triethylamine (2 eq.) at 0 ℃. The mixture was stirred at room temperature for 2 hours and poured into 20mL of saturated aqueous ammonium chloride solution. 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 600mg of 1- (methylsulfonyl) -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole. MS (method B) m/z 264[ M+1] +; t=2.21 min.
Step 2: preparation of N- (1- (methylsulfonyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide
610mg ammonium chloride (5 eq) and 600mg iron (5 eq) were added to a solution of 0.6g (1 eq) 1- (methylsulfonyl) -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole in 18mL ethanol and 2mL water. The reaction mixture was heated at 80 ℃ with vigorous stirring for 10 minutes, and the mixture was filtered by washing with ethanol over celite and concentrated under reduced pressure. The crude material was diluted with 20mL ethyl acetate and washed with 20mL saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and concentrated in vacuo.
A solution of the residue in 3mL of tetrahydrofuran was added dropwise to a solution of 1.08mL of acetic anhydride (5 equivalents) in 1.55mL of formic acid (18 equivalents) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The residue was purified on silica (eluting with 5% methanol in dichloromethane) to give 250mg of N- (1- (methylsulfonyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide. MS (method B) m/z 262[ M+1] +; t=0.78 min.
Intermediate 19: n- (1-methyl-3- (((2R, 3S) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide and N- (1-methyl-3- (((2S, 3R) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (racemic trans)
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)
2.53g (1.3 eq) of 2-methyl-oxetan-3-ol and 14.68g (2 eq) of cesium carbonate are added to a solution of 4g (1 eq) of 1-methyl-3, 4-dinitro-1H-pyrazole (commercially available) in 100mL of acetonitrile. The mixture was heated at 65 ℃ for 3 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 (elution with a gradient of 10% to 50% ethyl acetate in heptane) to give 2.18g of the first mixture and 1.18g of the second mixture.
The first mixture was characterized by NMR as a racemic trans mixture of 1-methyl-3- (((2 r,3 s) -2-methyloxetan-3-yl) oxy) -4-nitro-1H-pyrazole and 1-methyl-3- (((2 s,3 r) -2-methyloxetan-3-yl) oxy) -4-nitro-1H-pyrazole. MS (method B) m/z 214[ M+1] +; t=1.05 min (racemic trans).
The second mixture was characterized by NMR as a racemic cis mixture of 1-methyl-3- (((2 s,3 s) -2-methyloxetan-3-yl) oxy) -4-nitro-1H-pyrazole and 1-methyl-3- (((2 r,3 r) -2-methyloxetan-3-yl) oxy) -4-nitro-1H-pyrazole. MS (method B) m/z 214[ M+1] +; t=1.02 min (racemic cis).
Step 2: preparation of N- (1-methyl-3- (((2R, 3S) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide and N- (1-methyl-3- (((2S, 3R) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (racemic trans)
A solution of 535mg (1 eq) of a mixture (racemic trans) of 1-methyl-3- (((2R, 3S) -2-methyloxetan-3-yl) oxy) -4-nitro-1H-pyrazole and 1-methyl-3- (((2S, 3R) -2-methyloxetan-3-yl) oxy) -4-nitro-1H-pyrazole in 170mL of methanol was treated with 0.26g of palladium on carbon (10%) for 1.5 hours under 2.5 bar of hydrogen. The mixture was filtered by washing with methanol and concentrated under reduced pressure. A solution of 943. Mu.L acetic anhydride (4 equivalents) in 1.73mL formic acid (18 equivalents) which had been premixed for 30 minutes was added dropwise to a solution of the residue in 12mL tetrahydrofuran at 0 ℃. The reaction mixture was stirred for 1 hour, allowed to warm to room temperature and then concentrated in vacuo. The residue was purified on silica gel (elution with a gradient of 0 to 100% ethyl acetate in heptane) to give 410mg of a mixture of N- (1-methyl-3- (((2 r,3 s) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide and N- (1-methyl-3- (((2 s,3 r) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (racemic trans). MS (method B) m/z 212[ M+1] +; t=0.81 min.
Intermediate 20:
n- (1-methyl-3- (((2S, 3S) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide and N- (1-methyl-3- (((2R, 3R) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (racemic cis)
A solution of 350mg (1 eq) of a mixture (racemic cis) of 1-methyl-3- (((2S, 3S) -2-methyloxetan-3-yl) oxy) -4-nitro-1H-pyrazole prepared in step 1 of intermediate 19 and 1-methyl-3- (((2R, 3R) -2-methyloxetan-3-yl) oxy) -4-nitro-1H-pyrazole in 40mL of methanol was treated with 0.1g of palladium on carbon (10%) under 2.5 bar of hydrogen for 1 hour. The mixture was filtered by washing with methanol and concentrated under reduced pressure. 619. Mu.L of acetic anhydride (4 eq.) in 1.13mL of formic acid (18 eq.) which had been premixed for 30 minutes was added dropwise to a solution of the residue in 10mL of tetrahydrofuran at 0 ℃. 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 (elution with a gradient of 0 to 100% ethyl acetate in heptane) to give 143mg of a mixture of N- (1-methyl-3- (((2 r,3 r) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide and N- (1-methyl-3- (((2 s,3 s) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (racemic cis). MS (method B) m/z 212[ M+1] +; t=0.75 min.
Intermediate 21: n- (1- (methyl-d 3) -3- (((2S, 3R) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide and N- (1- (methyl-d 3) -3- (((2R, 3S) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (racemic trans)
Step 1: preparation of 1- (methyl-d 3) -3, 4-dinitro-1H-pyrazole
6.42g (1.4 eq.) of methyl iodide-d 3 and 8.83g (2 eq.) of potassium carbonate are added to a solution of 5g (1 eq.) of 3, 4-dinitro-1H-pyrazole (commercially available) in 150mL of acetonitrile at 0 ℃. The mixture was stirred at room temperature for 6.5 hours, then poured into ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was taken up on silica gel (with heptaneGradient elution of 20% to 50% ethyl acetate) to give 4.8g of 1- (methyl-d 3) -3, 4-dinitro-1H-pyrazole. 1 H NMR (400 MHz, DMSO-d 6) delta, 9.1 (s, 1H) in ppm.
Step 2: preparation of 1- (methyl-d 3) -3- (((2S, 3R) -2-methyloxetan-3-yl) oxy) -4-nitro-1H-pyrazole and 1- (methyl-d 3) -3- (((2R, 3S) -2-methyloxetan-3-yl) oxy) -4-nitro-1H-pyrazole (rac-trans) and 1- (methyl-d 3) -3- (((2S, 3S) -2-methyloxetan-3-yl) oxy) -4-nitro-1H-pyrazole and 1- (methyl-d 3) -3- (((2R, 3R) -2-methyloxetan-3-yl) oxy) -4-nitro-1H-pyrazole (rac-cis)
3.16g (1.5 eq) of 2-methyloxetan-3-ol and 15.63g (2 eq) of cesium carbonate are added to a solution of 4.2g (1 eq) of 1- (methyl-d 3) -3, 4-dinitro-1H-pyrazole in 115mL of acetonitrile. The mixture was heated at 65 ℃ 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 2.2g of the first mixture and 1.25g of the second mixture.
The first mixture was characterized by NMR as a racemic trans mixture of 1- (methyl-d 3) -3- (((2 s,3 r) -2-methyloxetan-3-yl) oxy) -4-nitro-1H-pyrazole and 1- (methyl-d 3) -3- (((2 r,3 s) -2-methyloxetan-3-yl) oxy) -4-nitro-1H-pyrazole. MS (method B) m/z 217[ M+1] +; t=1.05 min.
The second mixture was characterized by NMR as a racemic cis mixture of 1- (methyl-d 3) -3- (((2 s,3 s) -2-methyloxetan-3-yl) oxy) -4-nitro-1H-pyrazole and 1- (methyl-d 3) -3- (((2 r,3 r) -2-methyloxetan-3-yl) oxy) -4-nitro-1H-pyrazole. MS (method B) m/z 217[ M+1] +; t=1.02 min.
Step 3: preparation of 1- (methyl-d 3) -3- (((2S, 3R) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-amine and 1- (methyl-d 3) -3- (((2R, 3S) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-amine (racemic trans)
In a microwave vial, a solution of 2.2g (1 eq) of 1- (methyl-d 3) -3- (((2 s,3 r) -2-methyloxetan-3-yl) oxy) -4-nitro-1H-pyrazole and 1- (methyl-d 3) -3- (((2 r,3 s) -2-methyloxetan-3-yl) oxy) -4-nitro-1H-pyrazole (rac-trans) in 40mL methanol was treated with 1.83g (2.8 eq) ammonium formate and 541mg palladium on carbon (10%) (0.05 eq). The reaction mixture was heated at 85 ℃ for 30 minutes. The mixture was washed with methanol over celite, filtered and concentrated under reduced pressure to give 1.9g of 1- (methyl-d 3) -3- (((2 s,3 r) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-amine and 1- (methyl-d 3) -3- (((2 r,3 s) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-amine (racemic trans). The crude material was taken to the next step without further purification.
Step 4: preparation of N- (1- (methyl-d 3) -3- (((2S, 3R) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide and N- (1- (methyl-d 3) -3- (((2R, 3S) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (racemic trans)
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A solution of 1.9g (1 eq) 1- (methyl-d 3) -3- (((2S, 3R) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-amine and 1- (methyl-d 3) -3- (((2R, 3S) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-amine (racemic trans) in 15mL of tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 3.87mL of acetic anhydride (4 eq) in 3.5mL of formic acid (8 eq) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 30 min, then concentrated in vacuo. The residue was purified on silica gel (eluting with 2% methanol in dichloromethane) to give a mixture of 1.7g N- (1- (methyl-d 3) -3- (((2 s,3 r) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide and N- (1- (methyl-d 3) -3- (((2 r,3 s) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (rac-trans). MS (method B) m/z 215[ M+1] +; t=1.62 min.
Intermediate 22:1- (methyl-d 3) -3- (((2S, 3S) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-amine and 1- (methyl-d 3) -3- (((2R, 3R) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-amine (racemic cis)
Step 1: preparation of 1- (methyl-d 3) -3- (((2S, 3S) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-amine and 1- (methyl-d 3) -3- (((2R, 3R) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-amine (racemic cis)
In a microwave vial, a solution of 1.25g (1 eq) 1- (methyl-d 3) -3- (((2 s,3 s) -2-methyloxetan-3-yl) oxy) -4-nitro-1H-pyrazole and 1- (methyl-d 3) -3- (((2 r,3 r) -2-methyloxetan-3-yl) oxy) -4-nitro-1H-pyrazole (racemic cis) (intermediate 21, step 2) in 20mL methanol was treated with 1.04g (2.8 eq) ammonium formate and 308mg palladium on carbon (0.05 eq). The reaction mixture was heated at 85 ℃ for 30 minutes. The mixture was washed with methanol over celite, filtered, and concentrated under reduced pressure to give 1g of 1- (methyl-d 3) -3- (((2 s,3 s) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-amine and 1- (methyl-d 3) -3- (((2 r,3 r) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-amine (racemic cis). The crude material was taken to the next step without further purification.
Step 2: preparation of N- (1- (methyl-d 3) -3- (((2S, 3S) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide and N- (1- (methyl-d 3) -3- (((2R, 3R) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (racemic cis)
A solution of 1.08g (1 eq) 1- (methyl-d 3) -3- (((2S, 3S) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-amine and 1- (methyl-d 3) -3- (((2R, 3R) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-amine (racemic cis) in 7mL of tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 2.2mL of acetic anhydride (4 eq) in 2mL of formic acid (8 eq) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 30 min, then concentrated in vacuo. The residue was purified on silica gel (eluting with 2% methanol in dichloromethane) to give 0.95g of a mixture of N- (1- (methyl-d 3) -3- (((2 s,3 s) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide and N- (1- (methyl-d 3) -3- (((2 r,3 r) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide as a beige solid (racemic cis). MS (method B) m/z 215[ M+1] +; t=1.55 min.
Intermediate 23: n- [1- (oxetan-3-yl) -3- [ (2, 2-trifluoro-1-methyl-ethoxy ] pyrazol-4-yl ] carboxamide (racemic)
Step 1: preparation of 1- [ (4-methoxyphenyl) methyl ] -4-nitro-3- [2, 2-trifluoro-1-methyl-ethoxy ] pyrazole (racemic)
To a solution of 1.5g (1 eq) of 1- (4-methoxybenzyl) -3, 4-dinitro-1H-pyrazole (intermediate 13, step 1) in 15mL of acetonitrile was added 0.66g (1.05 eq) of racemic 1, 1-trifluoro-2-propanol and 3.55g (2 eq) of cesium carbonate. The mixture was heated at 80 ℃ 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 triturated in 10mL isopropyl ether, the precipitate filtered and dried in vacuo to give 2.0g of rac 1- [ (4-methoxyphenyl) methyl ] -4-nitro-3- [2, 2-trifluoro-1-methyl-ethoxy ] pyrazole. MS (method B) m/z 346[ M+1] +; t=1.86 min.
Step 2: preparation of 4-nitro-3- [2, 2-trifluoro-1-methyl-ethoxy ] -1H-pyrazole (racemic)
8.1g (2.5 eq) of ammonium cerium (IV) nitrate dissolved in 40mL of water are added to a solution of 2.g (1 eq) of racemic 1- [ (4-methoxyphenyl) methyl ] -4-nitro-3- [2, 2-trifluoro-1-methyl-ethoxy ] pyrazole in 40mL of acetonitrile. The mixture was stirred at room temperature for 2 hours and poured into 20mL of 1M sodium thiosulfate solution and 20mL of methylene chloride. The aqueous layer was separated and extracted three times with dichloromethane. The combined organic layers were combined, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated in 40mL diethyl ether and the solid filtered and dried in vacuo to give 1.1g of rac 4-nitro-3- [2, 2-trifluoro-1-methyl-ethoxy ] -1H-pyrazole. MS (method B) m/z 226[ M+1] +; t=1.39 min.
Step 3: preparation of racemic 4-nitro-1- (oxetan-3-yl) -3- [2, 2-trifluoro-1-methyl-ethoxy ] pyrazole
588. Mu.L (1.3 eq) of 3-iodo-oxetane and 1.3g (2 eq) of potassium carbonate were added to a solution of 1.1g (1 eq) of rac 4-nitro-3- [2, 2-trifluoro-1-methyl-ethoxy ] -1H-pyrazole in 16mL of N, N-dimethylformamide. The mixture was heated at 80 ℃ for 24 hours and 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 washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified on silica gel (gradient elution with 0 to 5% ethyl acetate in dichloromethane) to give 700mg of rac 4-nitro-1- (oxetan-3-yl) -3- [2, 2-trifluoro-1-methyl-ethoxy ] pyrazole. MS (method B) m/z 282[ M+1] +; t=1.57 min.
Step 4: preparation of racemic 1- (oxetan-3-yl) -3- [2, 2-trifluoro-1-methyl-ethoxy ] pyrazol-4-amine
In a microwave vial, a solution of 450mg (1 eq) of rac-4-nitro-1- (oxetan-3-yl) -3- [2, 2-trifluoro-1-methyl-ethoxy ] pyrazole in 15mL methanol was treated with 620mg (6 eq) ammonium formate and 170mg palladium on carbon (10%). The reaction mixture was heated at 70 ℃ for 20 minutes. The mixture was filtered by washing with methanol over celite and concentrated under reduced pressure. The residue was taken up in dichloromethane, the solid filtered and the filtrate concentrated under reduced pressure to give 500mg of racemic 1- (oxetan-3-yl) -3- [2, 2-trifluoro-1-methyl-ethoxy ] pyrazol-4-amine. The crude material was taken to the next step without further purification.
Step 5: preparation of racemic N- [1- (oxetan-3-yl) -3- [2, 2-trifluoro-1-methyl-ethoxy ] pyrazol-4-yl ] carboxamide
A solution of 500mg (1 eq) of racemic 1- (oxetan-3-yl) -3- [2, 2-trifluoro-1-methyl-ethoxy ] pyrazol-4-amine in 3mL of tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 750. Mu.L acetic anhydride (3 eq) in 700. Mu.L formic acid (6 eq) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at 5 ℃ for 30 minutes and at room temperature for 1 hour, then concentrated in vacuo. The residue was diluted in ethyl acetate and poured into saturated aqueous 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 (gradient elution with 0 to 5% methanol in dichloromethane) to give 530mg of racemic N- [1- (oxetan-3-yl) -3- [2, 2-trifluoro-1-methyl-ethoxy ] pyrazol-4-yl ] carboxamide. MS (method B) m/z 280[ M+1] +; t=1.20 min.
Intermediate 24: n- (1-cyclopropyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide
Step 1: preparation of 1-cyclopropyl-4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole
To a solution of 0.6g (1 eq) of 4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole) (intermediate 13, step 3) in 22mL of 1, 2-dichloroethane was added 0.59g (2 eq) of cyclopropylboronic acid, 0.87g (1 eq) of 4 '-di-tert-butyl-2, 2' -bipyridine, 0.7g (2 eq) of sodium carbonate and 0.59g (1 eq) of copper (II) acetate. The mixture was refluxed for 3 hours, then allowed to cool to room temperature, poured into 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 0.6g of 1-cyclopropyl-4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole. MS (method A) m/z 226[ M+1] +; t=1.69 min.
Step 2: preparation of 1-cyclopropyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-amine
A solution of 0.6g (1 eq) 1-cyclopropyl-4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole in 15mL of methanol was treated with 442mg ammonium formate (2.8 eq) and 261mg (0.05 eq) palladium on carbon (10%). The reaction mixture was heated at 70℃for 15 minutes. The mixture was filtered by washing with methanol over celite 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.
Step 3: preparation of N- (1-cyclopropyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide
A solution of 478mg (1 eq.) of 1-cyclopropyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-amine in 2mL of tetrahydrofuran was added dropwise to a solution of 0.924mL of acetic anhydride (4 eq.) in 1.69mL of formic acid (18 eq.) premixed for 30 minutes at room temperature. The reaction mixture was stirred at 0 ℃ for 30 min, then concentrated in vacuo. The residue was taken up on silica gel (7N NH in heptane/ethyl acetate/MeOH 3 (50/45/5) elution) to yield 390mg of N- (1-cyclopropyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide. MS (method B) M/z224[ M+1 ]]+；t＝1.26min。
Intermediate 25: n- [1- [2, 2-difluoro-1-methyl-ethyl ] -3- (oxetan-3-yloxy) pyrazol-4-yl ] carboxamide
Step 1: preparation of 1, 1-difluoropropan-2-yl methanesulfonate (racemic)
1.5mL (1.05 eq.) of triethylamine was added to a solution of 1g (1 eq.) of racemic 1, 1-difluoropropan-2-ol in 20mL of dichloromethane. The mixture was cooled at 0 ℃ and 1.8g (1 eq) of methanesulfonic anhydride was added. The reaction mixture was warmed to room temperature and stirred for 2 hours, then poured into 50mL of ethyl acetate and 50mL of diethyl ether. The organic layer was washed three times with 10mL of water, then dried over sodium sulfate and concentrated in vacuo to give 1.5g of racemic 1, 1-difluoropropan-2-ylmethane sulfonate.
1 H NMR(400MHz,CDCl 3 ) Delta, 1.45 (m, 3H) in ppm; 2.98 (s, 3H); 4.80 (m, 1H); 5.75 (dt, j=4.5 and 53hz,1 h).
Step 2: preparation of 1- [2, 2-difluoro-1-methyl-ethyl ] -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole (racemic)
282mg (1.5 eq) of racemic 1, 1-difluoropropan-2-ylmethylsulfonate and 704mg of cesium carbonate are added to a solution of 200mg (1 eq) of 4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole (intermediate 13, step 3) in 10mL of acetonitrile. The mixture was heated at 80℃for 18 hours. The mixture was filtered over celite, washed twice with 5mL of acetonitrile and concentrated under reduced pressure. The residue was purified on silica gel (gradient elution with 0 to 40% ethyl acetate in cyclohexane) to give 100mg of rac 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.
Step 3: preparation of N- [1- [2, 2-difluoro-1-methyl-ethyl ] -3- (oxetan-3-yloxy) pyrazol-4-yl ] carboxamide (racemic)
101mg of ammonium chloride (5 eq) and 106mg of iron (5 eq) were added to a solution of 100mg of rac 1- [2, 2-difluoro-1-methyl-ethyl ] -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole in 8mL of ethanol and 1.2mL of water. The reaction mixture was heated at 80 ℃ with vigorous stirring for 10 minutes, and filtered through celite washing with ethanol, and concentrated under reduced pressure. The crude material was diluted with 20mL ethyl acetate and washed with 20mL saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate and concentrated in vacuo. A solution of the residue in 3mL of tetrahydrofuran was added dropwise to a solution of 179 μl of acetic anhydride (5 eq.) in 258 μl of formic acid (18 eq.) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The residue was purified on silica (eluting with 5% methanol in dichloromethane) to give 60mg of racemic N- [1- [2, 2-difluoro-1-methyl-ethyl ] -3- (oxetan-3-yloxy) pyrazol-4-yl ] carboxamide as a brown oil. MS (method E) m/z 262[ M+1] +; t=0.92 min.
Intermediate 26: n- (1- (methyl-d 3) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide
Step 1: preparation of 1- (methyl-d 3) -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole
126 μl (1.5 eq) of methyl iodide-d 3 (commercially available) and 880mg of cesium carbonate were added to a solution of 250mg (1 eq) of 4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole (intermediate 13, step 3) in 10ml of n, n-dimethylformamide. The mixture was stirred at room temperature for 1 hour and poured into a mixture of 20mL ethyl acetate and 20mL diethyl ether. The organic layer was washed 3 times with 10mL of water, then dried over sodium sulfate, and concentrated in vacuo. The residue was purified on silica gel (gradient elution with 0 to 80% ethyl acetate in cyclohexane) to give 215mg of 1- (methyl-d 3) -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole. MS (method B) m/z 280[ M+1] +; t=1.20 min.
Step 2: preparation of N- (1- (methyl-d 3) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide
284mg of ammonium chloride (5 eq) and 297mg of iron (5 eq) were added to a solution of 215mg of 1- (methyl-d 3) -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole in 8mL of ethanol and 1.2mL of water. The reaction mixture was heated at 80 ℃ with vigorous stirring for 10 minutes, and the mixture was filtered by washing with ethanol over celite and concentrated under reduced pressure. The crude material was diluted with 20mL ethyl acetate and washed with 20mL saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate and concentrated in vacuo.
A solution of the residue in 5mL of tetrahydrofuran was added dropwise to a solution of 503 μl of acetic anhydride (5 equivalents) in 722 μl of formic acid (18 equivalents) that had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The residue was purified on silica (eluting with 5% methanol in dichloromethane) to give 150mg of N- (1- (methyl-d 3) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide. MS (method B) m/z 201[ M+1] +; t=0.62 min.
Intermediate 27: n- (1- (2-cyanopropan-2-yl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide
Step 1: preparation of methyl 2- (3, 4-dinitro-1H-pyrazol-1-yl) -2-methylpropionate
1.6mL (1 eq.) of methyl 2-bromo-2-methylpropionate and 8.2g (2 eq.) of cesium carbonate are added to a solution of 2g (1 eq.) of 3, 4-dinitro-1H-pyrazole (commercially available) in 30mL of N, N-dimethylformamide. The mixture was heated at 80 ℃ for 4h, then allowed to cool to room temperature, and poured into 50mL of ethyl acetate and 100mL of diethyl ether. The organic layer was washed 3 times with 50mL of water, dried over sodium sulfate, and concentrated in vacuo. The residue is purified on silica gel (gradient elution with 0 to 40% ethyl acetate in cyclohexane) to give 1g of methyl 2- (3, 4-dinitro-1H-pyrazol-1-yl) -2-methylpropionate. MS (method E) m/z 257[ M+1] +; t=1.23 min.
Step 2: preparation of methyl 2-methyl-2- (4-nitro-3- (oxetan-3-yloxy) -1H-pyrazol-1-yl) propanoate
574mg (2 eq) of oxetan-3-ol and 3.1g (2.5 eq) of cesium carbonate are added to a solution of 1g (1 eq) of methyl 2- (3, 4-dinitro-1H-pyrazol-1-yl) -2-methylpropionate in 50mL of acetonitrile. The mixture was heated at 130 ℃ for 1 hour, then allowed to cool to room temperature, and poured into 30mL of ethyl acetate and 50mL of diethyl ether. The organic layer was washed twice with 20mL of water, dried over sodium sulfate, and concentrated in vacuo. The residue was purified on silica gel (gradient elution with 0 to 40% ethyl acetate in cyclohexane) to give 602mg of methyl 2-methyl-2- (4-nitro-3- (oxetan-3-yloxy) -1H-pyrazol-1-yl) propionate. MS (method E) m/z 286[ M+1] +; t=1.12 min.
Step 3: preparation of 2-methyl-2- (4-nitro-3- (oxetan-3-yloxy) -1H-pyrazol-1-yl) propanamide
2.34mL (4 eq.) of 12N aqueous sodium hydroxide was added to a solution of 2g (1 eq.) of methyl 2-methyl-2- (4-nitro-3- (oxetan-3-yloxy) -1H-pyrazol-1-yl) propanoate in 8mL of methanol. The mixture was heated at 40 ℃ for 1 hour, then allowed to cool to room temperature, and the pH was adjusted to about 1 with 2N aqueous HCl. The mixture was concentrated in vacuo. The residue was purified on silica gel (elution with a gradient of 0 to 10% methanol in dichloromethane) to give 1.8g of the corresponding acid. To the residue dissolved in 100mL of methylene chloride was added 1.3g (1.18 eq) of 1,1' -carbonyldiimidazole. The mixture was stirred at room temperature for 18 hours, then 2.9mL (5 eq) ammonium hydroxide (12N) was added. The mixture was stirred for an additional 15min and concentrated in vacuo. The residue was purified on silica gel (elution with a gradient of 0 to 10% methanol in dichloromethane) to give 1.5g 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.
Step 4: preparation of 2-methyl-2- (4-nitro-3- (oxetan-3-yloxy) -1H-pyrazol-1-yl) propionitrile
4.64mL (6 eq) of triethylamine are added to a solution of 1.5g (1 eq) 2-methyl-2- (4-nitro-3- (oxetan-3-yloxy) -1H-pyrazol-1-yl) propanamide in 15mL of tetrahydrofuran. The mixture was cooled at 0 ℃ and 3.14mL (4 eq.) of trifluoroacetic anhydride was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour, then poured into 50mL of diethyl ether and 20mL of water. The organic layer was dried over sodium sulfate and concentrated in vacuo to give 1g of 2-methyl-2- (4-nitro-3- (oxetan-3-yloxy) -1H-pyrazol-1-yl) propionitrile. MS (method E) m/z 253[ M+1] +; t=1.11 min.
Step 5: preparation of N- (1- (2-cyanopropan-2-yl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide
1.06g ammonium chloride (5 eq) and 1.11g iron (5 eq) were added to a solution of 1g 2-methyl-2- (4-nitro-3- (oxetan-3-yloxy) -1H-pyrazol-1-yl) propionitrile in 16mL ethanol and 4mL water. The reaction mixture was heated at 80 ℃ with vigorous stirring for 10 minutes, and the mixture was filtered by washing with ethanol over celite and concentrated under reduced pressure. The crude material was diluted with 20mL ethyl acetate and washed with 20mL saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate and concentrated in vacuo.
A solution of the residue in 10mL of tetrahydrofuran was added dropwise to a solution of 1.87mL of acetic anhydride (5 equivalents) in 2.69mL of formic acid (18 equivalents) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The residue was purified on silica (eluting with 5% methanol in dichloromethane) to give 750mg of N- (1- (2-cyanopropan-2-yl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide. MS (method E) m/z 251[ M+1] +; t=0.94 min.
Intermediate 28: (3-cyclopropoxy-1- (1, 1-difluoropropan-2-yl) -1H-pyrazol-4-yl) carboxamide
Step 1: preparation of 3-cyclopropoxy-1- (1, 1-difluoropropan-2-yl) -4-nitro-1H-pyrazole (racemic)
Starting with 300mg of 3-cyclopropoxy-4-nitro-1H-pyrazole, 200mg of racemic 3-cyclopropoxy-1- (1, 1-difluoropropan-2-yl) -4-nitro-1H-pyrazole were prepared according to the basic procedure described in step 2, intermediate 25. MS (method E) m/z 248[ M+1] +; t=1.27 min.
Step 2: preparation of N- (3-cyclopropoxy-1- (1, 1-difluoropropan-2-yl) -1H-pyrazol-4-yl) carboxamide (rac)
216mg of ammonium chloride (5 eq) and 226mg of iron (5 eq) are added to a solution of 200mg of racemic 3-cyclopropoxy-1- (1, 1-difluoropropan-2-yl) -4-nitro-1H-pyrazole in 8mL of ethanol and 1.2mL of water. The reaction mixture was heated at 80 ℃ with vigorous stirring for 10 minutes, and the mixture was filtered by washing with ethanol over celite and concentrated under reduced pressure. The crude material was diluted with 20mL ethyl acetate and washed with 20mL saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate and concentrated in vacuo.
A solution of the residue in 4mL of tetrahydrofuran was added dropwise to a solution of 382 μl of acetic anhydride (5 equivalents) in 549 μl of formic acid (18 equivalents) that had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The residue was purified on silica (eluting with 5% methanol in dichloromethane) to give 45mg of racemic N- (3-cyclopropoxy-1- (1, 1-difluoropropan-2-yl) -1H-pyrazol-4-yl) carboxamide. MS (method E) m/z 246[ M+1] +; t=1.01 min.
Intermediate 29: n- [3- (cyclopropyloxy) -1- (methyl-d 3) pyrazol-4-yl ] carboxamide
Step 1: preparation of trimethyl- [2- [ (4-nitropyrazol-1-yl) methoxy ] ethyl ] silane
10g (1 eq) of 4-nitro-1H-pyrazole (commercially available) were dissolved in 100mL of dry tetrahydrofuran under an argon atmosphere. The mixture was cooled to-5 ℃ and 4.24g (1.2 eq.) sodium hydride (60% in mineral oil) was added in portions. The mixture was stirred at room temperature for 10min, cooled to 0 ℃, and then 18mL (1.15 eq) of 2- (trimethylsilyl) ethoxymethyl chloride (SEM-Cl) were added dropwise. The mixture was stirred at room temperature for 1.5h and quenched by addition of 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 21.34g of trimethyl- [2- [ (4-nitropyrazol-1-yl) methoxy ] ethyl ] silane. MS (method E) m/z 242[ M-H ]; t=1.95 min.
Step 2: preparation of 2- [ (3-chloro-4-nitro-pyrazol-1-yl) methoxy ] ethyl-trimethyl-silane
53mL (1.2 eq) of 1N lithium bis (trimethylsilyl) amide in tetrahydrofuran was added dropwise to a solution of 10.8g (1 eq) of trimethyl- [2- [ (4-nitropyrazol-1-yl) methoxy ] ethyl ] silane in 80mL dry tetrahydrofuran at-78 ℃. The mixture was allowed to stir at-50 ℃ for 30 minutes, then cooled back to-78 ℃, and then a solution of 13.66g (1.3 eq.) of perchloroethane in 50mL of anhydrous tetrahydrofuran was added dropwise. After stirring at-70 ℃ 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 10g of 2- [ (3-chloro-4-nitro-pyrazol-1-yl) methoxy ] ethyl-trimethyl-silane. MS (method E), without ionization, t=1.60 min.
Step 3: preparation of 2- [ [3- (cyclopropyloxy) -4-nitro-pyrazol-1-yl ] methoxy ] ethyl-trimethyl-silane
A suspension of 576mg (2 equivalents) of sodium hydride (60% in mineral oil) in 20mL of anhydrous tetrahydrofuran was cooled to-10℃and 837mg (2 equivalents) of cyclopropyl alcohol was added. After stirring for 30 minutes, 2g (1 eq) of 2- [ (3-chloro-4-nitro-pyrazol-1-yl) methoxy ] ethyl-trimethyl-silane in 10mL of anhydrous tetrahydrofuran was added. The mixture was stirred at 5 ℃ 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 2.1g of 2- [ [3- (cyclopropyloxy) -4-nitro-pyrazol-1-yl ] methoxy ] ethyl-trimethyl-silane. The residue was used in the next step without further purification. MS (method H), without ionization, t=1.25 min.
Step 4: preparation of [3- (cyclopropyloxy) -4-nitro-pyrazol-1-yl ] methanol
100mL (4.8 eq) of 1N hydrochloric acid solution was added to a solution of 6.28g (1 eq) of 2- [ [3- (cyclopropyloxy) -4-nitro-pyrazol-1-yl ] methoxy ] ethyl-trimethyl-silane in 200mL of dry acetonitrile. After heating at 40 ℃ for 3 hours, the reaction was cooled to room temperature and the solvent was removed in vacuo. The aqueous layer was extracted four times with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica gel (gradient elution with 0 to 50% ethyl acetate in cyclohexane) to give 4.72g of [3- (cyclopropyloxy) -4-nitro-pyrazol-1-yl ] methanol. MS (method G) m/z 200[ M+1] +; t=1.49 min.
Step 5: preparation of 3- (cyclopropyloxy) -4-nitro-1H-pyrazole
2.86g (1 eq) 3- (cyclopropyloxy) -4-nitro-pyrazol-1-yl]Methanol in 20mL methanol and 100mL 7N NH in MeOH 3 The solution in (2) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give 2.5g of 3- (cyclopropyloxy) -4-nitro-1H-pyrazole. MS m/z 170[ M+1]]+；t＝0.88min。
Step 6: preparation of 3- (cyclopropyloxy) -4-nitro-1- (methyl-d 3) pyrazole
mu.L (1.5 eq) of methyl iodide-d 3 (commercially available) and 308mg (2 eq) of cesium carbonate are added to a solution of 80mg (1 eq) of 3- (cyclopropyloxy) -4-nitro-1H-pyrazole in 10mL of dry acetonitrile. The mixture was heated at 80℃for 1 hour. After cooling to room temperature, the mixture was filtered by washing with acetonitrile and the solvent was concentrated. The residue was purified on silica gel (gradient elution with 0 to 40% ethyl acetate in cyclohexane) to give 75mg of 3- (cyclopropyloxy) -4-nitro-1- (methyl-d 3) pyrazole. MS (method E) m/z 187[ M+1] +; t=0.94 min.
Step 7: preparation of N- [3- (cyclopropyloxy) -1- (methyl-d 3) pyrazol-4-yl ] carboxamide
112.5mg (5.0 eq) of iron powder and 108.0mg (5.0 eq) of ammonium chloride are added to a solution of 75mg (1 eq) of 3- (cyclopropyloxy) -4-nitro-1- (methyl-d 3) pyrazole in a mixture of 8mL of ethanol and 2mL of water. The mixture was heated at 80 ℃ for 30 minutes and then allowed to cool to room temperature. The reaction mixture was filtered by washing with ethanol over celite, and the filtrate was concentrated under reduced pressure. The residue was taken up in 10mL of dry tetrahydrofuran and added dropwise to a solution of 190 μl (5 eq.) of acetic anhydride in 273 μl (18 eq.) of formic acid, which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The residue was purified on silica gel (elution with a gradient of 0 to 10% methanol in dichloromethane) to give 25mg of N- [3- (cyclopropyloxy) -1- (methyl-d 3) pyrazol-4-yl ] carboxamide. MS (method E) m/z 214[ M+1] +; t=1.37 min.
Intermediate 30: n- [1- (1-cyano-1-methyl-ethyl) -3- (cyclopropyloxy) pyrazol-4-yl ] carboxamide
Step 1: preparation of methyl 2- [3- (cyclopropyloxy) -4-nitro-pyrazol-1-yl ] -2-methyl-propionate
2.6g (2.5 eq) potassium carbonate was added to a solution of 1.5g (1 eq) [3- (cyclopropyloxy) -4-nitro-pyrazol-1-yl ] methanol (intermediate 29, step 4) in 45mL dry N, N-dimethylformamide. The reaction mixture was heated at 70℃for 2 hours, then 1.3mL (1.3 eq.) of methyl 2-bromo-2-methylpropionate was added. The resulting mixture was stirred at 70 ℃ for an additional 3 hours, then water was added to quench the reaction. The aqueous layer was extracted with ethyl acetate/diethyl ether. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel (gradient elution with 0 to 10% ethyl acetate in cyclohexane) to give 1.78g of methyl 2- [3- (cyclopropyloxy) -4-nitro-pyrazol-1-yl ] -2-methyl-propionate as a colorless oil. MS (method E) m/z 270[ M+1] +; t=1.63 min.
Step 2: preparation of 2- [3- (cyclopropyloxy) -4-nitro-pyrazol-1-yl ] -2-methyl-propionitrile
1.78g (1 eq) 2- [3- (cyclopropyloxy) -4-nitro-pyrazol-1-yl]7N NH of methyl-2-methyl-propionate in 60mL MeOH 3 The solution was stirred at room temperature for 2 days, and then the reaction mixture was concentrated in vacuo. The residue was taken up in 30mL of dry tetrahydrofuran and 1mL (1.1 eq.) of trifluoroacetic anhydride and 2mL (2 2 equivalents) triethylamine. The reaction mixture was stirred for 1 hour, followed by addition of water and diethyl ether to quench the reaction. The aqueous layer was separated and extracted with diethyl ether. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 1.35g of 2- [3- (cyclopropyloxy) -4-nitro-pyrazol-1-yl]-2-methyl-propionitrile. The residue was used without further purification. MS (method E) m/z 237[ M+1]]+；t＝1.25min。
Step 3: preparation of N- [1- (1-cyano-1-methyl-ethyl) -3- (cyclopropyloxy) pyrazol-4-yl ] carboxamide
58.0mg (5.0 eq) of iron powder and 59.0mg (5.0 eq) of ammonium chloride are added to a solution of 50mg (1 eq) of 2- [3- (cyclopropyloxy) -4-nitro-pyrazol-1-yl ] -2-methyl-propionitrile in 4mL of ethanol and 2mL of water. The mixture was heated at 80 ℃ for 30 minutes and then allowed to cool to room temperature. The reaction mixture was filtered by washing with ethanol over celite, and the filtrate was concentrated under reduced pressure. The residue was taken up in 10mL 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 premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The residue was purified on silica gel (elution with a gradient of 0 to 10% methanol in dichloromethane) to give 46mg of N- [1- (1-cyano-1-methyl-ethyl) -3- (cyclopropyloxy) pyrazol-4-yl ] carboxamide. MS m/z 235[ M+1] +; t=1.03 min.
Intermediate 31: n- [1- (1-cyano-1-methyl-ethyl) -3-isopropoxy-pyrazol-4-yl ] carboxamide
Step 1: preparation of methyl 2- (3-isopropoxy-4-nitro-pyrazol-1-yl) -2-methyl-propionate
(1 eq.) of 3-isopropoxy-4-nitro-1H-pyrazole (commercially available) was dissolved in 70mL of dry N, N-dimethylformamide under an argon atmosphere. The mixture was cooled to-5 ℃ and 941mg (1.35 eq.) sodium hydride (60% in mineral oil) was added in portions. The reaction mixture was stirred at 0 ℃ for 30 minutes, and then 3.04mL (1.35 eq.) of methyl 2-bromo-2-methylpropionate was added. The resulting mixture was stirred for 2 days, and then water was added to quench the reaction. 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 (gradient elution with 0 to 60% ethyl acetate in cyclohexane) to give 3.3g of methyl 2- (3-isopropoxy-4-nitro-pyrazol-1-yl) -2-methyl-propionate. MS (method E) m/z 272[ M+1] +; t=1.76 min.
Step 2: preparation of 2- (3-isopropoxy-4-nitro-pyrazol-1-yl) -2-methyl-propionitrile
3g (1 eq) methyl 2- (3-isopropoxy-4-nitro-pyrazol-1-yl) -2-methyl-propionate were reacted in 100mL of 7N NH in MeOH 3 The solution in (2) was heated at 100 ℃ for 18 hours, then the reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was taken up in 50mL of anhydrous tetrahydrofuran, cooled to 0 ℃ and 2.06mL (1.2 eq) of trifluoroacetic anhydride and 4.24mL (2.5 eq) of triethylamine were added. The reaction mixture was stirred at room temperature for 1 hour, and then water and diethyl ether were added to quench the reaction. 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% to 15% ethyl acetate in cyclohexane) to give 2.6g of 2- (3-isopropoxy-4-nitro-pyrazol-1-yl) -2-methyl-propionitrile after concentration in vacuo.
MS (method F): m/z 239[ M+1] +; t=1.67 min.
Step 3: preparation of N- [1- (1-cyano-1-methyl-ethyl) -3-isopropoxy-pyrazol-4-yl ] carboxamide
3.05g of iron (5 eq.) are added to a solution of 2.6g of 2- (3-isopropoxy-4-nitro-pyrazol-1-yl) -2-methyl-propionitrile in 90mL of ethanol, 10mL of water and 5mL of acetic acid at 80 ℃. The reaction mixture was stirred vigorously at 80 ℃ for 20 minutes, and the mixture was cooled and filtered washing with ethanol over celite and concentrated under reduced pressure. The crude material was diluted with 100mL ethyl acetate and washed with 50mL saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate and concentrated in vacuo.
A solution of the residue in 15mL of tetrahydrofuran was added dropwise to a solution of 4.12mL of acetic anhydride (4 equivalents) in 3.35mL of formic acid (8 equivalents) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then quenched with 100mL of ethyl acetate and 100mL of 10% aqueous sodium carbonate under vigorous stirring for 30 min. The organic layer was separated and washed twice with 50ml 10% aqueous sodium carbonate, then concentrated in vacuo. The residue was taken up in 100mL toluene and concentrated in vacuo. The residue was triturated in 100ml 70/30 pentane/ether mixture and the solid filtered to give 2.06g N- [1- (1-cyano-1-methyl-ethyl) -3-isopropoxy-pyrazol-4-yl ] carboxamide. MS (method F): m/z 237[ M+1] +; t=1.37 min.
Intermediate 32: n- (3- ((1-acetyl-2, 2-dimethyl azetidin-3-yl) oxy) -1-methyl-1H-pyrazol-4-yl) carboxamide (rac)
Step 1:2, 2-dimethyl-3- ((1-methyl-4-nitro-1H-pyrazol-3-yl) oxy) azetidine-1-carboxylic acid tert-butyl ester(racemization)Is prepared from
482mg (1.3 eq) of racemic 3-hydroxy-2, 2-dimethyl-azetidine-1-carboxylic acid tert-butyl ester and 1.5g (2 eq) of cesium carbonate are added to a solution of 400mg (1 eq) of 1-methyl-3, 4-dinitro-1H-pyrazole (commercially available) in 8mL of acetonitrile. The mixture was heated at 80 ℃ 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 20mL of saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified on silica gel (elution with a gradient of 0 to 20% ethyl acetate in dichloromethane) to give 460mg of racemic 2, 2-dimethyl-3- ((1-methyl-4-nitro-1H-pyrazol-3-yl) oxy) azetidine-1-carboxylic acid tert-butyl ester.
MS (method B) m/z 237[ M+1] +; t=1.69 min.
Step 2: preparation of 3- ((2, 2-dimethyl azetidin-3-yl) oxy) -1-methyl-4-nitro-1H-pyrazole (racemic)
5.5mL (19 eq) of trifluoroacetic acid are added to a solution of 1.2g (1 eq) of racemic 2, 2-dimethyl-3- ((1-methyl-4-nitro-1H-pyrazol-3-yl) oxy) azetidine-1-carboxylic acid tert-butyl ester in 30mL of dichloromethane. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, then dissolved in 10mL of methanol, and treated with 30mL of 7M methanolic ammonia solution for 1 hour, and concentrated in vacuo. The residue was purified on silica gel (eluted with a gradient of 0 to 5%7m methanolic ammonia in dichloromethane) to give 460mg 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.
Step 3: preparation of 1- (2, 2-dimethyl-3- ((1-methyl-4-nitro-1H-pyrazol-3-yl) oxy) azetidin-1-yl) ethanol-1-one (rac)
1.14mL (4 eq) of triethylamine was added to a solution of 460mg (1 eq) of racemic 3- ((2, 2-dimethylazetidin-3-yl) oxy) -1-methyl-4-nitro-1H-pyrazole in 23mL of tetrahydrofuran. The mixture was cooled to 0 ℃ to 5 ℃ and 292 μl (2 eq) of acetyl chloride was added. The mixture was stirred at 0 ℃ 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 20mL of saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified on silica gel (elution with a gradient of 0 to 5% methanol in dichloromethane) to give 360mg of racemic 1- (2, 2-dimethyl-3- ((1-methyl-4-nitro-1H-pyrazol-3-yl) oxy) azetidin-1-yl) ethanol-1-one. MS (method B) m/z 269[ M+1] +; t=1.13 min.
Step 4: preparation of 1- (3- ((4-amino-1-methyl-1H-pyrazol-3-yl) oxy) -2, 2-dimethyl azetidin-1-yl) ethanol-1-one (rac)
In a microwave vial, a solution of 310mg (1 eq) of racemic 1- (2, 2-dimethyl-3- ((1-methyl-4-nitro-1H-pyrazol-3-yl) oxy) azetidin-1-yl) ethanol-1-one in 12mL methanol was treated with 515mg ammonium formate (7 eq) and 86mg palladium on carbon (10%). The reaction mixture was heated at 70℃for 10 minutes. The mixture was filtered by washing with methanol over celite and concentrated under reduced pressure. The residue was taken up in dichloromethane, filtered and the filtrate concentrated under reduced pressure to give 260mg of racemic 1- (3- ((4-amino-1-methyl-1H-pyrazol-3-yl) oxy) -2, 2-dimethyl azetidin-1-yl) ethanol-1-one. MS (method A) m/z 239[ M+1] +; retention time: dead volume
Step 5: preparation of N- (3- ((1-acetyl-2, 2-dimethyl azetidin-3-yl) oxy) -1-methyl-1H-pyrazol-4-yl) carboxamide (rac)
A solution of 264mg (1 eq) of racemic 1- (3- ((4-amino-1-methyl-1H-pyrazol-3-yl) oxy) -2, 2-dimethylazetidin-1-yl) ethanol-1-one in 2.6mL of tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 416. Mu.L of acetic anhydride (3 eq) in 374. Mu.L of formic acid (6 eq) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at 5 ℃ for 30 minutes and then concentrated in vacuo. The residue was taken up in toluene and concentrated in vacuo. The residue was purified on silica gel (elution with a gradient of 0 to 5% methanol in dichloromethane) to give 250mg of racemic N- (3- ((1-acetyl-2, 2-dimethyl azetidin-3-yl) oxy) -1-methyl-1H-pyrazol-4-yl) carboxamide. MS (method B) m/z 267[ M+1] +; t=0.92 min.
Intermediate 33: -methyl 2- (4-carboxamide-3- (oxetan-3-yloxy) -1H-pyrazol-1-yl) propanoate (rac)
Step 1: preparation of methyl (rac) 2- (4-nitro-3- (oxetan-3-yloxy) -1H-pyrazol-1-yl) propionate
923 μl (1 eq) of racemic methyl-2-bromopropionate was added to a solution of 1500mg (1 eq) of 4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole (intermediate 13, step 3) and 5280mg (2 eq) of cesium carbonate in 45mL of acetonitrile. The mixture was heated at 80 ℃ for 2.5 hours and then allowed to cool to room temperature. The mixture was poured into ethyl acetate and water. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were washed with 20mL of saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified on silica gel (gradient elution with 10% to 50% ethyl acetate in heptane) to give 594mg of rac-2- (4-nitro-3- (oxetan-3-yloxy) -1H-pyrazol-1-yl) propionic acid methyl ester. MS method B: m/z 272[ M+1] +; t=1.19 min.
Step 2: preparation of methyl (rac) 2- (4-amino-3- (oxetan-3-yloxy) -1H-pyrazol-1-yl) propionate
335mg of iron (3 eq) and 321mg of ammonium chloride (3 eq) were added to a solution of 542mg (1 eq) of racemic methyl 2- (4-nitro-3- (oxetan-3-yloxy) -1H-pyrazol-1-yl) propionate in 20mL of ethanol, 5mL of water. The reaction mixture was stirred vigorously at 90 ℃ for 2.5 hours, and the mixture was cooled to room temperature, filtered over celite washing with ethanol, and concentrated under reduced pressure. The crude material was diluted with 100mL ethyl acetate and washed with 50mL saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give 454mg of rac-2- (4-amino-3- (oxetan-3-yloxy) -1H-pyrazol-1-yl) propionic acid methyl ester, which was used in the next step without further purification.
Step 3: preparation of methyl (rac) 2- (4-carboxamide-3- (oxetan-3-yloxy) -1H-pyrazol-1-yl) propanoate
A solution of 454mg (1 eq) of racemic methyl 2- (4-amino-3- (oxetan-3-yloxy) -1H-pyrazol-1-yl) propanoate in 14mL of tetrahydrofuran was added dropwise to a solution of 0.71mL of acetic anhydride (4 eq) in 0.57mL of formic acid (8 eq) premixed for 55 minutes at room temperature at 5 ℃. The reaction mixture was stirred at 5 ℃ for 5 minutes, at room temperature for 1.5 hours, and then concentrated in vacuo. The residue was purified on silica gel (gradient elution with 10% to 30% acetone in dichloromethane) to give 366mg of rac-2- (4-carboxamido-3- (oxetan-3-yloxy) -1H-pyrazol-1-yl) propionic acid methyl ester. MS method a: m/z 270[ M+1] +; t=1.26 min.
Intermediate 34:3- (cyclopropyloxy) -4-carboxamido-benzoic acid methyl ester
Step 1: preparation of 3- (cyclopropyloxy) -4-nitro-benzoic acid methyl ester
A solution of 0.843mL (2 eq.) of cyclopropyl alcohol in 35mL of anhydrous tetrahydrofuran was stirred to 0deg.C under argon. 7.83mL (1.2 eq.) of [ bis (trimethylsilyl) amino ] lithium (1M in THF) was added dropwise. The resulting mixture was stirred at 0 ℃ for 30 minutes, and then 1.3g (1 eq) of methyl 3-fluoro-4-nitro-benzoate in 40mL of anhydrous tetrahydrofuran was added dropwise. The mixture was stirred at room temperature for 4 hours, cooled to 0 ℃, and quenched with 50mL of saturated ammonium chloride solution and extracted with ethyl acetate (50 mL,3 times). 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 380mg of methyl 3- (cyclopropyloxy) -4-nitro-benzoate. MS (method H): m/z 238[ M+1] +; t=1.53 min.
Step 2: preparation of methyl 4-amino-3- (cyclopropyloxy) benzoate
186mg (3 eq) ammonium chloride and 194mg (3 eq) iron were added to a stirred solution of 275mg (1 eq) methyl 3- (cyclopropyloxy) -4-nitro-benzoate in 7mL ethanol and 2mL water. The reaction mixture was heated at 90℃for 1 hour. The mixture was filtered by washing with ethanol over celite 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 (eluted with a gradient of 2% to 5% methanol in dichloromethane) to give 280mg of 4-amino-3- (cyclopropyloxy) benzoate. MS (method H) m/z 208[ M+1] +; t=1.69 min.
Step 3: preparation of 3- (cyclopropyloxy) -4-carboxamido-benzoic acid methyl ester
A solution of 280mg (1 eq) methyl 4-amino-3- (cyclopropyloxy) benzoate in 4mL tetrahydrofuran was added dropwise to a solution of 0.510mL acetic anhydride (4 eq) in 0.414mL formic acid (8 eq) that had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 2 hours 30 minutes, and then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate and then with water. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 250mg of methyl 3- (cyclopropyloxy) -4-carboxamido-benzoate. MS (method A) m/z 236[ M+1] +; t=1.99 min.
Intermediate 35: 4-carboxamide-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
1.4g (1.9 eq, 60% on oil dispersion) of sodium are added in portions to a solution of 2.23g (2 eq) oxetan-3-ol in 50mL of anhydrous tetrahydrofuran, cooled to 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 hour, and then a solution of 3g (1 eq) of methyl 3-fluoro-4-nitro-benzoate in 15mL of anhydrous tetrahydrofuran was added. The mixture was warmed to room temperature and stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted three times with 50mL 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 (gradient elution with 20% to 50% ethyl acetate in heptane) to give 900mg 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 50mL ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel (gradient elution with 5% to 10% methanol in dichloromethane) to give 1.5g of 4-nitro-3- (oxetan-3-yloxy) benzoic acid. MS (method A) m/z 240[ M+1] +; t=1.69 min.
Step 2: preparation of methyl 4-amino-3- (oxetan-3-yloxy) benzoate
In a microwave vial, a solution of 500mg (1 eq.) of methyl 4-nitro-3- (oxetan-3-yloxy) benzoate in 10mL of methanol was treated with 355mg ammonium formate (2.8 eq.) and 210mg (0.1 eq.) palladium on carbon (10%). The reaction mixture was heated at 85 ℃ for 15 minutes. The mixture was filtered by washing with methanol over celite and concentrated under reduced pressure to give 440mg of methyl 4-amino-3- (oxetan-3-yloxy) benzoate. MS (method A) m/z 254[ M+1] +; t=1.55 min.
Step 3: preparation of methyl 4-carboxamide-3- (oxetan-3-yloxy) benzoate
A solution of 440mg (1 eq) of methyl 4-amino-3- (oxetan-3-yloxy) benzoate in 4mL of tetrahydrofuran was added dropwise to a solution of 0.75mL of acetic anhydride (4 eq) in 0.68mL of formic acid (8 eq) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 30min and then concentrated in vacuo to give 435mg of methyl 4-carboxamido-3- (oxetan-3-yloxy) benzoate. MS (method A) m/z 252[ M+1] +; t=1.59 min.
Intermediate 36: (N- (3- ((2-oxaspiro [3.3] heptan-5-yl) oxy) -1-methyl-1H-pyrazol-4-yl) carboxamide
Step 1: preparation of 3- ((2-oxaspiro [3.3] heptan-5-yl) oxy) -1-methyl-4-nitro-1H-pyrazole
430mg (1.3 eq) of 2-oxaspiro [3.3] heptane-5-ol (commercially available) and 1.9g (2 eq) of cesium carbonate are added to a solution of 500mg (1 eq) of 1-methyl-3, 4-dinitro-1H-pyrazole (commercially available) in 25mL of acetonitrile. The mixture was heated at 70 ℃ overnight and 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 595mg 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.
Step 2: preparation of N- (3- ((2-oxaspiro [3.3] heptan-5-yl) oxy) -1-methyl-1H-pyrazol-4-yl) carboxamide
In a microwave vial, a solution of 600mg (1 eq) of 3- ((2-oxaspiro [3.3] heptan-5-yl) oxy) -1-methyl-4-nitro-1H-pyrazole in 16mL of methanol was treated with 448mg ammonium formate (2.8 eq) and 267mg (0.1 eq) palladium on carbon (10%). The reaction mixture was heated at 70℃for 10 minutes. The mixture was filtered by washing with methanol over celite and concentrated under reduced pressure. The residue was dissolved in 2mL of tetrahydrofuran, and the solution was added dropwise to a cooled (0 ℃) solution of 946 μl acetic anhydride (4 eq.) in 1.73mL of formic acid (18 eq.) that had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at 5 ℃ for 5 minutes, at room temperature for 1 hour, and then concentrated in vacuo. The residue was taken up in 50mL of toluene and concentrated in vacuo to give 395mg of N- (3- ((2-oxaspiro [3.3] heptan-5-yl) oxy) -1-methyl-1H-pyrazol-4-yl) carboxamide. MS (method A) m/z 238[ M+1] +; t=1.39 min.
Intermediate 37: n- (1- (methoxymethyl) -3- (((2R, 3S) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide and N- (1- (methoxymethyl) -3- (((2S, 3R) -2-methyloxetan)Alk-3-yloxy) -1H-pyrazol-4-yl-carboxamide (racemic trans))
Step 1: preparation of 1- (methoxymethyl) -3, 4-dinitro-1H-pyrazole
357mg (1.4 eq) of chloro (methoxy) methane and 883mg (2 eq) of potassium carbonate were added to a solution of 0.5g (1 eq) of 3, 4-dinitro-1H-pyrazole (commercially available) in 15mL of acetonitrile. The mixture was stirred at room temperature for 2 hours, then poured into ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue is purified on silica gel (eluting with 20% to 50% ethyl acetate in heptane) to give 480 mg of 1- (methoxymethyl) -3, 4-dinitro-1H-pyrazole. 1 H NMR (400 MHz, DMSO-d 6) delta, in ppm: 3.35 (s, 3H); 5.5 (s, 2H); 9.32 (s, 1H).
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)
714mg (1.25 eq) of 2-methyloxetan-3-ol and 4.23g (2 eq) of cesium carbonate are added to a solution of 1310mg (1 eq) of 1- (methoxymethyl) -3, 4-dinitro-1H-pyrazole in 17mL of acetonitrile. The mixture was heated at 80 ℃ 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 (eluted with 10% to 50% ethyl acetate in heptane) to give 501mg 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 by NMR as racemic trans (MS (method A) M/z244[ M+1] +; t=1.17 min) 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 and 940mg as racemic cis (MS (method A) M/z244[ M+1] +; t=1.17 min).
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)
In a microwave vial, a solution of 501mg (1 eq) of a racemic mixture of 1- (methoxymethyl) -3- (((2 r,3 s) -2-methyloxetan-3-yl) oxy) -4-nitro-1H-pyrazole and 1- (methoxymethyl) -3- (((2 s,3 r) -2-methyloxetan-3-yl) oxy) -4-nitro-1H-pyrazole in 15mL of methanol was treated with 371mg of ammonium formate (2.8 eq) and 220mg (0.05 eq) of palladium on carbon (10%). The reaction mixture was heated at 70℃for 15 minutes. The mixture was filtered by washing with methanol over celite and concentrated under reduced pressure. The crude material was taken to the next step without further purification.
Step 4: preparation of N- (1- (methoxymethyl) -3- (((2R, 3S) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide and N- (1- (methoxymethyl) -3- (((2S, 3R) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (racemic trans)
439mg (1 eq) 1- (methoxymethyl) -3- (((2R, 3S) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-amine was reacted with 1- (methoxymethyl) -3- (((2S, 3R) A solution of the racemic mixture of 2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-amine in 2mL of tetrahydrofuran was added dropwise to a solution of 779 μl of acetic anhydride (4 equivalents) in 1.76mL of formic acid (18 equivalents) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at 0 ℃ for 1 hour. The residue was concentrated in vacuo and taken up on silica gel (7N NH in MeOH with heptane/AcOEt/ 3 (50/45/5) elution) to give 387mg of a mixture of N- (1- (methoxymethyl) -3- (((2 r,3 s) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide and N- (1- (methoxymethyl) -3- (((2 s,3 r) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (racemic trans). MS (method B) m/z 242[ M+1]]++, of the material; t=0.85 min (racemic trans).
Intermediate 38: n- (3-isopropoxy-1-methyl-1H-pyrazol-4-yl) carboxamide
Step 1: preparation of 3-isopropoxy-1-methyl-4-nitro-1H-pyrazole
438 μl (1.2 eq) of methyl iodide and 1.61g (2 eq) of potassium carbonate were added to a solution of 1g (1 eq) of 3-isopropoxy-4-nitro-1H-pyrazole (commercially available) in 30mL of N-methylpyrrolidone. The mixture was heated at 70 ℃ for 1 hour and poured into a mixture of 100mL ethyl acetate and 100mL diethyl ether. The organic layer was washed 3 times with 100mL of water and then dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica gel (eluting with a 85/15 cyclohexane/ethyl acetate mixture) to give 1g 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.
Step 2: preparation of 3-isopropoxy-1-methyl-1H-pyrazol-4-amine
1.51g of iron (5 equivalents) are added to a solution of 1g of 3-isopropoxy-1-methyl-4-nitro-1H-pyrazole in 50mL of ethanol, 1mL of water and 10mL of acetic acid at 80 ℃. The reaction mixture was stirred vigorously at 80 ℃ for 20 minutes, and the mixture was cooled to room temperature, filtered over celite, washed with ethanol, and concentrated under reduced pressure. The crude material was diluted with 100mL ethyl acetate and washed with 50mL saturated aqueous sodium carbonate solution. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica gel (eluting with 5% methanol in dichloromethane) to give 650mg of 3-isopropoxy-1-methyl-1H-pyrazol-4-amine. MS (method E); m/z 156[ M+1] +; t=0.78 min.
Step 3: preparation of N- (3-isopropoxy-1-methyl-1H-pyrazol-4-yl) carboxamide
A solution of 3g 3-isopropoxy-1-methyl-1H-pyrazol-4-amine in 10mL tetrahydrofuran was added dropwise to a solution of 5.91mL acetic anhydride (4 equivalents) in 4.8mL formic acid (8 equivalents) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then quenched with 100mL of ethyl acetate and 100mL of 10% aqueous sodium carbonate under vigorous stirring for 30 min. The organic layer was separated and washed twice with 50ml 10% aqueous sodium carbonate, then concentrated in vacuo. The residue was purified on silica gel (eluting with a 70/30 cyclohexane/ethyl acetate mixture) to give 2.18g N- (3-isopropoxy-1-methyl-1H-pyrazol-4-yl) carboxamide. MS (method E); m/z 184[ M+1] +; t=0.80 min.
Intermediate 39: (R) -N- (1- (1-cyanoethyl) -3-isopropoxy-1H-pyrazol-4-yl) carboxamide and (S) -N- (1- (1-cyanoethyl) -3-isopropoxy-1H-pyrazol-4-yl) carboxamide
Step 1: preparation of (R) -2- (3-isopropoxy-4-nitro-1H-pyrazol-1-yl) propionitrile and (S) -2- (3-isopropoxy-4-nitro-1H-pyrazol-1-yl) propionitrile
1.21mL (1.2 eq) of 2-bromopropionitrile and 3.23g (2 eq) of potassium carbonate were added to a solution of 2g (1 eq) of 3-isopropoxy-4-nitro-1H-pyrazole (commercially available) in 20mL of 1-methyl-2-pyrrolidone (NMP). The mixture was stirred at room temperature for 1 hour, 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 2.2g of a racemic mixture of (R) -2- (3-isopropoxy-4-nitro-1H-pyrazol-1-yl) propionitrile and (S) -2- (3-isopropoxy-4-nitro-1H-pyrazol-1-yl) propionitrile. MS (method B) m/z 225[ M+1] +; t=1.34 min.
Step 2: preparation of (R) -2- (4-amino-3-isopropoxy-1H-pyrazol-1-yl) propionitrile and (S) -2- (4-amino-3-isopropoxy-1H-pyrazol-1-yl) propionitrile
680mg of ammonium chloride (3 equivalents) and 710mg of iron (3 equivalents) were added to a solution of 950mg (1 equivalent) (R) -2- (3-isopropoxy-4-nitro-1H-pyrazol-1-yl) propionitrile in a racemic mixture of (S) -2- (3-isopropoxy-4-nitro-1H-pyrazol-1-yl) propionitrile in 25mL of ethanol and 7mL of water. The reaction mixture was heated at 90 ℃ for 7 hours and then allowed to cool to room temperature. The mixture was filtered by washing with ethanol over celite 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 850mg of a racemic mixture of (R) -2- (4-amino-3-isopropoxy-1H-pyrazol-1-yl) propionitrile and (S) -2- (4-amino-3-isopropoxy-1H-pyrazol-1-yl) propionitrile. MS (method B) m/z 195[ M+1] +; t=0.59 min.
Step 3: preparation of (R) -N- (1- (1-cyanoethyl) -3-isopropoxy-1H-pyrazol-4-yl) carboxamide and (S) -N- (1- (1-cyanoethyl) -3-isopropoxy-1H-pyrazol-4-yl) carboxamide
A solution of 1.4g (1 eq) (R) -2- (4-amino-3-isopropoxy-1H-pyrazol-1-yl) propionitrile in 15mL tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 2.72mL acetic anhydride (4 eq) in 2.21mL formic acid (8 eq) which had been premixed for 30 minutes at room temperature. 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 and 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 1.1g of a racemic mixture of (R) -N- (1- (1-cyanoethyl) -3-isopropoxy-1H-pyrazol-4-yl) carboxamide and (S) -N- (1- (1-cyanoethyl) -3-isopropoxy-1H-pyrazol-4-yl) carboxamide. MS (method B) m/z 223[ M+1] +; t=2.27 min.
Chiral separation of 1.1g of the racemic mixture gave 488mg of the first eluting isomer and 503mg of the second eluting isomer (conditions: column Chiralpak AY,20 μm,230X 100mm; liquid phase: heptane 90/ethanol 10; flow rate 400 mL/min).
Peak 1 (isomer 1): MS (method B) m/z 223[ M+1] +; t=2.27 min.
Peak 2 (isomer 2): MS (method B) m/z 223[ M+1] +; t=2.27 min.
Intermediate 40: n- (1- (1-cyanoethyl) -3-cyclopropoxy-1H-pyrazol-4-yl) carboxamide
Step 1: preparation of (R) -2- (3-cyclopropoxy-4-nitro-1H-pyrazol-1-yl) propionitrile and (S) -2- (3-cyclopropoxy-4-nitro-1H-pyrazol-1-yl) propionitrile
491. Mu.L (1.2 eq.) of 2-bromopropionitrile and 1.31g (2 eq.) of potassium carbonate were added to a solution of 0.8g (1 eq.) of 3-cyclopropoxy-4-nitro-1H-pyrazole (intermediate 29, step 5) in 8mL of N, N-Dimethylformamide (DMF). The mixture was stirred at room temperature for 3.5 hours, then poured into ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified on silica gel (eluting with 50% ethyl acetate in heptane) to give 755mg of a racemic mixture of (R) -2- (3-cyclopropoxy-4-nitro-1H-pyrazol-1-yl) propionitrile and (S) -2- (3-cyclopropoxy-4-nitro-1H-pyrazol-1-yl) propionitrile. MS (method A) m/z 223[ M+1] +; t=1.96 min.
Step 2: preparation of (R) -2- (4-amino-3-cyclopropyloxy-1H-pyrazol-1-yl) propionitrile and (S) -2- (4-amino-3-cyclopropyloxy-1H-pyrazol-1-yl) propionitrile
545mg of ammonium chloride (3 equivalents) and 570mg of iron (3 equivalents) were added to a solution of 755mg (1 equivalent) (R) -2- (3-cyclopropoxy-4-nitro-1H-pyrazol-1-yl) propionitrile in a racemic mixture of (S) -2- (3-cyclopropoxy-4-nitro-1H-pyrazol-1-yl) propionitrile in 20mL of ethanol and 5mL of water. The reaction mixture was heated at 90 ℃ for 1.5 hours and then allowed to cool to room temperature. The mixture was filtered by washing with ethanol over celite and concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The crude material was taken to the next step without further purification.
Step 3: preparation of (R) -N- (1- (1-cyanoethyl) -3-cyclopropoxy-1H-pyrazol-4-yl) carboxamide and (S) -N- (1- (1-cyanoethyl) -3-cyclopropoxy-1H-pyrazol-4-yl) carboxamide
A solution of 0.65g (1 eq) (R) -2- (4-amino-3-cyclopropoxy-1H-pyrazol-1-yl) propionitrile and (S) -2- (4-amino-3-cyclopropoxy-1H-pyrazol-1-yl) propionitrile in 7mL tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 1.28mL acetic anhydride (4 eq) in 2.33mL formic acid (18 eq) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, and then concentrated under reduced pressure to give 620mg of (R) -N- (1- (1-cyanoethyl) -3-cyclopropoxy-1H-pyrazol-4-yl) carboxamide as a racemic mixture with (S) -N- (1- (1-cyanoethyl) -3-cyclopropoxy-1H-pyrazol-4-yl) carboxamide. MS (method A) m/z 221[ M+1] +; t=1.42 min.
Intermediate 41: n- (3-cyclopropoxy-1-isopropyl-1H-pyrazol-4-yl) carboxamide
Step 1: preparation of 3-cyclopropoxy-1-isopropyl-4-nitro-1H-pyrazole
603mg (1.2 eq) of 2-iodopropane and 817mg (2 eq) of potassium carbonate are added to a solution of 0.5g (1 eq) of 3-cyclopropoxy-4-nitro-1H-pyrazole (intermediate 29, step 5) in 15mL of N, N-Dimethylformamide (DMF). The mixture was heated at 80 ℃ for 1 hour and poured into a mixture of 100mL ethyl acetate and 100mL diethyl ether. The organic layer was washed 3 times with 100mL of water, dried over sodium sulfate, and concentrated in vacuo. The residue was purified on silica gel (eluting with 80/20 heptane/ethyl acetate mixture) to give 279 mg of 3-cyclopropoxy-1-isopropyl-4-nitro-1H-pyrazole. MS (method A) m/z 212[ M+1] +; t=2.17 min.
Step 2: preparation of 3-cyclopropoxy-1-isopropyl-1H-pyrazol-4-amine
In a microwave vial, a solution of 273mg (1 eq.) of 3-cyclopropoxy-1-isopropyl-4-nitro-1H-pyrazole in 8mL of methanol was treated with 236mg ammonium formate (2.8 eq.) and 138mg (0.1 eq.) of palladium on carbon (10%). The reaction mixture was heated at 70℃for 10 minutes. The mixture was filtered by washing with methanol over celite and concentrated under reduced pressure. The crude material was taken to the next step without further purification.
Step 3: preparation of N- (3-cyclopropyloxy-1-isopropyl-1H-pyrazol-4-yl) carboxamide
A solution of 234mg of 3-cyclopropoxy-1-isopropyl-1H-pyrazol-4-amine in 2mL of tetrahydrofuran was added dropwise to a solution of 488. Mu.L of acetic anhydride (4 equivalents) in 892. Mu.L of formic acid (18 equivalents) which had been premixed for 30 minutes at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 hour, then concentrated in vacuo. The residue was purified on silica gel (eluting with a 50/50 heptane/ethyl acetate mixture) to give 155mg of N- (3-cyclopropoxy-1-isopropyl-1H-pyrazol-4-yl) carboxamide. MS (method a); m/z 210[ M+1] +; t=1.55 min.
Intermediate 42: n- (3, 3-difluorocyclobutoxy) -1-methyl-1H-pyrazol-4-yl) carboxamide
Step 1: preparation of 5- (3, 3-difluorocyclobutoxy) -4-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole
A suspension of 288mg (2 eq.) of sodium hydride (60% in mineral oil) in 10mL of dry tetrahydrofuran was cooled to-10℃and 779mg (2 eq.) of 3, 3-difluorocyclobutan-1-ol was added. After stirring for 30min, 1g (1 eq) of 2- [ (3-chloro-4-nitro-pyrazol-1-yl) methoxy ] ethyl-trimethyl-silane (intermediate 29, step 2) in 5mL of dry tetrahydrofuran was added. The mixture was allowed to stir at 5 ℃ 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 1.5g 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.
Step 2: preparation of 3- (3, 3-difluorocyclobutoxy) -1-methyl-4-nitro-1H-pyrazole
32mL (7.5 eq) of a 1N hydrochloric acid solution are added to a solution of 1.5g (1 eq) of 5- (3, 3-difluorocyclobutoxy) -4-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole in 32mL of dry acetonitrile. After heating to 40 ℃ for 4 hours, the reaction was cooled to room temperature and neutralized to pH 7 by adding 32mL of 1N sodium hydroxide solution in water. The reaction mixture was extracted twice with 50mL ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give 711mg of a yellow solid dissolved in 25mL of N-methylpyrrolidone. 244. Mu.L (1.2 eq.) of methyl iodide and 897mg (2 eq.) of potassium carbonate were added to this solution. The mixture was heated at 80 ℃ for 2 hours and poured into a mixture of 200mL ethyl acetate and 200mL diethyl ether. The organic layer was washed 3 times with 100mL of water, then dried over magnesium sulfate, and concentrated in vacuo. The residue was purified on silica gel (eluting with 80/20 to 50/50 heptane/ethyl acetate mixtures) to give 720 mg of 3- (3, 3-difluorocyclobutoxy) -1-methyl-4-nitro-1H-pyrazole. MS (method B) m/z 234[ M+1] +; t=1.25 min.
Step 3: preparation of 3- (3, 3-difluorocyclobutoxy) -1-methyl-1H-pyrazol-4-amine
946mg ammonium chloride (5 eq) and 988mg iron (5 eq) were added to a solution of 825mg (1 eq) 3- (3, 3-difluorocyclobutoxy) -1-methyl-4-nitro-1H-pyrazole in 25mL ethanol and 3.8mL water. The reaction mixture was heated at 80 ℃ for 1 hour, then allowed to cool to room temperature. The mixture was filtered by washing with ethanol over celite and concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 579mg 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.
Step 4: preparation of N- (3, 3-difluorocyclobutoxy) -1-methyl-1H-pyrazol-4-yl) carboxamide
A solution of 579mg of 3- (3, 3-difluorocyclobutoxy) -1-methyl-1H-pyrazol-4-amine in 7mL of tetrahydrofuran was added dropwise to a solution of 1.08mL of acetic anhydride (4 equivalents) in 875. Mu.L of formic acid (8 equivalents) cooled to 0℃which had been premixed for 30 minutes. The reaction mixture was stirred at 0 ℃ for 10 minutes and 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 374mg of N- (3, 3-difluorocyclobutoxy) -1-methyl-1H-pyrazol-4-yl) carboxamide. MS (method B); m/z 232[ M+1] +; t=0.97 min.
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
2g (1 eq) of methyl 2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylate (intermediate 1) in 200mL of 7N ammonia solution in methanol in a sealed tube are stirred at room temperature for 3 days. The mixture was then concentrated under reduced pressure. The residue was triturated in 50mL of diethyl ether and the insoluble material filtered and dried in vacuo to give 1.8g of 2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide. MS (method B) m/z 209[ M+1] +; t=0.88 min.
Step 2: preparation of 2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
4.25mL (3.6 eq.) of trifluoroacetic anhydride and 5.31mL (4.5 eq.) of triethylamine are added to a solution of 1.75g of 2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide (1 eq.) in 31mL of anhydrous tetrahydrofuran under argon at 0deg.C. The mixture was stirred at 0 ℃ to room temperature for 1 hour and then poured into 200mL of water. The precipitate was filtered in vacuo and triturated with ether to give 1.3g of 2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile. MS (method A) m/z 191[ M+1] +; t=1.72 min.
Intermediate 44: n- (1-ethyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide
Step 1: preparation of 1-ethyl-4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole
mu.L (1.5 eq) of ethyl iodide and 1.23g (2 eq) of cesium carbonate are added to a solution of 350mg (1 eq) of 4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole (intermediate 13, step 3) in 10mL of N, N-dimethylformamide. The mixture was stirred at room temperature for 1 hour and poured into a mixture of 100mL of ethyl acetate and 100mL of diethyl ether. The organic layer was washed three times with 150mL of water, dried over sodium sulfate, and concentrated in vacuo. The residue was purified on silica gel (gradient elution with 0 to 80% ethyl acetate in cyclohexane) to give 374mg of 1-ethyl-4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole. MS (method E) m/z 214[ M+1] +; t=0.97 min.
Step 2: preparation of N- (1-ethyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide
Starting from 373mg of 1-ethyl-4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole, 200mg of N- (1-ethyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide were prepared according to the basic procedure described in step 2, intermediate 26. MS (method E) m/z 212[ M+1] +; t=0.78 min.
Intermediate 45: n- [ 3-isopropoxy-1- (methyl-d 3) pyrazol-4-yl ] carboxamide
Step 1: preparation of 3-isopropoxy-4-nitro-1- (methyl-d 3) pyrazole
Starting from 1.5g of 3-isopropoxy-4-nitro-1H-pyrazole, 1.43g of 3-isopropoxy-4-nitro-1- (methyl-d 3) pyrazole were prepared according to the basic procedure described in step 1, intermediate 26. MS (method E) m/z 189[ M+1] +; t=1.11 min.
Step 2: preparation of N- [ 3-isopropoxy-1- (methyl-d 3) pyrazol-4-yl ] carboxamide
170mg of ammonium chloride (5 eq) and 178mg of iron (5 eq) were added to a solution of 120mg of 3-isopropoxy-4-nitro-1- (methyl-d 3) pyrazole in 8mL of ethanol and 1.2mL of water. The reaction mixture was heated at 80 ℃ with vigorous stirring for 10 minutes, and the mixture was filtered by washing with ethanol over celite and concentrated under reduced pressure. The crude material was diluted with 20mL ethyl acetate and washed with 20mL saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate and concentrated in vacuo to form a residue.
A solution of the residue in 3mL of tetrahydrofuran was added dropwise to a solution of 301 μl of acetic anhydride (5 equivalents) in 433 μl of formic acid (18 equivalents) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The residue was purified on silica gel (eluting with 5% methanol in dichloromethane) to give 95mg of N- [ 3-isopropoxy-1- (methyl-d 3) pyrazol-4-yl ] carboxamide. MS (method E) m/z 187[ M+1] +; t=0.83 min.
Intermediate 46: (S) -N- (3- (2-butoxy) -1-methyl-1H-pyrazol-4-yl) carboxamide
Step 1: preparation of (S) -5- (2-butoxy) -4-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole
785mg of (S) -5- (2-butoxy) -4-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole were prepared according to the basic procedure described in step 3, intermediate 29 starting from 1g of 5-chloro-4-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole. MS (method F) m/z without ionization; t=2.14 min.
Step 2: preparation of (S) - (5- (2-butoxy) -4-nitro-1H-pyrazol-1-yl) methanol
785mg of (S) -5- (2-butoxy) -4-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole was converted to 495mg of (S) - (5- (2-butoxy) -4-nitro-1H-pyrazol-1-yl) methanol according to the basic procedure described in intermediate 29, step 4. The crude material was taken to the next step without further purification.
Step 3: preparation of (S) -3- (2-butoxy) -1-methyl-4-nitro-1H-pyrazole
mu.L (1.1 eq) of methyl iodide and 1.16g of potassium carbonate (2.5 eq) are added to a solution of 495mg (1 eq) (S) - (5- (2-butoxy) -4-nitro-1H-pyrazol-1-yl) methanol in 30mL of N, N-dimethylformamide. The mixture was stirred at 60 ℃ for 2 hours, then cooled to room temperature, and poured into a mixture of 100mL ethyl acetate and 100mL diethyl ether. The organic layer was washed three times with 150mL of water, then dried over sodium sulfate, and concentrated in vacuo. The residue was purified on silica gel (gradient elution with 0 to 60% ethyl acetate in cyclohexane) to give 367mg of (S) -3- (2-butoxy) -1-methyl-4-nitro-1H-pyrazole. MS (method E) m/z 200[ M+1] +; t=1.23 min.
Step 4: preparation of (S) -N- (3- (2-butoxy) -1-methyl-1H-pyrazol-4-yl) carboxamide
375mg of (S) -3- (2-butoxy) -1-methyl-4-nitro-1H-pyrazole were converted into 179mg of (S) -N- (3- (2-butoxy) -1-methyl-1H-pyrazol-4-yl) carboxamide according to the basic procedure described in intermediate 29, step 7. MS (method E) m/z 198[ M+1] +; t=0.95 min.
Intermediate 47: (R) -N- (3- (2-butoxy) -1-methyl-1H-pyrazol-4-yl) carboxamide
Step 1: preparation of (R) -5- (2-butoxy) -4-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole
According to the basic procedure described in intermediate 29, step 3, 1g of 5-chloro-4-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole was converted to 889mg of (R) -5- (2-butoxy) -4-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole. MS (method F) m/z without ionization; t=2.14 min.
Step 2: preparation of (R) - (5- (2-butoxy) -4-nitro-1H-pyrazol-1-yl) methanol
890mg of (R) -5- (2-butoxy) -4-nitro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole were converted into 607mg of (R) - (5- (2-butoxy) -4-nitro-1H-pyrazol-1-yl) methanol according to the basic procedure described in intermediate 29, step 4. MS (method E) m/z 216[ M+1] +; t=1.09 min.
Step 2: preparation of (R) -3- (2-butoxy) -1-methyl-4-nitro-1H-pyrazole
According to the basic procedure described in step 3, intermediate 46, 620mg of (R) - (5- (2-butoxy) -4-nitro-1H-pyrazol-1-yl) methanol was converted to 440mg of (R) -3- (2-butoxy) -1-methyl-4-nitro-1H-pyrazole. MS (method E) m/z 200[ M+1] +; t=1.23 min.
Step 3: preparation of (R) -N- (3- (2-butoxy) -1-methyl-1H-pyrazol-4-yl) carboxamide
According to the basic procedure described in intermediate 46, step 4, 440mg of (R) -3- (2-butoxy) -1-methyl-4-nitro-1H-pyrazole was converted to 175mg of (R) -N- (3- (2-butoxy) -1-methyl-1H-pyrazol-4-yl) carboxamide. MS (method E) m/z 198[ M+1] +; t=0.95 min.
Intermediate 48: (N- (2, 2-dimethyl-3, 4-dihydro-2H-pyrano [3,2-b ] pyridin-8-yl) carboxamide
Step 1: preparation of 2, 2-dimethyl-2, 3-dihydro-4H-pyrano [3,2-b ] pyridin-4-one
4.52mL of pyrrolidine (1.5 eq) was added to a solution of 5g (1 eq) of 1- (3-hydroxypyridin-2-yl) ethanol-1-one in 100mL of toluene in a closed vessel. The mixture was stirred at room temperature for 15 minutes. Then, 5.4mL (2 eq) of acetone was added and the reaction mixture was stirred at 40 ℃ for 24 hours. An additional 4mL (1.5 eq) of acetone was added and the mixture stirred at room temperature for a further 15 hours, then filtered through a pad of silica gel (elution with a gradient of 0 to 100% ethyl acetate in cyclohexane) to give 3.29g 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.
Step 2: preparation of 2, 2-dimethyl-3, 4-dihydro-2H-pyrano [3,2-b ] pyridin-4-ol
A solution of 1g (1 eq) 2, 2-dimethyl-2, 3-dihydro-4H-pyrano [3,2-b ] pyridin-4-one in 10mL ethanol was added dropwise with stirring to a solution of 160mg (0.75 eq) sodium borohydride in 5mL ethanol. The reaction mixture was stirred at reflux for 2 hours, and then cooled to room temperature, and concentrated in vacuo. The residue was dissolved in 200mL of ethyl acetate and washed with 150mL of saturated aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate and then concentrated in vacuo, and the residue was purified on silica gel (elution with a gradient of 0 to 5% methanol in dichloromethane) to give 5000 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.
Step 3: preparation of 2, 2-dimethyl-2H-pyrano [3,2-b ] pyridine
A solution of 820mg (1 eq) of 2, 2-dimethyl-3, 4-dihydro-2H-pyrano [3,2-b ] pyridin-4-ol and 87mg (0.1 eq) of p-toluenesulfonic acid hydrate in 50mL of toluene in a Dean-Stark apparatus (Dean & Stark trap) was refluxed for 5 hours, and water was removed periodically. After cooling to room temperature and concentration in vacuo, the residue was purified on silica gel (elution with a gradient of 0 to 5% methanol in dichloromethane) to give 442mg of 2, 2-dimethyl-2H-pyrano [3,2-b ] pyridine. MS (method E) m/z 162[ M+1] +; t=0.83 min.
Step 4: preparation of 2, 2-dimethyl-3, 4-dihydro-2H-pyrano [3,2-b ] pyridine
A solution of 440mg (1 eq.) of 2, 2-dimethyl-2H-pyrano [3,2-b ] pyridine in 15mL of methanol was treated with 286mg palladium on carbon (10% by weight) (0.1 eq.) in a Parr apparatus under 2.5 bar of hydrogen for 1.5 hours. After filtration over celite, rinsing with 30mL of methanol and concentration in vacuo, the residue was purified on silica gel (gradient elution with 0 to 70% ethyl acetate in cyclohexane) to give 445mg 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.
Step 5: preparation of 2, 2-dimethyl-3, 4-dihydro-2H-pyrano [3,2-b ] pyridine 5-oxide
1.78g (2.1 eq.) of 3-chloroperbenzoic acid (70% weight purity) are added to a solution of 560mg (1 eq.) of 2, 2-dimethyl-3, 4-dihydro-2H-pyrano [3,2-b ] pyridine in 250mL of dichloromethane at 0deg.C. The reaction mixture was stirred at room temperature for 18 hours and then washed with 100ml of saturated aqueous sodium carbonate solution, and the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica gel (elution with a gradient of 0 to 5% methanol in dichloromethane) to give 290mg 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.
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
2mL (28.6 eq) of nitric acid was added dropwise to a solution of 280mg (1 eq) of 2, 2-dimethyl-3, 4-dihydro-2H-pyrano [3,2-b ] pyridine 5-oxide in 2mL of acetic acid. The reaction mixture was stirred at 85 ℃ for 5 hours and then cooled to room temperature and poured into a mixture of 200g ice and 10ml 12n aqueous sodium hydroxide solution. The aqueous layer was saturated with sodium chloride and extracted three times with 150mL of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 290mg 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/z 209[ M+1] +; t=1.26 min and m/z 225[ m+1] +; t=1.03 min.
Step 7: preparation of N- (2, 2-dimethyl-3, 4-dihydro-2H-pyrano [3,2-b ] pyridin-8-yl) carboxamide
290mg 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 ] pyridin 5-oxide were reduced and formylated according to the basic procedure described in intermediate 31, step 3, to give 150mg of N- (2, 2-dimethyl-3, 4-dihydro-2H-pyrano [3,2-b ] pyridin-8-yl) carboxamide. MS (method E) m/z 207[ M+1] +; t=1.07 min.
Intermediate 49: n- (3-isopropoxy-1- [ (1R) -1, 1-trifluoropropan-2-yl ] -1H-pyrazol-4-yl) carboxamide and N- (3-isopropoxy-1- [ (1S) -1, 1-trifluoropropan-2-yl ] -1H-pyrazol-4-yl) carboxamide
Step 1: preparation of 3-isopropoxy-4-nitro-1- (1, 1-trifluoropropan-2-yl) -1H-pyrazole (racemic)
1.74g (1.5 eq) of racemic 1, 1-trifluoropropan-2-yl 1,2, 3, 4-nonafluorobutane-1-sulfonate (commercially available) and 1.22g (3 eq.) of potassium carbonate was added to a solution of 0.5g (1 equivalent) 3-isopropoxy-4-nitro-1H-pyrazole (commercially available) in 2mL dimethylformamide. The mixture was heated at 80 ℃ for 1.5 hours and 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 360mg of rac 3-isopropoxy-4-nitro-1- (1, 1-trifluoropropan-2-yl) -1H-pyrazole. MS (method D) m/z 268[ M+1] +; t=1.29 min.
Step 2: preparation of N- (3-isopropoxy-1- (1, 1-trifluoropropan-2-yl) -1H-pyrazol-4-yl) carboxamide (Racemosome)
A solution of 550mg (1 eq.) of racemic 3-isopropoxy-4-nitro-1- (1, 1-trifluoropropan-2-yl) -1H-pyrazole in 80mL of methanol was hydrogenated in the presence of 100mg (0.05 eq.) of palladium on carbon (10%) under 2.5 bar of hydrogen. The mixture was filtered by washing with dichloromethane over celite and concentrated under reduced pressure. A solution of the crude material dissolved in 12mL of tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 777. Mu.L acetic anhydride (4 eq.) in 632. Mu.L formic acid (8 eq.) that had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at 0 ℃ for 1 hour, allowed to warm to room temperature, then poured into 10% aqueous sodium carbonate solution and stirred for 15 minutes. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified on silica gel (gradient elution with 0 to 20% ethyl acetate in heptane) to give 510mg of racemic N- (3-isopropoxy-1- (1, 1-trifluoropropan-2-yl) -1H-pyrazol-4-yl) carboxamide. MS (method D) m/z 266[ M+1] +; t=0.99 min.
Intermediate 50: (3S, 4S) -4-methoxytetrahydrofuran-3-ol
7.5G of lipase AMANO AK (cf. ALDRICH: amano lipase from Pseudomonas fluorescens; catalog No. 534730-50G) are added to a solution of 30G (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 150mL of vinyl acetate in 300mL of heptane. The suspension was stirred at 22 ℃ for 5 days and then filtered through a pad of celite. The filter cake was rinsed twice with 50mL 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 11.72g of (3 s,4 s) -4-methoxytetrahydrofuran-3-ol.
1 H NMR(400MHz,CDCl 3 ) Delta, in ppm, 2.61 (width s, 1H); 3.39 (s, 3H); 3.76 (m, 3H); 3.94 (dd, j=4.04 and 10hz,1 h); 4.05 (dd, j=4.3 and 9.7hz,1 h); 4.29 (m, 1H).
Intermediate 51: (R) -N- (2-methyl-3, 4-dihydro-2H- [1,4] dioxepino [2,3-b ] pyridin-9-yl) carboxamide
Step 1: preparation of (S) -4- ((tert-butyldimethylsilyl) oxy) butan-2-ol
4.07g (1.1 eq) imidazole was added to a solution of 5g (1 eq) (S) -butane-1, 3-diol in 50ml N, N-dimethylformamide under argon. The mixture was cooled to 0deg.C and 9.2g (1.1 eq.) of t-butyldimethylsilyl chloride was added. The reaction mixture was stirred at room temperature for 24 hours and then diluted with 150mL of diethyl ether and 100mL of water. The organic layer was washed three times with 50mL of water, dried over sodium sulfate, and concentrated in vacuo. The residue was purified on silica gel (elution with a gradient of 0 to 10% ethyl acetate in cyclohexane) to give 9g of (S) -4- ((tert-butyldimethylsilyl) oxy) butan-2-ol.
1 H NMR (400 MHz, CDCl 3) delta, 0,1 (s, 6H) in ppm; 0,89 (s, 9H); 1,19 (d, j=6.3 hz,3 h); 1,64 (m, 2H); 3.30 (width s, 1H); 3,81(m,1H)；3,88(m,1H)；4,02(m,1H)。
step 2: preparation of (R) -3- ((2-chloropyridin-3-yl) oxy) butan-1-ol
9.11g (1.1 eq) triphenylphosphine and 6.45mL (1.05 eq) diisopropyl azodicarboxylate were added continuously dropwise to a solution of 6.78g (1.05 eq) (S) -4- ((tert-butyldimethylsilyl) oxy) butan-2-ol and 4.09g (1 eq) 2-chloropyridin-3-ol in 80mL tetrahydrofuran at 0deg.C. The reaction mixture was stirred at 0 ℃ to room temperature for 1 hour and then diluted with 150mL of diethyl ether and 100mL of water. The organic layer was washed with 50mL of water, dried over sodium sulfate, and concentrated in vacuo. The residue was purified on silica gel (gradient elution with 0 to 10% ethyl acetate in cyclohexane) to give 8.24g of silylated intermediate. The resulting compound was dissolved in 250mL of acetonitrile and 50mL of 1n aqueous hydrogen chloride, and the reaction mixture was stirred for 1 hour, and then carefully poured into 200mL of saturated aqueous sodium bicarbonate and 400mL of methylene chloride. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica gel (gradient elution with 0 to 70% ethyl acetate in cyclohexane) to give 4.4g of (R) -3- ((2-chloropyridin-3-yl) oxy) butan-1-ol. MS (method F) m/z 202[ M+1] +; t=1.17 min.
Step 3: preparation of (R) -2-methyl-3, 4-dihydro-2H- [1,4] dioxepino [2,3-b ] pyridine
A solution of 2.5g (1 eq) (R) -3- ((2-chloropyridin-3-yl) oxy) butan-1-ol in 40mL 1-methyl-2-pyrrolidone was added over 30 minutes to a suspension of 644mg (1.3 eq) sodium hydride (60% by weight in mineral oil) in 50mL 1-methyl-2-pyrrolidone under argon at 95 ℃. The reaction mixture was stirred at 90 ℃ to 100 ℃ for 2 hours, and then cooled to room temperature, and poured into 200mL of a 50/50 mixture of diethyl ether and ethyl acetate and 100mL of water. The aqueous layer was extracted with 50mL of ethyl acetate and the organic layers were combined and washed four times with 50mL of water and then dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica gel (gradient elution with 0 to 50% ethyl acetate in cyclohexane) to give 1g of (R) -2-methyl-3, 4-dihydro-2H- [1,4] dioxepino [2,3-b ] pyridine. MS (method F) m/z 166[ M+1] +; t=1.11 min.
Step 4: preparation of (R) -2-methyl-3, 4-dihydro-2H- [1,4] dioxepino [2,3-b ] pyridine-9-carboxylic acid
5.7mL (1.5 eq.) of a 1.6N butyllithium solution in heptane are slowly added to a solution of 1g (1 eq.) of (R) -2-methyl-3, 4-dihydro-2H- [1,4] dioxepino [2,3-b ] pyridine in 30mL anhydrous tetrahydrofuran under argon at-60℃while maintaining the temperature below-55 ℃. The reaction mixture was stirred at-60 ℃ for 1 hour 30 minutes. The temperature was allowed to slowly warm to room temperature with stirring, then diluted with 50mL of diethyl ether and 20mL of water. The organic layer was discarded and the alkaline aqueous layer was acidified with 10ml of 10% aqueous citric acid. After extraction 5 times with a 75/25 mixture of dichloromethane/isopropanol, the organic layers were combined, dried over sodium sulfate and concentrated in vacuo. The residue was triturated in 10mL of a 60/40 mixture of pentane/diethyl ether to give 390mg 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.
Step 5: preparation of tert-butyl (R) - (2-methyl-3, 4-dihydro-2H- [1,4] dioxepino [2,3-b ] pyridin-9-yl) carbamate
To a solution of 395mg (1 eq) (R) -2-methyl-3, 4-dihydro-2H- [1,4] dioxepino [2,3-b ] pyridine-9-carboxylic acid in 10mL of anhydrous toluene and 10mL of t-butanol under argon are added 316. Mu.L (1.2 eq) of triethylamine and 503. Mu.L (1.2 eq) of diphenylphosphorylazide. The reaction mixture was stirred at room temperature for 2 hours 30 minutes. 7.6mg of copper (II) chloride (0.03 eq.) and a further 10mL of t-butanol are then added and the mixture is stirred at 110℃for 1 hour 30 minutes and then cooled to room temperature and diluted with 30mL of diethyl ether, 30mL of ethyl acetate and 20mL of water. The organic layer was washed with 10mL of water and 10mL of brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified on silica gel (gradient elution with 0 to 30% ethyl acetate in cyclohexane) to give 450mg 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.
Step 6: preparation of (R) -N- (2-methyl-3, 4-dihydro-2H- [1,4] dioxepino [2,3-b ] pyridin-9-yl) carboxamide
A solution of 450mg (1 eq) (R) - (2-methyl-3, 4-dihydro-2H- [1,4] dioxepino [2,3-b ] pyridin-9-yl) carbamic acid tert-butyl ester in 10mL dichloromethane and 10mL 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/tetrahydrofuran, then taken up in 5mL of tetrahydrofuran and added to a premix solution of 492. Mu.L of formic acid (8 eq.) and 606. Mu.L of acetic anhydride (4 eq.). After stirring at room temperature for 2 hours, the reaction mixture was poured into 20mL of dichloromethane and 10mL of 10% aqueous sodium carbonate solution. The biphasic mixture was stirred vigorously for 10 minutes, and the aqueous layer was extracted with an additional 20mL of dichloromethane. The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo. The residue was triturated in 10mL of a 50/50 mixture of pentane/diethyl ether to give 238mg of (R) -N- (2-methyl-3, 4-dihydro-2H- [1,4] dioxepino [2,3-b ] pyridin-9-yl) carboxamide. MS (method F) m/z 209[ M+1] +; t=0.84 min.
Intermediate 52: n- (3- ((2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide (rac)
Step 1: preparation of 3- ((2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -4-nitro-1H-pyrazole (racemic)
0.365g (1.25 eq) of 2, 2-dimethyloxetan-3-ol and 1.86g (2 eq) of cesium carbonate are added to a solution of 0.5g (1 eq) of 1- (methyl-d 3) -3, 4-dinitro-1H-pyrazole (intermediate 21, step 1) in 25mL of acetonitrile. The mixture was heated at 80 ℃ 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 470mg of 3- ((2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -4-nitro-1H-pyrazole (rac). MS (method A) m/z 231[ M+1] +; t=1.66 min.
Step 2: n- (3- ((2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide (rac)
In a microwave vial, a solution of 0.66g (1 eq) 3- ((2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -4-nitro-1H-pyrazole (rac) in 15mL methanol was treated with 1.26g (7 eq) ammonium formate and 202mg palladium on carbon (10%) (0.07 eq). The reaction mixture was heated at 70℃for 15 minutes. The mixture was filtered by washing with methanol over celite and concentrated under reduced pressure to give 0.62g of 3- ((2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-amine (rac). The crude material was taken to the next step without further purification.
A solution of 0.57g (1 eq) 3- ((2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-amine (rac) in 20mL tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 1.16g acetic anhydride (4 eq) in 2.4g formic acid (18 eq) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 3 hours, then concentrated in vacuo. The residue was purified on silica gel (eluting with 5% methanol in dichloromethane) to give 0.51g N- (3- ((2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide (rac). MS (method A) m/z 229[ M+1] +; t=1.26 min.
Intermediate 53: n- (3-cyclopropoxy-1- (2-methoxyethyl) -1H-pyrazol-4-yl) carboxamide
Step 1: preparation of 1- (2-methoxyethyl) -3, 4-dinitro-1H-pyrazole
1.21g (1.4 eq) of 1-bromo-2-methoxy-ethane and 1.75g (2 eq) of potassium carbonate are added to a solution of 1g (1 eq) of 3, 4-dinitro-1H-pyrazole (commercially available) in 10mL of dimethylformamide. The mixture was heated at 80 ℃ 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 is purified on silica gel eluting with dichloromethane and then with 1% methanol in dichloromethane to give 1.0g of 1- (2-methoxyethyl) -3, 4-dinitro-1H-pyrazole. MS (method B) t=1.19 min; no quality is detected
Step 2: preparation of 3-cyclopropoxy-1- (2-methoxyethyl) -4-nitro-1H-pyrazole
1.25 equivalents of cyclopropyl alcohol and 2 equivalents of cesium carbonate are added to a solution of 0.98g (1 equivalent) of 1- (2-methoxyethyl) -3, 4-dinitro-1H-pyrazole in 20mL of acetonitrile. The mixture was heated at 80 ℃ 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 823mg of 3-cyclopropoxy-1- (2-methoxyethyl) -4-nitro-1H-pyrazole. MS (method B) m/z 228[ M+1] +; t=1.22 min.
Step 3: preparation of N- (3-cyclopropoxy-1- (2-methoxyethyl) -1H-pyrazol-4-yl) carboxamide
In a microwave vial, a solution of 0.825g (1 eq.) of 3-cyclopropoxy-1- (2-methoxyethyl) -4-nitro-1H-pyrazole in 10mL of methanol was treated with 1.6g (7 eq.) of ammonium formate and 100mg (0.025 eq.) of palladium on carbon (10%). The reaction mixture was heated at 70℃for 15 minutes. The mixture was washed with methanol over celite, filtered and concentrated under reduced pressure to give 015 mg of 3-cyclopropoxy-1- (2-methoxyethyl) -1H-pyrazol-4-amine. The crude material was taken to the next step without further purification.
A solution of 0.71g (1 eq) 3-cyclopropoxy-1- (2-methoxyethyl) -1H-pyrazol-4-ylamine in 15mL tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 1.47g acetic anhydride (4 eq) in 3g formic acid (18 eq) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 20 min, then concentrated in vacuo. The residue was purified on silica gel (eluting with 5% methanol in dichloromethane) to give 455mg of N- (3-cyclopropoxy-1- (2-methoxyethyl) -1H-pyrazol-4-yl) carboxamide. MS (method A) m/z 226[ M+1] +; t=1.21 min.
Intermediate 54: n- (1- (methyl-d 3) -3- ((tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (rac)
Step 1: preparation of 1- (methyl-d 3) -4-nitro-3- ((tetrahydrofuran-3-yl) oxy) -1H-pyrazole (rac)
0.38g (1.25 eq) tetrahydrofuran-3-ol and 2.23g (2 eq) cesium carbonate are added to a solution of 0.6g (1 eq) 1- (methyl-d 3) -3, 4-dinitro-1H-pyrazole (intermediate 21, step 1) in 12mL acetonitrile. The mixture was heated at 80 ℃ 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 245mg of 1- (methyl-d 3) -4-nitro-3- ((tetrahydrofuran-3-yl) oxy) -1H-pyrazole. MS (method B) m/z 217[ M+1] +; t=0.97 min.
Step 2: preparation of N- (1- (methyl-d 3) -3- ((tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (rac)
In a microwave vial, a solution of 0.245g (1 eq) 1- (methyl-d 3) -4-nitro-3- ((tetrahydrofuran-3-yl) oxy) -1H-pyrazole in 4mL of methanol was treated with 0.5g (7 eq) ammonium formate and 30mg (0.025 eq) palladium on carbon (10%). The reaction mixture was heated at 100℃for 10 minutes. The mixture was filtered by washing with methanol over celite and concentrated under reduced pressure to give 1- (methyl-d 3) -3- ((tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-amine. The crude material was taken to the next step without further purification.
A solution of 0.21g (1 eq) 1- (methyl-d 3) -3- ((tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-amine in 5mL tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 0.47g acetic anhydride (4 eq) in 0.9g formic acid (18 eq) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 90 minutes, 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 140mg of N- (1- (methyl-d 3) -3- ((tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide. MS (method A) m/z 215[ M+1] +; t=0.98 min.
Intermediates 55 and 56: cis-N- (1- ((4-hydroxy-4-methylcyclohexyl) -3-isopropoxy-1H-pyrazol-4-yl) carboxamide and trans-N- (1- ((4-hydroxy-4-methylcyclohexyl) -3-isopropoxy-1H-pyrazol-4-yl) carboxamide
Step 1: preparation of 3-isopropoxy-4-nitro-1- (1, 4-dioxaspiro [4.5] decan-8-yl) -1H-pyrazole
4.6g (1.5 eq) triphenylphosphine was added to a solution of 2g (1 eq) 3-isopropoxy-4-nitro-1H-pyrazole (commercially available) and 1.85g (1 eq) 1, 4-dioxaspiro [4.5] decan-8-ol in 30mL tetrahydrofuran. The mixture was cooled to 0deg.C and 3.55g (1.5 eq) diisopropyl azodicarboxylate (DIAD) was added. The mixture was stirred at room temperature overnight and then diluted with 100mL of ethyl acetate and 50mL 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 1.45g of 3-isopropoxy-4-nitro-1- (1, 4-dioxaspiro [4.5] decan-8-yl) -1H-pyrazole. MS (method B) m/z 312[ M+1] +; t=1.61 min.
Step 2: preparation of 4- (3-isopropoxy-4-nitro-1H-pyrazol-1-yl) cyclohexan-1-one
A solution of 0.7g (1 eq) 3-isopropoxy-4-nitro-1- (1, 4-dioxaspiro [4.5] decan-8-yl) -1H-pyrazole in 12mL acetone and 2.5mL water was treated with 0.68g (1.2 eq) pyridinium-p-toluenesulfonate (PPTS) in a microwave vial. The reaction mixture was heated at 120 ℃ for 30 minutes. The mixture was concentrated under reduced pressure and taken up in 50mL of ethyl acetate and 20mL 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 500mg 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.
Step 3: preparation of N- (3-isopropoxy-1- (4-oxocyclohexyl) -1H-pyrazol-4-yl) carboxamide
800mg of ammonium chloride (5 eq) and 836mg of iron (5 eq) were added to a solution of 800g of 4- (3-isopropoxy-4-nitro-1H-pyrazol-1-yl) cyclohexane-1-one in 20mL of ethanol and 2.5mL of water. The reaction mixture was heated at 80 ℃ with vigorous stirring for 90 minutes, and the mixture was filtered by washing with ethanol over celite and concentrated under reduced pressure.
A solution of the residue in 5mL of tetrahydrofuran was added dropwise at 0deg.C to a solution of 2.24g acetic anhydride (8 equivalents) in 4.4g formic acid (35 equivalents) that had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 50 minutes, then concentrated in vacuo. The residue was purified on silica gel (eluting with 5% methanol in dichloromethane) to give 170mg of N- (3-isopropoxy-1- (4-oxocyclohexyl) -1H-pyrazol-4-yl) carboxamide. MS (method A) M/z266[ M+1] +; t=1.55 min.
Step 4: preparation of cis-N- (1- ((4-hydroxy-4-methylcyclohexyl) -3-isopropoxy-1H-pyrazol-4-yl) carboxamide and trans-N- (1- ((4-hydroxy-4-methylcyclohexyl) -3-isopropoxy-1H-pyrazol-4-yl) carboxamide
311. Mu.L of methylmagnesium bromide (3M in tetrahydrofuran) (1.5 eq.) was added to a solution of 165mg of N- (3-isopropoxy-1- (4-oxocyclohexyl) -1H-pyrazol-4-yl) carboxamide in 8mL of tetrahydrofuran at-78 ℃. The reaction mixture was stirred at-78 ℃ for 10 minutes, then 104 μl of methyl magnesium bromide (3M in tetrahydrofuran) (0.5 eq.) was added, and the mixture was stirred at-78 ℃ for 1 hour. The reaction was quenched with 3mL of saturated aqueous ammonium chloride and extracted with 20mL 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 50mg of N- (1- ((4-hydroxy-4-methylcyclohexyl) -3-isopropoxy-1H-pyrazol-4-yl) carboxamide (cis) =intermediate 55.ms (method B) m/z 282[ m+1] +; t=1.19 min, and 30mg of N- (1- ((4-hydroxy-4-methylcyclohexyl) -3-isopropoxy-1H-pyrazol-4-yl) carboxamide (trans) =intermediate 56.ms (method B) m/z 282[ m+1] +; t=1.1 min.
Intermediates 57 and 58: cis-N- (3-cyclopropoxy-1- (hydroxy-4-methylcyclohexyl) -1H-pyrazol-4-yl) carboxamide and trans-N- (3-cyclopropoxy-1- (hydroxy-4-methylcyclohexyl) -1H-pyrazol-4-yl) carboxamide
Step 1: preparation of 3, 4-dinitro-1- (1, 4-dioxaspiro [4.5] decan-8-yl) -1H-pyrazole
10g (1.5 eq) triphenylphosphine was added to a solution of 4g (1 eq) 3, 4-dinitro-1H-pyrazole and 4g (1 eq) 1, 4-dioxaspiro [4.5] decan-8-ol in 60mL tetrahydrofuran. The mixture was cooled to 0deg.C and 7.68g (1.5 eq) diisopropyl azodicarboxylate (DIAD) was added. The mixture was stirred at room temperature for 72 hours, then diluted with 200mL of ethyl acetate and 100mL 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 1.6g of 3, 4-dinitro-1- (1, 4-dioxaspiro [4.5] dec-8-yl) -1H-pyrazole. MS (method a) t=1.47 min-no mass
Step 2: preparation of 3-cyclopropoxy-4-nitro-1- (1, 4-dioxaspiro [4.5] decan-8-yl) -1H-pyrazole
220mg of cyclopropyl alcohol (1.25 eq) and 2g of cesium carbonate (2 eq) are added to a solution of 900mg (1 eq) of 3, 4-dinitro-1- (1, 4-dioxaspiro [4.5] decan-8-yl) -1H-pyrazole in 20mL of acetonitrile. The mixture was heated at 80 ℃ for 5 hours, then allowed to cool to room temperature, and diluted with ethyl acetate and water. The organic layer was washed with water, brine, and 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 700mg 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.
Step 3: preparation of 4- (3-cyclopropoxy-4-nitro-1H-pyrazol-1-yl) cyclohexan-1-one
A solution of 0.7g (1 eq) 3-cyclopropoxy-4-nitro-1- (1, 4-dioxaspiro [4.5] decan-8-yl) -1H-pyrazole in 12mL acetone and 2.5mL water was treated with 0.68g (1.2 eq) pyridinium-p-toluenesulfonate (PPTS) in a microwave vial. The reaction mixture was heated at 120 ℃ for 30 minutes. The mixture was concentrated under reduced pressure, and the residue was taken up in 50mL of ethyl acetate and 20mL 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 500mg 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.
Step 4: preparation of N- (3-cyclopropoxy-1- (4-oxocyclohexyl) -1H-pyrazol-4-yl) carboxamide
363mg of ammonium chloride (5 eq) and 380mg of iron (5 eq) are added to a solution of 360mg of 4- (3-cyclopropoxy-4-nitro-1H-pyrazol-1-yl) cyclohexane-1-one in 12mL of ethanol and 2mL of water. The reaction mixture was heated at 80 ℃ with vigorous stirring for 90 minutes, and the mixture was filtered by washing with ethanol over celite and concentrated under reduced pressure.
A solution of the residue in 12mL of tetrahydrofuran was added dropwise at 0deg.C to a solution of 1.1g of acetic anhydride (8 equivalents) in 2.2g of formic acid (35 equivalents) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 4 hours, then concentrated in vacuo. The residue was purified on silica gel (eluting with 5% methanol in dichloromethane) to give 80mg of N- (3-cyclopropoxy-1- (4-oxocyclohexyl) -1H-pyrazol-4-yl) carboxamide. MS (method A) m/z 264[ M+1] +; t=1.09 min.
Step 5: preparation of cis-N- (3-cyclopropoxy-1- (hydroxy-4-methylcyclohexyl) -1H-pyrazol-4-yl) carboxamide and trans-N- (3-cyclopropoxy-1- (hydroxy-4-methylcyclohexyl) -1H-pyrazol-4-yl) carboxamide
380. Mu.L of methyl magnesium bromide (3M in tetrahydrofuran) (2.5 eq.) was added to a solution of 120mg of N- (3-cyclopropoxy-1- (4-oxocyclohexyl) -1H-pyrazol-4-yl) carboxamide in 6mL of tetrahydrofuran at-78 ℃. The reaction mixture was stirred at-78 ℃ for 1 hour. 3mL of saturated aqueous ammonium chloride and 20mL 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 35mg of N- (3-cyclopropoxy-1- (hydroxy-4-methylcyclohexyl) -1H-pyrazol-4-yl) carboxamide (cis) =intermediate 57.MS (method A) m/z 280[ M+1] +; t=1.53 min. And 25mg of N- (3-cyclopropoxy-1- (hydroxy-4-methylcyclohexyl) -1H-pyrazol-4-yl) carboxamide (trans) =intermediate 58.MS (method A) m/z 280[ M+1] +; t=1.39 min.
Intermediate 59: n- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- ((tetrahydro-2H-pyran-4-yl) oxy) -1H-pyrazol-4-yl) carboxamide
Step 1: preparation of 1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3, 4-dinitro-1H-pyrazole
1.97g (1.3 eq) of 2-bromoethoxy-tert-butyl-dimethyl-silane and 1.75g (2 eq) of potassium carbonate are added to a solution of 2g (1 eq) of 3, 4-dinitro-1H-pyrazole (commercially available) in 20mL of dimethylformamide. The mixture was heated at 80 ℃ 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 purified on silica gel (eluting with 20% ethyl acetate in heptane dichloromethane, then 50% ethyl acetate in heptane) to give 3.9g of 1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3, 4-dinitro-1H-pyrazole. MS (method a) t=3.01 min, no mass was detected
Step 2: preparation of 1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -4-nitro-3- ((tetrahydro-2H-pyran-4-yl) oxy) -1H-pyrazole
1.3g of tetrahydropyran-4-ol (2 equivalents) and 4.2g of cesium carbonate (2 equivalents) are added to a solution of 2g (1 equivalent) of 1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3, 4-dinitro-1H-pyrazole in 100mL of acetonitrile. The mixture was heated at 80 ℃ overnight, then 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 purified on silica gel (eluting with 20% ethyl acetate in heptane dichloromethane, then 50% ethyl acetate in heptane) to give 385mg of 1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -4-nitro-3- ((tetrahydro-2H-pyran-4-yl) oxy) -1H-pyrazole. MS (method A) m/z 372[ M+1] +; t=2.92 min.
Step 3: preparation of N- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- ((tetrahydro-2H-pyran-4-yl) oxy) -1H-pyrazol-4-yl) carboxamide
In a microwave vial, a solution of 0.54g (1 eq) 1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -4-nitro-3- ((tetrahydro-2H-pyran-4-yl) oxy) -1H-pyrazole in 10mL of methanol was treated with 641mg (7 eq) ammonium formate and 150mg palladium on carbon (10%). The reaction mixture was heated at 70℃for 15 minutes. The mixture was filtered by washing with methanol over celite 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 to the next step without further purification.
A solution of (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- ((tetrahydro-2H-pyran-4-yl) oxy) -1H-pyrazol-4-amine in 10mL of tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 618mg acetic anhydride (4 eq.) in 1.26g formic acid (18 eq.) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 2 hours, then concentrated in vacuo. The residue was purified on silica gel (eluting with 5% methanol in dichloromethane) to give 324mg of N- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- ((tetrahydro-2H-pyran-4-yl) oxy) -1H-pyrazol-4-yl) carboxamide. MS (method B) m/z 370[ M+1] +; t=4.05 min.
Intermediate 60: n- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide
Step 1: preparation of 1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole
176mg of oxetan-3-ol (1.5 eq) and 1.03g of cesium carbonate (2 eq) are added to a solution of 500mg (1 eq) of 1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3, 4-dinitro-1H-pyrazole (step 1 of intermediate 59) in 25mL of acetonitrile. The mixture was heated at 80 ℃ 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 470 mg of 1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole. MS (method A) m/z 344[ M+1] +; t=2.8 min.
Step 2: preparation of N- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide
In a microwave vial, a solution of 0.48g (1 eq) 1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole in 10mL of methanol was treated with 612mg (7 eq) ammonium formate and 150mg palladium on carbon (10%). The reaction mixture was heated at 70℃for 15 minutes. The mixture was filtered by washing with methanol over celite and concentrated under reduced pressure to give 1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-amine.
Crude 1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-amine in 10mL of tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 592mg acetic anhydride (4 eq) in 1.2g formic acid (18 eq) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 2 hours, then concentrated in vacuo. The residue was purified on silica gel (eluting with 5% methanol in dichloromethane) to give 308mg of N- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide. MS (method A) m/z 342[ M+1] +; t=2.35 min
Intermediate 61: n- (3- (3-hydroxy-2, 2-dimethylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide
Step 1: preparation of 2, 2-dimethyl-3- ((1- (methyl-d 3) -4-nitro-1H-pyrazol-3-yl) oxy) cyclobutan-1-ol (rac)
To a solution of 650mg (1 eq) of 1- (methyl-d 3) -3, 4-dinitro-1H-pyrazole (intermediate 21, step 1) in 15mL of acetonitrile was added 690mg of 2, 2-dimethylcyclobutane-1, 3-diol (1.6 eq) and 2.4g of cesium carbonate (2 eq). The mixture was heated at 80 ℃ 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 dichloromethane, then 50% ethyl acetate in heptane) to give 298mg of 2, 2-dimethyl-3- ((1- (methyl-d 3) -4-nitro-1H-pyrazol-3-yl) oxy) cyclobutan-1-ol. MS (method A) m/z 345[ M+1] +; t=1.58 min.
Step 2: preparation of N- (3- (3-hydroxy-2, 2-dimethylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide (rac)
In a microwave vial, a solution of 0.43g (1 eq) 2, 2-dimethyl-3- ((1- (methyl-d 3) -4-nitro-1H-pyrazol-3-yl) oxy) cyclobutan-1-ol in 13mL methanol was treated with 768mg (7 eq) ammonium formate and 60mg palladium on carbon (10%). The reaction mixture was heated at 70℃for 15 minutes. The mixture was filtered by washing with methanol over celite and concentrated under reduced pressure to give 3- ((4-amino-1- (methyl-d 3) -1H-pyrazol-3-yl) oxy) -2, 2-dimethylcyclobutan-1-ol. The crude material was taken to the next step without further purification.
A solution of 3- ((4-amino-1- (methyl-d 3) -1H-pyrazol-3-yl) oxy) -2, 2-dimethylcyclobutan-1-ol in 4mL of tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 800mg acetic anhydride (4 eq.) in 1.62g formic acid (18 eq.) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 2 hours, then concentrated in vacuo. The residue was purified on silica gel (eluting with 5% methanol in dichloromethane, then 10% methanol in dichloromethane) to give 250mg of N- (3- (3-hydroxy-2, 2-dimethylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide. MS (method A) m/z 243[ M+1] +; t=1.22 min.
Intermediate 62: n- (1- (1-methoxypropane-2-yl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide (racemic)
Step 1: preparation of 1- (1-methoxypropane-2-yl) -3, 4-dinitro-1H-pyrazole (racemization)
987mg (1.2 eq) of 2-iodo-1-methoxy-propane and 1.14g (2 eq) of potassium carbonate are added to a solution of 650mg (1 eq) of 3, 4-dinitro-1H-pyrazole (commercially available) in 10mL of dimethylformamide. The mixture was heated at 80 ℃ for 6 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, then 50% ethyl acetate in heptane) to give 765mg of 1- (1-methoxypropane-2-yl) -3, 4-dinitro-1H-pyrazole. MS (method a) t=1.97 min, no mass was detected.
Step 2: preparation of 1- (1-methoxypropane-2-yl) -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole (racemic)
194mg of oxetan-3-ol (1.5 eq) and 1.13g of cesium carbonate (2 eq) are added to a solution of 400mg (1 eq) of 1- (1-methoxypropane-2-yl) -3, 4-dinitro-1H-pyrazole in 20mL of acetonitrile. The mixture was heated at 80 ℃ for 3 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, then 50% ethyl acetate in heptane) to give 428mg of 1- (1-methoxypropane-2-yl) -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole. MS (method A) m/z 258[ M+1] +; t=1.87 min.
Step 3: preparation of N- (1- (1-methoxypropane-2-yl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide (Racemosome)
In a microwave vial, a solution of 0.44g (1 eq) 1- (1-methoxypropane-2-yl) -4-nitro-3- (oxetan-3-yloxy) -1H-pyrazole in 10mL of methanol was treated with 750mg (7 eq) ammonium formate and 150mg palladium on carbon (10%). The reaction mixture was heated at 70℃for 15 minutes. The mixture was washed with methanol over celite, filtered and concentrated under reduced pressure to give 1- (1-methoxypropane-2-yl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-amine.
Crude 1- (1-methoxypropane-2-yl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-amine in 10mL of tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 694mg acetic anhydride (4 equivalents) in 1.4g formic acid (18 equivalents) that had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 2 hours, then concentrated in vacuo. The residue was purified on silica gel (eluting with 5% methanol in dichloromethane, then 10% methanol in dichloromethane) to give 365mg of N- (1- (1-methoxypropane-2-yl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide. MS (method A) m/z 256[ M+1] +; t=1.31 min.
Intermediate 63: n- (3-Cyclopropoxy-1- (1-methoxypropane-2-yl) -1H-pyrazol-4-yl) carboxamide (Racemosome)
Step 1: preparation of 3-cyclopropoxy-1- (1-methoxypropane-2-yl) -4-nitro-1H-pyrazole (racemic)
152mg of cyclopropyl alcohol (1.5 eq) and 1.13g of cesium carbonate (2 eq) are added to a solution of 400mg (1 eq) of 1- (1-methoxypropane-2-yl) -3, 4-dinitro-1H-pyrazole (step 1, intermediate 62) in 20mL of acetonitrile. The mixture was heated at 80 ℃ 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 433 mg of 3-cyclopropoxy-1- (1-methoxypropane-2-yl) -4-nitro-1H-pyrazole. MS (method B) m/z 242[ M+1] +; t=1.4 min.
Step 2: preparation of N- (3-cyclopropoxy-1- (1-methoxypropane-2-yl) -1H-pyrazol-4-yl) carboxamide (Racemosome)
In a microwave vial, a solution of 0.54g (1 eq.) of 3-cyclopropoxy-1- (1-methoxypropane-2-yl) -4-nitro-1H-pyrazole in 12mL of methanol was treated with 977mg (7 eq.) of ammonium formate and 150mg of palladium on carbon (10%). The reaction mixture was heated at 70℃for 15 minutes. The mixture was washed with methanol over celite, filtered and concentrated under reduced pressure to give 3-cyclopropoxy-1- (1-methoxypropane-2-yl) -1H-pyrazol-4-amine.
Crude 3-cyclopropoxy-1- (1-methoxypropane-2-yl) -1H-pyrazol-4-amine in 10mL of tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 903mg acetic anhydride (4 eq.) in 1.8g formic acid (18 eq.) that had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 2 hours, then concentrated in vacuo. The residue was purified on silica gel (eluting with 5% methanol in dichloromethane) to give 364mg of N- (3-cyclopropoxy-1- (1-methoxypropane-2-yl) -1H-pyrazol-4-yl) carboxamide. MS (method A) m/z 240[ M+1] +; t=1.48 min.
Intermediate 64: n- (3- ((5, 5-dimethyltetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide (rac)
Step 1: preparation of 3- ((5, 5-dimethyltetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -4-nitro-1H-pyrazole (rac)
To a solution of 650mg (1 eq) of 1- (methyl-d 3) -3, 4-dinitro-1H-pyrazole (intermediate 21, step 1) in 25mL of acetonitrile are added 463mg of 5, 5-dimethyltetrahydrofuran-3-ol (1.25 eq) and 1.7g of cesium carbonate (2 eq). The mixture was heated at 80 ℃ overnight, then 200mg of 5, 5-dimethyltetrahydrofuran-3-ol were added. The mixture was heated at 80 ℃ for 24 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 dichloromethane, then 50% ethyl acetate in dichloromethane) to give 292mg of 3- ((5, 5-dimethyltetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -4-nitro-1H-pyrazole. MS (method A) m/z 245[ M+1] +; t=1.78 min.
Step 2: preparation of N- (3- ((5, 5-dimethyltetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide (rac)
In a microwave vial, a solution of 0.49g (1 eq) 3- ((5, 5-dimethyltetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -4-nitro-1H-pyrazole in 10mL of methanol was treated with 875mg (7 eq) ammonium formate and 150mg palladium on carbon (10%). The reaction mixture was heated at 70℃for 15 minutes. The mixture was filtered by washing with methanol over celite and concentrated under reduced pressure to give 3- ((5, 5-dimethyltetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-amine.
Crude 3- ((5, 5-dimethyltetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-amine in 10mL of tetrahydrofuran was added dropwise to a cooled (0 ℃) solution of 808mg acetic anhydride (4 eq) in 1.64g formic acid (18 eq) that had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 2 hours, then concentrated in vacuo. The residue was purified on silica gel (eluting with 5% methanol in dichloromethane) to give 250mg of N- (3- ((5, 5-dimethyltetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide. MS (method A) m/z 243[ M+1] +; t=1.38 min.
Intermediate 65: n- (1- (methyl-d 3) -3- (((3R, 4R) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide and N- (1- (methyl-d 3) -3- (((3S, 4S) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (rac)
Step 1: preparation of (3S, 4S) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-ol and (3R, 4R) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-ol (rac)
To a solution of 2.4g of trans-tetrahydrofuran-3, 4-diol (commercially available) (1 equivalent) in 70mL of acetonitrile was added 2.36g of imidazole (1.5 equivalent) and 6g of tert-butyl-chloro-diphenyl-silane (0.94 equivalent). The reaction mixture was stirred at 70 ℃ for 22 hours. The reaction was quenched by the addition of 60mL of water. 200mL of methylene chloride was added and the two phases were separated. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified on silica gel (elution with a gradient of 2% to 10% methanol in dichloromethane) to give 4.3g of (3 s,4 s) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-ol and (3 r,4 r) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-ol. MS (method a) t=2.91 min-no mass was detected.
Step 2: preparation of 1- (methyl-d 3) -3- (((3S, 4S) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -4-nitro-1H-pyrazole and 1- (methyl-d 3) -3- (((3R, 4R) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -4-nitro-1H-pyrazole (rac)
2.17g of (3S, 4S) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-ol and (3R, 4R) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-ol (1.1 eq) and 3.7g of cesium carbonate (2 eq) are added to a solution of 1.01g (1 eq) 1- (methyl-d 3) -3, 4-dinitro-1H-pyrazole (intermediate 21, step 1) in 50mL of acetonitrile. The mixture was heated at 80 ℃ 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 DCM, then 20% ethyl acetate in dichloromethane) to give 1.23g of 1- (methyl-d 3) -3- (((3 s,4 s) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -4-nitro-1H-pyrazole and 1- (methyl-d 3) -3- (((3 r,4 r) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -4-nitro-1H-pyrazole (rac). MS (method B) m/z 471[ M+1] +; t=2.16 min.
Step 3: preparation of N- (1- (methyl-d 3) -3- (((3R, 4R) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide and N- (1- (methyl-d 3) -3- (((3S, 4S) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (rac)
In a microwave vial, a solution of 0.7g (1 eq) of 1- (methyl-d 3) -3- (((3 s,4 s) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -4-nitro-1H-pyrazole and 1- (methyl-d 3) -3- (((3 r,4 r) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -4-nitro-1H-pyrazole (rac) in 20mL of methanol was treated with 657g (7 eq) ammonium formate and 250mg palladium on carbon (10%). The reaction mixture was heated at 100℃for 15 minutes. The mixture was washed with methanol over celite and filtered and concentrated under reduced pressure to give 1- (methyl-d 3) -3- (((3 r,4 r) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-amine and 1- (methyl-d 3) -3- (((3 s,4 s) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-amine (rac).
Crude 1- (methyl-d 3) -3- (((3R, 4R) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-amine and 1- (methyl-d 3) -3- (((3S, 4S) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-amine (rac) in 10mL of tetrahydrofuran were added dropwise to a cooled (0 ℃) solution of 607mg acetic anhydride (4 equivalents) in 1.23g formic acid (18 equivalents) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 2 hours, then concentrated in vacuo. The residue was purified on silica gel (eluting with 5% methanol in dichloromethane) to give 819mg of N- (1- (methyl-d 3) -3- (((3 r,4 r) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide and N- (1- (methyl-d 3) -3- (((3 s,4 s) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (rac). MS (method A) M/z469[ M+1] +; t=3 min.
Intermediate 66: n- (1- (methyl-d 3) -3- ((4-oxotetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (rac)
Step 1: preparation of N- (3- (((3S, 4S) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide and N- (3- (((3R, 4R) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide (rac)
6.4mL of tetrabutylammonium fluoride (1M in THF) (1.5 eq) was added to a solution of a racemic mixture of 2g N- (1- (methyl-d 3) -3- (((3R, 4R) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide and N- (1- (methyl-d 3) -3- (((3S, 4S) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (1 eq) in 50mL of THF cooled to 0deg.C. The reaction mixture was stirred at room temperature for 15 minutes, and then concentrated under reduced pressure. The residue was purified on silica gel (eluting with 10% methanol in dichloromethane) to give 913mg of N- (3- (((3 s,4 s) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide and N- (3- (((3 r,4 r) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide (rac). MS (method A) m/z 231[ M+1] +; t=0.62 min.
Step 2: preparation of N- (1- (methyl-d 3) -3- ((4-oxotetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (rac)
Dimethyl sulfoxide (2.4 equivalents) in 4mL of methylene chloride was added to a solution of 893mg of oxalyl chloride (1.2 equivalents) in 10mL of methylene chloride at-78deg.C. The reaction mixture was stirred at-78 ℃ for 15 min, then 1.35g N- (3- (((3 s,4 s) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide and N- (3- (((3 r,4 r) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide (rac) (1 eq) in 4mL of dichloromethane were added. The reaction mixture was stirred at-78 ℃ for 45 minutes, then 3g of triethylamine (5 equivalents) was added, and the reaction mixture was stirred at-78 ℃ for 1 hour and at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and purified on silica gel (elution with a gradient of 0 to 100% ethyl acetate in dichloromethane) to give 460mg of N- (1- (methyl-d 3) -3- ((4-oxotetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (rac). MS (method B) m/z 229[ M+1] +; t=0.72 min.
Step 3: preparation of N- (3- ((4-hydroxy-4-methyltetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide (rac)
754. Mu.L of methyl magnesium bromide (3M in tetrahydrofuran) (2 eq) was added to a solution of 258mg of N- (1- (methyl-d 3) -3- ((4-oxotetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide in 8mL of tetrahydrofuran at 0deg.C. The reaction mixture was stirred at 0 ℃ for 1 hour, then quenched with 10mL of saturated aqueous ammonium chloride and extracted with 20mL of ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified on silica (eluting with a gradient of 0 to 50% ethyl acetate in heptane) to give 37mg of N- (3- ((4-hydroxy-4-methyltetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide. MS (method A) m/z 245[ M+1] +; t=1.06 min.
Intermediate 67: n- (1- (methyl-d 3) -3- (((3R, 4S) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide and N- (1- (methyl-d 3) -3- (((3S, 4R) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (rac)
Step 1: preparation of 4- ((tert-butyldiphenylsilyl) oxy) dihydrofuran-3 (2H) -one (rac)
To a solution of 3.42g of 4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-ol (rac) (step 1, intermediate 65) (1 eq) in 70mL of dichloromethane was added 4.65g of Dess-martin periodate (Dess-Martin periodinane) (1.1 eq). The reaction mixture was stirred at 35 ℃ for 3 hours, then cooled to room temperature, and quenched with NaHCO 3 The saturated aqueous solution was quenched and extracted with 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 purified on silica gel (elution with a gradient of ethyl acetate (0/100) to (50/50) in heptane) to give 2.87g of 4- ((tert-butyldiphenylsilyl) oxy) dihydrofuran-3 (2H) -one (racemic). MS (method B) t=2.13 min; no quality is detected
Step 2: preparation of (3R, 4S) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-ol and (3S, 4R) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-ol (rac)
100mg of sodium borohydride (0.7 eq.) are added to a solution of 1.3g of 4- ((tert-butyldiphenylsilyl) oxy) dihydrofuran-3 (2H) -one (racemic) (1 eq.) at 0deg.C. The reaction mixture was stirred at 0 ℃ for 30 min and concentrated in vacuo. The residue was purified on silica gel (elution with a gradient of ethyl acetate (80/20) to (50/50) in heptane) to give 500mg (3R, 4S) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-ol and (3S, 4R) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-ol (rac). MS (method B) t=1.99 min;
Step 3: preparation of 1- (methyl-d 3) -3- (((3R, 4S) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -4-nitro-1H-pyrazole and 1- (methyl-d 3) -3- (((3S, 4R) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -4-nitro-1H-pyrazole
668mg (3R, 4S) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-ol and (3S, 4R) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-ol (1 eq) and 1.3g cesium carbonate (2 eq) are added to a solution of 380mg (1 eq) 1- (methyl-d 3) -3, 4-dinitro-1H-pyrazole (intermediate 21, step 1) in 25mL acetonitrile. The mixture was heated at 80 ℃ 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 dichloromethane, then 20% ethyl acetate in dichloromethane) to give 2918 mg of 1- (methyl-d 3) -3- (((3 r,4 s) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -4-nitro-1H-pyrazole and 1- (methyl-d 3) -3- (((3 s,4 r) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -4-nitro-1H-pyrazole (rac) -estimated purity of 45%. The crude material was taken to the next step without further purification.
Step 4: preparation of N- (1- (methyl-d 3) -3- (((3R, 4S) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide and N- (1- (methyl-d 3) -3- (((3S, 4R) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (rac)
In a microwave vial, a solution of 0.3g (1 eq) 1- (methyl-d 3) -3- (((3R, 4S) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -4-nitro-1H-pyrazole and 1- (methyl-d 3) -3- (((3S, 4R) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -4-nitro-1H-pyrazole (rac) -estimated purity of 45% in 10mL methanol was treated with 271mg (13 eq) ammonium formate and 100mg palladium on carbon (10%). The reaction mixture was heated at 100℃for 15 minutes. The mixture was washed with methanol over celite and filtered and concentrated under reduced pressure to give 1- (methyl-d 3) -3- (((3R, 4S) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-amine and 1- (methyl-d 3) -3- (((3S, 4R) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-amine.
Crude 1- (methyl-d 3) -3- (((3R, 4S) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-amine and 1- (methyl-d 3) -3- (((3S, 4R) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-amine in 10mL of tetrahydrofuran were added dropwise to a cooled (0 ℃) solution of 93mg acetic anhydride (4 eq) in 188mg formic acid (18 eq) which had been premixed for 30 minutes at room temperature. The reaction mixture was stirred at room temperature for 2 hours, then concentrated in vacuo. The residue was purified on silica gel (eluting with 0 to 10% methanol in dichloromethane) to give 84mg of N- (1- (methyl-d 3) -3- (((3R, 4S) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide and N- (1- (methyl-d 3) -3- (((3S, 4R) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (rac). MS (method A) m/z 469[ M+1] +; t=2.79 min.
Intermediate 68: n- (3- (3-hydroxy-2, 4-tetramethylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide
According to the procedure described for intermediate 61, 2-dimethylcyclobutane-1, 3-diol was replaced with 2, 4-tetramethylcyclobutane-1, 3-diol to give 259mg of N- (3- (3-hydroxy-2, 4-tetramethylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide. MS (method B) m/z 471[ M+1] +; t=1.05 min and m/z 471[ m+1] +; t=1.08 min.
Intermediate 69: n- (3- (2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide (racemic cis)
Step 1: preparation of 2- (benzyloxy) -1-methylcyclobutan-1-ol (racemic cis) and 2- (benzyloxy) -1-methylcyclobutan-1-ol (racemic trans)
14.2mL of methylmagnesium bromide (3M in tetrahydrofuran) (1.5 eq.) was added to a solution of 5g of 2-benzyloxycyclobutanone (commercially available) in 120mL of tetrahydrofuran at-78 ℃. The reaction mixture was stirred at room temperature for 2.5 hours, then quenched with 100mL of saturated aqueous ammonium chloride and extracted with 200mL of ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure and purified on silica (eluting with 20% ethyl acetate in heptane) to give 2.64g of 2- (benzyloxy) -1-methylcyclobutan-1-ol (racemic cis) and 1.32g of 2- (benzyloxy) -1-methylcyclobutan-1-ol (racemic trans).
MS (method a) t=2.08 min, no mass (racemic cis and t=1.92 min; no mass (racemic trans) was detected).
Step 2: preparation of 1-methylcyclobutane-1, 2-diol (racemic cis)
A solution of 500mg of 2- (benzyloxy) -1-methylcyclobutan-1-ol (racemic cis) in 20mL of methanol was treated with 200mg of palladium on carbon (10%) under 4.5 bar of hydrogen for 10 hours. The mixture was filtered by washing with dichloromethane and concentrated under reduced pressure. The residue was taken up in dichloromethane and concentrated twice under reduced pressure to give 258mg of 1-methylcyclobutane-1, 2-diol (racemic cis). 1 H NMR(400MHz,CDCl 3 ) Delta, in ppm, 1.30 (s, 3H); 1.76 (m, 1H); 1.82 (m, 1H); 1.94 (m, 1H); 2.09 (m, 1H); 2.97 (width s, 2H); 3.92 (width t, j=6hz, 1 h).
Step 3: preparation of 1-methyl-2- ((1- (methyl-d 3) -4-nitro-1H-pyrazol-3-yl) oxy) cyclobutan-1-ol (racemic cis)
204mg (1.4 eq) of 1-methylcyclobutane-1, 2-diol (racemic cis) and 395mg (2 eq) of potassium carbonate are added to a solution of 250mg (1 eq) of 1- (methyl-d 3) -3, 4-dinitro-1H-pyrazole (intermediate 21, step 1) in 12mL of acetonitrile in a screw cap tube. The mixture was heated at 80 ℃ for 45h, then filtered and concentrated in vacuo. The residue was purified on silica gel (gradient elution with 0 to 60% ethyl acetate in cyclohexane) to give 126mg of 1-methyl-2- ((1- (methyl-d 3) -4-nitro-1H-pyrazol-3-yl) oxy) cyclobutan-1-ol (racemic cis). MS (method F) m/z 231[ M+1] +; t=1.18 min.
Step 4: preparation of N- (3- (2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide (racemic cis)
A solution of 150mg of 1-methyl-2- ((1- (methyl-d 3) -4-nitro-1H-pyrazol-3-yl) oxy) cyclobutan-1-ol (racemic cis) in 20mL of methanol and 20mL of ethyl acetate was treated with 50mg of palladium on carbon (10%) under 3 bar of hydrogen for 2H. The mixture was filtered by washing with ethyl acetate and concentrated under reduced pressure. The residue was taken up in 2mL THF and added at 0 ℃ to a mixture of 0.25mL acetic anhydride and 0.2mL formic acid, which had been premixed for 2h at room temperature. The mixture was stirred at 0 ℃ for 1h, then quenched with 20mL ethyl acetate and 20mL 10% aqueous sodium carbonate with vigorous stirring. The aqueous layer was extracted 4 times with 5mL of dichloromethane and the organic layers were combined, dried over sodium sulfate and concentrated in vacuo to give 145mg of N- (3- (2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide (racemic cis). MS (method F) m/z 229[ M+1] +; t=0.24 and 1.08min (large de-doubled peak).
Intermediate 70: n- (3- (2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide (racemic trans).
Step 1: preparation of 1-methylcyclobutane-1, 2-diol (racemic trans)
900mg of 2-benzyloxy-1-methyl-cyclobutanol (racemic trans) was found to yield 480mg of 1-methylcyclobutane-1, 2-diol (racemic trans) according to step 2 of example 69.
1 H NMR(400MHz,CDCl 3 ) Delta, in ppm, 1.29 (s, 3H); 1.35 (t, j=10 hz,1 h); 1.54 (q, j=11 hz,1 h); 1.77 (t, j=10 hz,1 h); 2.05 (m, 1H); 2.79 (s, 2H); 4.07 (t, j=8.5 hz,1 h).
Step 2: preparation of 1-methyl-2- ((1- (methyl-d 3) -4-nitro-1H-pyrazol-3-yl) oxy) cyclobutan-1-ol (racemic trans)
According to step 3 of example 69, 300mg of 1-methylcyclobutane-1, 2-diol (racemic trans) gave 108mg of 1-methyl-2- ((1- (methyl-d 3) -4-nitro-1H-pyrazol-3-yl) oxy) cyclobutan-1-ol (racemic trans). MS (method F) m/z 231[ M+1] +; t=1.21 min.
Step 3: preparation of N- (3- (2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide (racemic trans).
According to step 4 of example 69, 108mg of 1-methyl-2- ((1- (methyl-d 3) -4-nitro-1H-pyrazol-3-yl) oxy) cyclobutan-1-ol (racemic trans) gave 96mg of N- (3- (2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide (racemic trans). MS (method F) m/z 229[ M+1] +; t=0.93 min.
Intermediate 71: n- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- ((tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (rac).
Step 1: preparation of 1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -4-nitro-3- ((tetrahydrofuran-3-yl) oxy) -1H-pyrazole (rac)
Step 1,1.4g of 1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3, 4-dinitro-1H-pyrazole (1 eq) and 580mg (1.5 eq) of tetrahydrofuran-3-ol (rac) according to example 60 gave 863mg of 1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -4-nitro-3- ((tetrahydrofuran-3-yl) oxy) -1H-pyrazole (rac). MS (method E) m/z 358[ M+1] +; t=1.64 min.
Step 2: preparation of N- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- ((tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (rac)
According to step 2 of example 60, 580mg of 1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -4-nitro-3- ((tetrahydrofuran-3-yl) oxy) -1H-pyrazole (1 eq) was obtained as 389mg of N- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- ((tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (rac). MS (method E) M/z356[ M+1] +; t=1.42 min.
Examples
The following examples are provided to describe the present disclosure in further detail. These examples demonstrate suitable methods of synthesizing representative compounds of the present disclosure. The absolute configuration of some of the compounds described in the examples has been assigned unless specifically indicated. When the compounds described in the examples are obtained as individual diastereomers or enantiomers but the absolute configuration is not determined, the compounds are indicated as "unknown absolute configuration". When the compounds described in the examples were obtained as a mixture, the compounds were indicated as "mixture".
Example 1:2- [ [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
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Step 1: preparation of 2-methylsulfanyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid
3.6g (1 eq) -methyl 2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6 carboxylate (intermediate 1) are added to a solution of 10.41g (3 eq) diisopropyl azodicarboxylate (DIAD) and 12.82g (3 eq) triphenylphosphine in 180mL anhydrous tetrahydrofuran, cooled at-10 ℃. The mixture was stirred at 0℃for 1 hour, then 4.39g (3S, 4S) -4-methyltetrahydrofuran-3-ol (purity 87%) (2.4 eq) (intermediate 2) were added. The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was dissolved in 160mL of tetrahydrofuran and 1.97g (5 eq.) of lithium hydroxide in 18mL of water was added. The mixture was stirred at room temperature for 1 hour, then diluted with 200mL of ethyl acetate and 50mL of water. NaOH 2N was added to reach pH 10. The two phases were separated. The aqueous layer was acidified to pH 1 with HCl 5N. The precipitate formed after acidification is filtered off, washed with water and dried in vacuo (overnight) then left at 40 ℃ for 3 hours to give 1.4g of 2-methylsulfanyl-7- [ (3 r,4 r) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid as a beige solid. The organic layer was dried over magnesium sulfate, concentrated in vacuo, and purified on silica (eluting with 50% ethyl acetate in heptane, then 20% methanol in DCM) to give an additional 2.9g of 2-methylsulfanyl-7- [ (3 r,4 r) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid as a beige solid. MS (method A) m/z 294[ M+1] +; t=1.72 min.
Step 2: preparation of 2-methylsulfanyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxamide
1.46g (2 eq) of bis (1H-imidazol-1-yl) methanone (CDI) are added to a solution of 1.32g of 2-methylsulfanyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid (1 eq) in 15mL of dimethylformamide. The mixture was stirred at room temperature for 1 hour and 3ml of 28% ammonium hydroxide solution was added. The reaction mixture was stirred at room temperature for 1 hour. Then, it was diluted with 100mL of ethyl acetate and washed with water. The organic layer was washed with 50mL of water and 50mL of brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude material was triturated in diisopropyl ether and the solid filtered to give 1.24g of 2-methylsulfanyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxamide as a beige color. MS (method A) m/z 293[ M+1] +; t=1.74 min.
Step 3: preparation of 2-methylsulfanyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
2.42mL (3.6 eq.) of trifluoroacetic anhydride are added to a solution of 1.4g 2-methylsulfanyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxamide (1 eq.) and 3.04mL (4.5 eq.) of triethylamine in 20mL of anhydrous tetrahydrofuran under argon at 0deg.C. The mixture was stirred at 0 ℃ to room temperature for 1 hour and quenched with 100mL ethyl acetate, 100mL diethyl ether and 100mL water with vigorous stirring. The organic layer was washed with 50mL of water and 50mL of brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified on silica (eluted with 0-50% ethyl acetate in cyclohexane) to give 1.3g of 2-methylsulfanyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile. MS (method A) m/z 275[ M+1] +; t=2.28 min.
Step 4: preparation of 2-methylsulfonyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
2.4g of 3-chloroperbenzoic acid (77% purity; 2.1 eq.) are added to a solution of 1.4g (1 eq.) of 2-methylsulfanyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile in 50mL of dichloromethane at 0deg.C. The mixture was stirred at 0 ℃ for 1 hour and at room temperature for 1 hour, then quenched with 50mL of dichloromethane and 50mL of 10% aqueous sodium carbonate. The organic layer was washed successively with 50mL of saturated aqueous sodium carbonate solution, 50mL of water and 50mL of brine, and then dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified on silica (eluted with 0-10% methanol in dichloromethane) to give 1.2g of 2-methylsulfonyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile. MS (method A) m/z 307[ M+1] +; t=1.64 min.
Step 5: preparation of 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
158mg (2.5 eq) of t-butylimino-tris (pyrrolidinyl) phosphane (BTPP) are added to 60mg (1 eq) of 2-methylsulfonyl-7- [ (3R, 4R) -4-methyltetrahydrof-n-3-yl ]Pyrrolo [2,3-d]Pyrimidine-6-carbonitrile and 56mg (1.2 eq) N- (3- ((1-acetylazetidin-3-yl) oxy) -1-methyl-1H-pyrazol-4-yl) carboxamide (intermediate 9) in 4mL of twoIn solution in methylformamide, and the mixture is stirred at room temperature for 4 hours and then diluted with 50mL of ethyl acetate and 50mL of water. The organic layer was washed twice with 50mL of water, then dried over magnesium sulfate, and concentrated under reduced pressure. The residue was taken up in 15mL of methanol and 307 mL of 7n methanolic ammonia solution and stirred for 1 hour, then concentrated under reduced pressure. The residue was taken up on silica (7N NH in MeOH with heptane/AcOEt/ 3 (elution of the mixture at a ratio of (80/18/2) to (50/45/5)) to give 46mg of 2- [ [3- (1-acetylazetidin-3-yl) oxy-1-methyl-pyrazol-4-yl)]Amino group]-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl]Pyrrolo [2,3-d]Pyrimidine-6-carbonitrile.
1 H NMR (400 MHz, DMSO-d 6) delta, in ppm: 1.05 (d, J=7Hz, 3H); 1.77 (s, 3H); 2.91 (m, 1H); 3.47 (m, 1H); 3.68 (s, 3H); 3.82 (m, 1H); 4.07-4.24 (m, 4H); 4.31 (br s, 1H); 4.44 (m, 1H); 4.77 (br s, 1H); 5.08 (m, 1H); 7.47 (s, 1H); 8.11 (br s, 1H); 8.83 (s, 1H); 9.01 (br s, 1H). MS (method B) m/z 437[ M+1 ] ]+；t＝1.34min。
Example 2 and example 3:2- [ [ 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 and 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
The racemic mixture (60 mg) (intermediate 5) of 2-methylsulfonyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidin-6-carbonitrile (80 mg) and N- (1-methyl-3- (((3S, 4R) -4-methyltetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide with N- (1-methyl-3- (((3R, 4S) -4-methyltetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide was generally followed by the procedure described in step 5 of example 1 to give 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 ] pyrimidin-6-carbonitrile and 2- [ [ 1-methyl-3- (((3R, 4S) -4-methyltetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl ] carboxamide Isomer mixtures of the formonitrile (95 mg) (referred to herein as 2- [ [ 1-methyl-3- [ (trans) -4-methyltetrahydrofuran-3-yl ] oxy-1H-pyrazol-4-yl ] amino ] -7- [ (3 r,4 r) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile).
Chiral separation of 82mg of the isomer mixture gave 33mg of the first eluting isomer and 29mg of the second eluting isomer (conditions: column Chiralcel OZ-H,5 μm,250X 30mm; liquid phase: heptane 25/ethanol 75/triethylamine 0.1%; flow rate: 40 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 MHz, DMSO-d 6) delta, in ppm: 1.02 (d, J=7Hz, 3H); 1.05 (d, j=7hz, 3 h); 2.41 (m, 1H); 2.92 (m, 1H); 3.33 (m, 1H); 3.47 (t, j=9hz, 2 h); 3.68 (s, 3H); 3.80 (d, j=10 hz,1 h); 3.90-3.99 (m, 2H); 4.12-4.24 (m, 2H); 4.29 (m, 1H); 4.68 (m, 1H); 4.77 (m, 1H); 7.47 (s, 1H); 8.10 (br s, 1H); 8.82 (s, 2H). MS (method B) m/z 424[ M+1 ]]++, of the material; t=1.56 min-example 2 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 MHz, DMSO-d 6) delta, in ppm: 1.02 (d, J=7Hz, 3H); 1.05 (d, j=7hz, 3 h); 2.41 (m, 1H); 2.92 (m, 1H); 3.33 (m, 1H); 3.47 (t, j=9hz, 2 h); 3.68 (s, 3H); 3.80 (d, j=10 hz,1 h); 3.90-3.99 (m, 2H); 4.12-4.24 (m, 2H); 4.29 (m, 1H); 4.68 (m, 1H); 4.77 (m, 1H); 7.47 (s, 1H); 8.10 (br s, 1H); 8.82 (s, 2H). MS (method B) m/z 424[ M+1 ]]++, of the material; t=1.56 min-example 3 (absolute configuration unknown)
Example 4 and example 5:2- [ [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 and 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-methylsulfonyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (80 mg) and N- [1- [2, 2-difluoro-1-methyl-ethyl ] -3- (oxetan-3-yloxy) pyrazol-4-yl ] carboxamide (69 mg) (intermediate 25) were generally followed by the procedure described in step 5 of example 1 to give 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 as a mixture with 2- [ [1- [ (1S) -2, 2-difluoro-1-methyl-ethyl ] -3- (oxetan-3-yloxy) pyrazol-4-yl ] amino ] -7- [ (3R, 2-difluoro-1-methyl-ethyl ] -3- (oxetan-3-yloxy) pyrazol-4-yl ] amino ] -7- [ (3, 4-methyl-4-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (known as a mixture in 1- [ [ 1S) -2- (2-difluoro-3-yloxy) pyrrol-6-carbonitrile (indicated as being the isomer in 1, step 5 Cyclobutan-3-yloxy) pyrazol-4-yl ] amino ] -7- [ (3 r,4 r) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
Chiral separation of 69mg of the isomer mixture gave 29mg of the first eluting isomer and 30mg of the second eluting isomer (conditions: column Phenomenex cellulose-4,5 μm,250X 30mm; liquid phase: heptane 55/ethanol 45/triethylamine 0.1%; flow rate: 45 mL/min).
Peak 1 (isomer 1): 1 H NMR (400 MHz, DMSO-d 6) delta, 1.03 (d, J=7Hz, 3H) in ppm; 1.48 (d, j=7hz, 3 h); 2.88 (m, 1H); 3.44 (t, j=9hz, 1 h); 4.15 (t, j=9hz, 2 h); 4.32 (m, 1H); 4.51 (m, 1H); 4.59 (m, 2H); 4.76 (m, 1H); 4.82 (t, j=7hz, 2 h); 5.35 (m, 1H); 6.15 (dt, j=4 and 56hz,1 h); 7.49 (s, 1H); 8.17 (br s, 1H); 8.85 (s, 1H); 9.03 (br s, 1H). MS (method B) M/z460[ M+1 ]]++, of the material; t=1.65 min-example 4 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 MHz, DMSO-d 6) delta, in ppm: 1.04 (d, J=7Hz, 3H); 1.49 (d, j=7hz, 3 h); 2.88 (quin, j=7hz, 1 h); 3.44 (t, j=9hz, 1 h); 4,09-4,21 (m, 2H); 4.31 (m, 1H); 4.51 (m, 1H); 4.58 (t, j=6hz, 2 h); 4.76 (m, 1H); 4.82 (t, j=7hz, 2 h); 5.35 (quin, j=6hz, 1 h); 6.13 (td, j=4 and 56hz,1 h); 7.49 (s, 1H); 8.17 (br s, 1H); 8.85 (s, 1H); 9.03 (br s, 1H). MS (method B) m/z460[ M+1 ]]++, of the material; t=1.65 min-example 5 (absolute configuration unknown)
Example 6 and example 7:2- ((1-methyl-3- (((2 r,3 s) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 2- ((1-methyl-3- (((2 s,3 r) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Racemic mixture (290 mg) (intermediate 19) of 2-methylsulfonyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (400 mg) and N- (1-methyl-3- (((2R, 3S) -2-methyltetrahydrofuran-3-yl) oxy) -1H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with N- (1-methyl-3- (((2S, 3R) -2-methyltetrahydrofan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide generally following the procedure described in step 5 of example 1 gave 2- ((1-methyl-3- (((2S, 3R) -2-methyltetrahydrofan-3-yl) oxy) -1H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 2- ((1-methyl-3- (((2S, 3R) -2-methyltetrahydrofan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide followed by intermediate 19 gives 2- ((1-methyl-3- (((2R, 3S) -2-methyltetrahydrofan-3-yl) oxy) -1H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile Isomer mixture of (421 mg) of (methyl tetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile, referred to herein as 2- ((1-methyl-3- (((trans) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile).
Chiral separation of 406mg of the isomer mixture gave 199mg of the first eluting isomer and 187mg of the second eluting isomer (conditions: column Chiralpak AD-H,20 μm,350x 76mm; liquid phase: heptane 50/ethanol 50/triethylamine 0.1%; flow rate: 400 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 MHz, DMSO-d 6) delta, in ppm: 1.06 (d, J=7Hz, 3H); 1.42 (d, j=6hz, 3 h); 2.88-2.97 (m, 1H); 3.47 (t, j=9hz, 1 h); 3.67 (s, 3H); 4.05-4.36 (m, 3H); 4.38-4.51 (m, 1H); 4.66 (t, j=7hz, 1 h); 4.75-4.84 (m, 2H); 4.84-4.93 (m, 1H); 7.48 (s, 1H); 8.09 (br s, 1H); 8.83 (s, 1H); 8.95 (br s, 1H). MS (method B) m/z 410[ M+1 ]]++, of the material; t=1.57 min-example 6 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 MHz, DMSO-d 6) delta, in ppm: 1.06 (d, J=7Hz, 3H); 1.42 (d, j=6hz, 3 h); 2.84-2.97 (m, 1H); 3.47 (t, j=9hz, 1 h); 3.67 (s, 3H); 4.05-4.34 (m, 2H); 4.38-4.45 (m, 1H); 4.66 (t, j=7hz, 1 h); 4.72-4.82 (m, 2H); 4.89 (m, 1H); 7.48 (s, 1H); 8.08 (br s, 1H); 8,83 (s, 1H); 8,95 (br s, 1H). MS (method B) m/z 410[ M+1 ]]++, of the material; t=1.56 min-example 7 (absolute configuration unknown)
Example 8:2- [ [ 1-methyl-3- (oxetan-3-yloxy) pyrazol-4-yl ] amino ] -7- [ (3 r,4 r) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
459mg (2.5 eq) of tert-butylimino-tris (pyrrolidinyl) phosphane (BTPP) was added to a solution of 180mg (1 eq) of 2-methylsulfonyl-7- [ (3 r,4 r) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 139mg (1.2 eq) of N- [ 1-methyl-3- (oxetan-3-yloxy) pyrazol-4-yl ] carboxamide (intermediate 4) in 20mL of dimethylformamide, which was prepared generally according to the procedure described in step 1-4 of example 1, and the mixture was stirred at room temperature for 1.5 hours, then diluted with 50mL of ethyl acetate and 50mL of water. The organic layer was washed 2 times with 50mL of water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was taken up in 5mL of methanol and 5mL of 7n methanolic ammonia solution, stirred for 30 minutes and then concentrated under reduced pressure. The residue was purified on silica eluting with a mixture of heptane/AcOEt (ratio (100/0) to (0/100)) to give 181mg of 2- [ [ 1-methyl-3- (oxetan-3-yloxy) pyrazol-4-yl ] amino ] -7- [ (3 r,4 r) -4-methyltetrahydrof-ran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (181 mg).
1 H NMR (400 MHz, DMSO-d 6) delta, in ppm: 1.05 (d, J=7Hz, 3H); 2.95 (m, 1H); 3.47 (t, j=9h)z, 1H); 3.66 (s, 3H); 4.11-4.24 (m, 2H); 4,30 (br s, 1H); 4.58 (m, 2H); 4.78 (m, 1H); 4.82 (t, j=7hz, 2 h); 5.32 (m, 1H); 7.48 (s, 1H); 8.08 (br s, 1H); 8.83 (s, 1H); 8.99 (br s, 1H). MS (method B) m/z 396[ M+1 ]]+；t＝1.46min。
Example 9:2- [ [1- [ 2-hydroxy-1-methyl-ethyl ] -3- (oxetan-3-yloxy) pyrazol-4-yl ] amino ] -7- [ (3 r,4 r) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Step 1: preparation of methyl 2- [4- [ [ 6-cyano-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidin-2-yl ] amino ] -3- (oxetan-3-yloxy) pyrazol-1-yl ] propionate
2-methylsulfonyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (200 mg) and racemic methyl 2- (4-carboxamido-3- (oxetan-3-yloxy) -1H-pyrazol-1-yl) propanoate (185 mg) (intermediate 33) gave methyl 2- [4- [ [ 6-cyano-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidin-2-yl ] amino ] -3- (oxetan-3-yloxy) pyrazol-1-yl ] propanoate (170 mg) which was used in the next step without further purification.
Step 2: preparation of 2- [ [1- [ 2-hydroxy-1-methyl-ethyl ] -3- (oxetan-3-yloxy) pyrazol-4-yl ] amino ] -7- [ (3R, 4R) -4-methyltetrahydrof-n-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (example 9)
Sodium borohydride (64 mg,7 eq) was added to a solution of methyl 2- [4- [ [ 6-cyano-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidin-2-yl ] amino ] -3- (oxetan-3-yloxy) pyrazol-1-yl ] propionate (110 mg,1 eq) in 5mL of methanol at 0deg.C. The reaction mixture was stirred at 0 ℃ for 1 hour, quenched with 10mL of saturated ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with 50mL of water and 50mL of brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified on silica eluting with a mixture of heptane/AcOEt/7N methanolic ammonia solution (ratio (80/18/2) to (50/45/5)) to give 24mg of 2- [ [1- [ 2-hydroxy-1-methyl-ethyl ] -3- (oxetan-3-yloxy) pyrazol-4-yl ] amino ] -7- [ (3 r,4 r) -4-methyltetrahydrof-N-ol-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (example 9).
1 H NMR (400 MHz, DMSO-d 6) delta, in ppm: 1.04 (d, J=6Hz, 3H); 1.33 (d, j=7hz, 3 h); 2.92 (m, 1H); 3.45 (m, 1H); 3.51 (m, 1H); 3.63 (m, 1H); 4.04-4.22 (m, 3H); 4.30 (m, 1H); 4.59 (m, 2H); 4.75-4.89 (m, 4H); 5.33 (m, 1H); 7.47 (s, 1H); 8.07 (br s, 1H); 8.83 (s, 1H); 8.91 (br s, 1H). MS (method B) m/z 440[ M+1 ] ]+；t＝1.36min。
Example 10 and example 11:7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] -2- [ [1- (oxetan-3-yl) -3- [ (1R) -2, 2-trifluoro-1-methyl-ethoxy ] pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] -2- [ [1- (oxetan-3-yl) -3- [ (1S) -2, 2-trifluoro-1-methyl-ethoxy ] pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Racemic mixture of 2-methylsulfonyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (100 mg) and N- [1- (oxetan-3-yl) -3- [ (1R) -2, 2-trifluoro-1-methyl-ethoxy ] pyrazol-4-yl ] carboxamide with N- [1- (oxetan-3-yl) -3- [ (1S) -2, 2-trifluoro-1-methyl-ethoxy ] pyrazol-4-yl ] carboxamide (96 mg) (intermediate 23) gave 7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] -2- [ [1- (oxetan-3-yl) -3- [ (1R) -2, 2-trifluoro-1-methyl-ethoxy ] pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 7- [ (3R) -4-methyltetrahydrofuran-4-yl ] -pyrazol-4-yl ] carboxamide (96 mg) (intermediate 23) Isomer mixtures of the base pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (129 mg) (referred to herein as 7- [ (3 r,4 r) -4-methyltetrahydrofuran-3-yl ] -2- [ [1- (oxetan-3-yl) -3- (2, 2-trifluoro-1-methyl-ethoxy) pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile).
The 93mg isomer mixture was subjected to chiral separation to give 39mg of the first eluting isomer and 40mg of the second eluting isomer (conditions: column Chiralpak AY-H,5 μm,250X 4.6mm; liquid phase: heptane 80/ethanol 20/triethylamine 0.1%; flow rate: 45 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 MHz, DMSO-d 6) delta, in ppm: 1.05 (d, J=7Hz, 3H); 1.48 (d, j=6hz, 3 h); 2.90 (m, 1H); 3.45 (t, j=9hz, 1 h); 4.18 (m, 2H); 4.30 (m, 1H); 4.76 (m, 1H); 4.85-4.93 (m, 4H); 5.30-5.42 (m, 2H); 7.48 (s, 1H); 8.27 (br s, 1H); 8.84 (s, 1H); 8.94 (br s, 1H). MS (method B) m/z 478[ M+1 ]]++, of the material; t=1.76 min-example 10 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 MHz, DMSO-d 6) delta, in ppm: 1.04 (d, J=7Hz, 3H); 1.48 (d, j=6hz, 3 h); 2.90 (quin, j=7hz, 1 h); 3.44 (t, j=9hz, 1 h); 4.07-4,23 (m, 2H); 4.29 (m, 1H); 4.72 (m, 1H); 4.82-4,98 (m, 4H); 5.26-5.47 (m, 2H); 7.48 (s, 1H); 8,26 (br s, 1H); 8.84 (s, 1H); 8.94 (br s, 1H). MS (method B) m/z 478[ M+1 ]]++, of the material; t=1.76 min-example 11 (absolute configuration unknown)
Example 12 and example 13:2- [ [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 and 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
A racemic mixture (48 mg) (intermediate 17) of 2-methylsulfonyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidin-6-carbonitrile (60 mg) and N- (3- (((3R, 4R) -4-methoxytetrahydrofuran-3-yl) oxy) -1-methyl-1H-pyrazol-4-yl) carboxamide with N- (3- (((3S, 4S) -4-methoxytetrahydrofuran-3-yl) oxy) -1-methyl-1H-pyrazol-4-yl) carboxamide gave 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 ] pyrimidin-6-carbonitrile with 2- [ [3- [ (3S, 4S) -4-methoxytetrahydrofuran-3-yl ] oxy ] -1-methyl-1H-pyrazol-4-yl ] carboxamide An isomeric mixture of nitriles (70 mg) (referred to herein as 2- [ [3- [ (trans) -4-methoxytetrahydrofuran-3-yl ] oxy-1-methyl-pyrazol-4-yl ] amino ] -7- [ (3 r,4 r) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile).
Chiral separation of 61mg of the isomer mixture gave 24mg of the first eluting isomer and 23mg of the second eluting isomer (conditions: column Phenomenex Lux Amylose-1, 250X 30mm; liquid phase: heptane 20/ethanol 80/triethylamine 0.1%; flow rate: 40 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 MHz, DMSO-d 6) delta, in ppm: 1.06 (d, J=7Hz, 3H); 2.92 (spt, j=7hz, 1 h); 3.34 (mmask, 3H); 3.48 (t, j=9hz, 1 h); 3.67 (m, 1H); 3.70 (s, 3H); 3.84 (d, j=10 hz,1 h); 3.93 (m, 2H); 4.04 (m, 1H); 4.16 (t, j=9hz, 1 h); 4.22 (t, j=8 hz,1 h); 4.34 (br s, 1H); 4.78 (dt, j=1 and 7hz,1 h); 4.96 (d, j=4hz, 1 h); 7.48 (s, 1H); 8.13 (br s, 1H); 8.83 (s, 1H); 8.93 (br s, 1H). MS (method B) m/z 440[ M+1 ]]++, of the material; t=1.5 min-example 12 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 MHz, DMSO-d 6) delta, in ppm: 1.06 (d, J=7Hz, 3H); 2.92 (spt, j=7.1h); 3.33 (mmask 3H); 3.48 (t, j=9hz, 1 h); 3.67 (m, 1H); 3.70 (s, 3H); 3.84 (d, j=10 hz,1 h); 3.93 (m, 2H); 4.04 (d, j=4hz, 1 h); 4.17 (t, j=9hz, 1 h); 4.22 (t, j=8 hz,1 h); 4.31 (br s, 1H); 4.78 (m, 1H); 4.96 (d, j=4hz, 1 h); 7.48 (s, 1H); 8.14 (br s, 1H); 8.83 (s, 1H); 8.92 (br s, 1H). MS (method B) m/z 440[ M+1 ]]++, of the material; t=1.5 min-example 13 (absolute configuration unknown)
Example 14:2- [ [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-methylsulfonyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (100 mg) and N- (1- ((methylsulfonyl) methyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide (48 mg) (intermediate 13) gave 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 (129 mg) (example 14).
1 H NMR (400 MHz, DMSO-d 6) delta, in ppm: 1.04 (d, J=7Hz, 3H); 2.88 (m, 1H); 2.99 (s, 3H); 3.45 (t, j=9hz, 1 h); 4.15 (t, j=9hz, 1 h); 4.20-4.30 (m, 2H); 4.5 (m, 2H); 4.80-4.90 (m, 3H); 5.34-5.54 (m, 3H); 7.52 (s, 1H); 8.27 (br s, 1H); 8.88 (s, 1H); 9.20 (br s, 1H). MS (method B) m/z 474[ M+1 ]]+；t＝1.36min。
Example 15 and example 16:2- ((1- (methyl-d 3) -3- (((2 r,3 s) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 2- ((1- (methyl-d 3) -3- (((2 s,3 r) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Racemic mixture (189 mg) (intermediate 21) of 2-methylsulfonyl-7- [ (3 r,4 r) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (245 mg) and N- (1- (methyl-d 3) -3- (((2 s,3 r) -2-methyltetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide with N- (1- (methyl-d 3) -3- (((2 r,3 s) -2-methyltetrahydrofan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide was generally followed by the procedure described in step 5 of example 1 to give 2- ((1- (methyl-d 3) -3- (((2 r,3 s) -2-methyltetrahydrofan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-methyltetrahydrofan-4-yl) amino) -7- ((3 r, 3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-1H-pyrazol-4-yl) carboxamide with 2- ((3 r, 3-methyltetrahydrofen-4-yl) oxy) -1H-pyrazol-4-yl) carboxamide -4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (267 mg) (referred to herein as 2- ((1- (methyl-d 3) -3- (((trans) -2-methyltetraoxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile).
Chiral separation of 262mg of the isomer mixture gave 113mg of the first eluting isomer and 96mg of the second eluting isomer (conditions: column Chiralpak AD-H,20 μm,350x 76mm; liquid phase: heptane 50/ethanol 50/triethylamine 0.1%; flow rate: 400mL/min, then column Amylose-1.5 μm,250x 30mm; liquid phase: heptane 80/ethanol 20/triethylamine 0.1%; flow rate: 45 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 MHz, DMSO-d 6) delta, in ppm: 1.05 (d, J=7Hz, 3H); 1.41 (d, j=6hz, 3 h); 2.92 (dqin, j=8 and 15hz,1 h); 3.46 (t, j=9hz, 1 h); 4.10-4.24 (m, 2H); 4.30 (m, 1H); 4.41 (dd, j=6 and 7hz,1 h); 4.65 (t, j=6hz, 1 h); 4.72-4.83 (m, 2H); 4.89 (m, 1H); 7.47 (s, 1H); 8.07 (br s, 1H); 8.82 (s, 1H); 8.96 (br s, 1H). MS (method B) m/z 413[ M+1 ]]++, of the material; t=1.5 min-example 15 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 MHz, DMSO-d 6) delta, in ppm: 1.05 (d, J=7Hz, 3H); 1.41 (d, j=6hz, 3 h); 2.92 (dqin, j=7 and 15hz,1 h); 3.46 (t, j=9hz, 1 h); 4.16 (q, j=9hz, 2 h); 4.29 (m, 1H); 4.40 (dd, j=6 and 7hz,1 h); 4.66 (t, j=7hz, 1 h); 4.71-4.84 (m, 2H); 4.89 (q, j=6hz, 1 h); 7.47 (s, 1H); 8.06 (br s, 1H); 8.82 (s, 1H); 8.95 (br s, 1H).MS (method B) m/z 413[ M+1 ]]++, of the material; t=1.49 min-example 16 (absolute configuration unknown)
Example 17 and example 18:2- ((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 and 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
Racemic mixture (87 mg) (intermediate 32) of 2-methylsulfonyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (110 mg) and (R) -N- (3- ((1-acetyl-2, 2-dimethylazetidin-3-yl) oxy) -1-methyl-1H-pyrazole-4-yl) carboxamide with (S) -N- (3- ((1-acetyl-2, 2-dimethylazetidin-3-yl) oxy) -1-methyl-1H-pyrazol-4-yl) carboxamide gave 2- ((3- (((R) -1-acetyl-2, 2-dimethylazetidin-3-yl) oxy) -1-methyl-1H-pyrazol-4-yl) amino) -7- ((3R, 4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-1-methyl-4-yl) carboxamide with (S) -2- ((3- (-acetyl-2, 2-dimethylazetidin-3-yl) oxy) -1- (-2-acetyl) -4-yl) carboxamide following the procedure described in step 5 of example 1 -methyl-1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (99 mg) (referred to herein as 2- ((3- ((1-acetyl-2, 2-dimethylazetidin-3-yl) oxy) -1-methyl-1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile).
The 94mg isomer mixture was subjected to chiral separation to give 34mg of the first eluting isomer and 35mg of the second eluting isomer (conditions: column Chiralcel OD-H,5 μm,250X 4.6mm; liquid phase: heptane 50/ethanol 50/triethylamine 0.1%; flow rate: 42 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 MHz, DMSO-d 6) delta, in ppm, 1.05 (d, J=)7Hz, 3H); 1.37 (s, 3H); 1.52 (s, 3H); 1.70 (s, 3H); 2.92 (spt, j=7hz, 1 h); 3.47 (t, j=9hz, 1 h); 3.67 (s, 3H); 3.96 (dd, j=5 and 10hz,1 h); 4.16 (t, j=9hz, 1 h); 4.22 (td, j=3 and 8hz,1 h); 4.26-4.40 (m, 2H); 4.76 (m, 1H); 4.80 (m, 1H); 7.47 (s, 1H); 8.10 (br s, 1H); 8.83 (s, 1H); 8.96 (br s, 1H). MS (method B) m/z 465[ M+1 ]]++, of the material; t=1.48 min-example 17 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 MHz, DMSO-d 6) delta, in ppm: 1.05 (d, J=7Hz, 3H); 1.37 (s, 3H); 1.52 (s, 3H); 1.70 (s, 3H); 2.92 (spt, j=7hz, 1 h); 3.47 (t, j=9hz, 1 h); 3.67 (s, 3H); 3.96 (dd, j=5 and 10hz,1 h); 4.16 (t, j=9hz, 1 h); 4.22 (td, j=3 and 8hz,1 h); 4.26-4.40 (m, 2H); 4.76 (m, 1H); 4.80 (m, 1H); 7.47 (s, 1H); 8.13 (br s, 1H); 8.83 (s, 1H); 8.98 (br s, 1H). MS (method B) m/z 465[ M+1 ]]++, of the material; t=1, 48 min-example 18 (absolute configuration unknown)
Example 19:2- ((1- (methyl-d 3) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
2-methylsulfonyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (40 mg) and N- (1- (methyl-d 3) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide (32 mg) (intermediate 26) were generally prepared according to the procedure described in step 5 of example 1 to give 2- ((1- (methyl-d 3) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- ((3R, 4R) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (35 mg).
1 H NMR (400 MHz, DMSO-d 6) delta in ppm 1.05 (d, J=6.8 Hz, 3H), 2.92 (m, 1H), 3.47 (t, J=8.8 Hz, 1H), 4.12-4.35 (m, 3H), 4.57 (m, 2H), 4.72-4.84 (m, 3H), 5.31 (tt, J=6.0 and 5.0Hz, 1H), 7.46 (s, 1H), 8.04 (br s, 1H), 8.82 (s, 1H), 8.92 (br s, 1H). MS (method D) m/z 399[ M+1]]+；t＝1.03min。
Example 20:2- ((4- (2-hydroxypropan-2-yl) -2- (oxetan-3-yloxy) phenyl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Step 1: preparation of methyl 4- ((6-cyano-7- ((3R, 4R) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3- (oxetan-3-yloxy) benzoate
Methyl 2-methylsulfonyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (100 mg) and 4-carboxamide-3- (oxetan-3-yloxy) benzoate (90 mg) (intermediate 35) were generally followed by the procedure described in step 5 of example 1 to give methyl 4- ((6-cyano-7- ((3R, 4R) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3- (oxetan-3-yloxy) benzoate (146 mg). MS (method A) m/z 450[ M+1] +; t=2.54 min.
Step 2: preparation of 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
467 μl (10 eq) of methyl magnesium bromide 3M in tetrahydrofuran is added to a solution of 63mg (1 eq) of methyl 4- ((6-cyano-7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3- (oxetan-3-yloxy) benzoate in 4.5mL of tetrahydrofuran at 0 ℃. The reaction mixture was stirred at 0 ℃ for 30 minutes, then 4 equivalents of methyl magnesium bromide 3M in tetrahydrofuran were added and the reaction mixture was stirred at 0 ℃ for 30 minutes. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with 50mL of water and 50mL of brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified on silica eluting with a mixture of heptane/AcOEt/7N methanolic ammonia solution (80/18/2) to give 35mg of 2- ((4- (2-hydroxypropan-2-yl) -2- (oxetan-3-yloxy) phenyl) amino) -7- ((3 r,4 r) -4-methyltetrahydrof-N-ol-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile as a yellow solid.
1 H NMR (400 MHz, DMSO-d 6) delta, 1.08 (d, J=7Hz, 3H) in ppm; 1.42 (s, 6H); 2.95 (m, 1H); 3.48 (t, j=9hz, 1 h); 4.12-4.31 (m, 3H); 4.63 (dd, j=5 and 7hz,2 h); 4.86 (q, j=8 hz,1 h); 4.93 (t, j=7hz, 2 h); 4.98 (s, 1H); 5.35 (m, 1H); 6.73 (d, j=2 hz,1 h); 7.07 (dd, j=2 and 8hz,1 h); 7.55 (s, 1H); 8.25 (d, j=8 hz,1 h); 8.43 (s, 1H); 8.91 (s, 1H). MS (method B) m/z 450[ M+1 ] ]+；t＝1.54min。
Example 21 and example 22:2- ((1-methyl-3- (((R) -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 and 2- ((1-methyl-3- (((S) -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-methylsulfonyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (100 mg) and N- (1-methyl-3- ((1, 1-trifluoropropan-2-yl) oxy) -1H-pyrazol-4-yl) carboxamide (82 mg) (intermediate 7) were typically followed by the procedure described in step 5 of example 1 to afford 2- ((1-methyl-3- (((R) -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 as a mixture with 2- ((1-methyl-3- (((S) -1, 1-trifluoropropan-2-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3- (((R) -1, 1-trifluoropropan-2-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3-methyltetrahydrofuran-3-yl) amino) -1H-pyrrol-3-yl ] amino (1, 2-methyltetrahydrofuran-3-yl) and (1, 3-d) pyrimidine-2-d ] pyrimidine-3-yl (2, 3-d) as a mixture known as 1- ((1, 90 mg) in this text 2-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
Chiral separation of 65mg of the isomer mixture gave 31mg of the first eluting isomer and 35mg of the second eluting isomer (conditions: column ChiralpaK AY-H,5 μm,250X 30mm; liquid phase: step gradient from heptane 70/ethanol 30/triethylamine 0.1% to heptane 30/ethanol 70/triethylamine 0.1%; flow rate: 40 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 MHz, DMSO-d 6) delta, in ppm: 1.05 (d, J=7Hz, 3H); 1.43 (d, j=6hz, 3 h); 2.91 (spt, j=7hz, 1 h); 3.46 (t, j=9hz, 1 h); 3.71 (s, 3H); 4.14 (t, j=8 hz,1 h); 4.21 (t, j=8 hz,1 h); 4.29 (m, 1H); 4.79 (m, 1H); 5.23 (spt, j=7hz, 1 h); 7.48 (s, 1H); 8.08 (br s, 1H); 8.82 (s, 1H); 8.86 (br s, 1H). MS (method B) m/z 436[ M+1 ]]++, of the material; t=1.76 min-example 21 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 MHz, DMSO-d 6) delta, in ppm: 1.05 (d, J=7Hz, 3H); 1.43 (d, j=6hz, 3 h); 2.91 (spt, j=7hz, 1 h); 3.46 (t, j=9hz, 1 h); 3.70 (s, 3H); 4.04-4.34 (m, 3H); 4.75 (m, 1H); 5.23 (spt, j=7hz, 1 h); 7.47 (s, 1H); 8.06 (br s, 1H); 8.82 (s, 1H); 8.86 (s is large, 1H). MS (method B) m/z 436[ M+1 ]]++, of the material; t=1.76 min-example 22 (absolute configuration unknown)
Examples 23 and 24:2- ((1- (methyl-d 3) -3- (((2 r,3 r) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 2- ((1- (methyl-d 3) -3- (((2 s,3 s) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
The racemic mixture (189 mg) (intermediate 22) of 2-methylsulfonyl-7- [ (3 r,4 r) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (245 mg) and N- (1- (methyl-d 3) -3- (((2 s,3 s) -2-methyltetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide with N- (1- (methyl-d 3) -3- (((2 r,3 r) -2-methyltetrahydrofan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide was generally according to the procedure described in step 5 of example 1 to give 2- ((1- (methyl-d 3) -3- (((2 r,3 r) -2-methyltetrahydrofan-3-yl) oxy) -7H-pyrrolo [2,3-d ] pyrimidine-6-H-pyrazol-4-yl) carboxamide with N- (1- (methyl-d 3) -3- (((2 r,3 r) -2-methyltetrahydrofan-4-yl) oxy) -1H-pyrazol-4-yl) carboxamide -4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile, a mixture of isomers (235 mg) (referred to herein as 2- ((1- (methyl-d 3) -3- (((cis) -2-methyltetralin-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile).
The chiral separation of 230mg of the isomer mixture gave 100mg of the first eluting isomer and 102mg of the second eluting isomer (conditions: column ChiralpaK AD,20 μm,250X 30mm; liquid phase: step gradient: heptane 60/ethanol 40; flow rate: 400 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 mhz, dmso-d 6) δ in ppm 1,05 (d, j=7hz, 3H); 1,30 (d, j=6hz, 3 h); 2,93 (spt, j=7hz, 1 h); 3,47 (t, j=9hz, 1 h); 4,16 (t, j=10 hz,1 h); 4,21 (t, j=8 hz,1 h); 4,32 (m, 1H); 4,46 (dd, j=5 and 7hz,1 h); 4,74 (dd, j=6 and 7hz,1 h); 4,81 (m, 1H); 5,04 (quin, j=6hz, 1 h); 5,30 (q, j=6hz, 1 h); 7,48 (s, 1H); 8,10 (br s, 1H); 8,83 (s, 1H); 8,99 (br s, 1H). MS (method B) m/z 413[ M+1 ]]++, of the material; t=1.46 min-example 23 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 MHz, DMSO-d 6) delta, in ppm: 1.05 (d, J=7Hz, 3H); 1.30 (d, j=6hz, 3 h); 2.90 (spt, j=7hz, 1 h); 3.46 (t, j=9hz, 1 h); 4.17 (m, 2H); 4.31 (m, 1H); 4.46 (dd, j=5 and 7hz,1 h); 4.72 (dd, j=6 and 7hz,1 h); 4.79 (m, 1H); 5.03 (quin, j=6hz, 1 h); 5.29 (td, j=5 and 6hz,1 h); 7.47 (s, 1H); 8.09 (br s, 1H); 8.83 (s, 1H); 8.97 (br s, 1H). MS (method B) m/z 413[ M+1 ]]++, of the material; t=1.46 min-example 24 (absolute configuration unknown)
The reaction of 2-methylsulfonyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with the appropriate formamide generally follows the procedure described in example 1 to give examples 25 to 43 in Table I.
TABLE I
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Example 44:2- ((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
Following the procedure described in example 1, starting with (3 r,4 r) -4-methyltetrahydrofuran-3-ol (intermediate 3) instead of (3 s,4 s) -4-methyltetrahydrofuran-3-ol in step 1 and substituting N- (3- ((1-acetylazetidin-3-yl) oxy) -1-methyl-1H-pyrazol-4-yl) carboxamide with N- [ 1-methyl-3- (oxetan-3-yloxy) pyrazol-4-yl ] carboxamide (intermediate 4) in step 5, 69mg of 2- ((1-methyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- ((3 s,4 s) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile is prepared.
1 H NMR (400 MHz, DMSO-d 6) delta, in ppm: 1.05 (d, J=7Hz, 3H); 2.92 (dqin, j=8 and 15hz,1 h); 3.47 (t, j=9hz, 1 h); 3.66 (s, 3H); 4.08-4.39 (m, 3H); 4.57 (dt, J=4 and 8Hz, 2H); 4.75 (m, 1H); 4.81 (t, j=7hz, 2 h); 5.31 (quin, j=6hz, 1 h); 7.47 (s, 1H); 8.08 (br s, 1H); 8.83 (s, 1H); 8.98 (br s, 1H). MS (method B) m/z 396[ M+1 ]]+；t＝1.40min。
Example 45 and example 46:2- ((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 and 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
Step 1: preparation of a racemic mixture of methyl 2-methylsulfanyl-7- [ (3S, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxylate and methyl 2-methylsulfanyl-7- [ (3R, 4S) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxylate
A racemic mixture (1.5 eq) of 0.82g (3R, 4S) -4-methyltetrahydrofuran-3-ol and (3S, 4R) -4-methyltetrahydrofuran-3-ol (commercially available) was added to a solution of 1.99g (1.4 eq) triphenylphosphine in 50mL tetrahydrofuran and 1g (1 eq) methyl 2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylate (intermediate 1). The reaction mixture was cooled to 0 ℃ and 1.6mL of diisopropyl azodicarboxylate (DIAD) (1.5 eq) was added. The mixture was stirred overnight at room temperature, concentrated under reduced pressure and purified on silica (eluting with 20% ethyl acetate in heptane) to give a racemic mixture of 1g of methyl 2-methylsulfanyl-7- [ (3 s,4 r) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxylate and methyl 2-methylsulfanyl-7- [ (3 r,4 s) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxylate. MS (method A) m/z 308[ M+1] +; t=2 min.
Step 2: preparation of racemic mixtures of 2-methylsulfanyl-7- [ (3S, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxamide with 2-methylsulfanyl-7- [ (3R, 4S) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxamide
A racemic mixture of 1g (1 eq) of methyl 2-methylsulfanyl-7- [ (3S, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxylate and methyl 2-methylsulfanyl-7- [ (3R, 4S) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxylate in 70mL of 7N ammonia solution in methanol in a sealed tube was stirred at room temperature for 3 days. The mixture was then concentrated under reduced pressure and purified on silica (eluting with 20% ethyl acetate in heptane) to give 0.715g of a racemic mixture of 2-methylsulfanyl-7- [ (3 s,4 r) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxamide and 2-methylsulfanyl-7- [ (3 r,4 s) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxamide. MS (method A) m/z 293[ M+1] +; t=1.66 min.
Step 3: preparation of racemic mixtures of 2-methylsulfanyl-7- [ (3S, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 2-methylsulfanyl-7- [ (3R, 4S) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
1.22mL (3.6 eq) of trifluoroacetic anhydride was added to a solution of 0.715g of a racemic mixture of 2-methylsulfanyl-7- [ (3S, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxamide and 2-methylsulfanyl-7- [ (3R, 4S) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxamide, 1.55mL (4.5 eq) of triethylamine in 21mL of anhydrous tetrahydrofuran under argon at 0deg.C. The mixture was stirred at room temperature for 4 hours and quenched with 100mL of ethyl acetate and 100mL of saturated aqueous sodium bicarbonate with vigorous stirring. The organic layer was washed with 50mL of water and 50mL of brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified on silica (eluted with 20% ethyl acetate in heptane) to give 0.68g of a racemic mixture of 2-methylsulfanyl-7- [ (3S, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 2-methylsulfanyl-7- [ (3R, 4S) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile. MS (method A) m/z 275[ M+1] +; t=2.19 min.
Step 4: preparation of a racemic mixture of 2-methylsulfonyl-7- [ (3S, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 2-methylsulfonyl-7- [ (3R, 4S) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
1.28g of 3-chloroperbenzoic acid (77% purity; 2.3 eq) are added to a solution of 0.68g (1 eq) of a racemic mixture of 2-methylsulfanyl-7- [ (3S, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 2-methylsulfanyl-7- [ (3R, 4S) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile in 20mL of dichloromethane at 0 ℃. The mixture was stirred at room temperature for 1 hour, then quenched with 50mL of dichloromethane and 40mL of 10% aqueous sodium thiosulfate. The organic layer was washed successively with 40mL of saturated aqueous sodium bicarbonate, 50mL of brine, then dried over magnesium sulfate and concentrated under reduced pressure to give 0.58g of a racemic mixture of 2-methylsulfonyl-7- [ (3S, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 2-methylsulfonyl-7- [ (3R, 4S) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile. MS (method A) m/z 307[ M+1] +; t=1.58 min.
Step 5: preparation of 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 with 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
In general following the procedure described in step 5 of example 1, racemic mixture (155 mg) of 2-methylsulfonyl-7- [ (3S, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 2-methylsulfonyl-7- [ (3R, 4S) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and N- (1-methyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide (105 mg) (intermediate 4) gave a mixture of 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 with 2- ((1-methyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- ((3S, 4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and (3 mg) (intermediate 4) to give a mixture of 2- ((1-methyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide (105 mg) (intermediate 4) as described herein as methyl-3 mg - ((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).
Chiral separation of 135mg of the mixture gave 58mg of the first eluting isomer and 59mg of the second eluting isomer (conditions: column Phenomenex Lux Amylose-1,5 μm,250X 4.6mm; liquid phase: heptane 20/ethanol 80/triethylamine 0.1%; flow rate: 40 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 MHz, DMSO-d 6) delta, 0.55 (d, J=7Hz, 3H) in ppm; 2.67 (m, 1H); 3.65 (s, 3H); 3.70 (m, 1H); 3.97 (t, j=8 hz,1 h); 4.31 (dd, j=8 and 10hz,1 h); 4.57 (q, j=6hz, 2 h); 4.65 (m, 1H); 4.81 (t, j=7hz, 2 h); 5.21 (m, 1H); 5.31 (m, 1H); 7.49 (s, 1H); 8.05 (d, j=2 hz,1 h); 8.82 (s, 1H); 8.91 (br s, 1H). MS (method D) m/z 396[ M+1 ]]++, of the material; t=2.63 min-example 45 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 MHz, DMSO-d 6) delta, 0.55 (d, J=7Hz, 3H) in ppm; 2.67 (m, 1H); 3.65 (s, 3H); 3.71 (m, 1H); 3.97 (t, j=8 hz,1 h); 4.31 (dd, j=8 and 10hz,1 h); 4.57 (q, j=6hz, 2 h); 4.66 (m, 1H); 4.81 (t, j=7hz, 2 h); 5.21 (br s, 1H); 5.31 (quin, j=6hz, 1 h); 7.49 (s, 1H); 8.05 (br s, 1H); 8.82 (s, 1H); 8.92 (br s, 1H). MS (method D) m/z 396[ M+1 ]]++, of the material; t=2.63 min-example 46 (absolute configuration unknown)
Example 47:2- ((3-isopropoxy-1-methyl-1H-pyrazol-4-yl) amino) -7- ((3S, 4R) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 2- ((3-isopropoxy-1-methyl-1H-pyrazol-4-yl) amino) -7- ((3R, 4S) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (racemic mixture)
A racemic mixture (60 mg) of 2-methylsulfonyl-7- [ (3S, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 2-methylsulfonyl-7- [ (3R, 4S) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile in 5mL of dimethylformamide (example 45, step 4), 38mg (1.05 eq) of N- (3-isopropoxy-1-methyl-1H-pyrazol-4-yl) carboxamide (intermediate 38) and 192mg (3 eq) of cesium carbonate were heated at 60℃for 1 hour. The mixture was cooled to room temperature and then diluted with 50mL of ethyl acetate and 50mL of water. The organic layer was washed twice with 50mL of water, then dried over magnesium sulfate, and concentrated under reduced pressure. The residue was taken up in 15ml of 7n methanolic ammonia solution and stirred for 30 minutes, then concentrated under reduced pressure. The residue was purified on silica (eluting with a dichloromethane/methanol mixture (98/2)) to give 43mg of a racemic mixture of 2- ((3-isopropoxy-1-methyl-1H-pyrazol-4-yl) amino) -7- ((3 s,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 2- ((3-isopropoxy-1-methyl-1H-pyrazol-4-yl) amino) -7- ((3 r,4 s) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (referred to herein as 2- ((3-isopropoxy-1-methyl-1H-pyrazol-4-yl) amino) -7- ((cis) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile).
1 H NMR (400 MHz, DMSO-d 6) delta, 0.55 (d, J=7Hz, 3H) in ppm; 1.26 (d, j=3 hz,3 h); 1.28 (d, j=3 hz,3 h); 2.68 (m, 1H); 3.67 (s, 3H); 3.72 (t, j=9hz, 1 h); 3.96 (m, 1H); 4.31 (dd, j=8 and 10hz,1 h); 4.59-4.81 (m, 2H); 5.24 (m, 1H); 7.48 (s, 1H); 8.05 (br s, 1H); 8.50 (br s, 1H); 8.81 (s, 1H). MS (method B) m/z 382[ M+1 ]]+；t＝1.51min。
Example 48, example 49, example 50 and example 51:2- ((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 and 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 and 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 and 2- ((1- ((S) -1-cyanoethyl) -3-isopropoxy-1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 2- ((1-cyanoethyl) -3-isopropoxy-1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile Carbonitrile
Following the procedure described in example 47, a racemic mixture (200 mg) of 2-methylsulfonyl-7- [ (3S, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 2-methylsulfonyl-7- [ (3R, 4S) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (step 4 of example 45) and racemic N- (1- (1-cyanoethyl) -3-isopropoxy-1H-pyrazol-4-yl) carboxamide (152 mg) (intermediate 39) gave 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 with 2- ((1- ((S) -1-cyanoethyl) -3-isopropoxy-1H-pyrazol-4-yl) amino) -7- ((3S, 4-methyltetrahydrofuran-3-yl) -7- ((3-4-d) amino) -7- ((3-methyl-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile An isomeric mixture of ((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 and 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 (referred to herein as 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) (160 mg).
160mg of the isomer mixture was subjected to chiral separation. The first separation gave 84mg of a mixture of 2 compounds and 66mg of a mixture of 2 other compounds (conditions: column Chiralpak-IC,20 μm,350X 76mm; liquid phase: heptane 20/ethanol 80; flow rate: 400 mL/min).
A first mixture of 2 compounds (84 mg) was separated by chiral chromatography to give 36mg of the first eluting isomer and 32mg of the second eluting isomer (conditions: column Chiralpak-AY-H,5 μm,250X 30mm; liquid phase: heptane 80/ethanol 20; flow rate: 45 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 MHz, DMSO-d 6) delta, 0.56 (d, J=7Hz, 3H) in ppm; 1.32 (d, j=6hz, 6 h); 1.80 (d, j=7hz, 3 h); 2.73 (m, 1H); 3.73 (t, j=9hz, 1 h); 3.99 (t, j=8 hz,1 h); 4.34 (dd, j=8 and 10hz,1 h); 4.71 (m, 1H); 4.81 (spt, j=7hz, 1 h); 5.22 (m, 1H); 5.55 (q, j=7hz, 1 h); 7.51 (s, 1H); 8.31 (m, 1H); 8.71 (br s, 1H); 8.86 (s, 1H). MS (method B) m/z421[ M+1 ]]++, of the material; t=1.7 min-example 48 (absolute configuration unknown)
Peak 2 (eluting isomer 2): 1 h NMR (400 MHz, DMSO-d 6) delta, 0.56 (d, J=7Hz, 3H) in ppm; 1.32 (dd, j=3 and 6hz,6 h); 1.79 (d, j=7hz, 3 h); 2.71 (m, 1H); 3.71 (t, j=9hz, 1 h); 3.99 (t, j=8 hz,1 h); 4.34 (dd, j=8 and 10hz,1 h); 4.64-4.90 (m, 2H); 5.23 (m, 1H); 5.54 (q, j=7hz, 1 h); 7.51 (s, 1H); 8.30 (br s, 1H); 8.71 (br s, 1H); 8,86 (s, 1H). MS (method B) M/z421[ M+1 ] ]++, of the material; t=1.7 min-example 49 (absolute configuration unknown)
A second mixture of 2 compounds (66 mg) was separated by chiral chromatography to give 34mg of the first eluting isomer and 39mg of the second eluting isomer (conditions: column Chiralpak-AY-H,5 μm,250X 30mm; liquid phase: heptane 60/ethanol 40; flow rate: 45 mL/min).
Peak 1 (eluting isomer 1): 1 h NMR (400 MHz, DMSO-d 6) delta, 0.56 (d, J=7Hz, 3H) in ppm; 1.31 (d, j=3 hz,3 h); 1.33 (d, J=3 Hz3H); 1.79 (d, j=7hz, 3 h); 2.70 (m, 1H); 3.71 (t, j=9hz, 1 h); 3.99 (t, j=8 hz,1 h); 4.33 (dd, j=9 and 11hz,1 h); 4.70 (m, 1H); 4.81 (spt, j=6hz, 1 h); 5.24 (m, 1H); 5.54 (q, j=6hz, 1 h); 7.51 (s, 1H); 8.30 (br s, 1H); 8.71 (br s, 1H); 8.86 (s, 1H). MS (method B) m/z 421[ M+1 ]]++, of the material; t=1.7 min-example 50 (absolute configuration unknown)
Peak 2 (eluting isomer 2): 1 h NMR (400 MHz, DMSO-d 6) delta, 0.56 (d, J=7Hz, 3H) in ppm; 1.32 (d, j=6hz, 6 h); 1.80 (d, j=7hz, 3 h); 2.70 (m, 1H); 3.73 (t, j=9hz, 1 h); 3.99 (t, j=8 hz,1 h); 4.34 (t, j=9hz, 1 h); 4.62-4.92 (m, 2H); 5.23 (m, 1H); 5.55 (q, j=7hz, 1 h); 7.51 (s, 1H); 8.32 (br s, 1H); 8.71 (br s, 1H); 8.86 (s, 1H). MS (method B) m/z 421[ M+1 ] ]++, of the material; t=1.7 min-example 51 (absolute configuration unknown)
Examples 52 and 53: (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 and (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
Step 1: preparation of 2- (methylthio) -7- (tetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
1.36g diisopropyl azodicarboxylate (DIAD) (3 eq.) was added to a solution of 1.67g (3 eq.) triphenylphosphine in 20mL tetrahydrofuran and 0.4g (1 eq.) of racemic 2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (intermediate 43) at 0deg.C. The reaction mixture was stirred at 0deg.C for 30 minutes, then 0.56g (3 eq) tetrahydrofuran-3-ol (commercially available) was added. The mixture was stirred at room temperature overnight, concentrated under reduced pressure and purified on silica (eluting with 10% to 50% ethyl acetate in heptane) to give 1.2g of racemic 2- (methylthio) -7- (tetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (purity 50%). MS (method A) m/z 261[ M+1] +; t=1.54 min.
The crude material was taken to the next step without further purification.
Step 2: preparation of 2- (methylsulfonyl) -7- (tetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
1.55g of 3-chloroperbenzoic acid (77% purity; 3 eq.) are added to a solution of 1.2g (1 eq.) of 2- (methylthio) -7- (tetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile in 30mL of dichloromethane at 0deg.C. The mixture was stirred at room temperature for 1 hour, then quenched with 50mL of dichloromethane and 40mL of 10% aqueous sodium thiosulfate. The organic layer was washed successively with 40mL of saturated aqueous sodium bicarbonate, 50mL of brine, then dried over magnesium sulfate, and concentrated under reduced pressure to give 0.8g of racemic 2- (methylsulfonyl) -7- (tetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile. The crude material was taken to the next step without further purification. MS (method A) m/z 293[ M+1] +; t=1.41 min.
Step 3: preparation of (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 and (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 example 52 and example 53
Racemic mixture (80 mg) (referred to herein as 2- ((1-methyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- (tetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with (S) -2- ((1-methyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- (tetrahydrofuran-3-yl) amino) was obtained according to the procedure described generally in step 5 of example 1, starting from racemic 2- (methylsulfonyl) -7- (tetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (200 mg) and N- [ 1-methyl-3- (oxetan-3-yloxy) pyrazol-4-yl ] carboxamide (intermediate 4) -d ] pyrimidine-6-carbonitrile).
Chiral separation of 73mg of the isomer mixture gave 22mg of the first eluting isomer and 21mg of the second eluting isomer (conditions: column Chiralpak AY,20 μm,230X 100mm; liquid phase: heptane 20/ethanol 80; flow rate: 400 mL/min).
Peak 1 (eluting isomer 1): 1 h NMR (400 MHz, DMSO-d 6) delta, in ppm: 2.44 (q, J=7Hz, 2H); 3.66 (s, 3H); 3.83 (q, j=7hz, 1 h); 3.95-4.19 (m, 3H); 4.56 (m, 2H); 4.80 (t, j=7hz, 2 h); 5.28 (m, 2H); 7.45 (s, 1H); 7.94 (br s, 1H); 8.80 (s, 1H); 8.86 (br s, 1H). MS (method B) m/z 382[ M+1 ] ]++, of the material; t=1.27 min-example 52 (absolute configuration unknown)
Peak 2 (eluting isomer 2): 1 h NMR (400 MHz, DMSO-d 6) delta, in ppm: 2.44 (q, J=7Hz, 2H); 3.66 (s, 3H); 3.83 (q, j=7hz, 1 h); 3.92-4.20 (m, 3H); 4.57 (m, 2H); 4.80 (t, j=7hz, 2 h); 5.27 (m, 2H); 7.45 (s, 1H); 7.93 (br s, 1H); 8.80 (s, 1H); 8.86 (br s, 1H). MS (method B) m/z 382[ M+1 ]]++, of the material; t=1.27 min-example 53 (absolute configuration unknown)
Example 54:7- ((3R, 4R) -4-methoxytetrahydrofuran-3-yl) -2- ((1- (oxetan-3-yl) -3- (((R) -1, 1-trifluoropropan-2-yl) oxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 7- ((3R, 4R) -4-methoxytetrahydrofuran-3-yl) -2- ((1- (oxetan-3-yl) -3- (((S) -1, 1-trifluoropropan-2-yl) oxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (mixture)
Step 1: preparation of 7- ((3R, 4R) -4-methoxytetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid
2.3mL of diisopropyl azodicarboxylate (DIAD) (1.5 eq.) was added to a solution of 3.03g (1.5 eq.) triphenylphosphine, 1.7g (1 eq.) methyl 2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylate (intermediate 1), and 1.44g (3S, 4S) -4-methoxytetrahydrofuran-3-ol (1.6 eq.) in 20mL tetrahydrofuran at 5 ℃. The mixture was heated at 60 ℃ for 20 hours, then cooled to 0 ℃, and 11.4mL (1.5 eq) of 1N aqueous sodium hydroxide solution was added. The reaction mixture was stirred at room temperature for 2 hours. 40mL of water and 40mL of diethyl ether were added. The aqueous layer was washed with 40mL of diethyl ether and then acidified to pH 1 with HCl 1N. The 7- ((3 r,4 r) -4-methoxytetrahydrofuran-3-yl) -2- (methylsulfanyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid precipitated after acidification was filtered off, washed with water and dried in vacuo to give 93mg of 7- ((3 r,4 r) -4-methoxytetrahydrofuran-3-yl) -2- (methylsulfanyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid. The crude material was used in the next step without further purification.
Step 2: preparation of methyl 7- ((3R, 4R) -4-methoxytetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylate
Sulfuric acid (1.34 mL,1.4 eq) is added dropwise to a solution of 1.93g (1 eq) 7- ((3R, 4R) -4-methoxytetrahydrofuran-3-yl) -2- (methylsulfanyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid in 35mL of methanol. The reaction mixture was heated at 60 ℃ for 16 hours. 0.6mL of sulfuric acid (0.6 eq.) was added and the reaction mixture was heated at 60℃for 24 hours. 0.6mL of sulfuric acid (0.6 eq.) was added and the reaction mixture was heated at 60℃for 4 hours and stirred at room temperature for 60 hours. The reaction mixture was poured into ice-cooled saturated sodium bicarbonate solution, stirred for 10 min and extracted twice with 50mL ethyl acetate. The combined organic layers were washed twice with 50mL of water, then dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified on silica gel (eluting with a mixture of heptane/ethyl acetate (95/5 to 70/30)) to give 960mg of a colorless oil, which was triturated in diethyl ether. The solid was filtered off and dried in vacuo to give 660mg of methyl 7- ((3 r,4 r) -4-methoxytetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylate. MS (method B) m/z 324[ M+1] +; t=2.85 min.
Step 3: preparation of 7- ((3R, 4R) -4-methoxytetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide
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0.36g (1 eq) of methyl 7- ((3R, 4R) -4-methoxytetrahydrofuranl-3-yl) -2- (methylsulfanyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylate in 75mL of 7N ammonia solution in methanol in a sealed tube is stirred at room temperature for 88 hours. The mixture is then concentrated under reduced pressure to give 330mg of 7- ((3R, 4R) -4-methoxytetrahydrofuran-3-yl) -2- (methylsulfanyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide. The crude material was used in the next step without further purification.
Step 4: preparation of 7- ((3R, 4R) -4-methoxytetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
0.56mL (3.6 eq) of trifluoroacetic anhydride was added to a solution of 0.34g of 7- ((3R, 4R) -4-methoxytetrahydrofuran-3-yl) -2- (methylsulfanyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide (1 eq), 0.7mL (4.5 eq) of triethylamine in 20mL of anhydrous tetrahydrofuran under argon at 0deg.C. The mixture was stirred at room temperature for 1 hour and quenched with 20mL of dichloromethane and 20mL of saturated aqueous sodium bicarbonate solution with vigorous stirring. The organic layer was washed with 50mL of water and 50mL of brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified on silica (eluted with 0 to 5% acetone in dichloromethane) to give 0.225g of 7- ((3R, 4R) -4-methoxytetrahydrofuran-3-yl) -2- (methylsulfanyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile. MS (method A) m/z 291[ M+1] +; t=2.05 min.
Step 5: preparation of 7- ((3R, 4R) -4-methoxytetrahydrofuran-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
435mg of 3-chloroperbenzoic acid (77% purity; 2.5 eq.) are added to a solution of 225mg (1 eq.) of 7- ((3R, 4R) -4-methoxytetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile in 10mL of dichloromethane at 0 ℃. The mixture was stirred at room temperature for 1 hour, then quenched with 10mL of dichloromethane and 10mL of 10% aqueous sodium thiosulfate. The organic layer was washed successively with 10mL of saturated aqueous sodium bicarbonate, 10mL of brine, then dried over magnesium sulfate and concentrated under reduced pressure to give 233mg of 7- ((3 r,4 r) -4-methoxytetrahydrofuran-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile. MS (method A) m/z 323[ M+1] +; t=1.15 min.
Step 6: preparation of 7- ((3R, 4R) -4-methoxytetrahydrofuran-3-yl) -2- ((1- (oxetan-3-yl) -3- (((R) -1, 1-trifluoropropan-2-yl) oxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 7- ((3R, 4R) -4-methoxytetrahydrofuran-3-yl) -2- ((1- (oxetan-3-yl) -3- (((S) -1, 1-trifluoropropan-2-yl) oxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (mixture)
Typically following the procedure described in step 5 of example 1, 7- ((3R, 4R) -4-methoxytetrahydrofuran-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (100 mg) and racemic N- [1- (oxetan-3-yl) -3- [ (2, 2-trifluoro-1-methyl-ethoxy ] pyrazol-4-yl ] carboxamide (intermediate 23) gave a mixture of 7- ((3R, 4R) -4-methoxytetrahydrofuran-3-yl) -2- ((1- (oxetan-3-yl) -3- (((R) -1, 1-trifluoropropan-2-yl) oxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 7- ((3R, 4R) -4-methoxytetrahydrofuran-3-yl) -2- ((1- (oxetan-3-yl) -3- (((S) -1, 1-trifluoro-2-yl) -1- (((R) -1, 1-trifluoro-2-yl) oxy) -1H-pyrazolo-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-carbonitrile in the present disclosure Is 7- ((3R, 4R) -4-methoxytetrahydrofuran-3-yl) -2- ((1- (oxetan-3-yl) -3- ((1, 1-trifluoropropan-2-yl) oxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile) (120 mg) -example 54.
1 H NMR (400 MHz, DMSO-d 6) delta ppm 1.48 (dd, J=7, 2Hz, 3H), 2.98 (s, 3H), 3.85-4.08 (m, 2H), 4.10-4.26 (m, 2H), 4.49 (m, 1H), 4.89 (d, J=7 Hz, 4H), 5.25-5.52 (m, 3H), 7.47 (s, 1H), 8.12 (br s, 1H), 8.81 (s, 1H), 8.84 (br s, 1H). MS (method B) m/z 494[ M+1 ] ]+；t＝1.62min。
Example 55:2- ((4- (2-hydroxypropan-2-yl) -2- (oxetan-3-yloxy) phenyl) amino) -7- ((3 r,4 r) -4-methoxytetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Step 1: preparation of methyl 4- ((6-cyano-7- ((3R, 4R) -4-methoxytetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3- (oxetan-3-yloxy) benzoate
Methyl 7- ((3R, 4R) -4-methoxytetrahydrofuran-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (step 5 of example 54) (70 mg) and 4-carboxamido-3- (oxetan-3-yloxy) benzoate (66 mg) (intermediate 35) were generally prepared according to the procedure described in step 5 of example 1 to give methyl 4- ((6-cyano-7- ((3R, 4R) -4-methoxytetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3- (oxetan-3-yloxy) benzoate (97 mg). MS (method A) m/z 466[ M+1] +; t=2.34 min.
Step 2: preparation of 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-example 55
695 μl (10 eq.) of methyl magnesium bromide 3M in tetrahydrofuran is added to 97mg (1 eq.) of 4- ((6-cyano-7- ((3R, 4R) -4-methoxy) at 0deg.C
Tetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3- (oxetan-3-yloxy) benzoic acid methyl ester in 7mL tetrahydrofuran. The reaction mixture was stirred at 0 ℃ for 1 hour, then the reaction mixture was quenched with saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with 50mL of water and 50mL of brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified on silica eluting with a mixture of heptane/AcOEt/7N methanolic ammonia solution (80/18/2) to give 42mg of 2- ((4- (2-hydroxypropan-2-yl) -2- (oxetan-3-yloxy) phenyl) amino) -7- ((3 r,4 r) -4-methoxytetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
1 H NMR (400 mhz, dmso-d 6) δppm:1.42 (s, 6H), 2.97 (s, 3H), 3.96 (dd, j=10, 4hz, 1H), 4.06 (dd, j=10, 5hz, 1H), 4.19 (m, 1H), 4.25 (t, j=9 hz, 1H), 4.48 (dd, j=9, 7hz, 1H), 4.62 (dd, j=7, 5hz, 2H), 4.92 (t, j=7 hz, 2H), 4.98 (s, 1H), 5.34 (quin, j=6 hz, 1H), 5.53 (q, j=7 hz, 1H), 6.73 (d, j=2 hz, 1H), 7.07 (dd, j=8, 2hz, 1H), 7.52 (s, 1H), 8.17 (d, j=9, 7hz, 1H), 8.42 (s, 1H). MS (method B) m/z 466[ M+1 ]]+；t＝1.44min。
Examples 56 and 57:2- ((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 and 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
According to the procedure described in example 47, 7- ((3R, 4R) -4-methoxytetrahydrofuran-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2, 3-d)]Pyrimidine-6-carbonitrile (120 mg) (step 5 of example 54) and(racemic mixture (racemic mixture) of R) -N- (1- (1-cyanoethyl) -3-isopropoxy-1H-pyrazol-4-yl) carboxamide and (S) -N- (1- (1-cyanoethyl) -3-isopropoxy-1H-pyrazol-4-yl) carboxamide (intermediate 39) gives 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 was reacted with 2- ((1- ((S) -1-cyanoethyl) -3-isopropoxy-1H-pyrazol-4-yl) amino) -7- ((3R, 4R) -4-methoxytetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d]Isomer mixtures of pyrimidine-6-carbonitrile (referred to herein as 2- ((1- (1-cyanoethyl) -3-isopropoxy-1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methoxytetrahydrofuran-3-yl) -7H-pyrrolo [2, 3-d)]Pyrimidine-6-carbonitrile) (95 mg).
The 89mg isomer mixture was subjected to chiral separation to give 32mg of the first eluting isomer and 31mg of the second eluting isomer (conditions: column ChiralpaK AY,20 μm,230X 10mm; liquid phase: heptane 80%/EtOH 20%/TEA 0.1%; flow rate: 400 mL/min).
Peak 1 (isomer 1): 1H NMR (400 MHz, DMSO-d 6) delta ppm 1.31 (d, J=6Hz, 6H), 1.78 (d, J=7Hz, 3H), 2.99 (s, 3H), 3.97 (m, 1H), 4.05 (m, 1H), 4.18 (m, 1H), 4.24 (t, J=9Hz, 1H), 4.55 (brdd, J=9, 8Hz, 1H), 4.81 (spt, J=6Hz, 1H), 5.47 (q, J=7Hz, 1H), 5.63 (q, J=7Hz, 1H), 7.48 (s, 1H), 8.16 (br s, 1H), 8.70 (br s, 1H), 8.83 (s, 1H). MS (method B) m/z 437[ M+1] +; t=1.57 min-example 56 (absolute configuration unknown)
Peak 2 (isomer 2): 1H NMR (400 MHz, DMSO-d 6) delta ppm:1.31 (d, J=6Hz, 6H), 1.78 (d, J=7Hz, 3H), 2.99 (s, 3H), 3.96 (m, 1H), 4.04 (m, 1H), 4.15-4.29 (m, 2H), 4.55 (brt, J=8Hz, 1H), 4.81 (spt, J=6Hz, 1H), 5.47 (q, J=8Hz, 1H), 5.62 (q, J=7Hz, 1H), 7.48 (s, 1H), 8.15 (br s, 1H), 8.71 (br s, 1H), 8.83 (s, 1H). MS (method B) m/z 437[ M+1] +; t=1.57 min-example 57 (absolute configuration unknown)
The reaction of 7- ((3R, 4R) -4-methoxytetrahydrofuran-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with the appropriate formamide generally follows the procedure described in examples 54 to 57 to give examples 58 to 69 in Table II.
Table II
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Example 70:7- ((3R, 4S) -4-methoxytetrahydrofuran-3-yl) -2- ((1-methyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 7- ((3S, 4R) -4-methoxytetrahydrofuran-3-yl) -2- ((1-methyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (racemic mixture)
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Step 1: preparation of methyl ((3S, 4R) -4-methoxytetrahydrofuran-3-yl) glycinate and methyl ((3R, 4S) -4-methoxytetrahydrofuran-3-yl) glycinate (racemic mixture)
4mL (1 eq.) of methyl 2-bromoacetate in solution in 10mL of tetrahydrofuran was slowly added to a cooled solution of 5g (1 eq.) of 4-methoxytetrahydrofuran-3-amine (commercially available) and 6mL of triethylamine (1 eq.) in 30mL of tetrahydrofuran at 0deg.C. After stirring at room temperature for 5 hours and completion of the reaction, the mixture was filtered. The filtrate was concentrated in vacuo and purified by column chromatography (eluent: dichloromethane 100%, then dichloromethane/methanol (95/5)) to give 7g of a racemic mixture of methyl ((3 s,4 r) -4-methoxytetrahydrofuran-3-yl) glycinate and methyl ((3 r,4 s) -4-methoxytetrahydrofuran-3-yl) glycinate.
Step 2: preparation of N- (5-formyl-2- (methylthio) pyrimidin-4-yl) -N- ((3S, 4R) -4-methoxytetrahydrofuran-3-yl) glycine methyl ester and N- (5-formyl-2- (methylthio) pyrimidin-4-yl) -N- ((3R, 4S) -4-methoxytetrahydrofuran-3-yl) glycine methyl ester (racemic mixture)
1.6mL of triethylamine (1.7 eq) was added to a solution of 1.25g of 4-chloro-2- (methylthio) pyrimidine-5-carbaldehyde (1 eq) and 1.4g of a racemic mixture of ((3S, 4R) -4-methoxytetrahydrofuran-3-yl) glycine methyl ester and ((3R, 4S) -4-methoxytetrahydrofuran-3-yl) glycine methyl ester (1.1 eq) in 15mL of tetrahydrofuran. The mixture was stirred at room temperature for 60 hours, diluted with 100mL of a 50/50 mixture of ethyl acetate/diethyl ether and poured into water. The organic layer was separated and washed twice with water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified on silica eluting with a mixture of heptane/ethyl acetate (100/0 to 70/30) to give a racemic mixture of methyl N- (5-formyl-2- (methylthio) pyrimidin-4-yl) -N- ((3 s,4 r) -4-methoxytetrahydrofuran-3-yl) glycine and methyl N- (5-formyl-2- (methylthio) pyrimidin-4-yl) -N- ((3 r,4 s) -4-methoxytetrahydrofuran-3-yl) glycine. MS (method A) m/z 342[ M+1] +; t=1.83 min.
Step 3: preparation of 7- ((3S, 4R) -4-methoxytetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid and 7- ((3R, 4S) -4-methoxytetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid (racemic mixture)
2.65mL (5 eq) of 1, 8-diazabicyclo [5.4.0] undec 7-ene were added dropwise to a solution of a racemic mixture (1 eq) of 1.16g N- (5-formyl-2- (methylthio) pyrimidin-4-yl) -N- ((3S, 4R) -4-methoxytetrahydrofuran-3-yl) glycine methyl ester and N- (5-formyl-2- (methylthio) pyrimidin-4-yl) -N- ((3R, 4S) -4-methoxytetrahydrofuran-3-yl) glycine methyl ester in 15mL acetonitrile. The reaction mixture was heated at 80℃for 1 hour. After cooling to room temperature, the reaction mixture was taken up in 100mL of ethyl acetate and washed with 1N aqueous HCl. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 32mL of tetrahydrofuran and 415mg of lithium hydroxide (5 equivalents) in 8.6mL of water was added. The reaction mixture was stirred at room temperature for 1 hour. 2N aqueous hydrochloric acid (to reach pH 7) was added, and then 100mL ethyl acetate was added. The organic layer was washed with 50mL of water and 50mL of brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 1.13g of a racemic mixture of 7- ((3S, 4R) -4-methoxytetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid and 7- ((3R, 4S) -4-methoxytetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid. MS (method A) m/z 310[ M+1] +; t=2.18 min.
Step 4: preparation of 7- ((3S, 4R) -4-methoxytetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide and 7- ((3R, 4S) -4-methoxytetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide (racemic mixture)
0.74g (1.25 eq) of bis (1H-imidazol-1-yl) methanone (CDI) is added to a racemic mixture of 1.13g 7- ((3S, 4R) -4-methoxytetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid and 7- ((3R, 4S) -4-methoxytetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid (1 eq) in 11mL dimethylformamide. The mixture was stirred at room temperature for 1 hour and 2.4ml of 28% ammonium hydroxide solution (5 eq) were added. The reaction mixture was stirred at room temperature for 2.5 hours, diluted with 100mL of ethyl acetate, and washed with water. The organic layer was washed with 50mL of water and 50mL of brine, dried over magnesium sulfate and concentrated under reduced pressure to give a racemic mixture of 0.53g of 7- ((3 s,4 r) -4-methoxytetrahydrofuran-3-yl) -2- (methylsulfanyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide and 7- ((3 r,4 s) -4-methoxytetrahydrofuran-3-yl) -2- (methylsulfanyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide. MS (method A) m/z 309[ M+1] +; t=1.81 min.
Step 5: preparation of 7- ((3S, 4R) -4-methoxytetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 7- ((3R, 4S) -4-methoxytetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (racemic mixture)
0.87mL (3.6 eq) of trifluoroacetic anhydride is added to a solution of 0.53g of a racemic mixture (1 eq) of 7- ((3S, 4R) -4-methoxytetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide and 7- ((3R, 4S) -4-methoxytetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide in 8mL of anhydrous tetrahydrofuran under argon at 0 ℃. The mixture was stirred at room temperature for 1 hour, poured into water and extracted twice with 50mL of ethyl acetate. The combined organic layers were washed twice with 50mL of water, then dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified on silica (eluting with a heptane/ethyl acetate mixture (100/0 to 50/50)) to give 344mg of a racemic mixture of 7- ((3 s,4 r) -4-methoxytetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 7- ((3 r,4 s) -4-methoxytetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile. MS (method A) m/z 291[ M+1] +; t=2.07 min.
Step 6: preparation of 7- ((3S, 4R) -4-methoxytetrahydrofuran-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 7- ((3R, 4S) -4-methoxytetrahydrofuran-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (racemic mixture)
797mg of 3-chloroperbenzoic acid (77% purity; 2.5 eq) is added to a solution of 344mg (1 eq) of a racemic mixture of 7- ((3 s,4 r) -4-methoxytetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 7- ((3 r,4 s) -4-methoxytetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile in 6mL of dichloromethane at 0 ℃. The mixture was stirred at room temperature for 1 hour, then quenched with 10mL of dichloromethane and 10mL of 10% aqueous sodium thiosulfate. The organic layer was washed successively with 10mL of saturated aqueous sodium bicarbonate, 10mL of brine, then dried over magnesium sulfate and concentrated under reduced pressure to give 363mg of a racemic mixture of 7- ((3 s,4 r) -4-methoxytetrahydrofuran-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 7- ((3 r,4 s) -4-methoxytetrahydrofuran-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile. MS (method A) M/z323[ M+1] +; t=1.49 min.
Step 7: preparation of 7- ((3R, 4S) -4-methoxytetrahydrofuran-3-yl) -2- ((1-methyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 7- ((3S, 4R) -4-methoxytetrahydrofuran-3-yl) -2- ((1-methyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (racemic mixture) -example 70
Following the procedure described in example 47, a racemic mixture (62 mg) of 7- ((3S, 4R) -4-methoxytetrahydrofuran-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 7- ((3R, 4S) -4-methoxytetrahydrofuran-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and N- (1-methyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide (intermediate 4) gave a mixture of 7- ((3R, 4S) -4-methoxytetrahydrofuran-3-yl) -2- ((1-methyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 7- ((3S, 4R) -4-methoxytetrahydrofuran-3-yl) -2- ((1-methyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide (intermediate 4) to give a racemic mixture of 7- ((3R, 4-methyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-carbonitrile (referred to herein as 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) -example 70.
1 H NMR (400 MHz, DMSO-d 6) delta ppm:3.22 (s, 3H), 3.66 (s, 3H), 3.78-4.00 (m, 2H), 4.03 (dd, J=9, 7Hz, 1H), 4.27 (t, J=9 Hz, 1H), 4.43 (br s, 1H), 4.50-4.57 (m, 2H), 4.75-4.83 (m, 2H), 4.86 (br s, 1H), 5.30 (quin, J=6 Hz, 1H), 7.49 (s, 1H), 7.81 (br s, 1H), 8.83 (s, 1H), 8.87 (br s, 1H). MS (method B) m/z 412[ M+1]]+；t＝1.28min。
Example 71:2- ((4- (2-hydroxy-propan-2-yl) -2- (oxetan-3-yloxy) phenyl) amino) -7- ((3S, 4R) -4-methoxytetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 2- ((4- (2-hydroxy-propan-2-yl) -2- (oxetan-3-yloxy) phenyl) amino) -7- ((3R, 4S) -4-methoxytetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (racemic mixture)
Step 1: preparation of methyl 4- ((6-cyano-7- ((3S, 4R) -4-methoxytetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3- (oxetan-3-yloxy) benzoate and methyl 4- ((6-cyano-7- ((3R, 4S) -4-methoxytetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3- (oxetan-3-yloxy) benzoate (racemic mixture)
A racemic mixture (100 mg) of 7- ((3S, 4R) -4-methoxytetrahydrofuran-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 7- ((3R, 4S) -4-methoxytetrahydrofuran-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (step 6 of example 70) and methyl 4-carboxamido-3- (oxetan-3-yloxy) benzoate (86 mg) (intermediate 35) gave a mixture of methyl 4- ((6-cyano-7- ((3S, 4R) -4-methoxytetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3- (oxetan-3-yloxy) benzoate with 4- ((6-cyano-7- ((3S, 4S) -4-methoxytetrahydrofuran-3-yl) -7H-pyrrolo [ 2-yloxy) pyrimidine-3- (oxetan-3-yl) benzoate (58 mg). MS (method A) m/z 466[ M+1] +; t=2.39 min.
Step 2: preparation of 2- ((4- (2-hydroxypropan-2-yl) -2- (oxetan-3-yloxy) phenyl) amino) -7- ((3S, 4R) -4-methoxytetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 2- ((4- (2-hydroxypropan-2-yl) -2- (oxetan-3-yloxy) phenyl) amino) -7- ((3R, 4S) -4-methoxytetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (racemic mixture) -example 71
415 μl (10 equiv.) of methyl magnesium bromide in tetrahydrofuran is added to a solution of 58mg (1 equiv.) of a racemic mixture of methyl 4- ((6-cyano-7- ((3 s,4 r) -4-methoxytetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3- (oxetan-3-yloxy) benzoate and methyl 4- ((6-cyano-7- ((3 r,4 s) -4-methoxytetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3- (oxetan-3-yloxy) benzoate in 4mL of tetrahydrofuran at 0deg.C. The reaction mixture was stirred at 0 ℃ for 30 minutes, then quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with 50mL of water and 50mL of brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified on silica (eluting with a mixture of heptane/AcOEt/7N methanolic ammonia solution (80/18/2)) to give 31mg of a racemic mixture of 2- ((4- (2-hydroxypropan-2-yl) -2- (oxetan-3-yloxy) phenyl) amino) -7- ((3 s,4 r) -4-methoxytetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 2- ((4- (2-hydroxypropan-2-yl) -2- (oxetan-3-yloxy) phenyl) amino) -7- ((3 r,4 s) -4-methoxytetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (referred to herein as a racemic mixture of 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, example 71.
1 H NMR (400 mhz, dmso-d 6) δppm:1.42 (s, 6H), 3.23 (s, 3H), 3.82 (dd, j=10, 3hz, 1H), 3.97-4.10 (m, 2H), 4.28 (t, j=9 hz, 1H), 4.49 (dt, j=6, 3hz, 1H), 4.59 (dd, j=7, 5hz, 2H), 4.86-4.98 (m, 3H), 5.00 (s, 1H), 5.31 (quin, j=6 hz, 1H), 6.74 (d, j=2 hz, 1H), 7.06 (dd, j=8, 2hz, 1H), 7.55 (s, 1H), 7.95 (d, j=8 hz, 1H), 8.61 (s, 1H), 8.91 (s, 1H). MS (method B) m/z 466[ M+1 ]]+；t＝1.45min。
Example 72 and example 73:7- ((3S, 4R) -4-ethyltetrahydrofuran-3-yl) -2- ((3-isopropoxy-1-methyl-1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 7- ((3R, 4S) -4-ethyltetrahydrofuran-3-yl) -2- ((3-isopropoxy-1-methyl-1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (racemic cis mixture)
7- ((3S, 4S) -4-ethyltetrahydrofuran-3-yl) -2- ((3-isopropoxy-1-methyl-1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 7- ((3R, 4R) -4-ethyltetrahydrofuran-3-yl) -2- ((3-isopropoxy-1-methyl-1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile- (racemic trans mixture)
Step 1: preparation of 4-ethyltetrahydrofuran-3-ol (racemic cis and trans isomers)
502mg (1.1 eq.) of sodium borohydride are added in portions to a solution of 1.38g (1 eq.) of racemic 4-ethyldihydrofuran-3 (2H) -one (commercially available) in a mixture of 15mL of anhydrous THF and 30mL of anhydrous ethanol at 0deg.C. The reaction mixture was stirred at room temperature for 1 hour, then cooled back to 0 ℃ and quenched by the addition of 20ml of 1n aqueous hydrogen chloride. The mixture was poured into 100mL of ethyl acetate and 100mL of brine with stirring, and the organic layer was concentrated in vacuo. The residue was dissolved in dichloromethane, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel (gradient elution with 0 to 60% ethyl acetate in cyclohexane) to give 898mg of a non-separable mixture of the racemic cis and racemic trans isomers of 4-ethyltetrahydrofuran-3-ol in a ratio of 1/2 (1H NMR) and as a colorless oil.
1 H NMR (400 mhz, cdcl 3) δ in ppm:
cis-isomer: 1.01 (t, j=7.5 hz, 3H), 1.30 (m, 1H), 1.61 (m, 1H), 1.90 (wide, 1H), 2.10 (m, 1H), 3.54 (dd, j=8 and 10.2hz, 1H), 3.94 (dd, j=9.8 and 4hz, 1H), 3.99 (t, j=8.4 hz, 1H), 4.12 (m, 1H), 4.31 (t, j=4.2 hz, 1H).
Trans isomer: 0.98 (t, j=7.5 hz, 3H), 1.34 (m, 1H), 1.48 (m, 1H), 1.90 (wide, 1H), 2.03 (m, 1H), 3.47 (dd, j=8.4 and 5hz, 1H), 3.72 (dd, j=10 and 2.3hz, 1H), 3.87 (m, 2H), 4.15 (m, 1H).
Step 2: preparation of 7- (4-ethyltetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid methyl ester (racemic cis and trans isomers)
3.05g (3 eq) triphenylphosphine and 1.14mL (1.5 eq) diisopropyl azodicarboxylate (DIAD) were added under argon to a solution of 865mg (1 eq) methyl 2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylate and 675mg (1.5 eq) of a mixture of the racemic cis and racemic trans isomers of 4-ethyltetrahydrofuran-3-ol in 40mL anhydrous tetrahydrofuran. The reaction mixture was stirred at 60℃for 2 hours, then poured into 100mL of ethyl acetate and 50mL of water. The aqueous layer was extracted with 20mL ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica gel (gradient elution with 0 to 30% ethyl acetate in cyclohexane) to give 1.23g of an inseparable mixture of the racemic cis and racemic trans isomers of methyl 7- (4-ethyltetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylate in a ratio of 36/64 (LC/MS). MS (method F): cis-isomer: m/z 322[ M+1] +; t=1.96 min; trans isomer: m/z 322[ M+1] +; t=1.90 min.
Step 3: preparation of 7- (4-ethyltetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide (racemic cis and trans isomers)
A solution of 1.23g (1 eq) of a mixture of the racemic cis and racemic trans isomers of 7- (4-ethyltetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid methyl ester in 70mL 7N methanolic ammonia (130 eq) in a closed vessel is heated at 100℃for 4 days under stirring. The reaction mixture was cooled, concentrated in vacuo and purified on silica gel (gradient elution with 0 to 70% ethyl acetate in cyclohexane) to give 563mg of the inseparable mixture of the racemic cis and racemic trans isomers of methyl 7- (4-ethyltetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide in a ratio of 33/67 (LC/MS). MS (method F): cis-isomer: m/z 307[ M+1] +; t=1.41 min; trans isomer: m/z 307[ M+1] +; t=1.36 min.
Step 4: preparation of 7- (4-ethyltetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (racemic cis and trans isomers)
1.16mL (4.5 eq) of triethylamine and 920. Mu.L (3.6 eq) of trifluoroacetic anhydride are successively added dropwise under argon to a cooled (0 ℃) solution of 563mg (1 eq) of a mixture of the racemic cis and racemic trans isomers of methyl 7- (4-ethyltetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide in 17mL of anhydrous tetrahydrofuran. The reaction mixture was allowed to stir at room temperature for 1 hour and then poured into 20mL of ethyl acetate and 20mL of 10% aqueous sodium carbonate solution with vigorous stirring for 15 min. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica gel (gradient elution with 0 to 20% ethyl acetate in cyclohexane) to give 597mg of the inseparable mixture of the racemic cis and racemic trans isomers of methyl 7- (4-ethyltetrahydrofuran3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile. MS (method G): cis-isomer: m/z 289[ M+1] +; t=2.18 min; trans isomer: m/z 289[ M+1] +; t=2.10 min.
Step 5: preparation of 7- ((3S, 4R) -4-ethyltetrahydrofuran-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 7- ((3R, 4S) -4-ethyltetrahydrofuran-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (racemic cis) and 7- ((3S, 4S) -4-ethyltetrahydrofuran-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 7- ((3R, 4R) -4-ethyltetrahydrofuran-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (racemic trans)
1.05g (2.05 eq) of m-chloroperbenzoic acid (70% purity) are added in portions to a cooled (0 ℃) solution of 597mg (1 eq) of a mixture of the racemic cis and racemic trans isomers of methyl 7- (4-ethyltetrahydrofuran-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile in 20mL of dichloromethane. The reaction mixture was allowed to stir at 0 ℃ for 15 minutes and then at room temperature for 1 hour, then diluted with 30mL of dichloromethane. The organic layer was washed successively with 10ml of 2n aqueous sodium bisulphite and twice with 20ml of 10% aqueous sodium carbonate, then dried over sodium sulphate and concentrated in vacuo. The residue was purified on silica gel (gradient elution with 0 to 70% ethyl acetate in cyclohexane) to give 97mg of the first mixture and 281mg of the second mixture.
The first mixture was characterized by NMR as a racemic cis mixture of 7- ((3S, 4R) -4-ethyltetrahydrofuran-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 7- ((3R, 4S) -4-ethyltetrahydrofuran-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile. MS (method F) m/z 321[ M+1] +; t=1.37 min
The second mixture was characterized by NMR as a racemic trans mixture of 7- ((3S, 4S) -4-ethyltetrahydrofuran-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 7- ((3R, 4R) -4-ethyltetrahydrofuran-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile. MS (method F) m/z 321[ M+1] +; t=1.34 min.
Step 6: preparation of 7- ((3S, 4R) -4-ethyltetrahydrofuran-3-yl) -2- ((3-isopropoxy-1-methyl-1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 7- ((3R, 4S) -4-ethyltetrahydrofuran-3-yl) -2- ((3-isopropoxy-1-methyl-1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile-racemic cis example 72
Following the procedure described in example 47, a racemic cis mixture (150 mg) of 7- ((3 s,4 r) -4-ethyltetrahydrofuran-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 7- ((3 r,4 s) -4-ethyltetrahydrofuran-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and N- (3-isopropoxy-1-methyl-1H-pyrazol-4-yl) carboxamide (90 mg) (intermediate 38) gave 145mg of 7- ((3 s,4 r) -4-ethyltetrahydrofuran-3-yl) -2- ((3-isopropoxy-1-methyl-1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile as a yellow solid as a mixture of 7- ((3 s,4 r) -4-ethyltetrahydrofuran-3-yl) -2- ((3-isopropoxy-1-methyl-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 7- ((3 r,4 s) -4-ethyltetrahydrofuran-3-yl) -2- ((3-isopropoxy-methyl-1H-pyrazol-4-yl) carboxamide -3-yl) -2- ((3-isopropoxy-1-methyl-1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile) -example 72.
1 H NMR (500 MHz, DMSO-d 6) delta ppm 0.65-0.78 (m, 3H), 0.85 (m, 1H), 0.97 (m, 1H), 1.26 (dd, J=6, 4Hz, 6H), 2.47 (m hidden, 1H), 3.67 (s, 3H), 3.82 (m, 1H), 4.01 (brt, J=8 Hz, 1H), 4.32 (dd, J=10, 8Hz, 1H), 4.53 (m, 1H), 4.71 (spt, J=6 Hz, 1H), 5.25 (m, 1H), 7.47 (s, 1H), 7.99 (br s, 1H), 8.48 (brs, 1H), 8.80 (s, 1H). MS (method D) m/z 396[ M+1 ]]+；t＝1.28min。
Step 7: preparation of 7- ((3S, 4S) -4-ethyltetrahydrofuran-3-yl) -2- ((3-isopropoxy-1-methyl-1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 7- ((3R, 4R) -4-ethyltetrahydrofuran-3-yl) -2- ((3-isopropoxy-1-methyl-1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile-racemic trans-example 73
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Following the procedure described in example 47, a racemic trans mixture (97 mg) of 7- ((3 s,4 s) -4-ethyltetrahydrofuran-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidin-6-carbonitrile with 7- ((3 r,4 r) -4-ethyltetrahydrofuran-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and N- (3-isopropoxy-1-methyl-1H-pyrazol-4-yl) carboxamide (58 mg) (intermediate 38) gave 79mg of 7- ((3 s,4 s) -4-ethyltetrahydrofuran-3-yl) -2- ((3-isopropoxy-1-methyl-1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile as a mixture with 7- ((3 r,4 r) -4-ethyltetrahydrofuran-3-yl) -2- ((3-isopropoxy-1-methyl-H-pyrazol-4-yl) carboxamide as the racemic mixture of 7- ((3 s, 4-ethyltetrahydrofuran-3-yl) -2- ((3-isopropoxy-1-H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile ) -2- ((3-isopropoxy-1-methyl-1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile).
1 H NMR (500 MHz, DMSO-d 6) delta ppm 0.79 (t, J=7Hz, 3H), 1.27 (dd, J=6, 1Hz, 6H), 1.44-1.58 (m, 2H), 2.77 (sxt, J=7Hz, 1H), 3.54 (t, J=8Hz, 1H), 3.67 (s, 3H), 4.07-4.28 (m, 3H), 4.71 (quin, J=6Hz, 1H), 4.88 (m, 1H), 7.46 (s, 1H), 8.01 (br s, 1H), 8.56 (br s, 1H), 8.80 (s, 1H). MS (method D) m/z 396[ M+1 ]]+；t＝1.30min。
Example 74:2- ((1- (2-cyanopropan-2-yl) -3-isopropoxy-1H-pyrazol-4-yl) amino) -7- (oxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Step 1: preparation of oxetan-3-yl glycine methyl ester
6.28g (1 eq.) of methyl 2-bromoacetate in 30mL of tetrahydrofuran are added to a solution of 3g (1 eq.) of 3-oxetane amine and 28mL of triethylamine (5 eq.) in 120mL of tetrahydrofuran and 60mL of dichloromethane at 0deg.C. The reaction mixture was stirred at room temperature for 17 days. The reaction mixture was filtered by washing with dichloromethane, concentrated under reduced pressure, and then taken up in 100mL of dichloromethane and 10mL of brine. The aqueous layer was separated and extracted twice with 10mL of dichloromethane. The combined organic layers were dried over MgSO 4 Dried and concentrated under reduced pressure to give 5.3g of methyl oxetan-3-yl glycinate, which was used in the next step without further purification.
Step 2: preparation of N- (5-formyl-2- (methylthio) pyrimidin-4-yl) -N- (oxetan-3-yl) glycine methyl ester
6.7mL of triethylamine (1.7 eq) was added to a solution of 5.34g of 4-chloro-2- (methylthio) pyrimidine-5-carbaldehyde (1 eq) in 100mL of tetrahydrofuran and 20mL of dichloromethane at 0deg.C. 5.34g of methyl oxetan-3-yl glycinate (1 eq) were added dropwise. The mixture was stirred at room temperature for 1 week. The reaction mixture was treated with 100mL ethyl acetate and 50mL NH 4 The Cl saturated aqueous solution was diluted. The organic layer was separated and the aqueous layer was extracted twice with 50mL ethyl acetate. The combined organic layers were washed twice with 50mL brine, then dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified on silica gel (gradient elution with 5% to 30% acetone in dichloromethane) to give 1.48g N- (5-formyl-2- (methylthio) pyrimidin-4-yl) -N- (oxetan-3-yl) glycine methyl ester. MS (method A) m/z 298[ M+1 ]]+；t＝1.64min。
Step 3: preparation of methyl 2- (methylthio) -7- (oxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylate
mu.L (5 eq.) 1, 8-diazabicyclo [5.4.0]Undec 7-ene was added dropwise to a solution of 191mg methyl N- (5-formyl-2- (methylthio) pyrimidin-4-yl) -N- (oxetan-3-yl) glycine (1 eq) in 8mL acetonitrile. The reaction mixture was refluxed for 2.5 hours. After cooling to room temperature, the reaction mixture was diluted with 10mL of ethyl acetate and quenched with 3.5mL of 1n aqueous HCl, and then with 3mL of NaHCO 3 The mixture was quenched with saturated aqueous solution and 5mL of 10% aqueous citric acid. The organic layer was separated and the aqueous layer was extracted twice with 10mL ethyl acetate. The combined organic layers were washed with 10mL of brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 180mg of 2- (methylthio) -7- (oxetan-3-yl) -7H-pyrrolo [2,3-d]Pyrimidine-6-carboxylic acid methyl ester. MS (method A) m/z 280[ M+1]]+；t＝2.06min。
Step 4: preparation of 2- (methylthio) -7- (oxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid
0.61g (5 eq) of lithium hydroxide in 10mL of water was added to a solution of 1.41g of methyl 2- (methylthio) -7- (oxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylate (1 eq) in 40mL of tetrahydrofuran. The mixture was stirred at room temperature for 3.5 hours, cooled to 0 ℃, and 0.85ml of 30% aqueous ammonium hydroxide was added. The reaction mixture was stirred at room temperature for 1.5 hours, then concentrated under reduced pressure. 18mL of 2N aqueous HCl and 20mL of ethyl acetate were added. The precipitate was filtered, washed with water, ethyl acetate and pentane, and then dried in vacuo to give 0.98g of 2- (methylthio) -7- (oxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid. MS (method A) m/z 266[ M+1] +; t=1.71 min.
Step 5: preparation of 2- (methylthio) -7- (oxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide
1.06g (1.5 eq) of bis (1H-imidazol-1-yl) methanone (CDI) was added to a solution of 1.15g of methyl 2- (methylthio) -7- (oxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylate (1 eq) in 11mL of dimethylformamide. The mixture was stirred at room temperature for 45 minutes, cooled to 0 ℃, and 0.85ml of 30% ammonium hydroxide solution was added. The reaction mixture was stirred at room temperature for 1.5 hours, diluted with 11mL ethyl acetate and 55mL water. After stirring for 20 minutes, the resulting precipitate was filtered, washed twice with ethyl acetate and once with pentane, and then dried in vacuo to give 0.88g of 2- (methylthio) -7- (oxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide. MS (method A) m/z 264[ M+1] +; t=1.46 min.
Step 6: preparation of 2- (methylthio) -7- (oxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
2.1mL (4.5 eq.) of triethylamine was added to 0.88g of 2- (methylthio) -7- (oxetan-3-yl) -7H-pyrrolo [2,3-d ] under argon at 0deg.C]Pyrimidine-6-carboxamide (1 eq.) was dissolved in 20mL of anhydrous tetrahydrofuran, then 1.68mL (3.6 eq.) of trifluoroacetic anhydride was added. The mixture was stirred at 0 ℃ to room temperature for 2.5 hours, and 20mL of dichloromethane and 20mL of NaHCO were used with stirring 3 Quenching with saturated aqueous solution. The organic layer was separated. The aqueous layer was extracted twice with 20mL of dichloromethane. The combined organic extracts were washed with 20mL brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified on silica (eluting with 10% -50% ethyl acetate in heptane). The concentrated target fraction was triturated with diisopropyl ether, filtered, washed with diisopropyl ether and pentane and then dried in vacuo to give 0.76g of 2- (methylthio) -7- (oxetan-3-yl) -7H-pyrrolo [2, 3-d)]Pyrimidine-6-carbonitrile. MS (method A) m/z 247[ M+1]]+；t＝1.88min。
Step 7: preparation of 2- (methylsulfonyl) -7- (oxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
1.72g of 3-chloroperbenzoic acid (77% purity; 2.5 eq.) are added to a solution of 0.75g (1 eq.) of 2- (methylthio) -7- (oxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile in 40mL of dichloromethane at 0deg.C. The mixture was stirred at 0 ℃ for 5 minutes and at room temperature for 5 hours. 0.34g (0.5 eq) of 3-chloroperbenzoic acid was added and the mixture stirred for 3 hours, 0.34g (0.5 eq) of 3-chloroperbenzoic acid was added and the mixture stirred for 45 minutes. Then, it was quenched with 20mL of dichloromethane and 20mL of saturated aqueous sodium thiosulfate. The organic layer was separated and 10mL of water, 10mL of brine and 10mL of dichloromethane were added. The precipitate was filtered, washed twice with dichloromethane, and dried in vacuo to give 0.29g of 2- (methylsulfonyl) -7- (oxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile. The mother liquor was extracted twice with 20mL of dichloromethane. The combined organic layers were washed twice with 20mL of saturated aqueous bicarbonate, twice with 20mL of brine, then dried over magnesium sulfate and concentrated under reduced pressure to give 0.57g of 2- (methylsulfonyl) -7- (oxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile. The combined solids yielded 0.86g of 2- (methylsulfonyl) -7- (oxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile. MS (method A) m/z 279[ M+1] +; t=1.21 min.
Step 8: preparation of 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-example 74
2- (methylsulfonyl) -7- (oxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (60 mg) and N- [1- (1-cyano-1-methyl-ethyl) -3-isopropoxy-pyrazol-4-yl ] carboxamide (51 mg) (intermediate 31) gave 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 (120 mg) -example 74, generally following the procedure described in step 5 of example 1.
1 H NMR (400 mhz, dmso-d 6) δ in ppm: 1.34 (d, j=6 hz, 6H), 1.91 (s, 6H), 4.83 (spt, j=6 hz, 1H), 5.01 (t, j=8 hz, 2H), 5.44 (br t, j=7 hz, 2H), 5.64 (m, 1H), 7.48 (s, 1H), 8.43 (br s, 1H), 8.83 (br s, 1H), 8.88 (s, 1H). MS (method C) m/z 407[ M+1 ]]+；t＝3.43min。
Example 75:2- ((3-isopropoxy-1-methyl-1H-pyrazol-4-yl) amino) -7- (oxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Following the procedure described in example 47, 2- (methylsulfonyl) -7- (oxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (example 74, step 7) (174 mg) and N- (3-isopropoxy-1-methyl-1H-pyrazol-4-yl) carboxamide (115 mg) (intermediate 38) gave 2- ((3-isopropoxy-1-methyl-1H-pyrazol-4-yl) amino) -7- (oxetan-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (149 mg) -example 75.
1 H NMR (400 mhz, dmso-d 6) delta ppm:1.28 (d, j=6 hz, 6H), 3.66 (s, 3H), 4.72 (spt, j=6 hz, 1H), 5.00 (t, j=7 hz, 2H), 5.36 (t, j=7 hz, 2H), 5.76 (quin, j=8 hz, 1H), 7.47 (s, 1H), 8.17 (br s, 1H), 8.62 (br s, 1H), 8.82 (s, 1H). MS (method B) m/z 354[ M+1 ]]+；t＝1.39min。
Example 76 and example 77:7- [ (2S, 3R) -2-Methyloxetan-3-yl ] -2- [ [ 1-methyl-3- (oxetan-3-yloxy) pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 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
Step 1: preparation of methyl (2-methyloxetan-3-yl) glycinate (Racemisation)
1.06mL (1 eq.) of methyl 2-bromoacetate was slowly added to a solution of 1g (1 eq.) of 2-methyl oxetan-3-amine and 2.43mL of triethylamine (1.5 eq.) in 30mL of tetrahydrofuran and 10mL of dichloromethane at 0deg.C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and quenched with water. The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure to give 1.92g of methyl racemic (2-methyloxetan-3-yl) glycinate, which was used in the next step without further purification.
Step 2: preparation of methyl N- (5-formyl-2- (methylthio) pyrimidin-4-yl) -N- (2-methyloxetan-3-yl) glycinate (rac)
2.6mL of triethylamine (1.7 eq) was added to a solution of 2g of 4-chloro-2- (methylthio) pyrimidine-5-carbaldehyde (1 eq) in 80mL of tetrahydrofuran and 18mL of dichloromethane at 0deg.C. 1.86g of methyl racemic (2-methyloxetan-3-yl) glycinate (1.1 eq) was added dropwise. The mixture was stirred at room temperature for 6 days. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted twice with 50mL ethyl acetate. The combined organic layers were washed twice with 50mL brine, then dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified on silica gel (eluting with 20% ethyl acetate in heptane) to give 1.5g of racemic methyl N- (5-formyl-2- (methylthio) pyrimidin-4-yl) -N- (2-methyloxetan-3-yl) glycinate. MS (method B) m/z 312[ M+1] +; t=1.24 min.
Step 3: preparation of methyl 7- (2-methyl-oxetan-3-yl) -2- (methylsulfanyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylate (Racemosome)
3.75mL (5 eq.) of 1, 8-diazabicyclo [5.4.0] undec 7-ene was added dropwise to a solution of 1.5g of racemic methyl N- (5-formyl-2- (methylthio) pyrimidin-4-yl) -N- (2-methyloxetan-3-yl) glycinate (1 eq.) in 20mL acetonitrile. The reaction mixture was refluxed for 30 minutes. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and quenched with 1N aqueous HCl. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel (eluting with 20% ethyl acetate in heptane) to give 0.93g of racemic methyl 7- (2-methyloxetan-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylate. MS (method B) m/z 294[ M+1] +; t=1.69 min.
Step 4: preparation of 7- (2-methyl-oxetan-3-yl) -2- (methylsulfanyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid (Racemosome)
To a solution of 0.93g of racemic methyl 7- (2-methyloxetan-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylate (1 eq) in 30mL of tetrahydrofuran was added 0.38g (5 eq) of lithium hydroxide in 8mL of water. The mixture was stirred at room temperature for 1 hour and then acidified by addition of 2N aqueous HCl. The mixture was extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 0.81g of racemic 7- (2-methyloxetan-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid. MS (method B) m/z 280[ M+1] +; t=1.31 min.
Step 5: preparation of 7- (2-Methyloxetan-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide (Racemosome)
0.74g (1.5 eq) of bis (1H-imidazol-1-yl) methanone (CDI) is added to a solution of 1.15g of racemic 7- (2-methyloxetan-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid (1 eq) in 10mL of dimethylformamide. The mixture was stirred at room temperature for 30 minutes, cooled to 0 ℃, and 1.88ml of 30% aqueous ammonium hydroxide was added. The reaction mixture was stirred at room temperature for 30 minutes, poured into 20mL of water, and extracted with ethyl acetate. The organic extract was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated in diisopropyl ether, the solid was filtered and dried in vacuo to give 0.83g of racemic 7- (2-methyloxetan-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide. The crude material was taken to the next step without further purification.
Step 6: preparation of 7- (2-methyl-oxetan-3-yl) -2- (methylsulfanyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (racemic)
1.89mL (4.5 eq) of triethylamine was added to a solution of 0.83g of racemic 7- (2-methyloxetan-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide (1 eq) in 25mL of anhydrous tetrahydrofuran under argon at 0℃followed by 1.49mL (3.6 eq) of trifluoroacetic anhydride. The mixture was stirred for 15 minutes to allow the temperature to warm to room temperature, then diluted with ethyl acetate, and quenched with saturated aqueous sodium bicarbonate. The organic layer was separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified on silica (eluted with 20% ethyl acetate in heptane). The concentrated target fraction was triturated with diisopropyl ether, filtered, washed with diisopropyl ether and pentane and then dried in vacuo to give 0.62g of racemic 7- (2-methyloxetan-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile. MS (method B) m/z 261[ M+1] +; t=1.50 min.
Step 7: preparation of 7- (2-methyl-oxetan-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (racemic)
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1.64g of 3-chloroperbenzoic acid (77% purity; 3 eq.) are added in portions to a solution of 0.62g (1 eq.) of racemic 7- (2-methyloxetan-3-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile in 20mL of dichloromethane at 0 ℃. The mixture was stirred for 1 hour to allow the temperature to warm to room temperature, then quenched with 50ml of 10% aqueous sodium thiosulfate. The organic layer was separated and washed with 50mL of 10% aqueous sodium thiosulfate, twice with 50mL of saturated aqueous sodium bicarbonate, and then dried over magnesium sulfate and concentrated under reduced pressure to give 0.6g of racemic 7- (2-methyloxetan-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile. The crude material was taken to the next step without further purification.
Step 8: preparation of 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 and 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
Generally following the procedure described in step 5 of example 1, a racemic mixture of 7- (2-methyloxetan-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (300 mg) and N- (1-methyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide (212 mg) (intermediate 4) gives a racemic mixture of 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 with 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 (herein referred to as trans-7-methyl-3- (oxetan-3-yloxy) pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile 6-carbonitrile) (275 mg).
The 267mg isomer mixture was subjected to chiral separation to give 117mg of the first eluting isomer and 117mg of the second eluting isomer (conditions: column Chiralpak AD,20 μm,350x 76mm; liquid phase: heptane 50/ethanol 50/triethylamine 0.1% for 19 min, then heptane 40/ethanol 60/triethylamine 0.1%; flow rate: 400 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 MHz, DMSO-d 6) delta in ppm 1.45 (d, J=6Hz, 3H), 3.64 (s, 3H), 4.57 (br t, J=6Hz, 2H), 4.75-4.86 (m, 3H), 5.12-5.27 (m, 2H), 5.32 (quin, J=6Hz, 1H), 5.56 (quin, J=6Hz, 1H), 7.48 (s, 1H), 8.01 (br s, 1H), 8.83(s, 1H), 8.95 (br s, 1H). MS (method B) m/z 382[ M+1 ]]++, of the material; t=1.43 min-example 76 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 mhz, dmso-d 6) δ in ppm: 1.45 (d, j=6 hz, 3H), 3.64 (s, 3H), 4.57 (t, j=6 hz, 2H), 4.75-4.85 (m, 3H), 5.12-5.26 (m, 2H), 5.32 (quin, j=6 hz, 1H), 5.56 (quin, j=6 hz, 1H), 7.48 (s, 1H), 8.02 (br s, 1H), 8.83 (s, 1H), 8.96 (br s, 1H). MS (method B) m/z 382[ M+1 ]]++, of the material; t=1.40 min-example 77 (absolute configuration unknown)
Example 78 and example 79:7- [ (2R, 3S) -2-Methyloxetan-3-yl ] -2- [ (1-methyl-3-propan-2-yloxy pyrazol-4-yl) amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 7- [ (2S, 3R) -2-Methyloxetan-3-yl ] -2- [ (1-methyl-3-propan-2-yloxy pyrazol-4-yl) amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
Following the procedure described in example 47, a racemic mixture of 7- (2-methyloxetan-3-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (300 mg) (example 76, step 7) (300 mg) and N- (3-isopropoxy-1-methyl-1H-pyrazol-4-yl) carboxamide (197 mg) (intermediate 38) gave a racemic mixture of 7- [ (2R, 3S) -2-methyloxetan-3-yl ] -2- [ (1-methyl-3-propan-2-yloxy pyrazol-4-yl) amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 7- [ (2S, 3R) -2-methyloxetan-3-yl ] -2- [ (1-methyl-3-propan-2-yloxy pyrazol-4-yl) amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (referred to herein as 7-trans) -2-methyloxetan-2-yloxy-pyrazol-4-yl) amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (260 mg) .
Chiral separation of 250mg of the isomer mixture gave 115mg of the first eluting isomer and 112mg of the second eluting isomer (conditions: column Chiralpak IC,20 μm,350x 76mm; liquid phase: heptane 50/ethanol 50; flow rate: 400 mL/min).
Peak 1 (isomer 1): 1 H NMR(400MHz,DMSO-d6)δppm:1.27(d,J＝6Hz,6H)1.45 (d, j=6 hz, 3H), 3.66 (s, 3H), 4.72 (spt, j=6 hz, 1H), 4.80 (t, j=7 hz, 1H), 5.11-5.32 (m, 2H), 5.56 (quin, j=6 hz, 1H), 7.48 (s, 1H), 8.00 (br s, 1H), 8.61 (br s, 1H), 8.81 (s, 1H). MS (method B) m/z 368[ M+1 ] ]++, of the material; t=1.58 min-example 78 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 MHz, DMSO-d 6) delta ppm:1.27 (d, J=6 Hz, 6H), 1.45 (d, J=6 Hz, 3H), 3.66 (s, 3H), 4.72 (spt, J=6 Hz, 1H), 4.80 (t, J=7 Hz, 1H), 5.12-5.32 (m, 2H), 5.56 (quin, J=6 Hz, 1H), 7.48 (s, 1H), 8.00 (br s, 1H), 8.61 (br s, 1H), 8.81 (s, 1H). MS (method B) m/z 368[ M+1]]++, of the material; t=1.66 min-example 79 (absolute configuration unknown)
Example 80:2- ((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
Step 1: preparation of 2- (methylsulfonyl) -7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Starting from 2- (methylsulfanyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (intermediate 43) (400 mg) and tetrahydro-2H-pyran-4-ol instead of tetrahydrofuran-3-ol, 198mg of 2- (methylsulfonyl) -7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile was prepared according to the procedure described in steps 1 and 2 of example 52. MS (method A) m/z 307[ M+1] +; t=1.6 min.
Step 2: preparation of 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
Following the general procedure in step 5 of example 1, 2- (methylsulfonyl) -7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (194 mg) and N- [ 1-methyl-3- (oxetan-3-yloxy) pyrazol-4-yl ] carboxamide (intermediate 4) gave 2- ((1-methyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3- ] pyrimidine-6-carbonitrile (83 mg).
1 H NMR (400 mhz, dmso-d 6) delta ppm:1.83 (dd, j=12, 3hz, 2H), 2.59 (m, 2H), 3.49 (t, j=11 hz, 2H), 3.66 (s, 3H), 4.04 (dd, j=12, 4hz, 2H), 4.56 (dd, j=8, 5hz, 2H), 4.69 (m, 1H), 4.81 (t, j=7 hz, 2H), 5.31 (m, 1H), 7.45 (s, 1H), 7.82 (br s, 1H), 8.81 (s, 1H), 8.90 (br s, 1H). MS (method B) m/z 396[ M+1 ]]+；t＝2.58min。
Example 81 and example 82: (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 and (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
Step 1: preparation of methyl 2- (methylthio) -7- (tetrahydro-2H-pyran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylate (racemic mixture)
3.17g (3 eq) triphenylphosphine, 2,47g (3 eq) rac-2H-pyran-3-ol and 2.45g (3 eq) diisopropyl azodicarboxylate (DIAD) were added to a solution of 900mg (1 eq) methyl 2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylate (intermediate 1) in 50mL anhydrous tetrahydrofuran under argon. The mixture was stirred at 50 ℃ for 3 hours and at room temperature for 15 hours, then an additional 3 equivalents of triphenylphosphine, 3 equivalents of tetrahydro-2H-pyran-3-ol and 3 equivalents of DIAD were added, and the mixture was stirred at 50 ℃ for an additional 1 hour 30 minutes, then concentrated under reduced pressure. The residue was purified on silica (eluting with 0-70% ethyl acetate in cyclohexane) to give 900mg of racemic 2- (methylthio) -7- (tetrahydro-2H-pyran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid methyl ester. MS (method F) m/z 308[ M+1] +; t=1.86 min.
Step 2: preparation of 2-methylsulfanyl-7-tetrahydropyran-3-yl-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid (racemic mixture)
2.93mL (4 eq) of 4N aqueous sodium hydroxide was added to a solution of 900mg (1 eq) of racemic methyl 2- (methylthio) -7- (tetrahydro-2H-pyran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylate in 10mL of methanol and 5mL of tetrahydrofuran. The mixture was stirred at room temperature for 1 hour 30 minutes and then concentrated under reduced pressure. The residue was dissolved in 20mL diethyl ether and 20mL water and extracted. The aqueous layer was acidified to ph=1 with HCl 2N and then extracted with 300mL ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated in vacuo to give 756mg of racemic 2-methylsulfanyl-7-tetrahydropyran-3-yl-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid. MS (method F) m/z 294[ M+1] +; t=1.53 min.
Step 3: preparation of 2-methylsulfonyl-7-tetrahydropyran-3-yl-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (racemic mixture)
Starting from 756mg of rac-2-methylsulfanyl-7-tetrahydropyran-3-yl-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid, 603mg of rac-2-methylsulfonyl-7-tetrahydropyran-3-yl-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile was prepared according to the procedure described in steps 2,3 and 4 of example 1. MS (method F) m/z 307[ M+1] +; t=1.27 min.
Step 4: preparation of (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 and (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
Generally following the procedure described in step 5 of example 1, racemic 2-methylsulfonyl-7-tetrahydropyran-3-yl-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (340 mg) and N- [ 1-methyl-3- (oxetan-3-yloxy) pyrazol-4-yl ] carboxamide (intermediate 4) gave a racemic mixture (216 mg) (referred to herein as 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 and (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 (hereinafter referred to as 2- ((1-methyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) Pyrrolo [2,3-d ] pyrimidine-6-carbonitrile).
The 216mg isomer mixture was subjected to chiral separation to give 95mg of the first eluting isomer and 94mg of the second eluting isomer (conditions: column Chiralpak AY,20 μm,230X 100mm; liquid phase: heptane 40/ethanol 60 to heptane 20/ethanol 80/triethylamine 0.1%; flow rate: 400 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 MHz, DMSO-d 6) delta ppm:1.77 (m, 2H), 2.03 (d, J=12 Hz, 1H), 2.59 (m, 1H), 3.31 (m, 1H), 3.67 (s, 3H), 3.90 (m, 2H), 4.03 (t, J=11 Hz, 1H), 4.47 (m, 1H), 4.54 (t, J=6 Hz, 2H), 4.80 (t, J=8 Hz, 2H), 5.31 (quin, J=6 Hz, 1H), 7.44 (s, 1H), 7.75 (s, 1H), 8.79 (s, 1H), 8.80 (br s, 1H)). MS (method B) m/z 396[ M+1 ]]++, of the material; t=1.47 min-example 81 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 mhz, dmso-d 6) delta ppm 1.69-1.85 (m, 2H), 2.03 (d, j=12 hz, 1H), 2.59 (m, 1H), 3.32 (m, 1H), 3.67 (s, 3H), 3.90 (m, 2H), 4.03 (t, j=11 hz, 1H), 4.47 (m, 1H), 4.54 (t, j=6 hz, 2H), 4.80 (t, j=7 hz, 2H), 5.32 (m, 1H), 7.44 (s, 1H), 7.75 (s, 1H), 8.79 (m, 2H). MS (Square)Method B) m/z 396[ M+1 ]]++, of the material; t=1.47 min-example 82 (absolute configuration unknown)
Example 83 and example 84:2- ((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 and 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
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Step 1: preparation of 3-methyltetrahydro-2H-pyran-4-yl acetate (racemic trans) and 3-methyltetrahydro-2H-pyran-4-yl acetate (racemic cis)
5.44g (1.25 eq) triethylamine, 5.49g (1.25 eq) acetic anhydride and 526mg (0.1 eq) N, N-dimethyl-4-aminopyridine (DMAP) were added to a solution of a commercially available mixture of trans and cis 3-methyltetrahydro-2H-pyran-4-ol in 5g (1 eq) racemic form (4 stereoisomers) in 75mL dichloromethane. The mixture was stirred at room temperature for 2 hours and then concentrated carefully to half at 40 ℃ under reduced pressure of 300 mbar. The resulting solution was diluted with 100mL of pentane and purified on silica (eluting with 0-100% diethyl ether in pentane) to give 3.45g of 3-methyltetrahydro-2H-pyran-4-yl acetate (racemic trans) and 2.15g of 3-methyltetrahydro-2H-pyran-4-yl acetate (racemic cis) successively.
3-methyltetrahydro-2H-pyran-4-yl acetate (racemic trans):
1 H NMR(400MHz,CDCl 3 ) Delta, 0.85 (d, j=6.7hz, 3 h) in ppm; 1.61 (m, 1H); 1.83 (m, 1H); 1.96 (m, 1H); 2.07 (s, 3H); 3.10 (dd, j=10.6 Hz and j=11.9 Hz,1 h); 3.46 (m, 1H); 3.87 (dd, j=4.7 Hz and j=11.8 Hz,1 h); 3.95 (m, 1H); 4.58 (td, j=4.6 Hz and j=10.1 Hz, 1) H)。
3-methyltetrahydro-2H-pyran-4-yl acetate (racemic cis):
1 H NMR(400MHz,CDCl 3 ) Delta, 0.86 in ppm (d, j=6.9hz, 3 h); 1.80 (m, 2H); 2.00 (m, 1H); 2.08 (s, 3H); 3.47 (dd, j=8.9 Hz and j=12 Hz,1 h); 3.60 (dd, j=4.2 Hz and j=11.2 Hz,1 h); 3.68 (m, 2H); 5.04 (q, j=4.5 hz,1 h).
Step 2: preparation of 3-methyltetrahydropyran-4-ol (racemic cis)
2.15g (1 eq) of 3-methyltetrahydro-2H-pyran-4-yl acetate (racemic cis) are added to 14.5mL (1.07 eq) of a 1N solution of precooled (-5 ℃ C.) sodium methoxide in methanol. The mixture was stirred at 0 ℃ for 1 hour 30 minutes and then quenched with 7.3mL (1.07 eq) of a 2N hydrogen chloride solution in diethyl ether. After addition of an additional 30mL of diethyl ether, the suspension was filtered through a pad of celite and the filter cake was rinsed twice with 15mL of diethyl ether. The filtrate was concentrated at 40 ℃ under reduced pressure of 120 mbar and the residue was purified on silica (eluting with 0-100% diethyl ether in pentane) to give (after concentration at 40 ℃ under reduced pressure of 120 mbar) 1.17g 3-methyltetrahydropyran-4-ol (racemic cis).
1 H NMR(400MHz,CDCl 3 ) Delta, 0.91 (d, j=7hz, 3 h) in ppm; 1.56 (br s, 1H); 1.70 (m, 1H); 1.80 (m, 1H); 1.90 (m, 1H); 3.56 (m, 3H); 3.80 (ddd, j=11.8 Hz, j=9.6 Hz and j=3.3 Hz,1 h); 3.93 (m, 1H).
Step 3: preparation of methyl 2-methylsulfanyl-7- [ (trans) -3-methyltetrahydropyran-4-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxylate (racemic trans)
1.75g (2 eq) triphenylphosphine, 568mg (1.5 eq) 3-methyltetrahydropyran-4-ol (racemic cis) and 1.32g (2 eq) diisopropyl azodicarboxylate (DIAD) were added to a solution of 750mg (1 eq) methyl 2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylate (intermediate 1) in 40mL anhydrous tetrahydrofuran under argon. The mixture was stirred at room temperature for 5 hours, then an additional 1 equivalent of triphenylphosphine, 1 equivalent of 3-methyltetrahydropyran-4-ol (racemic cis) and 1 equivalent of DIAD were added, and the mixture was stirred at 50 ℃ for 2 hours, then concentrated under reduced pressure. The residue was purified on silica (eluting with 0-50% ethyl acetate in cyclohexane) to give 870g of methyl 2-methylsulfanyl-7- [ (trans) -3-methyltetrahydropyran-4-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxylate (racemic trans). MS (method F) m/z 322[ M+1] +; t=1.91 min.
Step 4: preparation of 2-methylsulfonyl-7- [ 3-methyltetrahydropyran-4-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (racemic trans)
700mg of 2-methylsulfonyl-7- [ 3-methyltetrahydropyran-4-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (racemic trans) were obtained according to steps 2 and 3,1.03g of 2-methylsulfanyl-7- [ 3-methyltetrahydropyran-4-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (racemic trans) of example 81. MS (method F) m/z 321[ M+1] +; t=1.34 min.
Step 5: preparation of 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 and 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
Generally following the procedure described in step 5 of example 1, 2-methylsulfonyl-7- [ 3-methyltetrahydropyran-4-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (racemic trans) (350 mg) and N- [ 1-methyl-3- (oxetan-3-yloxy) pyrazol-4-yl ] carboxamide (226 mg) (intermediate 4) gave 303mg of 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 as a mixture with 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 (305 mg) was referred to as racemic amino-3-oxetan-2-methyl-3- ((3-oxetan-3-yloxy) -7H-pyrazol-4-yl) amino group (305 mg) ((trans) -3-methyltetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile).
Chiral separation of 303mg of the isomer mixture gave 142mg of the first eluting isomer and 138mg of the second eluting isomer (conditions: column Chiralpak IC,20 μm, 350x76.5 mm; liquid phase: heptane 20/ethanol 80; flow rate: 400 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 mhz, dmso-d 6) δppm 0.55 (d, j=7hz, 3H), 1.84 (dd, j=13, 4hz, 1H), 2.47 (m hidden, 1H), 2.73 (m, 1H), 3.13 (t, j=12 hz, 1H), 3.51 (t, j=11 hz, 1H), 3.66 (s, 3H), 3.96 (dd, j=11, 4hz, 1H), 4.04 (dd, j=11, 4hz, 1H), 4.25 (br s, 1H), 4.56 (t, j=6 hz, 2H), 4.81 (t, j=7hz, 2H), 5.31 (quin, j=6 hz, 1H), 7.47 (s, 1H), 7.80 (br s, 1H), 8.82 (s, 1H), 8.87 (br s, 1H). MS (method B) m/z 410[ M+1 ]]++, of the material; t=1.43 min-example 83 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 mhz, dmso-d 6) δppm 0.55 (d, j=7hz, 3H), 1.84 (d, j=12 hz, 1H), 2.43 (m hidden, 1H), 2.70 (br s, 1H), 3.13 (t, j=11 hz, 1H), 3.51 (t, j=11 hz, 1H), 3.66 (s, 3H), 3.96 (dd, j=11, 4hz, 1H), 4.04 (dd, j=12, 4hz, 1H), 4.25 (br s, 1H), 4.56 (t, j=6 hz, 2H), 4.81 (t, j=7hz, 2H), 5.31 (quin, j=6 hz, 1H), 7.47 (s, 1H), 7.80 (br s, 1H), 8.82 (s, 1H), 8.86 (br s, 1H). MS (method B) m/z 410[ M+1 ]]++, of the material; t=1.43 min-example 84 (absolute configuration unknown)
Example 85 and example 86:2- ((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 and 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
Step 1: preparation of 3-methyltetrahydropyran-4-ol (racemic trans)
3.45g (1 eq) of 3-methyltetrahydro-2H-pyran-4-yl acetate (racemic trans) are added to 23.5mL (1.07 eq) of a 1N solution of precooled (-5 ℃ C.) sodium methoxide in methanol. The mixture was stirred at 0 ℃ for 1 hour 30 minutes and then quenched with 11.8mL (1.07 eq) of a 2N hydrogen chloride solution in diethyl ether. After addition of an additional 50mL of diethyl ether, the suspension was filtered through a pad of celite and the filter cake was rinsed twice with 20mL of diethyl ether. The filtrate was concentrated at 40 ℃ under reduced pressure of 120 mbar and the residue was purified on silica (eluting with 0-100% diethyl ether in pentane) to give (after concentration at 40 ℃ under reduced pressure of 120 mbar) 1.78g 3-methyltetrahydropyran-4-ol (racemic trans).
1 H NMR(400MHz,CDCl 3 ) Delta, 0.92 (d, j=6.6 hz,3 h) in ppm; 1.58 (m, 2H); 1.84 (br s, 1H); 1.88 (m, 1H); 2.98 (t, j=11.1 hz,1 h); 3.31 (td, j=10 Hz and j=4.7 Hz,1 h); 3.40 (td, j=11.5 Hz and j=2.3 Hz,1 h); 3.82 (dd, j=4.4 Hz and j=11.6 Hz,1 h); 3.96 (m, 1H).
Step 2: preparation of methyl 2-methylsulfanyl-7- [ (cis) -3-methyltetrahydropyran-4-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxylate (racemic cis)
1.75g (2 eq) triphenylphosphine, 568mg (1.5 eq) 3-methyltetrahydropyran-4-ol (racemic trans) and 1.32g (2 eq) diisopropyl azodicarboxylate (DIAD) were added to a solution of 750mg (1 eq) methyl 2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylate (intermediate 1) in 40mL anhydrous tetrahydrofuran under argon. The mixture was stirred at room temperature for 5 hours, then an additional 1 equivalent of triphenylphosphine, 1 equivalent of rac (trans) -3-methyltetrahydropyran-4-ol and 1 equivalent of DIAD were added, and the mixture was stirred at 50 ℃ for 2 hours, then concentrated under reduced pressure. The residue was purified on silica (eluting with 0-70% ethyl acetate in cyclohexane) to give 610mg of methyl 2-methylsulfanyl-7- [ 3-methyltetrahydropyran-4-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxylate (racemic cis). MS (method F) m/z 322[ M+1] +; t=1.88 min.
Step 3: preparation of 2-methylsulfanyl-7- [ 3-methyltetrahydropyran-4-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxamide (racemic cis)
610mg (1 eq) of methyl 2-methylsulfanyl-7- [ 3-methyltetrahydropyran-4-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxylate (racemic cis) in 50mL of 7N ammonia solution in methanol in a sealed tube are stirred at 80℃for 3 days. The mixture was then concentrated under reduced pressure to give 503mg of 2-methylsulfanyl-7- [ 3-methyltetrahydropyran-4-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxamide (racemic cis). MS (method E) m/z 307[ M+1] +; t=1.07 min.
Step 4: preparation of 2-methylsulfonyl-7- [ 3-methyltetrahydropyran-4-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (racemic cis)
Starting from 503mg of 2-methylsulfanyl-7- [ 3-methyltetrahydropyran-4-yl ] pyrrolo [2,3-d ] pyrimidine-6-carboxamide (racemic cis), 473mg of 2-methylsulfonyl-7- [ 3-methyltetrahydropyran-4-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (racemic cis) were prepared according to the procedure described in steps 3 and 4 of example 1. MS (method F) m/z 321[ M+1] +; t=1.29 min.
Step 5: preparation of 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 and 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
Racemic 2-methylsulfonyl-7- [ (cis) -3-methyltetrahydropyran-4-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (250 mg) and N- [ 1-methyl-3- (oxetan-3-yloxy) pyrazol-4-yl ] carboxamide (intermediate 4) generally follows the procedure described in step 5 of example 1 to give a racemic mixture of 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 with 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 (168 mg) (referred to herein as cis-3-oxetan-3-amino) -1-methyl-3- (oxetan-3-yloxy) -7H-pyrazolo-4-yl group Formula) -3-methyltetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
Chiral separation of 162mg of the isomer mixture gave 42mg of the first eluting isomer and 46mg of the second eluting isomer (conditions: column Chiralpak IF,5 μm,250X 30mm; liquid phase: heptane 35/ethanol 65; flow rate: 45 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 mhz, dmso-d 6) δppm 0.92 (d, j=7hz, 3H), 1.82 (d, j=11hz, 1H), 2.18 (s, 1H), 3.15 (m, 1H), 3.52 (t, j=11hz, 1H), 3.63 (m, 1H), 3.67 (s, 3H), 3.74 (m, 1H), 4.06 (dd, j=11, 4hz, 1H), 4.55 (t, j=6hz, 2H), 4.80 (t, j=7hz, 2H), 4.97 (dt, j=13, 4hz, 1H), 5.30 (quin, j=6hz, 1H), 7.46 (s, 1H), 7.76 (s, 1H), 8.80 (br s, 1H), 8.80 (s, 1H). MS (method B) m/z 410[ M+1 ]]++, of the material; t=1.45 min-example 85 (absolute configurationUnknown
Peak 2 (isomer 2): 1 h NMR (400 mhz, dmso-d 6) δppm 0.92 (d, j=7hz, 3H), 1.82 (d, j=11hz, 1H), 2.19 (m, 1H), 3.17 (m, 1H), 3.51 (t, j=11hz, 1H), 3.63 (m, 1H), 3.67 (s, 3H), 3.74 (m, 1H), 4.06 (dd, j=11, 5hz, 1H), 4.55 (t, j=6hz, 2H), 4.80 (t, j=7hz, 2H), 4.97 (dt, j=13, 4hz, 1H), 5.30 (quin, j=6hz, 1H), 7.46 (s, 1H), 7.76 (s, 1H), 8.80 (br s, 1H), 8.80 (s, 1H). MS (method B) m/z 410[ M+1 ]]The method comprises the steps of carrying out a first treatment on the surface of the t=1.44 min-example 86 (absolute configuration unknown)
Examples 87 and 88:7- [ (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 and 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
Step 1: preparation of methyl (S) -N- (5-formyl-2- (methylthio) pyrimidin-4-yl) -N- (1-methoxypropane-2-yl) glycinate
3.8mL of triethylamine (1.7 eq) was added to a solution of 3g of 4-chloro-2- (methylthio) pyrimidine-5-carbaldehyde (1 eq) in 100mL of tetrahydrofuran and 20mL of dichloromethane at 0deg.C. 3.2g of methyl (S) - (1-methoxypropane-2-yl) glycinate (1.25 eq) were added dropwise. The mixture was stirred at room temperature for 3 days, diluted with ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted twice with 50mL ethyl acetate. The combined organic layers were washed twice with 50mL brine, then 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 4.9g of methyl (S) -N- (5-formyl-2- (methylthio) pyrimidin-4-yl) -N- (1-methoxypropane-2-yl) glycinate. MS (method A) m/z 314[ M+1] +; t=1.95 min.
Step 2: preparation of methyl (S) -7- (1-methoxypropane-2-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylate
55.68mL (5 eq.) of 1, 8-diazabicyclo [5.4.0] undec 7-ene were added dropwise to a solution of 28g (S) -methyl (5-formyl-2- (methylthio) pyrimidin-4-yl) -N- (1-methoxypropane-2-yl) glycine (1 eq.) in 350mL acetonitrile. The reaction mixture was refluxed for 1 hour. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and quenched with 1N aqueous HCl. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel (eluting with 20% ethyl acetate in heptane) to give 15g of methyl (S) -7- (1-methoxypropane-2-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylate. MS (method A) m/z 296[ M+1] +; t=2.11 min.
Step 3: preparation of (S) -7- (1-methoxypropane-2-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide
15g of (S) -7- (1-methoxypropane-2-yl) -2- (methylthio) -7H-pyrrolo [2,3-d]Pyrimidine-6-carboxylic acid methyl ester (1 eq) in 400mL 7N NH in methanol 3 The solution (in a sealed tube) was stirred at room temperature for 3 days, and then concentrated under reduced pressure to give 12.5g(S) -7- (1-methoxypropane-2-yl) -2- (methylthio) -7H-pyrrolo [2,3-d]Pyrimidine-6-carboxamide. MS (method A) m/z 281[ M+1]]+；t＝1.77min。
Step 4: preparation of (S) -7- (1-methoxypropane-2-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
28.2mL (4.5 eq.) of triethylamine was added to a solution of 12.5g (S) -7- (1-methoxypropane-2-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxamide (1 eq.) in 300mL of anhydrous tetrahydrofuran under argon at 0℃followed by 22.33mL (3.6 eq.) of trifluoroacetic anhydride. The mixture was stirred for 45 minutes to allow the temperature to warm to room temperature, then diluted with ethyl acetate, and quenched with saturated aqueous sodium bicarbonate. The organic layer was separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure to give 16g of (S) -7- (1-methoxypropane-2-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile. MS (method A) m/z 263[ M+1] +; t=2.33 min.
Step 5: preparation of (S) -7- (1-methoxypropane-2-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
23.68g of 3-chloroperbenzoic acid (77% purity; 3 eq.) are added in portions to a solution of 16g (1 eq.) of (S) -7- (1-methoxypropane-2-yl) -2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile in 300mL of dichloromethane at 0 ℃. The mixture was stirred for 3 hours to allow the temperature to warm to room temperature, then quenched with 150ml of 10% aqueous sodium thiosulfate. The organic layer was separated, washed with 150mL of 10% aqueous sodium thiosulfate, twice with 150mL of saturated aqueous bicarbonate, then dried over magnesium sulfate and concentrated under reduced pressure. The crude material was triturated with diisopropyl ether and the solid was filtered to give 10g (S) -7- (1-methoxypropane-2-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile. MS (method A) m/z 295[ M+1] +; t=1.68 min.
Step 6: preparation of 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 and 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
Following the general procedure described in step 5 of example 1, (S) -7- (1-methoxypropane-2-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (120 mg) and N- (1-methyl-3- (((2 r, 3S) -2-methyl oxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide were reacted with racemic mixture of N- (1-methyl-3- (((2S, 3 r) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (91 mg) (intermediate 19) to give 7- [ (1S) -2-methoxy-1-methyl-ethyl ] -2- [ [ 1-methyl-3- [ (2S, 3 r) -2-methyloxetan-3-yl ] oxy-pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 7- [ (1S) -2-methoxy-1-methyl-ethyl ] -1H-pyrazol-4-yl ] carboxamide An isomeric mixture of benzo [2,3-d ] pyrimidine-6-carbonitrile (119 mg) (referred to herein as 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).
The 110mg isomer mixture was subjected to chiral separation to give 50mg of the first eluting isomer and 60mg of the second eluting isomer (conditions: column Chiralpak AY,20 μm,250X 4.6mm; liquid phase: methanol 15/ethanol 85 to methanol 40/ethanol 60; flow rate: 200 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 mhz, dmso-d 6) δppm:1.41 (d, j=6 hz, 3H), 1.55 (d, j=7 hz, 3H), 3.19 (s, 3H), 3.64 (dd, j=11, 5hz, 1H), 3.68 (s, 3H), 3.98 (t, j=10 hz, 1H), 4.38 (dd, j=7, 6hz, 1H), 4.65 (t, j=7 hz, 1H), 4.77 (quin, j=6 hz, 1H), 4.84-4.98 (m, 2H), 7.42 (s, 1H), 7.72 (s, 1H), 8.74 (br s, 1H), 8.79 (s, 1H). MS (method C) m/z398[ M+1 ]]++, of the material; t=2.82 min-example 87 (absolute configuration unknown)
Peak 2 (isomer 2): 1 H NMR(400MHz,DMSO-d6)δppm:1.40(d,J＝6Hz,3H),1.54(d,J＝7Hz,3H),3.19(s,3H),3.64(dd,J＝10,5Hz,1H),3.67(s,3H),3.97(t,J＝10Hz,1H),4.37(dd,J＝7,6Hz,1H),4.64(t,J＝7Hz,1H),4.77(quin, j=6 hz, 1H), 4.88 (q, j=5 hz, 1H), 4.89 (m, 1H), 7.41 (s, 1H), 7.72 (s, 1H), 8.71 (br s, 1H), 8.78 (s, 1H). MS (method B) M/z398[ M+1 ]]++, of the material; t=1.47 min example 88 (absolute configuration unknown)
Examples 89 and 90:7- [ (1S) -2-methoxy-1-methyl-ethyl ] -2- [ [3- [ (2S, 3R) -2-methyloxetan-3-yl ] oxy-1- (methyl-d 3) pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 7- [ (1S) -2-methoxy-1-methyl-ethyl ] -2- [ [3- [ (2R, 3S) -2-methyloxetan-3-yl ] oxy-1- (methyl-d 3) pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Following the general procedure described in step 5 of example 1, (S) -7- (1-methoxypropane-2-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (200 mg) (step 5 of example 87) and N- (1- (methyl-d 3) -3- (((2 r, 3S) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide were reacted with a racemic mixture of N- (1- (methyl-d 3) -3- (((2S, 3 r) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (160 mg) (intermediate 21) to give 7- [ (1S) -2-methoxy-1-methyl-ethyl ] -2- [ (3- [ (2S, 3 r) -2-methyloxetan-3-yl ] oxy-1- (methyl-d 3-pyrazol-4-yl) amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 1- [ (2S) -2-methoxy-1-methyl-ethyl ] -2- [ (2S) -2-methyloxetan-3- [ -ethyl ] -2- [ (2S, 3-yl ] oxy-1-methyl- [ -2-methyl- ] Isomer mixtures of (219 mg) of (methyl-d 3) -2-methoxy-1-methyl-ethyl ] -2- [ [3- [ (trans) -2-methyloxetan-3-yl ] oxy-1- (methyl-d 3) pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (referred to herein as 7- [ (1S) -2-methoxy-1-methyl-ethyl ] -2- [ [3- [ (trans) -2-methyloxetan-3-yl ] oxy-1- (methyl-d 3) pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile).
The 212mg isomer mixture was subjected to chiral separation to give 98mg of the first eluting isomer and 95mg of the second eluting isomer (conditions: column Chiralpak AY,20 μm,250X 4.6mm; liquid phase: methanol 15/ethanol 85 to methanol 40/ethanol 60; flow rate: 200 mL/min).
Peak 1 (isomer 1): 1 H NMR(400MHz,DMSO-d6)δppm:1.40(d,J＝6Hz,3H),1.54 (d, j=7 hz, 3H), 3.18 (s, 3H), 3.64 (dd, j=10, 5hz, 1H), 3.97 (t, j=10 hz, 1H), 4.38 (dd, j=7, 6hz, 1H), 4.64 (t, j=7 hz, 1H), 4.76 (quin, j=6 hz, 1H), 4.83-4.96 (m, 2H), 7.41 (s, 1H), 7.72 (s, 1H), 8.73 (br s, 1H), 8.78 (s, 1H). MS (method C) m/z 401[ M+1 ]]++, of the material; t=2.81 min-example 89 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 mhz, dmso-d 6) δppm:1.41 (d, j=6 hz, 3H), 1.54 (d, j=7 hz, 3H), 3.19 (s, 3H), 3.64 (dd, j=10, 5hz, 1H), 3.97 (t, j=10 hz, 1H), 4.37 (dd, j=7, 6hz, 1H), 4.64 (t, j=7 hz, 1H), 4.77 (quin, j=6 hz, 1H), 4.88 (q, j=7 hz, 1H), 4.89 (m, 1H), 7.42 (s, 1H), 7.72 (s, 1H), 8.77 (br s, 1H), 8.78 (s, 1H). MS (method C) m/z 401[ M+1 ]]++, of the material; t=2.81 min-example 90 (absolute configuration unknown)
(S) -7- (1-methoxypropane-2-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile was reacted with the appropriate formamide to give examples 91 to 93 in Table III, generally following the procedure described in example 88.
Table III
Example 94:2- ((1-methyl-3- (oxetan-3-yloxy) -1H-pyrazol-4-yl-5-d) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
99mg (1 eq) of 2- [ [ 1-methyl-3- (oxetan-3-yloxy) pyrazol-4-yl]Amino group]-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl]Pyrrolo [2,3-d]Pyrimidine-6-carbonitrile (example 8) was dissolved in 4mL of anhydrous 1, 4-dioxane in a microwave vial, and 5-10mol% of ruthenium complex B (ruthenium catalyst B- (Ru (O) 2 CAd) 2 (pair of)Cymene) is based on ChemCatChem 2019,11,1-6). A homogeneous orange solution was obtained. 2ml of 99.9% deuterium oxide was added at room temperature and the reaction mixture was heated at 100℃under irradiation of. Mu.W for 4 hours. The crude reaction mixture was evaporated to dryness, dissolved in 1mL of dichloromethane and purified on silica (eluting with 50/50 to 10/90 heptane/ethyl acetate). By dissolving the gum obtained in 50/50 heptane/ethyl acetate and subsequently with 1% NH in methanol 3 90mg of 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) are obtained]Pyrimidine-6-carbonitrile.
1 H NMR (400 mhz, dmso-d 6) delta ppm:1.05 (d, j=7hz, 3H), 2.93 (m, 1H), 3.47 (t, j=9hz, 1H), 3.65 (s, 3H), 4.09-4.26 (m, 2H), 4.29 (m, 1H), 4.53-4.62 (m, 2H), 4.76 (t, j=6hz, 1H), 4.81 (t, j=7hz, 2H), 5.31 (quin, j=6hz, 1H), 7.46 (s, 1H), 8.82 (s, 1H), 8.90 (br s, 1H). MS (method C) m/z 397[ M+1 ]]+；t＝2.7min。
Typically, deuterium oxide is reacted with the appropriate cyanogen following the procedure described in example 94 to give examples 95 to 98 in table IV.
Table IV
Examples 99 and 100:2- ((3- (((R) -2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 2- ((3- (((S) -2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
212mg (1 eq) of t-butylimino-tris (pyrrolidinyl) phosphane (BTPP) was added to a solution of 200mg (1 eq) (S) -7- (1-methoxypropane-2-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (200 mg) (step 5 of example 87) and 163mg (1.05 eq) of N- (3- ((2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide (intermediate 52) in 18mL of acetonitrile, and the mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The residue was taken up in 10mL methanol and 50mL 7n methanolic ammonia solution and stirred for 15 minutes, then concentrated under reduced pressure. The residue was purified on silica (eluting with a gradient of 20% to 50% ethyl acetate in dichloromethane) to give 225mg of an isomeric mixture of 2- ((3- (((R) -2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 2- ((3- (((S) -2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (referred to herein as 2- ((3- ((2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7-S-methoxypyrimidin-6-carbonitrile.
The 218mg isomer mixture was subjected to chiral separation to give 109mg of the first eluting isomer and 110mg of the second eluting isomer (conditions: column Chiralpak AY,20 μm,250X 4.6mm; liquid phase: heptane 20/EtOH 80/TEA 0.1, then heptane 50/EtOH 50/TEA 0.1; flow rate: 400 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 MHz, DMSO-d 6) delta ppm 1.31 (s, 3H) 1.43 (s, 3H) 1.55 (d, J=7Hz, 3H) 3.19 (s, 3H) 3.65 (dd, J=11, 5Hz, 1H) 3.96 (t, J=11 Hz, 1H) 4.29 (dd, J=7, 6Hz, 1H) 4.55 (t, J=7Hz, 1H) 4.82-5.01 (m, 2H) 7.42 (s, 1H) 7.73 (s, 1H) 8.67 (br s, 1H) 8.79 (s, 1H); MS (method B) m/z 415[ M+1 ]]++, of the material; t=1.52 min-example 99 (absolute configuration unknown)
Peak 2 (isomer 2): 1 H NMR(400MHz,DMSO-d6)δppm:1.31(s,3H)1.43(s,3H)1.55(d,J＝7Hz,3H)3.19(s,3h) 3.65 (dd, j=11, 5hz, 1H) 3.96 (t, j=11 hz, 1H) 4.29 (dd, j=7, 6hz, 1H) 4.55 (t, j=7 hz, 1H) 4.82-5.01 (m, 2H) 7.42 (s, 1H) 7.73 (s, 1H) 8.67 (br s, 1H) 8.79 (s, 1H); MS (method B) m/z 415[ M+1 ]]++, of the material; t=1.52 min-example 100 (absolute configuration unknown)
Examples 101 and 102:7- ((S) -1-methoxypropane-2-yl) -2- ((1- (methyl-d 3) -3- (((R) -tetrahydrofurane-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 7- ((S) -1-methoxypropane-2-yl) -2- ((1- (methyl-d 3) -3- (((S) -tetrahydrofurane-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Following the procedure described in example 99, (S) -7- (1-methoxypropane-2-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (195 mg) (step 5 of example 87) and N- (1- (methyl-d 3) -3- ((tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (142 mg) (intermediate 54) gave a mixture of 7- ((S) -1-methoxypropane-2-yl) -2- ((1- (methyl-d 3) -3- (((R) -tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 7- ((S) -1-methoxypropane-2-yl) -2- ((1- (methyl-d 3- (((S) -tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile as a mixture of (7 mg) S) -1-methoxypropane-2-yl) -2- ((1- (methyl-d 3) -3- ((tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
The 210mg isomer mixture was subjected to chiral separation to give 94mg of the first eluting isomer and 100mg of the second eluting isomer (conditions: column Chiralpak AY,20 μm,300X 100mm; liquid phase: methanol 20/ethanol 80/0.1TEA to methanol 50/ethanol 50/0.1TEA; flow rate: 400 mL/min).
Peak 1 (isomer 1): 1 H NMR(400MHz,DMSO-d6)δppm 1.55(d,J＝7Hz,3H)1.98-2.18(m,2H)3.20(s,3H)3.60-3.74(m,2H)3.76-3.86(m,3H)3.97(t,J＝10Hz,1H)4.92(m,1H)5.11(m,1H)7.41(s,1H)7.73(br s,1H)8.50-8.63(m1H) 8.78 (s, 1H); MS (method B) m/z 401[ M+1 ] ]++, of the material; t=1.41 min-example 101 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 MHz, DMSO-d 6) delta ppm 1.55 (d, J=7Hz, 3H) 1.98-2.18 (m, 2H) 3.20 (s, 3H) 3.60-3.74 (m, 2H) 3.76-3.86 (m, 3H) 3.97 (t, J=10Hz, 1H) 4.92 (m, 1H) 5.11 (m, 1H) 7.41 (s, 1H) 7.73 (br s, 1H) 8.50-8.63 (m, 1H) 8.78 (s, 1H); MS (method B) m/z 401[ M+1 ]]++, of the material; t=1.41 min-example 102 (absolute configuration unknown)
(S) -7- (1-methoxypropane-2-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile was reacted with the appropriate formamide to give examples 103 to 108 in Table V, generally following the procedure described in example 99.
Table V
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Examples 109 and 110:2- ((3- (((S) -5, 5-dimethyltetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3R, 4R) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 2- ((3- (((R) -5, 5-dimethyltetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3R, 4R) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Following the general procedure in example 99, 2-methylsulfonyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (150 mg) (step 4 of example 1) and N- (3- ((5, 5-dimethyltetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide (119 mg) (intermediate 64) gave a mixture of 2- ((3- (((S) -5, 5-dimethyltetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3R, 4R) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 2- ((3- (((R) -5, 5-dimethyltetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7-methyltetrahydrofuran-4-yl) amino) -7- ((3, 4-d) pyrimidine-6-carbonitrile as a mixture in the present article (3- ((5, 5-dimethyltetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile) (192 mg).
Chiral separation of 141mg of the isomer mixture gave 66mg of the first eluting isomer and 60mg of the second eluting isomer (conditions: column Chiralpak AD,20 μm,76x 230mm; liquid phase: heptane 40/ethanol 60/0.1TEA; flow rate: 400 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 mhz, dmso-d 6) delta ppm 1.06 (d, j=7hz, 3H), 1.18 (s, 3H), 1.24 (s, 3H), 1.98 (br d, j=14hz, 1H), 2.06 (dd, j=14, 7hz, 1H), 2.85-3.04 (m, 1H), 3.47 (t, j=9hz, 1H), 3.89 (br d, j=10hz, 1H), 4.00 (dd, j=10, 5hz, 1H), 4.11-4.42 (m, 3H), 4.71-4.83 (m, 1H), 5.04-5.15 (m, 1H), 7.47 (s, 1H), 7.94-8.15 (m, 1H), 8.62-8.78 (m, 1H), 8.81 (s, 1H); MS (method B) m/z 441[ M+1 ]]++, of the material; t=1.59 min-example 109 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 mhz, dmso-d 6) delta ppm 1.06 (d, j=7hz, 3H), 1.18 (s, 3H), 1.25 (s, 3H), 1.97 (br d, j=14hz, 1H), 2.07 (dd, j=14, 7hz, 1H), 2.87-3.00 (m, 1H), 3.48 (t, j=9hz, 1H), 3.90 (d, j=10 hz, 1H), 4.00 (dd, j=10, 5hz, 1H), 4.11-4.38 (m, 3H), 4.72-4.86 (m, 1H), 5.04-5.14 (m, 1H), 7.47 (s, 1H), 7.91-8.15 (m, 1H), 8.59-8.77 (m, 1H), 8.82 (s, 1H); MS (method B) m/z 441[ M+1 ]]++, of the material; t=1.59 min-example 110 (absolute configuration unknown)
Examples 111 and 112:2- ((1- (methyl-d 3) -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 and 2- ((1- (methyl-d 3) -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
Following the general procedure described in example 99, 2-methylsulfonyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (250 mg) (step 4 of example 1) and N- (1- (methyl-d 3) -3- ((tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (rac) (175 mg) (intermediate 54) gave 2- ((1- (methyl-d 3) -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 as a mixture with 2- ((1- (methyl-d 3) -3- (((R) -tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3, 4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile as a isomer in (1- ((1, 3, 2-d) methyl-d) nitrile) d3 -3- ((tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile) (242 mg).
Chiral separation of 242mg of the isomer mixture gave 112mg of the first eluting isomer and 122mg of the second eluting isomer (conditions: column Chiralpak AY,20 μm,230X 100mm; liquid phase: methanol 30/ethanol 70/0.1TEA; flow rate: 400 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 mhz, dmso-d 6) delta ppm 1.06 (d, j=7hz, 3H) 2.02-2.18 (m, 2H) 2.93 (sept, j=8hz, 1H) 3.48 (t, j=8hz, 1H) 3.68-3.76 (m, 1H) 3.78-3.89 (m, 3H) 4.17 (t, j=10hz, 1H) 4.22 (t, j=8hz, 1H) 4.25-4.37 (m, 1H) 4.72-4.85 (m, 1H) 5.11 (m, 1H) 7.47 (s, 1H) 7.95-8.16 (m, 1H) 8.65-8,83 (m, 1H) 8.82 (s, 1H); MS (method B) M/z413[ M+1 ] ]++, of the material; t=1.46 min-example 111 (absolute configuration unknown).
Peak 2 (isomer 2): 1 h NMR (400 mhz, dmso-d 6) delta ppm 1.06 (d, j=7hz, 3H) 2.02-2.18 (m, 2H) 2.93 (sept, j=8hz, 1H) 3.48 (t, j=8hz, 1H) 3.68-3.76 (m, 1H) 3.78-3.89 (m, 3H) 4.17 (t, j=10hz, 1H) 4.22 (t, j=8hz, 1H) 4.25-4.37 (m, 1H) 4.72-4.85 (m, 1H) 5.11 (m, 1H) 7.47 (s, 1H) 7.95-8.16 (m, 1H) 8.65-8,83 (m, 1H) 8.82 (s, 1H); MS (method B) M/z413[ M+1 ]]++, of the material; t=1.46 min-example 112 (absolute configuration unknown).
Example 113:2- ((3-cyclopropoxy-1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Following the general procedure in example 99, 2-methylsulfonyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (150 mg) (step 4 of example 1) and N- (3-cyclopropoxy-1- (2-methoxyethyl) -1H-pyrazol-4-yl) carboxamide (111 mg) (intermediate 53) gave 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 (115 mg).
1 H NMR (400 mhz, dmso-d 6) delta ppm 0.55-0.75 (m, 4H), 1.06 (d, j=7hz, 3H), 2.93 (spt, j=7hz, 1H), 3.25 (s, 3H), 3.47 (t, j=9hz, 1H), 3.68 (t, j=5hz, 2H), 4.04-4.13 (m, 3H), 4.16 (t, j=9hz, 1H), 4.23 (br t, j=8hz, 1H), 4.25-4,35 (m, 1H), 4.79 (br q, j=8hz, 1H), 7.47 (s, 1H), 7.96-8.15 (m, 1H), 8.65-8,80 (m, 1H), 8.81 (s, 1H); MS (method B) m/z 424[ M+1 ] ]+；t＝1.6min
Examples 114 and 115:2- ((3- (((3S, 4S) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3R, 4R) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 2- ((3- (((3R, 4R) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3R, 4R) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Step 1: preparation of 2- ((3- (((3S, 4S) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3R, 4R) -4-methyltetrahydrof-oro [2,3-d ] pyrimidine-6-carbonitrile and 2- ((3- (((3R, 4R) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3R, 4R) -4-methyltetrahydrof-n-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Following the general procedure in example 99, a racemic mixture (306 mg) (intermediate 65) of 2-methylsulfonyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3 yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (200 mg) (step 4 of example 1) and N- (1- (methyl-d 3) -3- (((3R, 4R) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide with N- (1- (methyl-d 3) -3- (((3S, 4S) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide gave 2- ((3- (((3S, 4S) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1- (methyl-d 3H-pyrazol-4-yl) amino) -7-tetrahydro-furan-3-yl) oxy) -1H-pyrazolo-4-yl ] carboxamide with 2- ((3- (-d-6-pyrrol-4-yl) carboxamide An isomeric mixture of (3 r,4 r) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (362 mg). MS (method B) m/z 667[ M+1] +; t=3.56 min.
Step 2: preparation of 2- ((3- (((3S, 4S) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3R, 4R) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 2- ((3- (((3R, 4R) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3R, 4R) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
1.6mL of tetrabutylammonium fluoride 1M (3 eq) in THF was added to a solution of a mixture of isomers of 2- ((3- (((3S, 4S) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3R, 4R) -4-methyltetrahydrof-hydrof-uran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 2- ((3- (((3R, 4R) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3R, 4R) -4-methyltetrahydrof-n-ol-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (362 mg) (1 eq) at 0deg.C. The reaction mixture was stirred at 0 ℃ for 5 minutes and then at room temperature for 30 minutes. The reaction mixture was poured into 50mL of ethyl acetate and 20mL of saturated aqueous ammonium chloride. The two layers were separated and the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel (eluting with a gradient of 5% to 20% methanol in dichloromethane) to give 192mg of an isomer mixture of 2- ((3- (((3 s,4 s) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyr-azol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrof-n-ol-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 2- ((3- (((3 r,4 r) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrof-n-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (referred to herein as 2- ((3 trans-4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-3-yl) oxy) -1- ((3, 4H-methyltetra-ol-6-carbonitrile.
The 111mg isomer mixture was subjected to chiral separation to give 46mg of the first eluting isomer and 44mg of the second eluting isomer (conditions: column Lux Amylose-1,5 μm,250x 30mm; liquid phase: heptane 20/ethanol 80/0.1TEA; flow rate: 40 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 mhz, dmso-d 6) delta ppm 1.06 (d, j=7hz, 3H) 2.92 (m, 1H) 3.48 (t, j=8 hz, 1H) 3.58 (br d, j=8 hz, 1H) 3.81 (br d, j=10 hz, 1H) 3.87-3.94 (m, 1H) 3.97 (br dd, j=10, 4hz, 1H) 4.17 (br t, j=8 hz, 1H) 4.23 (br t, j=8 hz, 1H) 4.27-4.36 (m, 2H) 4.72-4.83 (m, 2H) 5.26 (d, j=3 hz, 1H) 7.93-8.22 (m, 1H) 8.67-8.90 (m, 1H) 8.81 (s, 1H); MS (method B) m/z 429[ M+1 ]]++, of the material; t=1.30 min-example 114 (absolute configuration unknown)
Peak 2 (isomer 2): 1 H NMR(400MHz,DMSO-d6)δppm 1.06(d,J＝7Hz,3H)2.92(m,1H)3.48(t,J＝8Hz,1H)3.58(br d,J＝8Hz,1H)3.81(br d,J＝10Hz,1H)3.87-3.94 (m, 1H) 3.97 (brdd, j=10, 4hz, 1H) 4.17 (br t, j=8 hz, 1H) 4.23 (br t, j=8 hz, 1H) 4.27-4.36 (m, 2H) 4.72-4.83 (m, 2H) 5.26 (d, j=3 hz, 1H) 7.47 (s, 1H) 7.93-8.22 (m, 1H) 8.67-8.90 (m, 1H) 8.81 (s, 1H); MS (method B) m/z 429[ M+1 ]]++, of the material; t=1.30 min-example 115 (absolute configuration unknown)
Examples 116 and 117:2- ((3- (((3S, 4S) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 2- ((3- (((3R, 4R) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Following the procedure described in example 114, 2-methylsulfonyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile was replaced with (S) -7- (1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (200 mg) (step 5 of example 87), to obtain 117mg of 2- ((3- (((3S, 4S) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile as a mixture with 2- ((3- (((3R, 4R) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [ 2-d ] pyrimidine-6-carbonitrile as a mixture in- ((2-3- ((3, 4-d) amino) pyrimidine-6-carbonitrile as described herein is known as trans-isomer -hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
Chiral separation of 117mg of the isomer mixture gave 50mg of the first eluting isomer and 54mg of the second eluting isomer (conditions: column Chiralpak AY,20 μm,350X 76mm; liquid phase: heptane 50/ethanol 50/0.1TEA; flow rate: 400 mL/min).
Peak 1 (isomer 1): 1 H NMR(400MHz,DMSO-d6)δppm 1.56(d,J＝7Hz,3H),3.20(s,3H),3.55(d,J＝9Hz,1H),3.66(dd,J＝11,5Hz,1H),3.78 (d, j=10 hz, 1H), 3.86 (dd, j=9, 4hz, 1H), 3.92-4.02 (m, 2H), 4.26-4.30 (m, 1H), 4.80 (d, j=3 hz, 1H), 4.86-5.04 (m, 1H), 5.26 (d, j=4 hz, 1H), 7.41 (s, 1H), 7.75 (s, 1H), 8.60 (br s, 1H), 8.78 (s, 1H); MS (method B) m/z 417[ M+1 ] ]++, of the material; t=1.28 min-example 116 (absolute configuration unknown).
Peak 2 (isomer 2): 1 h NMR (500 mhz, dmso-d 6) delta ppm 1.55 (d, j=7hz, 3H), 3.19 (s, 3H), 3.54 (br d, j=9hz, 1H), 3.65 (dd, j=11, 5hz, 1H), 3.78 (d, j=10 hz, 1H), 3.85 (dd, j=9, 4hz, 1H), 3.92-4.03 (m, 2H), 4.22-4.30 (m, 1H), 4.79 (d, j=4 hz, 1H), 4.87-5.01 (m, 1H), 5.28 (d, j=4 hz, 1H), 7.41 (s, 1H), 7.75 (br s, 1H), 8.52-8.73 (m, 1H), 8.78 (s, 1H); MS (method B) m/z 417[ M+1 ]]++, of the material; t=1.28 min-example 117 (absolute configuration unknown).
Examples 118 and 119:2- ((3- (((S) -2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3R, 4R) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 2- ((3- (((R) -2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3R, 4R) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Following the procedure described in example 99, (S) -7- (1-methoxypropane-2-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile was replaced with 2-methylsulfonyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (90 mg) (step 4 of example 1), 56mg of 2- ((3- (((S) -2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3R, 4R) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile was obtained as a mixture with 2- ((3- (((R) -2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- (methyl-pyrazol-3-yl) oxy) -1- (methyl-pyrazol-4-yl) amino) -7- ((3-methyltetrahydrofuran-3-yl) pyrimidine-6-carbonitrile, known as the present isomer in 2- ((2, 3-d) 2- ((2-methyl-2-d) pyrrolo [2,3-d ] pyrimidine-6-carbonitrile -dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
The 56mg isomer mixture was subjected to chiral separation to give 17mg of the first eluting isomer and 27mg of the second eluting isomer (conditions: column Chiralpak AY,20 μm,230X 100mm; liquid phase: heptane 20/ethanol 80/0.1TEA; flow rate: 400 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 mhz, dmso-d 6) delta ppm 1.06 (d, j=7hz, 3H), 1.33 (s, 3H), 1.44 (s, 3H), 2.84-2.97 (m, 1H), 3.47 (t, j=9hz, 1H), 4.10-4.41 (m, 4H), 4.57 (t, j=7hz, 1H), 4.74-4.83 (m, 1H), 4.96 (t, j=6hz, 1H), 7.47 (s, 1H), 7.89-8.20 (m, 1H), 8.83 (s, 1H), 8.86-9.00 (m, 1H); MS (method B) m/z 427[ M+1 ]]++, of the material; t=1.54 min-example 118 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 mhz, dmso-d 6) delta ppm 1.06 (d, j=7hz, 3H), 1.33 (s, 3H), 1.43 (s, 3H), 2.84-3.01 (m, 1H), 3.48 (t, j=9hz, 1H), 4.11-4.39 (m, 4H), 4.58 (t, j=7hz, 1H), 4.74-4.84 (m, 1H), 4.96 (t, j=6hz, 1H), 7.47 (s, 1H), 7.96-8.18 (m, 1H), 8.83 (s, 1H), 8.85-9.02 (m, 1H); MS (method B) m/z 427[ M+1 ]]++, of the material; t=1.55 min-example 119 (absolute configuration unknown)
Examples 120 and 121: (S) -2- ((3- ((2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and (R) -2- ((3- ((2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Following the procedure described in example 99, (S) -7- (1-methoxypropane-2-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile was replaced with 2- (methylsulfonyl) -7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3d ] pyrimidine-6-carbonitrile (250 mg) (step 1 of example 80), 185mg of (S) -2- ((3- ((2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile was obtained as a mixture with (R) -2- ((3- ((2, 2-dimethyloxetan-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile known as the isomer of (2- ((2, 3-dimethyl-oxetan-3-d) amino) -7- (tetrahydro-2H-pyran-4-yl) -7-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile Azetidin-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
Chiral separation of 185mg of the isomer mixture gave 77mg of the first eluting isomer and 77mg of the second eluting isomer (conditions: column Chiralpak AY,20 μm,350X 76mm; liquid phase: heptane 70/ethanol 30/0.1TEA; flow rate: 400 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 MHz, DMSO-d 6) delta ppm 1.31 (s, 3H), 1.43 (s, 3H), 1.79-1.91 (m, 2H), 2.53-2.63 (m, 2H), 3.42-3.58 (m, 2H), 4.05 (brdd, J=12, 5Hz, 2H), 4.19-4.44 (m, 1H), 4.57 (t, J=7Hz, 1H), 4.66-4.79 (m, 1H), 4.84-5.08 (m, 1H), 7.46 (s, 1H), 7.83 (br s, 1H), 8.70-8.93 (m, 2H). MS (method B) m/z 427[ M+1 ] ]++, of the material; t=1.50 min-example 120 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 mhz, dmso-d 6) delta ppm 1.30 (s, 3H) 1.43 (s, 3H) 1.84 (d, j=8 hz, 2H) 2.50-2.65 (m partially hidden, 2H) 3.50 (t, j=8 hz, 2H) 4.05 (d, j=8 hz, 2H) 4.31 (t, j=6 hz, 1H) 4.57 (t, j=7 hz, 1H) 4.65-4.80 (m, 1H) 4.96 (t, j=6 hz, 1H) 7.46 (s, 1H) 7.73-7.95 (m, 1H) 8.71-8.92 (m, 2H). MS (method B) m/z 427[ M+1 ]]++, of the material; t=1.49 min-example 121 (absolute configuration unknown)
Example 122:2- ((3-cyclopropoxy-1- (2-methoxyethyl) -1H-pyrazol-4-yl) amino) -7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Following the general procedure in example 99, 2- (methylsulfonyl) -7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3d ] pyrimidine-6-carbonitrile (170 mg) (step 1 of example 80) and N- (3-cyclopropoxy-1- (2-methoxyethyl) -1H-pyrazol-4-yl) carboxamide (107 mg) (intermediate 53) gave 87mg of 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-example 122.
1 H NMR (400 MHz, DMSO-d 6) delta ppm 0.55-0.77 (m, 4H), 1.75-1.90 (m, 2H), 2.49-2.66 (m partially hidden, 2H), 3.25 (s, 3H), 3.49 (br t, J=12 Hz, 2H), 3.67 (t, J=5 Hz, 2H), 3.96-4.18 (m, 5H), 4.71 (m, 1H), 7.44 (s, 1H), 7.76-8.00 (m, 1H), 8.56-8.74 (m, 1H), 8.79 (s, 1H). MS (method B) m/z 424[ M+1 ] ]+；t＝1.51min。
Example 123:2- ((1- (methyl-d 3) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Following the general procedure in example 99, 2- (methylsulfonyl) -7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3d ] pyrimidine-6-carbonitrile (120 mg) (step 1 of example 80) and (1- (methyl-d 3) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide (79 mg) (intermediate 26) gave 81mg of 2- ((1- (methyl-d 3) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile-example 123.
1 H NMR (400 mhz, dmso-d 6) delta ppm 1.84 (br dd, j=12, 3hz, 2H) 2.53-2.66 (m, 2H) 3.41-3.59 (m, 2H) 4.05 (br dd, j=11, 4hz, 2H) 4.57 (dd, j=8, 5hz, 2H) 4.71 (m, 1H) 4.81 (t, j=7 hz, 2H) 5.29-5.36 (m, 1H) 7.45 (s, 1H) 7.82 (br s, 1H) 8.67-8.96 (m, 1H) 8,81 (s, 1H); MS (method B) m/z 399[ M+1 ]]+；t＝1.33min。
Examples 124 and 125:2- ((1- (methyl-d 3) -3- (((2 s,3 r) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 2- ((1- (methyl-d 3) -3- (((2 r,3 s) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Following the general procedure described in example 99, 2- (methylsulfonyl) -7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3d ] pyrimidine-6-carbonitrile (400 mg) (step 1 of example 80) and N- (1- (methyl-d 3) -3- (((2S, 3R) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide and N- (1- (methyl-d 3) -3- (((2R, 3S) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (racemic trans) (280 mg) (intermediate 21) gave 327mg of 2- ((1- (methyl-d 3) -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 (racemic trans) (280 mg) (intermediate 21) to 2- ((1- (methyl-d 3) -3- (((2S, 3R) -3-yl) oxy) amino) Pyrazol-4-yl) amino) -7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile the isomeric mixture (referred to herein as 2- ((1- (methyl-d 3) -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).
Chiral separation was performed on 327mg of the isomer mixture to give 137mg of the first eluting isomer and 149mg of the second eluting isomer (conditions: column Chiralpak AY,20 μm,230X 100mm; liquid phase: heptane 60/ethanol 40/0.1TEA; flow rate: 400 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 mhz, dmso-d 6) delta ppm 1.42 (d, j=6 hz, 3H) 1.80-1.88 (m, 2H) 2.52-2.66 (m, 2H) 3.44-3.56 (m, 2H) 4.05 (brdd, j=11, 4hz, 2H) 4.41 (dd, j=7, 6hz, 1H) 4.66 (t, j=7 hz, 1H) 4.64-4.75 (m, 1H) 4.79 (quin, j=6 hz, 1H) 4.87-4.92 (m, 1H) 7.45 (s, 1H) 7.82 (br s, 1H) 8.70-8.95 (m, 1H) 8.81 (s, 1H); MS (method B) m/z 413[ M+1 ]]++, of the material; t=1.43 min-example 124 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 mhz, dmso-d 6) delta ppm 1.42 (d, j=6 hz, 3H) 1.80-1.88 (m, 2H) 2.52-2.66 (m, 2H) 3.44-3.56 (m, 2H) 4.05 (brdd, j=11, 4hz, 2H) 4.41 (dd, j=7, 6hz, 1H) 4.66 (t, j=7 hz, 1H) 4.64-4.75 (m, 1H) 4.79 (quin, j=6 hz, 1H) 4.87-4.92 (m, 1H) 7.45 (s, 1H) 7.82 (br s, 1H) 8.70-8.95 (m, 1H) 8.81 (s, 1H); MS (method B) m/z 413[ M+1 ]]++, of the material; t=1.43 min-example 125 (absolute configurationUnknown type).
Example 126 and example 127: (R) -2- ((3-cyclopropoxy-1- (1-methoxypropane-2-yl) -1H-pyrazol-4-yl) amino) -7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and (S) -2- ((3-cyclopropoxy-1- (1-methoxypropane-2-yl) -1H-pyrazol-4-yl) amino) -7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Following the procedure described in example 99, 2- (methylsulfonyl) -7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3d ] pyrimidine-6-carbonitrile (200 mg) (step 1 of example 80) and N- (3-cyclopropoxy-1- (1-methoxypropane-2-yl) -1H-pyrazol-4-yl) carboxamide (intermediate 63) gave 145mg of the mixture of (R) -2- ((3-cyclopropoxy-1- (1-methoxypropane-2-yl) -1H-pyrazol-4-yl) amino) -7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with (S) -2- ((3-cyclopropoxy-1- (1-methoxypropane-2-yl) -1H-pyrazol-4-yl) amino) -7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile as a mixture in this isomer (1-methoxypropan-2- (3-methoxypropan-2-yl) -2, 3-d ] pyrimidine-6-carbonitrile was designated as the isomer of (1-methoxypropan-2-yl) -2- (tetrahydro-2H-pyran-4-yl) -7H-pyrazolo-4-yl) Amino) -7- (tetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
Chiral separation of 134mg of the isomer mixture gave 57mg of the first eluting isomer and 63mg of the second eluting isomer (conditions: column Chiralcel OD-H,5 μm,250X 30mm; liquid phase: heptane 70/ethanol 30/0.1TEA; flow rate: 40 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 MHz, DMSO-d 6) delta ppm 0.54-0.79 (m, 4H), 1.40 (d, J=7Hz, 3H), 1.85 (br d, J=11Hz, 2H), 2.50-2.70 (m, 2H), 3.24 (s, 3H), 3.42-3.71 (m, 4H), 3.98-4.17 (m, 3H), 4.24-4.41 (m, 1H), 4.59-4.77 (m, 1H), 7.44 (s, 1H), 7.83-8.02 (m, 1H), 8.58-8.75 (m, 1H), 8.80 (s, 1H); MS (method B) m/z 438[ M+1 ]]++, of the material; t=1.62 min-example 126 (absolute configuration unknown)
Peak 2 (isomer 2): 1 H NMR(400MHz,DMSO-d6)δppm 0.58-0.74(m,4H),1.39(d,J＝7Hz,3H),1.85(br d,J＝10Hz2H), 2.52-2.67 (m, 2H), 3.24 (s, 3H), 3.42-3.73 (m, 4H), 3.99-4.16 (m, 3H), 4.35 (dq, j=13, 7hz, 1H), 4.60-4.76 (m, 1H), 7.44 (s, 1H), 7.84-8.04 (m, 1H), 8.58-8.76 (m, 1H), 8.80 (s, 1H); MS (method B) m/z 438[ M+1 ]]++, of the material; t=1.62 min-example 127 (absolute configuration unknown)
Example 128:2- ((1- (1-methoxypropane-2-yl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Following the general procedure in example 99, 2-methylsulfonyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (150 mg) (step 4 of example 1) and N- (1- (1-methoxypropane-2-yl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide (intermediate 62) gave 170mg of 2- ((1- (1-methoxypropane-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-example 128.
1 H NMR (400 MHz, DMSO-d 6) delta ppm 1.05 (d, J=7Hz, 3H) 1.23-1.43 (m, 3H) 2.82-3.03 (m, 1H) 3.16-3.26 (m, 3H) 3.39-3.53 (m, 2H) 3.53-3.64 (m, 1H) 4.04-4.23 (m, 2H) 4.23-4.40 (m, 2H) 4.54-4.65 (m, 2H) 4.67-4.80 (m, 1H) 4.77-4.89 (m, 2H) 5.34 (qt, J=6Hz, 1H) 7.47 (s, 1H) 7.91-8.17 (m, 1H) 8.75-9.00 (m, 1H) 8.82 (s, 1H); MS (method B) M/z454[ M+1 ]]+；t＝1.56min。
Example 129 and example 130:7- ((S) -1-methoxypropane-2-yl) -2- ((1- ((S) -1-methoxypropane-2-yl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 7- ((S) -1-methoxypropane-2-yl) -2- ((1- ((R) -1-methoxypropane-2-yl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Following the procedure described in example 99, (S) -7- (1-methoxypropane-2-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (150 mg) (step 5 of example 87) and N- (1- (1-methoxypropane-2-yl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide (intermediate 62) gave 160mg of 7- ((S) -1-methoxypropane-2-yl) -2- ((1- ((S) -1-methoxypropane-2-yl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile as a mixture with 7- ((S) -1-methoxypropane-2-yl) -2- ((1- ((R) -1-methoxypropane-2-yl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-4-carbonitrile as isomer (referred to herein as the isomer of 7 (7-carbonitrile - ((S) -1-methoxypropane-2-yl) -2- ((1- (1-methoxypropane-2-yl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile).
Chiral separation of 156mg of the isomer mixture gave 67mg of the first eluting isomer and 68mg of the second eluting isomer (conditions: column Whelk 01SS,10 μm,250X 76.5mm; liquid phase: heptane 20/ethanol 80/0.1TEA; flow rate: 300 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 mhz, dmso-d 6) delta ppm 1.33 (d, j=7hz, 3H), 1.56 (d, j=7hz, 3H), 3.19 (s, 3H), 3.22 (s, 3H), 3.50 (dd, j=10, 5hz, 1H), 3.56 (dd, j=10, 7hz, 1H), 3.64 (dd, j=10, 5hz, 1H), 4.01 (t, j=10 hz, 1H), 4.24-4.38 (m, 1H), 4.53-4.62 (m, 2H), 4.76-4.92 (m, 3H), 5.34 (quin, j=6hz, 1H), 7.40 (s, 1H), 7.81 (s, 1H), 8.74 (br s, 1H), 8.80 (s, 1H); MS (method B) m/z 442[ M+1 ]]++, of the material; t=1.51 min-example 129 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 mhz, dmso-d 6) delta ppm 1.33 (d, j=7hz, 3H), 1.56 (d, j=7hz, 3H), 3.19 (s, 3H), 3.22 (s, 3H), 3.50 (dd, j=10, 5hz, 1H), 3.56 (dd, j=10, 7hz, 1H), 3.64 (dd, j=11, 5hz, 1H), 4.01 (t, j=10 hz, 1H), 4.25-4.39 (m, 1H), 4.51-4.64 (m, 2H), 4.75-4.96 (m, 3H), 5.33 (quin, j=6hz, 1H), 7.40 (s, 1H), 7.81 (s, 1H), 8.74 (br s, 1H), 8.80 (s, 1H); MS (method B) m/z 442[ M+1 ]]++, of the material; t=1.52 min-example 130 (absolute configuration unknown)
Example 131:2- ((3- (((3S, 4 r) -4-hydroxy-4-methyltetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 2- ((3- (((3 r, 4S) -4-hydroxy-4-methyltetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (referred to herein as 2- ((cis-4-hydroxy-4-methyltetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Following the general procedure in example 99, (S) -7- (1-methoxypropane-2-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (45 mg) (step 5 of example 87) and N- (1- (methyl-d 3) -3- ((4-oxotetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide (rac) (37 mg) (intermediate 66) gave 2- ((3- (((3S, 4 r) -4-hydroxy-4-methyltetrahydrof-N-ol-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile as a reaction with 2- ((3- (((3S) -4-hydroxy-4-methyltetrahydrof-N-ol-3-yl) oxy) -1H-pyrazol-4-yl) amino) -1- ((3S, 4S) -1H-pyrazol-3-yl) amino) -1H-pyrazolo-4-yl) amino) -7- ((S) -2-methoxypyrrol-2-d Isomer mixtures of pyrimidine-6-carbonitrile.
1 H NMR (400 mhz, dmso-d 6) delta ppm 1.28 (s, 3H), 1.61 (br d, j=7hz, 3H), 3.22 (s, 3H), 3.55 (d, j=8hz, 1H), 3.66 (d, j=8hz, 1H), 3.71 (dd, j=11, 5hz, 1H), 3.79 (br dd, j=10, 3hz, 1H), 4.02 (br t, j=10 hz, 1H), 4.15 (dd, j=10, 5hz, 1H), 4.54 (m, 1H), 4.99-5.12 (m, 1H), 5.14 (s, 1H), 7.45 (s, 1H), 7.95 (br s, 1H), 8.84 (s, 1H), 9.21-9.47 (m, 1H); MS (method B) m/z 431[ M+1 ]]+；t＝1.36min
Examples 132 and 133:2- ((3- (cis-3-hydroxy-2, 4-tetramethylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 2- ((3- (trans-3-hydroxy-2, 4-tetramethylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Following the general procedure in example 99, (S) -7- (1-methoxypropane-2-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (150 mg) (step 5 of example 87) and N- (3- (3-hydroxy-2, 4-tetramethylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide (138 mg) (intermediate 68) gave 90mg of a mixture of cis and trans isomers of 2- ((3- (3-hydroxy-2, 4-tetramethylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
Chiral separation of 90mg of the isomer mixture gave 31mg of the first eluting isomer and 14mg of the second eluting isomer (conditions: column Chiralpak AD-H,5 μm,250X 30mm; liquid phase: heptane 90/ethanol 10/0.1TEA; flow rate: 45 mL/min).
Peak 1 (isomer 1): 1 h NMR (500 mhz, dmso-d 6) delta ppm 0.89 (br s, 3H), 0.90 (br s, 3H), 1.12 (s, 3H), 1.13 (s, 3H), 1.56 (d, j=8 hz, 3H), 3.20 (s, 3H), 3.24 (br s, 1H), 3.66 (br dd, j=11, 5hz, 1H), 3.94-3.99 (m, 1H), 4.00 (s, 1H), 4.70-4.76 (m, 1H), 4.90-5.02 (m, 1H), 7.42 (s, 1H), 7.70 (br s, 1H), 8.39 (br s, 1H), 8.78 (s, 1H); MS (method B) m/z 457[ M+1 ]]++, of the material; t=1.63 min-example 132 (absolute configuration unknown)
Peak 2 (isomer 2): 1 H NMR (500 mhz, dmso-d 6) delta ppm 0.96 (br s, 3H), 0.97 (br s, 3H), 1.03 (br s, 3H), 1.04 (br s, 3H), 1.56 (d, j=7hz, 2H), 3.20 (s, 3H), 3.40 (d, j=4hz, 1H), 3.66 (dd, j=10, 5hz, 1H), 3.96 (t, j=10hz, 1H), 4.16 (s, 1H), 4.74 (d, j=4hz, 1H), 4.89-5.05 (m, 2H), 7.42 (s, 1H), 7.71 (br s, 1H), 8.45 (br s, 1H), 8.78 (s, 1H); MS (method B) M/z457[ M+1 ]]++, of the material; t=1.62 min-example 133 (absolute configuration unknown)
Example 134 and example 135:2- ((3- (3-hydroxy-2, 2-dimethylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (isomer 1) and 2- ((3- (3-hydroxy-2, 2-dimethylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (isomer 2)
Following the general procedure in example 99, (S) -7- (1-methoxypropane-2-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (226 mg) (step 5 of example 87) and N- (3- (3-hydroxy-2, 2-dimethylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide (186 mg) (intermediate 61) gave 260mg of an isomeric mixture.
Chiral separation of 241mg of the isomer mixture gave 124mg of the first eluting isomer and 117mg of the second eluting isomer (conditions: column Chiralpak AY,20 μm,230X 100mm; liquid phase: heptane 80/ethanol 20/0.1TEA, then heptane 20/ethanol 80/0.1TEA; flow rate: 400 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 mhz, dmso-d 6) delta ppm 0.89 (s, 3H), 1.12 (s, 3H), 1.56 (d, j=7hz, 3H), 1.85 (dt, j=12, 8hz, 1H), 2.49-2.59 (m partial concealment, 1H), 3.20 (s, 3H), 3.40-3.50 (m, 1H), 3.66 (dd, j=10, 5hz, 1H), 3.97 (t, j=10 hz, 1H), 4.18 (t, j=8 hz, 1H), 4.81 (d, j=6hz, 1H), 4.86-5.00 (m, 1H), 7.41 (s, 1H), 7.69 (s, 1H), 8.45 (br s, 1H), 8.78 (s, 1H); MS (method B) m/z 429[ M+1 ]]++, of the material; t=1.45 min-example 134
Peak 2 (isomer 2): 1 h NMR (400 mhz, dmso-d 6) delta ppm 0.90 (s, 3H), 1.13 (s, 3H), 1.56 (d, j=7hz, 3H), 1.85 (dt, j=11, 8hz, 1H), 2.51 (s, 1H), 3.20 (s, 3H), 3.39-3.49 (m, 1H), 3.65 (dd, j=11, 5hz, 1H), 3.97 (t, j=10 hz, 1H), 4.18 (t, j=8 hz, 1H), 4.80 (d, j=6 hz, 1H), 4.87-5.00 (m, 1H), 7.41 (s, 1H), 7.69 (s, 1H), 8.45 (br s, 1H), 8.78 (s, 1H); MS (method B) m/z 429[ M+1 ]]++, of the material; t=1.45 min-example 135
Example 136 and example 137:2- ((3- (((3S, 4R) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 2- ((3- (((3R, 4S) -4-hydroxytetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Following the procedure described in example 114 (step 1 and step 2), 2-methylsulfonyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile was replaced with (S) -7- (1-methoxypropane-2-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (50 mg) (step 5 of example 87) and N- (3- (((3R, 4R) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide and N- (3- (((3S, 4S) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide (rac) was replaced with N- (1- (methyl-d 3) -3- (((3R, 4S) -4-tert-butyldiphenylsilyl) oxy) tetrahydrofuran-3-yl) and N- (3- (-methyl-d 3-yl) tetrahydropyrazol-4-yl) carboxamide (rac) The replacement of (rac) (80 mg) (intermediate 67) of- (1-methyl-d 3) -3- (((3S, 4 r) -4- ((tert-butyldiphenylsilyl) oxy) tetrahydrofurane-3-yl) oxy) -1H-pyrazol-4-yl) carboxamide gives 27mg of a isomeric mixture (referred to herein as 2- ((3 cis-4-hydroxy-tetrahydro-3-yl) pyrimidin-6-carbonitrile) of 2- ((3- (((3 r,4 r) -4-hydroxytetrahydrofurane-3-yl) oxy) -1- (methyl-d 3-yl) amino) -1- (1-methoxy-propan-2-yl) -7- ((S) -1H-methoxy-2-yl) pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 2- ((3- (((3 r, 4S) -4-hydroxytetrahydrofurane-3-yl) oxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxy-propan-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile Pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
Chiral separation of 27mg of the isomer mixture gave 11mg of the first eluting isomer and 11mg of the second eluting isomer (conditions: column i-amyose-3, 5 μm,250X 30mm; liquid phase: heptane 60/ethanol 40/0.1TEA; flow rate: 1 mL/min).
Peak 1 (isomer 1): 1 H NMR(400MHz,DMSO-d6)δppm 1.60(d,J＝7Hz,3H),3.21(s,3H),3.54-3.60(m,1H),3.70(dd,J＝11,5Hz,1H),3.80(dd, j=10, 4hz, 1H), 3.84-3.90 (m, 1H), 3.96-4.08 (m, 2H), 4.27-4.34 (m, 1H), 4.81-4.88 (m, 1H), 4.99-5.08 (m, 1H), 5.10 (br d, j=7 hz, 1H), 7.44 (s, 1H), 7.92 (br s, 1H), 8.82 (s, 1H), 9.13 (br s, 1H); MS (method B) m/z 417[ M+1 ]]++, of the material; t=1.28 min-example 136 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 mhz, dmso-d 6) delta ppm 1.60 (d, j=7hz, 3H), 3.21 (s, 3H), 3.53-3.61 (m, 1H), 3.70 (dd, j=10, 5hz, 1H), 3.80 (dd, j=10, 4hz, 1H), 3.83-3.91 (m, 1H), 3.97-4.08 (m, 2H), 4.28-4.34 (m, 1H), 4.81-4.87 (m, 1H), 5.00-5.08 (m, 1H), 5.10 (br d, j=8 hz, 1H), 7.44 (s, 1H), 7.91 (br s, 1H), 8.82 (s, 1H), 9.14 (br s, 1H); MS (method B) m/z 417[ M+1 ]]++, of the material; t=1.28 min-example 137 (absolute configuration unknown)
Example 138: (S) -2- ((1- (2-hydroxyethyl) -3- ((tetrahydro-2H-pyran-4-yl) oxy) -1H-pyrazol-4-yl) amino) -7- (1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Step 1: preparation of 2- ((1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- ((tetrahydro-2H-pyran-4-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Following the general procedure in example 99, (S) -7- (1-methoxypropane-2-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (200 mg) (step 5 of example 87) and N- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- ((tetrahydro-2H-pyran-4-yl) oxy) -1H-pyrazol-4-yl) carboxamide (251 mg) (intermediate 59) gave 280mg of 2- ((1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- ((tetrahydro-2H-pyran-4-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile. MS (method A) m/z 556[ M+1] +; t=3.19 min.
Step 2: preparation of (S) -2- ((1- (2-hydroxyethyl) -3- ((tetrahydro-2H-pyran-4-yl) oxy) -1H-pyrazol-4-yl) amino) -7- (1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
1.51mL of 1N tetrabutylammonium fluoride THF solution (3 eq) was added to a solution of 280mg (1 eq) 2- ((1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- ((tetrahydro-2H-pyran-4-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile in 14mL THF at 0deg.C. The mixture was stirred at 0 ℃ for 30min and then diluted with 50mL of ethyl acetate and 20mL of saturated ammonium chloride solution under stirring. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica (elution with a gradient of 5% to 20% methanol in dichloromethane) to give 188mg of (S) -2- ((1- (2-hydroxyethyl) -3- ((tetrahydro-2H-pyran-4-yl) oxy) -1H-pyrazol-4-yl) amino) -7- (1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile-example 138.
1 H NMR (400 mhz, dmso-d 6) delta ppm 1.57 (d, j=7hz, 3H) 1.59-1.74 (m, 2H) 1.98 (br d, j=12hz, 2H) 3.20 (s, 3H) 3.42 (br t, j=9hz, 2H) 3.56-3.76 (m, 3H) 3.79-3.92 (m, 2H) 3.92-4.12 (m, 3H) 4.65 (m, 1H) 4.83 (t, j=5hz, 1H) 4.87-4.99 (m, 1H) 7.41 (s, 1H) 7.83 (br s, 1H) 8.48-8.67 (m, 1H) 8.79 (s, 1H); MS (method B) m/z 442[ M+1]]+；t＝1.30min。
Example 139: (S) -2- ((1- (2-hydroxyethyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- (1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Step 1: preparation of 2- ((1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Following the procedure in example 99, (S) -7- (1-methoxypropane-2-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (260 mg) (step 5 of example 87) and N- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide (302 mg) (intermediate 60) gave 133mg of 2- ((1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile. MS (method A) m/z 528[ M+1] +; t=3.04 min.
Step 2: preparation of (S) -2- ((1- (2-hydroxyethyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- (1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Following the procedure in step 2 of example 138, 133mg of 2- ((1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- (oxetan-3-yloxy) -1H-pyrazolo-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile gave 42mg of (S) -2- ((1- (2-hydroxyethyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- (1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile-example 139.
1 H NMR (400 mhz, dmso-d 6) delta ppm 1.56 (d, j=7hz, 3H) 3.19 (s, 3H) 3.60-3.72 (m, 3H) 3.95 (t, j=6hz, 2H) 4.01 (t, j=10hz, 1H) 4.57 (br t, j=6hz, 2H) 4.76-4.85 (m, 3H) 4.82-4.95 (m, 1H) 5.33 (quin, j=6hz, 1H) 7.41 (s, 1H) 7.81 (br s, 1H) 8.62-8.77 (m, 1H) 8.79 (s, 1H); MS (method B) m/z 414[ M+1 ]]+；t＝1.22min。
Example 140 and example 141:2- ((3- ((1S, 2R) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3R, 4R) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 2- ((3- ((1R, 2S) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3R, 4R) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
120mg (1.1 eq) of tert-butylimino-tris (pyrrolidinyl) phosphane (BTPP) are added to a solution of 102mg (0.95 eq) (2-methylsulfonyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3 yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (step 4 of example 1) and 80mg (1 eq) of N- (3- (2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide (racemic cis) (intermediate 69) in 5mL of acetonitrile and the mixture is stirred at room temperature for 2 hours, then concentrated in vacuo, the residue is taken up in 2mL of methanol and 2.5mL of 7N methanolic ammonia solution and stirred for 30 minutes, then concentrated under reduced pressure the residue is purified on silica (gradient elution with 0 to 100% ethyl acetate in cyclohexane), to give 114mg of an isomer mixture of 2- ((3- ((1 s,2 r) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 2- ((3- ((1 r,2 s) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (referred to herein as 2- ((3- (cis-2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3 r, 3-d ] pyrimidine-6-carbonitrile).
Chiral separation of 100mg of the isomer mixture gave 38mg of the first eluting isomer and 36mg of the second eluting isomer (conditions: column Chiralpak AD,20 μm,300X 76mm; liquid phase: heptane 30/ethanol 70/0.1TEA; flow rate: 400 mL/min).
Peak 1 (isomer 1): 1 H NMR(400MHz,DMSO-d6)δppm 1.07(d, j=7 hz, 3H), 1.26 (s, 3H), 1.67-1.90 (m, 2H), 1.94-2.15 (m, 2H), 2.89-3.05 (m, 1H), 3.51 (t, j=9 hz, 1H), 4.21 (br t, j=9 hz, 1H), 4.26-4.31 (m, 1H), 4.37-4.51 (m, 1H), 4.58 (m, 1H), 4.74-4.92 (m, 1H), 5.36 (s, 1H), 7.48 (s, 1H), 8.16-8.43 (m, 1H), 8.86 (s, 1H), 9.27-9.50 (m, 1H). MS (method B) m/z 427[ M+1 ]]++, of the material; t=1.49 min-example 140 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 MHz, DMSO-d 6) delta ppm 1.07 (d, J=7Hz, 3H), 1.26 (s, 3H), 1.67-1.90 (m, 2H), 1.94-2.15 (m, 2H), 2.89-3.05 (m, 1H), 3.51 (t, J=9Hz, 1H), 4.21 (br t, J=9Hz, 1H), 4.26-4.31 (m, 1H), 4.37-4.51 (m, 1H), 4.58 (m, 1H), 4.74-4.92 (m, 1H), 5.36 (s, 1H), 7.48 (s, 1H), 8.16-8.43 (m, 1H), 8.86 (s, 1H), 9.27-9.50 (m, 1H); MS (method B) m/z 427[ M+1 ]]++, of the material; t=1.50 min-example 141 (absolute configuration unknown)
Example 142, example 143, and example 144:2- ((3- ((1S, 2S) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3R, 4R) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 2- ((3- ((1R, 2R) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3R, 4R) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Following the general procedure in example 140, (2-methylsulfonyl-7- [ (3R, 4R) -4-methyltetrahydrofuran-3-yl)]Pyrrolo [2,3-d]Pyrimidine-6-carbonitrile (120 mg) (step 4 of example 1) and N- (3- (2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide (racemic trans) (89 mg) (intermediate 70) gave 104mg of 2- ((3- ((1S, 2S) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3R, 4R) -4-methyltetrahydrof-N-ol-3-yl) -7H-pyrrolo [2, 3-d)]Pyrimidine-6-carbonitrile was reacted with 2- ((3- ((1R, 2R) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((3R, 4R) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d]Isomer mixtures of pyrimidine-6-carbonitrile (referred to herein as 2- ((3- (trans-2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1)H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d]Pyrimidine-6-carbonitrile). 1 HNMR (400 mhz, dmso-d 6) delta ppm 1.05 (d, j=7hz, 3H), 1.23 (br s, 3H), 1.39-1.62 (m, 2H), 1.67-1.76 (m, 1H), 2.02-2.13 (m, 1H), 2.86-3.00 (m, 1H), 3.47 (t, j=9hz, 1H), 4.17 (t, j=9hz, 1H), 4.22 (t, j=8hz, 1H), 4.31 (m, 1H), 4.55-4.68 (m, 1H), 4.75-4.82 (m, 1H), 5.06 (s, 0,52H), 5.07 (s, 0,48H), 7.46 (s, 1H), 8.06 (br s, 1H), 8.65 (br s, 1H), 8.82 (s, 1H). MS (method D) m/z 427[ M+1 ] ]++, of the material; t=1.10 min-example 142
Chiral separation of 94mg of the isomer mixture gave 41mg of the first eluting isomer and 47mg of the second eluting isomer (conditions: column Chiralpak AY,20 μm,230X 100mm; liquid phase: heptane 50/ethanol 50/0.1TEA, then heptane 20/ethanol 80/0.1TEA; flow rate: 400 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 mhz, dmso-d 6) delta ppm 1.06 (d, j=7hz, 3H), 1.24 (s, 3H), 1.41-1.63 (m, 2H), 1.70 (m, 1H), 2.03-2.13 (m, 1H), 2.85-3.00 (m, 1H), 3.48 (t, j=9hz, 1H), 4.17 (t, j=9hz, 1H), 4.23 (t, j=8hz, 1H), 4.28-4.41 (m, 1H), 4.64 (t, j=8hz, 1H), 4.73-4.88 (m, 1H), 5.07 (s, 1H), 7.47 (s, 1H), 8.06 (br s, 1H), 8.65 (br s, 1H), 8.82 (s, 1H); MS (method B) m/z 427[ M+1 ]]++, of the material; t=1.48 min-example 143 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 mhz, dmso-d 6) delta ppm 1.06 (d, j=7hz, 3H), 1.24 (s, 3H), 1.41-1.63 (m, 2H), 1.70 (m, 1H), 2.03-2.13 (m, 1H), 2.85-3.00 (m, 1H), 3.48 (t, j=9hz, 1H), 4.17 (t, j=9hz, 1H), 4.23 (t, j=8hz, 1H), 4.28-4.41 (m, 1H), 4.64 (t, j=8hz, 1H), 4.73-4.88 (m, 1H), 5.07 (s, 1H), 7.47 (s, 1H), 8.06 (br s, 1H), 8.65 (br s, 1H), 8.82 (s, 1H); MS (method B) m/z 427[ M+1 ]]++, of the material; t=1.48 min-example 144 (absolute configuration unknown)
Examples 145, 146 and 147:2- ((3- ((1S, 2R) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 2- ((3- ((1R, 2S) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Following the general procedure in example 140, (S) -7- (1-methoxypropane-2-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d]Pyrimidine-6-carbonitrile (95 mg) (step 5 of example 87) and N- (3- (2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide (racemic cis) (81 mg) (intermediate 69) gave 104mg of 2- ((3- ((1S, 2R) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2, 3-d)]Pyrimidine-6-carbonitrile was reacted with 2- ((3- ((1R, 2S) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d]Isomer mixtures of pyrimidine-6-carbonitrile (referred to herein as 2- ((3- (cis-2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2, 3-d) ]Pyrimidine-6-carbonitrile). 1 H NMR (400 mhz, dmso-d 6) delta ppm 1.25 (s, 3H), 1.60 (d, j=7hz, 3H), 1.71-1.90 (m, 2H), 1.94-2.12 (m, 2H), 3.21 (s, 3H), 3.70 (dd, j=10, 5hz, 1H), 4.02 (br t, j=10 hz, 1H), 4.54-4.62 (m, 1H), 4.98-5.13 (m, 1H), 5.29 (s, 1H), 7.43 (s, 1H), 7.89 (br s, 1H), 8.82 (s, 1H), 9.04-9.32 (br s, 1H); MS (method D) m/z 415[ M+1 ]]++, of the material; t=1.06 min-example 145 (absolute configuration unknown).
Chiral separation of 94mg of the isomer mixture gave 42mg of the first eluting isomer and 43mg of the second eluting isomer (conditions: column Chiralpak AY,20 μm,230x 100mm; liquid phase: heptane 70/ethanol 30/0.1TEA; flow rate: 1 mL/min): 400 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 mhz, dmso-d 6) delta ppm 1.26 (s, 3H), 1.61 (d, j=7hz, 3H), 1.68-1.91 (m, 2H), 1.93-2.19 (m, 2H), 3.22 (s, 3H), 3.71 (dd, j=11, 5hz, 1H), 4.02 (t, j=10hz, 1H), 4.50-4.64 (m, 1H), 4.89-5.15 (m, 1H), 5.30 (br s, 1H), 7.44 (s, 1H), 7.90 (br s, 1H), 8.83 (s, 1H), 9.21 (br s, 1H); MS (method B) m/z 415[ M+1 ]]++, of the material; t=1.45 min-example 146 (absolute configuration unknown)
Peak 2 (isomer 2): 1 H NMR(400MHz,DMSO-d6)δppm 1.26(s,3H),1.61(d,J＝7Hz,3H),1.68-1.91(m,2H) 1.93-2.19 (m, 2H), 3.22 (s, 3H), 3.71 (dd, j=11, 5hz, 1H), 4.02 (t, j=10 hz, 1H), 4.50-4.64 (m, 1H), 4.89-5.15 (m, 1H), 5.30 (br s, 1H), 7.44 (s, 1H), 7.90 (br s, 1H), 8.83 (s, 1H), 9.21 (br s, 1H); ) The method comprises the steps of carrying out a first treatment on the surface of the MS (method B) m/z 415[ M+1 ] ]++, of the material; t=1.45 min-example 147 (absolute configuration unknown)
Example 148, example 149 and example 150:2- ((3- ((1S, 2S) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 2- ((3- ((1R, 2R) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Following the general procedure in example 140, (S) -7- (1-methoxypropane-2-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d]Pyrimidine-6-carbonitrile (115 mg) (step 5 of example 87) and N- (3- (2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) carboxamide (racemic trans) (89 mg) (intermediate 70) gave 112mg of 2- ((3- ((1S, 2S) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2, 3-d)]Pyrimidine-6-carbonitrile was reacted with 2- ((3- ((1R, 2R) -2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d]Isomer mixtures of pyrimidine-6-carbonitrile (referred to herein as 2- ((3- (trans-2-hydroxy-2-methylcyclobutoxy) -1- (methyl-d 3) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2, 3-d) ]Pyrimidine-6-carbonitrile); 1 h NMR (400 mhz, dmso-d 6) delta ppm 1.19 (s, 3H), 1.34-1.61 (m, 2H), 1.55 (d, j=7 hz, 3H), 1.64-1.76 (m, 1H), 1.98-2.14 (m, 1H), 3.19 (s, 3H), 3.65 (dd, j=11, 5hz, 1H), 3.97 (t, j=10 hz, 1H), 4.62 (t, j=8 hz, 1H), 4.85-4.99 (m, 1H), 5.04 (s, 1H), 7.40 (s, 1H), 7.72 (s, 1H), 8.48 (br s, 1H), 8.77 (s, 1H); MS (method D) m/z 415[ M+1 ]]++, of the material; t=1.06 min-example 148.
Chiral separation of 99mg of the isomer mixture gave 44mg of the first eluting isomer and 43mg of the second eluting isomer (conditions: column Chiralpak AY-H,20 μm,250X 4.6mm; liquid phase: heptane 70/ethanol 30/0.1TEA; flow rate: 1 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 mhz, dmso-d 6) delta ppm 1.19 (s, 3H), 1.36-1.62 (m, 2H), 1.56 (d, j=7hz, 3H), 1.63-1.75 (m, 1H), 1.99-2.14 (m, 1H), 3.20 (s, 3H), 3.66 (dd, j=10, 5hz, 1H), 3.97 (t, j=10 hz, 1H), 4.62 (t, j=8 hz, 1H), 4.83-5.00 (m, 1H), 5.05 (s, 1H), 7.41 (s, 1H), 7.72 (s, 1H), 8.49 (br s, 1H), 8.78 (s, 1H); MS (method B) m/z 415[ M+1 ]]++, of the material; t=1.44 min-example 149 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 mhz, dmso-d 6) delta ppm 1.19 (s, 3H), 1.36-1.62 (m, 2H), 1.56 (d, j=7hz, 3H), 1.63-1.75 (m, 1H), 1.99-2.14 (m, 1H), 3.20 (s, 3H), 3.66 (dd, j=10, 5hz, 1H), 3.97 (t, j=10 hz, 1H), 4.62 (t, j=8 hz, 1H), 4.83-5.00 (m, 1H), 5.05 (s, 1H), 7.41 (s, 1H), 7.72 (s, 1H), 8.49 (br s, 1H), 8.78 (s, 1H); MS (method B) m/z 415[ M+1 ] ]++, of the material; t=1.44 min-example 150 (absolute configuration unknown)
Example 151, example 152, and example 153:2- ((1- (2-hydroxyethyl) -3- (((R) -tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 2- ((1- (2-hydroxyethyl) -3- (((S) -tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Step 1: preparation of 2- ((1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- (((R) -tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 2- ((1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- (((S) -tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Following the general procedure in example 139, (S) -7- (1-methoxypropane-2-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (200 mg) (step 5 of example 87) and N- [1- [2- [ tert-butyl (dimethyl) silyl ] oxyethyl ] -3-tetrahydrofuran-3-yloxy-pyrazol-4-yl ] carboxamide (rac) (242 mg) (intermediate 71) gave 311mg of 2- ((1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- (((R) -tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile with 2- ((1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- (((S) -tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7-methoxy-propane- ((2-methoxy) propane Isomer mixtures of 7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile. MS (method E) m/z 542[ M+1] +; t=1.77 min.
Step 2: preparation of 2- ((1- (2-hydroxyethyl) -3- (((R) -tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile and 2- ((1- (2-hydroxyethyl) -3- (((S) -tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
1.72mL of 1N tetrabutylammonium fluoride THF solution (3 eq) was added to 311mg (1 eq) of 2- ((1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- (((R) -tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2, 3-d) at 0deg.C]Pyrimidine-6-carbonitrile was reacted with 2- ((1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- (((S) -tetrahydrofurane-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d]A mixture of pyrimidine-6-carbonitrile isomers in 20mL of THF. The mixture was stirred at 0 ℃ for 30min and then diluted with 50mL of ethyl acetate and 20mL of saturated ammonium chloride solution under stirring. The organic layer was treated with sodium sulfateDried, filtered and concentrated under reduced pressure. The residue was purified on silica (elution with a gradient of 0 to 5% methanol in dichloromethane) to give 221mg of 2- ((1- (2-hydroxyethyl) -3- (((R) -tetrahydrofuranl-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2, 3-d) ]Pyrimidine-6-carbonitrile was reacted with 2- ((1- (2-hydroxyethyl) -3- (((S) -tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d]Mixtures of isomers of pyrimidine-6-carbonitrile (referred to herein as 2- ((1- (2-hydroxyethyl) -3- ((tetrahydrofuran-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((S) -1-methoxypropane-2-yl) -7H-pyrrolo [2, 3-d)]Pyrimidine-6-carbonitrile). 1 H NMR (400 MHz, DMSO-d 6) delta ppm 1.55 (d, J=7Hz, 3H), 1.97-2.17 (m, 2H), 3.19 (s, 3H), 3.58-3.75 (m, 4H), 3.76-3.90 (m, 3H), 3.94-4.06 (m, 3H), 4.83 (t, J=5Hz, 1H), 4.85-4.97 (m, 1H), 5.07-5.17 (m, 1H), 7.40 (s, 1H), 7.82 (br s, 1H), 8.58 (br s, 1H), 8.78 (s, 1H); MS (method D) m/z 428[ M+1 ]]++, of the material; t=0.87 min-example 151.
Chiral separation of 210mg of the isomer mixture gave 96mg of the first eluting isomer and 95mg of the second eluting isomer (conditions: column Chiralpak AY,20 μm,230x 100mm; liquid phase: heptane 70/ethanol 30/0.1TEA; flow rate: 1 mL/min): 400 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 MHz, DMSO-d 6) delta ppm 1.55 (d, J=7Hz, 3H), 1.97-2.17 (m, 2H), 3.19 (s, 3H), 3.58-3.75 (m, 4H), 3.76-3.90 (m, 3H), 3.94-4.06 (m, 3H), 4.83 (t, J=5Hz, 1H), 4.85-4.97 (m, 1H), 5.07-5.17 (m, 1H), 7.40 (s, 1H), 7.82 (br s, 1H), 8.58 (br s, 1H), 8.78 (s, 1H); MS (method B) m/z 428[ M+1 ] ]++, of the material; t=1.26 min-example 152 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 MHz, DMSO-d 6) delta ppm 1.55 (d, J=7Hz, 3H), 1.97-2.17 (m, 2H), 3.19 (s, 3H), 3.58-3.75 (m, 4H), 3.76-3.90 (m, 3H), 3.94-4.06 (m, 3H), 4.83 (t, J=5Hz, 1H), 4.85-4.97 (m, 1H), 5.07-5.17 (m, 1H), 7.40 (s, 1H), 7.82 (br s, 1H), 8.58 (br s, 1H), 8.78 (s, 1H); MS (method B) m/z 428[ M+1]]++, of the material; t=1.26 min-example 153 (absolute configuration unknown)
Example 154: (S) -2- ((2-cyclopropoxy-4- (2-hydroxypropan-2-yl) phenyl) amino) -7- (1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
Step 1: preparation of methyl (S) -4- ((6-cyano-7- (1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3-cyclopropoxybenzoate
Following the general procedure in example 99, (S) -7- (1-methoxypropane-2-yl) -2- (methylsulfonyl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (300 mg) (step 5 of example 87) and methyl 3- (cyclopropyloxy) -4-carboxamido-benzoate (240 mg) (intermediate 34) gave 415mg of methyl (S) -4- ((6-cyano-7- (1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3-cyclopropoxybenzoate. MS (method E) m/z 422[ M+1] +; t=1.16 min.
Step 2: preparation of (S) -2- ((2-cyclopropoxy-4- (2-hydroxypropan-2-yl) phenyl) amino) -7- (1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile
1.64mL (5 eq) of methyl magnesium bromide 3M in diethyl ether was added to a solution of 415mg (1 eq) (S) -methyl 4- ((6-cyano-7- (1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) amino) -3-cyclopropoxy benzoate in 25mL of tetrahydrofuran at 0 ℃. The reaction mixture was stirred at room temperature for 60 minutes, then an additional 3 equivalents of methyl magnesium bromide 3M in diethyl ether was added at 0 ℃ and the reaction mixture was stirred at room temperature for 30 minutes. 3 other equivalents of methyl magnesium bromide 3M in diethyl ether (17 equivalents total) were added 3 times (until the reaction was complete). The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted 2 times with 100mL ethyl acetate. The organic layer was washed with 50mL of water and 50mL of brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified on silica (elution with a gradient of 0 to 100% ethyl acetate in cyclohexane) to give 198mg of (S) -2- ((2-cyclopropoxy-4- (2-hydroxypropan-2-yl) phenyl) amino) -7- (1-methoxypropane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile-example 154.
1 H NMR (400 mhz, dmso-d 6) delta ppm 0.70-0.85 (m, 4H), 1.46 (s, 6H), 1.60 (d, j=7hz, 3H), 3.20 (s, 3H), 3.70 (dd, j=10, 5hz, 1H), 3.87-3.97 (m, 1H), 4.01 (t, j=10 hz, 1H), 4.85-4.97 (m, 1H), 4.97 (s, 1H), 7.06 (dd, j=9, 2hz, 1H), 7.46 (s, 1H), 7.47 (d, j=2 hz, 1H), 8.08 (s, 1H), 8.10 (d, j=1 hz, 1H), 8.85 (s, 1H); MS (method B) m/z 413[ M+1 ]]+；t＝1.05min。
Example 155 and example 156:2- ((1- (methyl-d 3) -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 and 2- ((1- (methyl-d 3) -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
Following the general procedure in example 99, 2-methylsulfonyl-7- [ 3-methyltetrahydropyran-4-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (racemic trans) (230 mg) (step 4 of examples 83 and 84) and N- (1- (methyl-d 3) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide (143 mg) (intermediate 26) gave 198mg of 2- ((1- (methyl-d 3) -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 as a mixture with 2- ((1- (methyl-d 3) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- ((3S, 4R) -3-methyltetrahydro-2H-pyran-4-yl) -7H-pyrrolo [ 2H-pyran-4-yl ] amino ] -7- ((3- (methyl-d 3-methyltetrahydro-4-yl) -7-pyrimidine-6-carbonitrile as a mixture in (rac-3- (methyl-d 3-yloxy) -1H-pyrazol-4-yl) amino group) Butan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- (trans-3-methyltetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
Chiral separation of 188mg of the racemic mixture yielded 73mg of the first eluting isomer and 79mg of the second eluting isomer (conditions: column Chiralpak IC,20 μm,350x 76mm; liquid phase (heptane+0.1 TEA) 30+/(ethanol+0.1 TEA) 70; flow rate: 400 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 MHz, DMSO-d 6) delta ppm 0.56 (d, J=7Hz, 3H), 1.85 (m, 1H), 2.68 (m, 2H), 3.08-3.20 (m, 1H), 3.46-3.59 (m, 1H), 3.96 (m, 1H), 4.01-4.10 (m, 1H), 4.18-4.38 (m, 1H), 4.48-4.68 (m, 2H), 4.71-4.92 (m, 2H), 5.32 (quin, J=6Hz, 1H), 7.47 (s, 1H), 7.81 (br s, 1H), 8.83 (s, 1H), 8.90 (br s, 1H); MS (method B) m/z 413[ M+1 ]]++, of the material; t=1.41 min-example 155 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 mhz, dmso-d 6) delta ppm 0.56 (d, j=7 hz, 3H), 1.85 (brdd, j=12, 3hz, 1H), 2.68 (m, 2H), 3.08-3.20 (m, 1H), 3.46-3.59 (m, 1H), 3.96 (dd, j=12, 5hz, 1H), 4.01-4.10 (m, 1H), 4.18-4.38 (m, 1H), 4.48-4.68 (m, 2H), 4.71-4.92 (m, 2H), 5.32 (quin, j=6 hz, 1H), 7.47 (s, 1H), 7.81 (br s, 1H), 8.83 (br s, 1H), 8.90 (s, 1H); MS (method B) m/z 413[ M+1 ]]++, of the material; t=1.41 min-example 156 (absolute configuration unknown)
Examples 157, 158 and 159:2- ((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 and 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
Following the general procedure in example 99, 2-methylsulfonyl-7- [ 3-methyltetrahydropyran-4-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (racemic trans) (125 mg) (step 4 of examples 83 and 84) and N- (3-cyclopropoxy-1- ((methylsulfonyl) methyl) -1H-pyrazol-4-yl) carboxamide (102 mg) (intermediate 16) gave 51mg of 2- ((3-cyclopropoxy-1- ((methylsulfonyl) methyl) -1H-pyrazolo-4-yl) amino) -7- ((3R, 4S) -3-methyltetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile as a mixture with 2- ((3-cyclopropoxy-1- ((methylsulfonyl) methyl) -1H-pyrazol-4-yl) amino) -7- ((3H-methyltetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-4-yl ] amino) -7H-pyrrolo [ 2H-pyrazol-4-yl ] amino ] -7-pyrrolo [2,3-d ] pyrimidine-6-yl ] pyrimidine-6-carbonitrile in this racemic mixture of 2- ((3R, 3-d ] pyrimidine-4-yl) amino-7-carbonyl-pyrazolo-2-carbonitrile was designated as racemic amino-3-yl ] pyrimidine-6-carbonyl-pyrimidine-6-carbonyl ) -7- (trans-3-methyltetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile.
1H NMR (400 MHz, DMSO-d 6) delta ppm 0.54 (d, J=7Hz, 3H), 0.63-0.82 (m, 4H), 1.82 (br d, J=9Hz, 1H), 2.52-2.76 (m, 2H), 3.02 (s, 3H), 3.17 (br t, J=11Hz, 1H), 3.54 (br t, J=12Hz, 1H), 3.94 (dd, J=12, 4Hz, 1H), 4.03 (dd, J=11, 4Hz, 1H), 4.08-4.19 (m, 1H), 4.27-4.48 (m, 1H), 5.53 (s, 2H), 7.49 (s, 1H), 8.08 (br s, 1H), 8.85 (s, 1H), 8.98 (br s, 1H); MS (method D) m/z 472[ M+1] +; t=1.14 min-example 157.
Chiral separation of 41mg of the racemic mixture gave 11mg of the first eluting isomer and 9mg of the second eluting isomer (conditions: column i-cellulose-5,5 μm,250X 30mm; liquid phase: ethanol 100%; flow rate: 40 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 mhz, dmso-d 6) delta ppm 0.54 (d, j=7hz, 3H), 0.62-0.77 (m, 4H), 1.82 (br dd, j=12, 4hz, 1H), 2.51-2.74 (m partially hidden, 2H), 3.02 (s, 3H), 3.17 (br t, j=11 hz, 1H), 3.54 (br t, j=12 hz, 1H), 3.94 (dd, j=11, 4hz, 1H), 4.03 (br dd, j=11, 4hz, 1H), 4.08-4.17 (m, 1H), 4.25-4.50 (m, 1H), 5.53 (s, 2H), 7.49 (s, 1H), 8.08 (br s, 1H), 8.85 (s, 1H), 8.87-9.04 (m, 1H); MS (method B) m/z 472[ M+1 ]]++, of the material; t=1.51 min-example 158 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 mhz, dmso-d 6) delta ppm 0.54 (d, j=7hz, 3H), 0.62-0.77 (m, 4H), 1.82 (br dd, j=12, 4hz, 1H), 2.51-2.74 (m partially hidden, 2H), 3.02 (s, 3H), 3.17 (br t, j=11 hz, 1H), 3.54 (br t, j=12 hz, 1H), 3.94 (dd, j=11, 4hz, 1H), 4.03 (br dd, j=11, 4hz, 1H), 4.08-4.17 (m, 1H), 4.25-4.50 (m, 1H), 5.53 (s, 2H), 7.49 (s, 1H), 8.08 (br s, 1H), 8.85 (s, 1H), 8.87-9.04 (m, 1H); MS (method B) m/z 472[ M+1 ]]++, of the material; t=1.51 min-example 159 (absolute configuration unknown)
Example 160 and example 161:2- ((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 and 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
Step 1: preparation of 2- ((1- (2- ((tert-Butyldimethylsilyl) oxy) ethyl) -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 and 2- ((1- (2- ((tert-Butyldimethylsilyl) oxy) ethyl) -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
Following the procedure in step 1 of example 151, 2-methylsulfonyl-7- [ 3-methyltetrahydropyran-4-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (racemic trans) (200 mg) (steps 4 of examples 83 and 84) and N- (1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) carboxamide (213 mg) (intermediate 60) gave 266mg of 2- ((1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -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 and 2- ((1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile [2,3-d ] pyrimidine-6-carbonitrile. MS (method E) m/z 554[ M+1] +; t=1.77 min.
Step 2: preparation of 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 and 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
According to the procedure in step 2 of example 151, 266mg of 2- ((1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -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 and 2- ((1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -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 give 188mg of 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 and 2- ((3S) -3-methyltetrahydro-4-yl) -7H-pyrrol-4-yl-carbonitrile Azetidin-3-yloxy) -1H-pyrazol-4-yl) amino) -7- ((3 s,4 r) -3-methyltetrahydro-2H-pyran-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile (referred to herein as 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).
The 177mg of the racemic mixture was chiral separated to yield 78mg of the first eluting isomer and 80mg of the second eluting isomer (conditions: column Chiralpak AY,20 μm,250X 100mm; liquid phase (heptane+0.1 TEA) 50+/(ethanol+0.1 TEA) 50; flow rate: 400 mL/min).
Peak 1 (isomer 1): 1 h NMR (400 MHz, DMSO-d 6) delta ppm 0.55 (d, J=7Hz, 3H), 1.80-1.88 (m, 1H), 2.45-2.55 (m hidden, 1H), 2.60-2.74 (m hidden, 1H), 3.10-3.18 (m, 1H), 3.47-3.56 (m, 1H), 3.65-3.73 (m, 2H), 3.92-3.98 (m, 3H), 4.00-4.08 (m, 1H), 4.20-4.43 (m, 1H), 4.54-4.62 (m, 2H), 4.76-4.86 (m, 3H), 5.33 (quin, J=6Hz, 1H), 7.47 (s, 1H), 7.91 (brs, 1H), 8.82 (s, 1H), 8.89 (brs, 1H); MS (method B) m/z 440[ M+1 ]]++, of the material; t=1.29 min-example 160 (absolute configuration unknown)
Peak 2 (isomer 2): 1 h NMR (400 MHz, DMSO-d 6) delta ppm 0.55 (d, J=7Hz, 3H), 1.80-1.88 (m, 1H), 2.45-2.55 (m hidden, 1H), 2.60-2.74 (m, 1H), 3.10-3.18 (m, 1H), 3.47-3.56 (m, 1H), 3.65-3.73 (m, 2H), 3.92-3.98 (m, 3H), 4.00-4.08 (m, 1H), 4.20-4.43 (m, 1H), 4.54-4.62 (m, 2H), 4.76-4.86 (m, 3H), 5.33 (quin, J=6Hz, 1H), 7.47 (s, 1H), 7.91 (br s, 1H), 8.82 (s, 1H), 8.br s, 1H; MS (method B) m/z 440[ M+1 ]]++, of the material; t=1.29 min-example 161 (absolute configuration unknown)
Pharmacology
The in vitro potency of a compound in inhibiting LRRK2 kinase can be determined by the procedure detailed below.
Determination of LRRK2-G2019S kinase Activity:
the measurement of activity was performed using the LRRK2-G2019S (human) kinase activity assay, as described below. UsingTechnique (ThermoFisher Scientific) potency of compounds was assessed in vitro.
Biological assays require full length LRRK2G2019S protein with dykdddk tag, a fluorescent peptide substrate named LRRKtide or ERM (RLGRDKYKTLRQIRQ provided by PolyPeptide Group), an ATP substrate, and test compounds at different concentrations. In a typical experiment, the reaction assay buffer contained 50mM Tris (pH 8.2), 1mM EGTA, 2.5mM MgCl2, 0.05% Triton X100, 0.15% BSA and 1mM DTT. Detection of the assay was performed using terbium-labeled anti-phospho-LRRKtide (ThermoFisher Scientific) diluted 1nM in TR-FRET buffer (ThermoFisher Scientific).
By Greiner small384 wells were subjected to the experimental procedure. The assay was started by a pre-incubation step of the full length LRRK2G2019S mutein with a dilution series of the reaction assay buffer and the test compound at room temperature for at least 30 minutes. Working solutions of the compounds were prepared in separate Greiner microplates.
By adding ATP/LRRKtide substrate mixture diluted in reaction assay bufferThe substance initiates a kinase reaction. The reaction mixture was incubated at room temperature (initial speed conditions) for at least 10 minutes. The reaction was stopped by adding terbium-labeled anti-LRRKtide diluted into the detection buffer supplemented with EDTA (ThermoFisher Scientific). Plates were incubated at room temperature for at least 30 minutes and with LanthaScreen TM In Envision TM Read on a multimode plate reader (PerkinElmer). The TR-FRET 520:495nm emission ratio is calculated and the IC50 value is determined from a dose response curve fitted to a four parameter logistic equation using the emission ratio. The activity relative to LRRK2 kinase in this test is given by the concentration (or IC 50) (in nM) that inhibits 50% of LRRK2 activity.
LRRK2 WT assay (assay a):
the kinase activity of LRRK2 (human) WTs was evaluated according to the same method as described in the LRRK2-G2019 kinase activity assay described above except that full length LRRK2 wild type with DYDDDDK tag was used instead of full length LRRK 2G 2019S with dykddk tag and 500uM ATP was used instead of 1.1mM ATP in the WT assay.
LRRK2 WT assay (assay B):
LRRK2 (human) was incubated with 50mM HEPES (pH 8.0), 0.2mM EDTA, 0.01% Brij-35, 1% (w/v) BSA, 5mM DTT, 250 mM m RLGRDKYKTLRQIRQ, 10mM magnesium acetate, and [8-33P ] -ATP (specific activity and concentration as desired).
The reaction was started by adding Mg/ATP mixture. After incubation for 40 minutes at room temperature, the reaction was stopped by adding phosphoric acid to a concentration of 0.5%. Then, 10 μl of the reaction was spotted onto a P30 filter pad and washed four times in 0.425% phosphoric acid for 4 minutes, and washed once in methanol, followed by drying and scintillation counting.
Biological data
The following table (table IV) shows IC50 values of the example compounds obtained as described above.
Table IV:
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data obtained with assay B.
"NT" was not tested.
The compounds of formula I and pharmaceutically acceptable salts thereof may be used for the manufacture of a medicament for the treatment of neurodegenerative diseases selected from parkinson's disease, multiple sclerosis, dementia with lewy bodies, HIV-induced dementia, amyotrophic lateral sclerosis, pick's disease, progressive supranuclear palsy and frontotemporal dementia.
According to one aspect thereof, the present disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder associated with LRRK2 kinase.
According to one aspect thereof, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a neurodegenerative disease selected from parkinson's disease, multiple sclerosis, dementia with lewy bodies, HIV-induced dementia, amyotrophic lateral sclerosis, pick's disease, progressive supranuclear palsy and frontotemporal lobar dementia.
According to another aspect thereof, the present disclosure relates to pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients. In some aspects, the pharmaceutical composition contains an effective dose of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and optionally at least one pharmaceutically acceptable excipient.
In some aspects, a pharmaceutical composition for oral or sublingual administration, a compound of formula (I) above, or a pharmaceutically acceptable salt thereof, may be administered to a patient in unit administration form as a mixture with one or more pharmaceutically acceptable excipients to treat the disorder or disease described above.
For example, a unit administration form of a compound according to the present disclosure in tablet form may comprise the following components:
the dosage of the active ingredient administered daily via the oral route may range from 0.1 to 20mg/kg, taken in one or more doses.
According to usual practice, the dosage for each patient is determined by the practitioner according to the mode of administration and the weight and response of the patient.
According to another aspect thereof, the present disclosure also relates to a method for treating a neurodegenerative disease selected from parkinson's disease, multiple sclerosis, dementia with lewy bodies, HIV-induced dementia, amyotrophic lateral sclerosis, pick's disease, progressive supranuclear palsy and frontotemporal dementia, comprising administering to a patient in need thereof an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Claims (20)

1. A compound of formula (I)
Wherein:
r1 is selected from aryl, ortho-fused bicyclic heteroaryl, and heteroaryl, wherein the ortho-fused bicyclic heteroaryl is unsubstituted or substituted with one or more- (C) 1 -C 3 ) -alkyl substitution; and wherein the aryl and heteroaryl groups are unsubstituted or substituted with one or more substituents independently selected from the group consisting of:
a) The deuterium atom is present in the form of a ring,
b) A fluorine atom is used as a carrier,
c) Alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl group, fluorine atom, deuterium atom, cyano group, alkoxy group, alkylamino group and dialkylamino group,
d) Cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, hydroxy or- (C) 1 -C 3 ) -an alkyl group substituted with a hydroxyl group,
e) Heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl,
f) Alkoxy, said alkoxy being unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy and fluorine atoms,
g) -O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, hydroxy or- (C) 1 -C 3 ) -an alkyl group substituted with a hydroxyl group,
h) An O-heterocycloalkyl group, said O-heterocycloalkyl group being unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy, hydroxy and alkylcarbonyl,
i) -an O-spiro group and a group,
j) Alkyl sulfonyl alkyl, and
k) An alkylsulfonyl group; and is also provided with
R2 is selected from alkoxyalkyl and heterocycloalkyl, wherein the heterocycloalkyl represented by R2 is attached via a carbon atom and is unsubstituted or substituted with alkyl, alkoxy or one or more fluoro;
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein
R1 is selected from aryl, ortho-fused bicyclic heteroaryl, and heteroaryl, wherein the ortho-fused bicyclic heteroaryl is unsubstituted or substituted with one or more- (C) 1 -C 3 ) -alkyl substitution; and wherein the aryl and heteroaryl groups are unsubstituted or taken by one or more substituents independently selected fromAnd (3) substitution:
a) The deuterium atom is present in the form of a ring,
b) A fluorine atom is used as a carrier,
c) Alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl group, fluorine atom, deuterium atom, cyano group, alkoxy group, alkylamino group and dialkylamino group,
d) Cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms or- (C) 1 -C 3 ) -an alkyl group substituted with a hydroxyl group,
e) Heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl,
f) Alkoxy, said alkoxy being unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy and fluorine atoms,
g) -O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms or- (C) 1 -C 3 ) -an alkyl group substituted with a hydroxyl group,
h) An O-heterocycloalkyl group, said O-heterocycloalkyl group being unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl,
i) -an O-spiro group and a group,
j) Alkyl sulfonyl alkyl, and
k) An alkylsulfonyl group;
or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1, wherein
R1 is selected from phenyl and heteroaryl, wherein the phenyl and heteroaryl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of:
a) A fluorine atom is used as a carrier,
b) Alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl group, fluorine atom, deuterium atom, cyano group, alkoxy group, alkylamino group and dialkylamino group,
c) Cycloalkyl, which is unsubstitutedOr by one or more fluorine atoms, hydroxyl groups or- (C) 1 -C 3 ) -an alkyl group substituted with a hydroxyl group,
d) Heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl,
e) Alkoxy, said alkoxy being unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy and fluorine atoms,
f) -O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, hydroxy or- (C) 1 -C 3 ) -an alkyl group substituted with a hydroxyl group,
g) An O-heterocycloalkyl group, said O-heterocycloalkyl group being unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy, hydroxy and alkylcarbonyl,
h) -an O-spiro group and a group,
i) Alkyl sulfonyl alkyl, and
j) An alkylsulfonyl group;
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1, having formula (Ia)
Wherein:
r3 is selected from hydrogen atom, - (C) 1 -C 3 ) -alkyl and- (C) 1 -C 3 ) -an alkoxy group;
m represents 1, 2 or 3; and is also provided with
n represents 0 or 1;
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1, having formula (Ia)
Wherein the method comprises the steps of
R1 is selected from phenyl and heteroaryl, wherein the phenyl and heteroaryl are unsubstituted or substituted with one or more substituents independently selected from the group consisting of:
a) A fluorine atom is used as a carrier,
b) Alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl group, fluorine atom, deuterium atom, cyano group, alkoxy group, alkylamino group and dialkylamino group,
c) Cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, hydroxy or- (C) 1 -C 3 ) -an alkyl group substituted with a hydroxyl group,
d) Heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl,
e) Alkoxy, said alkoxy being unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy and fluorine atoms,
f) -O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, hydroxy or- (C) 1 -C 3 ) -an alkyl group substituted with a hydroxyl group,
g) An O-heterocycloalkyl group, said O-heterocycloalkyl group being unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy, hydroxy and alkylcarbonyl,
h) -an O-spiro group and a group,
i) Alkyl sulfonyl alkyl, and
j) An alkylsulfonyl group;
m represents 1 or 2; and is also provided with
n represents 0 or 1;
or a pharmaceutically acceptable salt thereof.
6. The compound according to any one of claims 1 to 5, having formula (Ib)
Wherein:
r3 is selected from hydrogen atom, - (C) 1 -C 3 ) -alkyl and- (C) 1 -C 3 ) -an alkoxy group;
r4 is selected from:
a) Alkoxy, said alkoxy being unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy and fluorine atoms,
b) -O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, hydroxy or- (C) 1 -C 3 ) -an alkyl group substituted with a hydroxyl group,
c) -O-heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy, hydroxy and alkylcarbonyl, and
d) -O-spiro group;
r5 is selected from:
a) The hydrogen atom is contained in the mixture,
b) Alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl group, fluorine atom, deuterium atom, cyano group, alkoxy group, alkylamino group and dialkylamino group,
c) Cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, hydroxy or- (C) 1 -C 3 ) -an alkyl group substituted with a hydroxyl group,
d) Heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl,
e) Alkyl sulfonyl alkyl, and
f) An alkylsulfonyl group;
r6 is selected from the group consisting of a hydrogen atom and a deuterium atom;
m represents 1, 2 or 3; and is also provided with
n represents 0 or 1;
or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 6, wherein
R3 is selected from- (C) 1 -C 3 ) -alkyl and- (C) 1 -C 3 ) -an alkoxy group;
r6 is a hydrogen atom;
m represents 1 or 2; and is also provided with
n represents 0 or 1;
or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 6, wherein
R3 is selected from- (C) 1 -C 3 ) -alkyl and- (C) 1 -C 3 ) -an alkoxy group;
r4 is selected from:
a) Alkoxy, said alkoxy being unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy and fluorine atoms,
b) -O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, hydroxy or- (C) 1 -C 3 ) -alkyl substitution, and
c) -O-heterocycloalkyl, said-O-heterocycloalkyl being unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy, hydroxy and alkylcarbonyl;
r5 is selected from:
a) Alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl group, fluorine atom, deuterium atom, cyano group, alkoxy group, alkylamino group and dialkylamino group,
b) Cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, hydroxy or- (C) 1 -C 3 ) -alkyl substitution, and
c) A heterocycloalkyl group, said heterocycloalkyl group being unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl;
R6 is a hydrogen atom;
m represents 1; and is also provided with
n represents 1;
or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 6, wherein
R3 is- (C) 1 -C 3 ) -an alkyl group;
r4 is selected from:
a) -O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, hydroxy or- (C) 1 -C 3 ) -alkyl substitution, and
b) An O-heterocycloalkyl group, said O-heterocycloalkyl group being unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy, hydroxy and alkylcarbonyl,
r5 is alkyl, which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy, fluoro, deuterium, cyano, alkoxy, alkylamino and dialkylamino;
r6 is a hydrogen atom;
m represents 1; and is also provided with
n represents 1;
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1, having formula (Ic)
Wherein:
r4 is selected from:
a) Alkoxy, said alkoxy being unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy and fluorine atoms,
b) -O-cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, hydroxy or- (C) 1 -C 3 ) -an alkyl group substituted with a hydroxyl group,
c) -O-heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy, hydroxy and alkylcarbonyl, and
d) -O-spiro group;
r5 is selected from:
a) The hydrogen atom is contained in the mixture,
b) Alkyl group which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl group, fluorine atom, deuterium atom, cyano group, alkoxy group, alkylamino group and dialkylamino group,
c) Cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms, hydroxy or- (C) 1 -C 3 ) -an alkyl group substituted with a hydroxyl group,
d) Heterocycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from alkyl, alkoxy and alkylcarbonyl,
e) Alkyl sulfonyl alkyl, and
f) An alkylsulfonyl group;
r6 is selected from the group consisting of a hydrogen atom and a deuterium atom;
r7 is- (C) 1 -C 3 ) -an alkyl group; and is also provided with
R8 is- (C) 1 -C 3 ) -an alkyl group;
or a pharmaceutically acceptable salt thereof.
11. A compound selected from the group consisting of:
2- ((1-methyl-3- (((2 r,3 s) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1-methyl-3- (((2 s,3 r) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- [ [ 1-methyl-3- (oxetan-3-yloxy) pyrazol-4-yl ] amino ] -7- [ (3 r,4 r) -4-methyltetrahydrofuran-3-yl ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1- (methyl-d 3) -3- (((2 r,3 s) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1- (methyl-d 3) -3- (((2 s,3 r) -2-methyloxetan-3-yl) oxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((1- (methyl-d 3) -3- (oxetan-3-yloxy) -1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -4-methyltetrahydrofuran-3-yl) -7H-pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
2- ((3-isopropoxy-1-methyl-1H-pyrazol-4-yl) amino) -7- ((3 r,4 r) -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- ((3 r,4 s) -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- ((3 s,4 r) -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, 3 r) -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- [ (2 r, 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, 3 r) -2-methyl-oxetan-3-yl ] oxy-1- (methyl-d 3) pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile;
7- [ (1S) -2-methoxy-1-methyl-ethyl ] -2- [ [3- [ (2 r, 3S) -2-methyl-oxetan-3-yl ] oxy-1- (methyl-d 3) pyrazol-4-yl ] amino ] pyrrolo [2,3-d ] pyrimidine-6-carbonitrile; and
2- [ [3- (cyclopropyloxy) -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.
12. A process for preparing a compound according to claim 1, the process comprising reacting a compound of formula (11X) with a compound of formula (15X):
wherein R1 and R2 are as defined for the compounds of formula (I) in 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. A method for treating a neurodegenerative disease, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.
15. The method of claim 14, wherein the neurodegenerative disease is selected from parkinson's disease, multiple sclerosis, HIV-induced dementia, amyotrophic lateral sclerosis, dementia with lewy bodies, pick's disease, progressive supranuclear palsy, and frontotemporal dementia.
16. The method of claim 14, wherein the neurodegenerative disease is parkinson's disease.
17. A medicament, characterized in that it comprises 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 a neurodegenerative disease.
19. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 18, wherein the neurodegenerative disease is selected from parkinson's disease, multiple sclerosis, HIV-induced dementia, amyotrophic lateral sclerosis, dementia with lewy bodies, pick's disease, progressive supranuclear palsy and frontotemporal dementia.
20. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 18, wherein the neurodegenerative disease is parkinson's disease.
CN202280055079.0A 2021-06-15 2022-06-14 Substituted pyrrolo [2,3-d ] pyrimidines, their preparation and their therapeutic use Pending CN117881681A (en)

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EP21315095.6 2021-06-15
EP22315117.6 2022-06-02
EP22315117 2022-06-02
PCT/EP2022/066231 WO2022263472A1 (en) 2021-06-15 2022-06-14 Substituted pyrrolo[2,3-d]pyrimidines, their preparation and their therapeutic application

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