Pyrrolopyrimidines as CFTR potentiators

Abstract

The present invention relates to pyrrolopyrimidines as CFTR potentiators. Specifically, the present invention relates to compounds of formula (I) wherein R 1a , R 1b , R 2 , R 3 , R 4 , W, Y and Z are as described herein, and pharmaceutically acceptable salts thereof. The compounds are potentiators of the cystic fibrosis transmembrane conductance regulator (CFTR). The present invention also discloses pharmaceutical compositions comprising the compound, optionally in combination with other therapeutic agents, and methods of enhancing CFTR in mammals, including humans, by administering the compound. These compounds can be used to treat cystic fibrosis (CF), asthma, bronchiectasis, chronic obstructive pulmonary disease (COPD), constipation, diabetes, dry eye, pancreatitis, sinusitis, Sjogren's syndrome and other CFTR-related diseases.

Description

[0001] This application is a divisional application of the invention patent application with the application date of November 17, 2017, application number of 201780083801.0, and title of "Pyrrolo[2,3-d]pyrimidine as a CFTR potentiator". Technical Field

[0002] The present invention relates to small molecule potentiators of the cystic fibrosis transmembrane conductance regulator (CFTR). The present invention also relates to pharmaceutical compositions comprising the potentiators, optionally in combination with other therapeutic agents, and methods of enhancing the efficacy of CFTR in mammals (including humans) by administering small molecule CFTR potentiators. The present invention also relates to the treatment of cystic fibrosis and other diseases in mammals (including humans) with CFTR potentiators. More specifically, the present invention relates to 2,5,6,7-tetrasubstituted-7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives for the treatment of cystic fibrosis (CF), asthma, bronchiectasis, chronic obstructive pulmonary disease (COPD), constipation, diabetes, dry eye, pancreatitis, sinusitis, Sjogren's syndrome, and other CFTR-related diseases. Background Art

[0003] Cystic fibrosis (CF) is the most common lethal genetic disease affecting Caucasians. CF is an autosomal recessive genetic disease with an incidence of between 1 in 2,000 live births and 1 in 3,000 live births (Cutting, G.R., Accurso, F., Ramsey, B.W., and Welsh, M.J., Online Metabolic & Molecular Bases of Inherited Disease, McGraw-Hill, 2013). More than 70,000 people are affected worldwide, approximately 33,000 of whom are in the United States (www.cff.org / What-is-CF / About-Cystic-Fibrosis / ). The hallmarks of CF are excessive mucus secretion and mucus clearance defects leading to airway obstruction, infection, and inflammation; pancreatic insufficiency; and elevated sweat chloride concentration. CF is a multi-system disease affecting the lungs, pancreas, and gastrointestinal, hepatobiliary, and reproductive tracts (R.D. Coakley et al., in Cystic Fibrosis, Eds. Hodson, M., Geddes, D., and Bush, A., Edward Arnold, Third Ed., 2007, pp. 59-68).

[0004] For most patients, the burden of care for supportive therapies that do not address the underlying cause of the disease is substantial. Supportive therapies include physical airway clearance techniques, inhaled medications (mucolytics, antibiotics, and hypertonic saline), oral anti-inflammatory medications, pancreatic enzyme replacements, and nutritional supplements (Cystic Fibrosis Foundation Patient Registry 2011 Annual Data Report to the Center Directors, Cystic Fibrosis Foundation, Bethesda, Maryland, 2012). The median age of survival for patients with cystic fibrosis is into the fourth decade of life.

[0005] Cystic fibrosis is caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene, which is an ion channel found in epithelial cells and other tissues. CFTR is present on the apical membranes of epithelial cells in the airways, intestine, pancreas, and sweat glands (G.R. Cutting, Accurso, F., Ramsey, B.W., and Welsh, M.J., Online Metabolic & Molecular Bases of Inherited Disease, McGraw-Hill, 2013). Mutations in CFTR are classified into six types (Welsh, M.J., and Smith, A.E., Cell, 1993, 73, 1251 - 1254 and Sloane, P.A., and Rowe, S.M., Curr. Opin. Pulm. Med., 2010, 16, 591 - 597): 1) premature termination due to deletions, nonsense, or frameshift mutations, 2) defective trafficking out of the endoplasmic reticulum due to improper folding, 3) improper gating, 4) reduced conductance due to changes in the channel pore, 5) reduced channel production due to altered splicing, and 6) increased endocytosis from the plasma membrane.

[0006] Nearly 2,000 different mutations in CFTR are known to cause CF. The deletion of Phe508 in CFTR (F508del) occurs in approximately 70% of CFTR alleles (Bobadilla, J.L. et al., Human Mutation, 2002, 19, 575 - 606). Approximately 50% of patients are homozygous for F508del and approximately 40% are heterozygous, such that at least one copy of F508del is present in approximately 90% of patients. G551D is the third most common mutation and is present in approximately 4% of patients (Cystic Fibrosis Foundation Patient Registry 2011 Annual Data Report to the Center Directors, Cystic Fibrosis Foundation, Bethesda, Maryland, 2012).

[0007] The F508del mutation results in loss of CFTR function due to both reduced channel density and impaired channel gating. The channel density at the apical membrane is reduced due to protein misfolding. The misfolded CFTR is recognized and degraded by the cellular quality control machinery (Ward, C.L. and Kopito, R.R., J. Biol. Chem., 1994, 269, 25710 - 25718). The function of F508del is further reduced because it has a significantly reduced probability of channel opening (gating defect) (Dalemans, W. et al., Nature, 1991, 354, 526 - 528). The G551D mutation results in a protein with normal folding but impaired gating (Illek, B. et al., Am. J. Physiol., 1999, 277, C833–C839).

[0008] Small molecules referred to as "correctors" have been shown to reverse the folding / transport defect of F508del CFTR and increase the density of CFTR channels on the plasma membrane (Pedemonte, N. et al., J. Clin. Invest., 2005, 115, 2564-2571, Van Goor, F. et al., Am. J. Physiol. Lung Cell. Mol. Physiol., 2006, 290, L1117-1130, VanGoor, F. et al., Proc. Nat. Acad. Sci. USA, 2011, 108, 18843-18848). "Potentiators" are small molecules that can increase the channel open probability of mutant CFTR, thus reversing the gating defect. Pharmacological correction of F508del is thought to require at least correctors and potentiators to address the folding and gating defects, while G551D may only benefit from potentiators.

[0009] (ivacaftor, VX-770) is a commercially available potentiator that can improve the gating properties of G551D. In patients with G551D, it significantly improves lung function (a 10-13% increase in the percentage of predicted FEV1), allows weight gain, and reduces the frequency of pulmonary exacerbations (Ramsey, B. W. et al., New Eng. J. Med., 2011, 365, 1663-1672, Davies, J. C. et al., Am. J. Resp. Crit. Care Med., 2013, 187, 1219-1225). It has also been approved for populations with G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, and S549R mutations, and its application to other mutations, including those with partial function, is being studied.

[0010] Although monotherapy with has not led to any significant improvement in homozygous F508del patients (Flume, P. A. et al., Chest, 2012, 142, 718-724), correctors (VX-809, lumacaftor or VX-661, tezacaftor) in combination with The combination results in a modest improvement in lung function (a 3 - 4% increase in predicted FEV1) (Wainwright, C.E. et al., N. Engl. J. Med., 2015, 373, 220 - 231, Pilewski, J.M. et al., J. Cystic Fibrosis, 2015, 14, Suppl. 1, S1). VX - 809 and The combination (referred to as ) is an approved therapy for patients homozygous for F508del.

[0011] For the G551D and F508del patient populations, improved therapies are expected to provide further benefits to patients. Most G551D patients are G551D / F508del compound heterozygotes, and treatment with the corrector VX - 661 and The combination results in a further enhancement of lung function compared to treatment with alone (Pilewski, J.M. et al., J. Cystic Fibrosis, 2015, 14, Suppl. 1, S1).

[0012] CFTR mutations associated with moderate CFTR dysfunction are also evident in patients with conditions that share some disease manifestations with cystic fibrosis but do not meet the diagnostic criteria for cystic fibrosis. In these patients, CFTR dysfunction can occur in the epithelial cell layer and result in abnormal mucus and endocrine secretions, which are similar to those that characterize cystic fibrosis. CFTR dysfunction can also be acquired. Chronic inhalation of particulate irritants, including cigarette smoke, pollution, and dust, can lead to a decrease in CFTR ion channel activity.

[0013] Modulation of CFTR activity would also benefit other diseases not directly caused by CFTR mutations, such as CFTR - mediated secretory diseases and other protein - folding diseases. CFTR regulates chloride and bicarbonate fluxes in many cell epithelia to control fluid movement, protein solubility, mucus viscosity, and enzyme activity. Defects in CFTR can lead to airway or duct obstruction in many organs, including the liver and pancreas. Potentiators are compounds that enhance the gating activity of CFTR present in the cell membrane. Any disease involving mucus thickening, impaired fluid regulation, impaired mucus clearance, or duct obstruction leading to inflammation and tissue damage may be a candidate for potentiators. Thus, there is a significant therapeutic need for novel small molecules as CFTR potentiators.

[0014] In addition to cystic fibrosis, CFTR - related diseases or other diseases that may benefit from modulation of CFTR activity include, but are not limited to, asthma, bronchiectasis, chronic obstructive pulmonary disease (COPD), constipation, diabetes, dry eye, pancreatitis, sinusitis, and dry syndrome SUMMARY OF THE INVENTION

[0015] A first embodiment of the first aspect of the present invention is a compound of formula I

[0016]

[0017] or a pharmaceutically acceptable salt thereof, wherein

[0018] W is selected from phenyl, which is optionally fused to a five- to six-membered cycloalkyl or a five- to six-membered heterocycloalkyl, the heterocycloalkyl containing one, two, three or four heteroatoms independently selected each time from N, O and S(O) n ;

[0019] a five- to ten-membered heteroaryl containing one, two, three or four heteroatoms independently selected each time from N, O and S(O) n ;

[0020] a four- to seven-membered heterocycloalkyl containing one, two, three or four heteroatoms independently selected each time from N, O and S(O) n ; and

[0021] C3-C7 cycloalkyl;

[0022] wherein the phenyl, heteroaryl, heterocycloalkyl and cycloalkyl are each independently optionally substituted by one, two, three, four or five R 5 substituents;

[0023] Y is a five-membered heteroaryl containing one, two, three or four heteroatoms independently selected each time from N, O and S(O) n ; wherein the heteroaryl is optionally substituted by one, two or three substituents independently selected from halogen, C 1- C6 alkyl and C 1- C6 haloalkyl;

[0024] Z is selected from phenyl, C 1- C6 alkyl, C3-C7 cycloalkyl, a five- or six-membered heteroaryl containing one, two or three heteroatoms independently selected each time from N, O and S(O) n ; and a four- to seven-membered heterocycloalkyl containing one, two or three heteroatoms independently selected each time from N, O and S(O) n ; wherein the phenyl, alkyl, cycloalkyl, heteroaryl and heterocycloalkyl are each independently optionally substituted by one, two, three, four or five R 6 substituents;

[0025] R 1a and R 1bEach independently selected from -H, -OH, halogen, C 1- 6-alkyl, C3-C7 cycloalkyl and a four- to seven-membered heterocycloalkyl containing one, two or three heteroatoms each independently selected from N, O and S(O) n ; wherein said C 1- 6-alkyl is optionally substituted with one, two or three substituents each independently selected from halogen, -OH, C1-C3 alkoxy, C3-C7 cycloalkyl and a four- to seven-membered heterocycloalkyl containing one, two or three heteroatoms each independently selected from N, O and S(O) n ; and wherein each C3-C7 cycloalkyl and each four- to seven-membered heterocycloalkyl is optionally substituted, each time it appears, independently with one, two or three substituents selected from -OH, halogen and C 1- 6-alkyl; or

[0026] R 1a and R 1b , together with the carbon to which they are attached, form a C3-C7 cycloalkyl or a four- to seven-membered heterocycloalkyl containing one, two or three heteroatoms each independently selected from N, O and S(O) n ; and wherein each C3-C7 cycloalkyl and each four- to seven-membered heterocycloalkyl is optionally substituted with one, two or three substituents independently selected from -OH, halogen and C 1- 6-alkyl,

[0027] R 2 is selected from -H, halogen, -CN, C 1- 6-alkyl and C 1- 6-haloalkyl;

[0028] R 3 and R 4 , each time it appears, is independently selected from -H, C 1- 6-alkyl and C 1- 6-haloalkyl;

[0029] R 5 , each time it appears, is independently selected from halogen, -CN, C 1- 6-alkyl, C 1- 6-haloalkyl, -OR 7 , -N(R 7 )2, -N(R 7 )C(=O)R 7 , -SR 7 , oxo, C2-C7 alkoxyalkyl, -S(=O)2C 1- 6-alkyl, -C(=O)R 7 and a four- to seven-membered heterocycloalkyl containing each time it appears independently selected from N, O and S(O) nA five-membered heteroaryl having one, two, three or four heteroatoms, wherein said heteroaryl is optionally independently selected from halogen, -CN, C 1- C6 alkyl, C 1- C6 haloalkyl, -OR 7 , -N(R 7 )2 and -SR 7 substituted by one, two or three substituents;

[0030] R 6 is independently selected from halogen, C 1- C6 alkyl and C 1- C6 haloalkyl, -OR 7 , -N(R 7 )2 and -SR 7 ;

[0031] R 7 is independently selected from -H, C 1- C6 alkyl, C 1- C6 haloalkyl, C 3- C7 cycloalkyl and C 1- C6 alkyl C 3- C7 cycloalkyl; and

[0032] n is independently 0, 1 or 2 at each occurrence.

[0033] A second embodiment of the first aspect of the present invention is a compound of the first embodiment, wherein R 3 and R 4 are both -H; or a pharmaceutically acceptable salt thereof.

[0034] A third embodiment of the first aspect of the present invention is a compound of the second embodiment, wherein Y is selected from pyrazole, triazole, imidazole or isoxazole, each of which is optionally substituted by C 1- C6 alkyl; or a pharmaceutically acceptable salt thereof.

[0035] A fourth embodiment of the first aspect of the present invention is a compound of the second embodiment or a pharmaceutically acceptable salt thereof, wherein the moiety Y-Z is selected from:

[0036]

[0037] or a pharmaceutically acceptable salt thereof.

[0038] A fifth embodiment of the first aspect of the present invention is a compound of the third embodiment, wherein W is phenyl, which is optionally substituted by one, two or three R 5 ; or a pharmaceutically acceptable salt thereof.

[0039] The sixth embodiment of the first aspect of the present invention is the compound of the third embodiment, wherein W is selected from pyrimidinyl, pyridinyl, pyrazinyl and pyrazolyl, each of which is optionally substituted by one, two or three R 5 ; or a pharmaceutically acceptable salt thereof.

[0040] The seventh embodiment of the first aspect of the present invention is the compound of the third embodiment, wherein W is C 3- C7 cycloalkyl, which is optionally substituted by one, two or three R 5 ; or a pharmaceutically acceptable salt thereof.

[0041] The eighth embodiment of the first aspect of the present invention is the compound of the sixth embodiment, wherein W is which is optionally substituted by one, two or three R 5 ;

[0042] R 5 is independently selected from -OCH3, -CHF2, -CF3 and -N(CH3)2 each time it appears; or a pharmaceutically acceptable salt thereof.

[0043] The ninth embodiment of the first aspect of the present invention is the compound of the third embodiment, wherein Z is selected from phenyl, C 3- C7 cycloalkyl and C 1- C6 alkyl, each of which is optionally substituted by one, two or three R 6 ; or a pharmaceutically acceptable salt thereof.

[0044] The tenth embodiment of the first aspect of the present invention is the compound of the ninth embodiment, wherein Z is phenyl, which is optionally substituted by one or two fluorine or chlorine atoms; or a pharmaceutically acceptable salt thereof.

[0045] The eleventh embodiment of the first aspect of the present invention is the compound of the ninth embodiment or a pharmaceutically acceptable salt thereof, wherein Z is C 1- C6 alkyl or C 3- C7 cycloalkyl; or a pharmaceutically acceptable salt thereof.

[0046] The twelfth embodiment of the first aspect of the present invention is the compound of the second embodiment, wherein R 2 is selected from: -H, -CN and -Br; or a pharmaceutically acceptable salt thereof.

[0047] The thirteenth embodiment of the first aspect of the present invention is a compound selected from:

[0048] 4-Amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0049] 4-Amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{ (1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0050] 4-Amino-7-{ (1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0051] 4-Amino-7-{ (1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0052] 4-Amino-7-{ (1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0053] 4-Amino-7-{ (1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0054] 4-Amino-7-{ (1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0055] 4-Amino-7-{ (1R)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0056] 4-Amino-7-{ (1R)-1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-(2-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0057] 4-Amino-7-{ (1S)-1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-(2-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0058] 4-Amino-7-{ (1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0059] 4-Amino-7-{ (1S)-1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0060] 4-Amino-7-{ (1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0061] 4-Amino-7-{ (1R)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0062] 4-Amino-7-{ (1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0063] 4-Amino-7-{ [1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0064] 4-Amino-7-{ [1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0065] 4-Amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{ [1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0066] 4-Amino-7-{ [1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0067] 6-Bromo-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0068] 5-[4-(Cyclopropoxy)phenyl]-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0069] 5-Cyclobutyl-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0070] 5-(4-Chlorophenyl)-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0071] 5-[6-(Cyclopropoxy)pyridin-3-yl]-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0072] 5-(6-Methoxypyridin-3-yl)-7-[(1S)-1-(1-phenyl-1H-1,2,3-triazol-4-yl)propyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0073] 7-[(1S)-1-(1-Phenyl-1H-1,2,3-triazol-4-yl)propyl]-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0074] 5-(4-Chlorophenyl)-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0075] 7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(3-methoxypyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0076] 7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0077] 5-(5-Fluoro-2-methoxypyridin-3-yl)-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0078] 5-[6-(Difluoromethoxy)pyridin-3-yl]-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0079] 7-{(1S)-1-[1-(3,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0080] 7-{(1S)-1-[1-(3,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0081] 7-{(1S)-1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0082] 7-{(1S)-1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0083] 7-{(1S)-1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-6-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0084] 7-{(1S)-1-[1-(2,3-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0085] 7-{(1S)-1-[1-(2,5-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0086] 7-{(1S)-1-[1-(2-Fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0087] 7-{(1S)-1-[2-(2,4-Difluorophenyl)-1H-imidazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0088] 7-{(1S)-1-[1-(2,5-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0089] 7-{(1S)-1-[1-(2,3-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0090] 7-{(1S)-1-[1-(2,4-Difluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0091] 7-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(2-methoxy-6-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0092] 7-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-[2-methoxy-6-(trifluoromethyl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0093] 4-Amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0094] 4-Amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0095] 4-Amino-7-{ (1S)-1-[1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0096] 4-Amino-7-{ (1R)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0097] 4-Amino-7-{ (1R)-1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0098] 4-Amino-7-{ (1R)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0099] 4-Amino-5-[2-(difluoromethoxy)pyrimidin-5-yl]-7-{ (1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0100] 4-Amino-5-(4-chlorophenyl)-7-{ [1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0101] 4-Amino-5-(4-chlorophenyl)-7-{ [1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0102] 5-(2-Fluoro-4-methoxyphenyl)-7-{ 1-[2-(2-fluorophenyl)-1H-imidazol-5-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0103] 5-(3-Fluoro-4-methylphenyl)-7-{ 1-[2-(2-fluorophenyl)-1H-imidazol-5-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0104] 7-{1-[2-(2-Fluorophenyl)-1H-imidazol-5-yl]ethyl}-5-[4-(2H-1,2,3-triazol-2-yl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0105] 5-(4-Ethoxy-3-fluorophenyl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0106] 5-(4-Chloro-2-methoxyphenyl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0107] 5-[4-(Difluoromethoxy)phenyl]-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0108] 7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[4-(methylthio)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0109] 5-[4-(Difluoromethoxy)phenyl]-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0110] 5-[2-Fluoro-4-(methylthio)phenyl]-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0111] 5-(4-Chloro-3-fluorophenyl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0112] 5-(3-Chloro-5-fluorophenyl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0113] 5-Cyclopropyl-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0114] 4-(4-Amino-7-{((1S)-1-(1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)ethyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorobenzonitrile;

[0115] 5-[4-(Cyclopropoxy)phenyl]-7-{((1S)-1-(1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0116] 5-(4-Methoxypyrimidin-5-yl)-7-[(1S)-1-(1-phenyl-1H-1,2,3-triazol-4-yl)propyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0117] 7-{((1S)-1-(1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)propyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0118] 5-[2-(Difluoromethyl)pyrimidin-5-yl]-7-{((1S)-1-(1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0119] 5-[2-(Dimethylamino)pyrimidin-5-yl]-7-{((1S)-1-(1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0120] 7-{((1R)-1-(1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)propyl}-5-(1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0121] 7-{((1S)-1-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)propyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0122] 7-{((1S)-1-(1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl)propyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0123] 7-{(1R)-1-[1-(3,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-6-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0124] 7-{(1S)-1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0125] 7-{(1R)-1-[1-(2,3-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0126] 5-Cyclopropyl-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0127] 7-{(S)-Cyclopropyl[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0128] 7-{(1S)-1-[1-(2-Fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0129] 5-(4-Chlorophenyl)-7-{(1S)-1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0130] 7-{(1S)-1-[3-(2-Fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-(2-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0131] 5-(5-Fluoro-2-methoxypyridin-3-yl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0132] 5-[2-(Difluoromethoxy)pyridin-3-yl]-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0133] 7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0134] 7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[4-methoxy-2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0135] 7-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-[4-methoxy-2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0136] 5-(4-Chlorophenyl)-7-{2-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propan-2-yl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0137] 5-(4-Chlorophenyl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0138] 5-(4-Chlorophenyl)-7-{[2-(2-fluorophenyl)-1H-imidazol-5-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0139] 5-(4-Chlorophenyl)-7-[(2-phenyl-1H-imidazol-5-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0140] 5-(4-Chlorophenyl)-7-[(3-cyclohexyl-1,2-oxazol-5-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0141] 7-({1-[4-(difluoromethyl)phenyl]-1H-pyrazol-4-yl}methyl)-5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0142] 7-{(1S)-1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0143] 4-Amino-5-[6-(cyclopropoxy)pyridin-3-yl]-7-{ (1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; and

[0144] 4-Amino-7-{ (1S)-1-[1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0145] or a pharmaceutically acceptable salt thereof.

[0146] A fourteenth embodiment of the first aspect of the present invention is a compound selected from:

[0147] 7-{ (1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0148] 4-Amino-7-{ [1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0149] 4-Amino-7-{ (1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0150] 4-Amino-7-{ (1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0151] 4-Amino-7-{ (1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0152] 4-Amino-7-{ (1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0153] 4-Amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0154] 4-Amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0155] 4-Amino-7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; and

[0156] 4-Amino-7-{[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile;

[0157] or a pharmaceutically acceptable salt thereof.

[0158] The fifteenth embodiment of the first aspect of the present invention is the compound 7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine or a pharmaceutically acceptable salt thereof.

[0159] The sixteenth embodiment of the first aspect of the present invention is the compound 4-amino-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically acceptable salt thereof.

[0160] The seventeenth embodiment of the first aspect of the present invention is the compound 4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically acceptable salt thereof.

[0161] The eighteenth embodiment of the first aspect of the present invention is the compound 4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically acceptable salt thereof.

[0162] The nineteenth embodiment of the first aspect of the present invention is the compound 4-amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically acceptable salt thereof.

[0163] The first embodiment of the second aspect of the present invention is a method for treating a patient in need of treatment for cystic fibrosis, asthma, bronchiectasis, chronic obstructive pulmonary disease (COPD), constipation, diabetes, dry eye disease, pancreatitis, sinusitis, or Sjögren's syndrome ( Syndrome), the method comprising administering to the patient in need of treatment a therapeutically effective amount of a compound according to any one of the first to nineteenth embodiments of the first aspect or a pharmaceutically acceptable salt of the compound.

[0164] The second embodiment of the second aspect of the present invention is a method for treating a patient in need of treatment for cystic fibrosis, the method comprising administering to the patient in need of treatment a therapeutically effective amount of a compound according to any one of the first to nineteenth embodiments of the first aspect or a pharmaceutically acceptable salt of the compound.

[0165] The first embodiment of the third aspect of the present invention is a compound according to any one of the first to nineteenth embodiments of the first aspect or a pharmaceutically acceptable salt thereof, for use in the treatment of cystic fibrosis.

[0166] The first embodiment of the fourth aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of the first to nineteenth embodiments of the first aspect or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0167] The second embodiment of the fourth aspect of the present invention is the pharmaceutical composition of the first embodiment of the fourth aspect, which further comprises one or more additional therapeutic agents.

[0168] The third embodiment of the fourth aspect of the present invention is the pharmaceutical composition of the second embodiment of the fourth aspect, wherein the one or more additional therapeutic agents are selected from CFTR potentiators, CFTR corrector agents, epithelial sodium channel (ENaC) inhibitors, CFTR amplifiers, CFTR stabilizers, read-through agents, oligonucleotide patches, autophagy inducers, and protein stability modulators.

[0169] The fourth embodiment of the fourth aspect of the present invention is the pharmaceutical composition of the third embodiment of the fourth aspect, wherein the CFTR potentiator is selected, each time it appears, from VX-770 (Ivacaftor), GLPG-1837, GLPG-2451, QBW-251, FDL-176, FDL-129, CTP-656, and PTI-P271.

[0170] The fifth embodiment of the fourth aspect of the present invention is the pharmaceutical composition of the third embodiment of the fourth aspect, wherein the CFTR corrector is selected, each time it appears, from VX-809 (lumacaftor), VX-661 (tezacaftor), VX-983, VX-152, VX-440, VX-659, GLPG2737, P247-A, GLPG-2222, GLPG-2665, GLPG-2851, FDL-169, and PTI-C1811.

[0171] The sixth embodiment of the fourth aspect of the present invention is the pharmaceutical composition of the third embodiment of the fourth aspect, wherein the epithelial sodium channel (ENaC) inhibitor is selected, each time it appears, from SPX-101, QBW-276, and VX-371.

[0172] The seventh embodiment of the fourth aspect of the present invention is the pharmaceutical composition of the third embodiment of the fourth aspect, wherein the CFTR amplifier is selected, each time it appears, from PTI-428 and PTI-130.

[0173] The eighth embodiment of the fourth aspect of the present invention is the pharmaceutical composition of the third embodiment of the fourth aspect, wherein the CFTR stabilizer is N-91115 (Cavosonstat).

[0174] The ninth embodiment of the fourth aspect of the present invention is the pharmaceutical composition of the third embodiment of the fourth aspect, wherein the read-through agent is ataluren (PTC124).

[0175] The tenth embodiment of the fourth aspect of the present invention is the pharmaceutical composition of the third embodiment of the fourth aspect, wherein the autophagy inducer is selected, each time it appears, from the combination of cysteamine and epigallocatechin gallate (EGCG) and CX-4945.

[0176] The first embodiment of the fifth aspect of the present invention is a method for treating a patient in need of treatment for cystic fibrosis, the method comprising administering to the patient in need of treatment a pharmaceutical composition according to any one of the first to tenth embodiments of the fourth aspect.

[0177] A first embodiment of the sixth aspect of the present invention is a pharmaceutical composition according to any one of the first to tenth embodiments of the fourth aspect, which is used for treating cystic fibrosis. Detailed description

[0178] Definitions

[0179] The term "alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon-based substituent (i.e., a substituent obtained by removing a hydrogen atom from a hydrocarbon); in one embodiment, it has one to six carbon atoms (i.e., C 1- C6 alkyl). Examples of these substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, and tert-butyl), pentyl, isopentyl, hexyl, and the like.

[0180] The term "haloalkyl" refers to such an alkyl in which at least one hydrogen on the alkyl is replaced by a halogen atom. The term "C 1- C6 haloalkyl" refers to a C 1- C6 alkyl as defined herein, in which one, two, three, four, five, or six hydrogen atoms are replaced by a halogen. In certain embodiments in which two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms are all the same as each other. In other embodiments in which two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms are not all the same as each other. Examples of haloalkyl include: chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2-chloro-3-fluoropentyl, and the like.

[0181] The term "alkoxy" refers to a straight-chain or branched-chain saturated hydrocarbon-based substituent further attached to an oxygen atom (i.e., a substituent obtained from a hydrocarbon by removing a hydrogen); in one embodiment, it has one to six carbon atoms (i.e., C 1- C6 alkoxy). Examples of such substituents include methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy), pentyloxy, and the like.

[0182] The term "cycloalkyl" refers to a carbocyclic substituent obtained by removing a hydrogen atom from a saturated carbocyclic molecule and having a specified number of carbon atoms. In one embodiment, the cycloalkyl substituent has three to seven carbon atoms (i.e., C 3- C7 cycloalkyl). Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "cycloalkyl" includes monocyclic, bicyclic, and tricyclic saturated carbocycles, as well as bridged and fused ring carbocycles, and spiro-fused ring systems.

[0183] As used herein, the term "heteroalkyl" refers to containing the specified heteroatoms N, O, or S(O) nA monocyclic ring system. The term "heterocyclyl" refers to a substituent obtained by removing hydrogen from a saturated or partially saturated ring structure containing a specified number of ring atoms, where at least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), and the remaining ring atoms are independently selected from carbon, oxygen, nitrogen, and sulfur. If the heterocyclyl substituent is further substituted by a group or substituent, the group or substituent can be bonded to a nitrogen heteroatom, or it can be appropriately bonded to a ring carbon atom. In some cases, the number of atoms in a cyclic substituent containing one or more heteroatoms (i.e., heteroaryl or heterocyclyl) is indicated by the prefix "x to y membered", where x is the minimum number of atoms forming the cyclic portion of the substituent and y is the maximum number. Thus, for example, "four to seven membered heterocyclyl" refers to a heterocyclyl containing 4 - 7 atoms (including one or more heteroatoms) in the cyclic portion of the heterocyclyl. Examples of monocyclic heterocyclyls include azetidinyl, oxetanyl, thietanyl, dihydrofuranyl, tetrahydrofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, dihydropyranyl, piperidinyl, morpholinyl, piperazinyl, azepinyl, oxepinyl, and diazepinyl.

[0184] The term "heteroaryl" refers to an aromatic ring structure containing a specified number of ring atoms, where at least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), and the remaining ring atoms are independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. Five - to six - membered heteroaryl is an aromatic ring system having five or six ring atoms, where at least one of the ring atoms is N, O, or S(O) n . Similarly, five - to ten - membered heteroaryl is an aromatic ring system having five to ten ring atoms, where at least one of the ring atoms is N, O, or S(O) n . Heteroaryl can be monocyclic or bicyclic fused.

[0185] Examples of heteroaryl substituents include six-membered ring substituents such as pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; five-membered ring substituents such as triazolyl, imidazolyl, furyl, phenylthio, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4-oxadiazolyl, and isothiazolyl; 6 / 5-fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6 / 6-fused rings such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1,4-benzoxazinyl. In a group having a heteroaryl substituent, the ring atom of the heteroaryl substituent bonded to the group can be at least one heteroatom, or it can be a ring carbon atom, where the ring carbon atom can be in the same ring with at least one heteroatom or where the ring carbon atom can be in a different ring with at least one heteroatom. Similarly, if the heteroaryl substituent is further substituted by a group or a substituent, the group or the substituent can be bonded to at least one heteroatom, or it can be bonded to a ring carbon atom, where the ring carbon atom can be in the same ring with at least one heteroatom, or where the ring carbon atom can be in a different ring with at least one heteroatom. The term "heteroaryl" also includes pyridyl N-oxide and groups containing a pyridine N-oxide ring. Examples of 2-fused ring heteroaryls include indolizinyl, pyranyl pyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridyl (including pyrido[3,4-b]-pyridyl, pyrido[3,2-b]-pyridyl, or pyrido[4,3-b]-pyridyl), pyrrolopyridyl, pyrazolopyridyl, imidazothiazolyl, and piperidinyl.

[0186] Other examples of fused ring heteroaryls include benzo-fused heteroaryls such as indolyl, isoindolyl, pseudindolyl, isoindazolyl, naphthyridinyl (including quinolinyl or isoquinolinyl), phthalazinyl, quinoxalinyl, benzodiazinyl (including cinnolinyl or quinazolinyl), benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl. When the above groups are derived from the groups listed above, they can be C-linked or N-linked where possible. For example, a group derived from pyrrole can be pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). In addition, a group derived from imidazole can be imidazol-1-yl (N-linked) or imidazol-2-yl (C-linked).

[0187] The term "halo" or "halogen" refers to fluorine (which may be depicted as -F), chlorine (which may be depicted as -Cl), bromine (which may be depicted as -Br), or iodine (which may be depicted as -I).

[0188] The term "hydrogen" refers to a hydrogen substituent and may be depicted as -H.

[0189] The term "hydroxy" or "hydroxyl" refers to -OH. Compounds having carbon atoms attached to one or more hydroxy substituents include, for example, alcohols, enols, and phenols.

[0190] The term "phenyl" refers to an aromatic ring having the group -C6H5, which is derived from benzene by removal of a hydrogen atom. The phenyl may optionally be fused to a five- or six-membered cycloalkyl or heterocycloalkyl ring to form a bicyclic compound. Examples of such bicyclic compounds include 1,2,3,4-tetrahydronaphthalene, 2,3-dihydrobenzo[1,4]oxazine, 2,3-dihydro-1H-indene, isoindoline, and 2,3-dihydrobenzo[1,4]dioxin.

[0191] If a substituent is described as "independently selected from" a group, each instance of the substituent is selected independently of the others. Thus, each substituent may be the same as or different from the other substituents.

[0192] As used herein, the terms "formula I", "formula (I)", "Formula (I)", or "Formula I" may refer to "the compounds of the present invention". These terms are also defined to include all forms of the formula I compounds, including hydrates, solvates, isomers, crystalline and non-crystalline forms, polymorphs, and metabolites. For example, the compounds of the present invention or their pharmaceutically acceptable salts may exist in non-solvated and solvated forms. When the solvent or water is tightly bound, the complex will have a defined stoichiometry, independent of humidity. However, when the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water / solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

[0193] The compounds of the present invention may exist as inclusion compounds or other complexes. Included within the scope of the present invention are complexes such as inclusion compounds, drug-host inclusion complexes, wherein the drug and the host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the compounds of the present invention containing two or more organic and / or inorganic components, which may be present in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized or non-ionized. For a review of such complexes, see J. Pharm. Sci., 64(8), 1269-1288, Haleblian, J.K. (August 1975).

[0194] The compounds of the present invention may have asymmetric carbon atoms. The carbon-carbon bonds of the compounds of the present invention may be described using solid lines (-), solid wedges or dashed wedges. Describing a bond connecting an asymmetric carbon atom using a solid line means indicating the inclusion of all possible stereoisomers at that carbon atom (e.g., a specific enantiomer, a racemic mixture, etc.). Describing a bond connecting an asymmetric carbon atom using a solid wedge or a dashed wedge means indicating the inclusion of only the stereoisomer shown. It is possible that the compounds of formula I may contain more than one asymmetric carbon atom. In these compounds, describing a bond connecting an asymmetric carbon atom using a solid line means indicating the inclusion of all possible stereoisomers. For example, unless otherwise stated, a compound of formula I may be meant to exist as enantiomers and diastereomers or as a racemate and mixtures thereof. Describing a bond connecting one or more asymmetric carbon atoms in a compound of formula I using a solid line and a solid or dashed wedge to describe a bond connecting other asymmetric carbon atoms in the same compound means indicating the presence of a mixture of diastereomers.

[0195] The stereoisomers of formula I include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, geometric isomers, rotational isomers, conformational isomers and tautomers of the compounds of the present invention, which include compounds exhibiting more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs). Also included are acid addition salts or base addition salts wherein the counterion is optically active, such as D-lactate or L-lysine, or racemic, such as DL-tartrate or DL-arginine.

[0196] When any racemate crystallizes, two different types of crystals are possible. The first type is the racemic compound (true racemate) mentioned above, in which a homogeneous form of crystal is produced containing equimolar amounts of the two enantiomers. The second type is a racemic mixture or conglomerate, in which two forms of crystals are produced in equimolar amounts, each crystal containing a single enantiomer.

[0197] The present invention includes tautomeric forms of the compounds of the present invention. Tautomerism ("tautomerization") occurs when structural isomers are interconvertible via a low energy barrier. This can take the form of proton tautomerism in compounds of the present invention containing, for example, an imino, keto or oxime group, or the so-called valence tautomerism in compounds containing an aromatic moiety. Thus, a single compound may exhibit more than one type of isomerism. The various ratios of tautomers in the solid and liquid forms depend on the various substituents on the molecule and the particular crystallization technique used to isolate the compound.

[0198] Examples of the types of potential tautomerism exhibited by the compounds of the present invention include

[0199]

[0200] The compounds of the present invention may be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, the salts of the compound may be advantageous due to one or more physical properties of the salt (such as enhanced pharmaceutical stability at different temperatures and humidities, or desired solubility in water or oil). In some cases, the salts of the compound may also be used as adjuvants for the separation, purification and / or resolution of the compound. When it is intended to administer the salt to a patient (as opposed to use, for example, in an in vitro environment), the salt is preferably pharmaceutically acceptable. The term "pharmaceutically acceptable salt" refers to salts prepared by combining a compound of formula I with an acid or a base, the anion of the acid or the cation of the base generally being considered suitable for human consumption. Pharmaceutically acceptable salts are particularly useful as products of the methods of the present invention because they have higher water solubility relative to the parent compound. For use in medicine, the salts of the compounds of the present invention are non-toxic "pharmaceutically acceptable salts". The salts included in the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of the present invention, which are generally prepared by reacting the free base with a suitable organic or inorganic acid.

[0201] Where possible, suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, boric acid, fluoroboric acid, phosphoric acid, metaphosphoric acid, nitric acid, carbonic acid, sulfonic acid and sulfuric acid, and organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isothionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, trifluoromethanesulfonic acid, succinic acid, toluenesulfonic acid, tartaric acid and trifluoroacetic acid. Suitable organic acids generally include, for example, aliphatic acids, alicyclic acids, aromatic acids, aralkyl acids, heterocyclic acids, carboxylic acids and sulfonic acid organic acids. Specific examples of suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartrate, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), mesylate, esylate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sulfamate, cyclohexylaminosulfonate, p-hydroxybutyrate, galactonate, galacturonate, adipate, alginate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecyl sulfate, ethanolheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectinate, 3-phenylpropionate, picrate, pivalate, thiocyanate and undecanoate.

[0202] In addition, when the compounds of the present invention bear an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, namely sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; and salts formed with suitable organic ligands such as quaternary ammonium salts. In another embodiment, the base salts are formed from bases that form non-toxic salts, which include aluminum, arginine, benzathine, choline, diethylamine, diamine, glycine, lysine, meglumine, alkanolamine, tromethamine and zinc salts.

[0203] Organic salts can be made from secondary, tertiary or quaternary amine salts, such as tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Basic nitrogen-containing groups can be quaternized with reagents such as lower alkyl (C 1-C6) Halides (such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (i.e., dimethyl, diethyl, dibutyl, and dialkyl sulfates), long-chain halides (such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (such as benzyl and phenethyl bromides), etc.

[0204] In one embodiment, half salts of acids and bases can also be formed, such as half sulfates and half calcium salts.

[0205] Also within the scope of the present invention are the so-called "prodrugs" of the compounds of the present invention. Thus, certain derivatives of the compounds of the present invention (which may themselves have little or no pharmacological activity) can be converted, for example, by hydrolytic cleavage into the compounds of the present invention having the desired activity when administered into or onto the body. These derivatives are referred to as "prodrugs". Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems”, Vol.14, ACS Symposium Series (T. Higuchi and V. Stella, Eds.), American Chemical Society, 1975 Washington, D.C. and "Bioreversible Carriers in Drug Design", Pergamon Press, 1987 (E.B. Roche, Ed.) American Pharmaceutical Association. Prodrugs according to the present invention can be prepared, for example, by substituting appropriate functional groups present in any compound of formula I with certain moieties known to those skilled in the art as, for example, the "pro-moieties" described in Bundgaard, H. 1985. Design of Prodrugs. New York: Elsevier.

[0206] The present invention also includes isotopically labeled compounds which are identical to those described in formula I except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 0, 17 0, 32 P,35 S, 18 F, and 36 Cl. Compounds of the invention containing the above isotopes and / or other isotopes of other atoms, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or said prodrugs are within the scope of the invention. Certain isotopically labeled compounds of the invention, for example those incorporating radioactive isotopes such as 3 H and 14 C, can be used for drug and / or substrate tissue distribution assays. Tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred because of their ease of preparation and detectability. In addition, substitution with heavier isotopes such as deuterium (i.e., 2 H) can provide certain therapeutic advantages, such as higher metabolic stability, e.g., an increased in vivo half-life or a reduced dosage requirement, and may thus be preferred in certain instances. Isotopically labeled compounds of formula I of the invention and their prodrugs can generally be prepared by substituting a non-isotopically labeled reagent with an isotopically labeled reagent that is readily available, by carrying out the following protocols and / or the methods disclosed in the Examples and Preparations.

[0207] DETAILED DESCRIPTION OF THE INVENTION

[0208] Generally, the compounds of the invention are administered in an amount effective to treat the disorders described herein. The compounds of the invention are administered by any suitable route, in the form of a pharmaceutical composition suitable for such route, and in a therapeutically effective dose for the intended treatment. A therapeutically effective dose of the compounds required to treat the progression of a medical disorder can be readily determined by those of ordinary skill in the art using preclinical and clinical methods familiar to the medical field.

[0209] Unless otherwise specified, the term "treating" as used herein refers to reversing, alleviating, inhibiting the progression of, or preventing the disease or disorder to which the term applies, or one or more symptoms of such disorder or condition. Unless otherwise specified, when "treating" is defined as above, the term "treatment" refers to the act of treating. The term "treating" also includes adjuvant and neoadjuvant treatment of a subject. The compounds of the invention can be administered orally. Oral administration can include swallowing such that the compound enters the gastrointestinal tract, or can be by buccal or sublingual administration, whereby the compound enters the bloodstream directly from the mouth.

[0210] In another embodiment, the compounds of the invention can also be administered directly into the bloodstream, muscle, or visceral organs. Suitable modes for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle (including micro-needle) syringes, needleless syringes, and infusion techniques. In another embodiment, the compounds of the invention can also be administered topically to the skin or mucosa, i.e., dermally or transdermally. In another embodiment, the compounds of the invention can also be administered intranasally or by inhalation. In another embodiment, the compounds of the invention can be administered rectally or vaginally. In another embodiment, the compounds of the invention can also be administered directly to the eye or ear.

[0211] The dosage regimen of the compounds and / or the compositions containing the compounds is based on a variety of factors, including the type, age, weight, sex, and medical condition of the patient; the severity of the disease; the route of administration; and the activity of the particular compound used. Thus, the dosage regimen can vary widely. Dosage levels on the order of about 0.01 mg to about 100 mg per kilogram of body weight per day can be used to treat the above-mentioned conditions. In one embodiment, the total daily dose of the compounds of the invention (administered as a single dose or in divided doses) is generally about 0.01 mg / kg to about 100 mg / kg. In another embodiment, the total daily dose of the compounds of the invention is about 0.1 mg / kg to about 50 mg / kg, and in another embodiment, about 0.5 mg / kg to about 30 mg / kg (i.e., mg of the compounds of the invention / kg body weight). In one embodiment, the dose is 0.01 mg / kg / day to 10 mg / kg / day. In another embodiment, the dose is 0.1 mg / kg / day to 1.0 mg / kg / day. Dosage unit compositions can contain this amount or multiples thereof to constitute the daily dose. In many cases, administration of the compound will be repeated several times within a day (usually not more than 4 times). If necessary, multiple daily doses can generally be used to increase the total daily dose.

[0212] For oral administration, the composition can be provided in the form of tablets containing about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, in the form of tablets containing about 1 mg to about 100 mg of the active ingredient. Intravenous, during a constant rate infusion, the dose can be about 0.1 mg / kg / minute to about 10 mg / kg / minute.

[0213] Suitable subjects according to the invention include mammalian subjects. Mammals according to the invention include, but are not limited to, dogs, cats, cows, goats, horses, sheep, pigs, rodents, lagomorphs, primates, etc., and include mammals in utero. In one embodiment, humans are suitable subjects. Human subjects can be of either sex and can be at any stage of development.

[0214] In another embodiment, the present invention includes the use of one or more compounds of the present invention in the preparation of a medicament for treating the disorders described herein.

[0215] For treating the above disorders, the compounds of the present invention can be administered as the compounds themselves. Alternatively, pharmaceutically acceptable salts are suitable for medical use because they have higher water solubility relative to the parent compounds.

[0216] In another embodiment, the present invention encompasses pharmaceutical compositions. Such pharmaceutical compositions comprise a compound of the present invention presented with a pharmaceutically acceptable carrier. The carrier can be solid, liquid, or both, and can be formulated with the compound into unit dose compositions, such as tablets, which can contain from 0.05% to 95% by weight of the active compound. The compounds of the present invention can be conjugated with suitable polymers as targeted drug carriers. Other pharmacologically active substances may also be present.

[0217] The compounds of the present invention can be administered by any suitable route, preferably in the form of a pharmaceutical composition suitable for such route, and in a dose effective for the intended treatment. For example, the active compounds and compositions can be administered orally, rectally, parenterally, or topically.

[0218] Oral administration of solid dosage forms can, for example, exist as separate units, such as hard or soft gelatin capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention.

[0219] In another embodiment, oral administration can be in the form of a powder or granules. In another embodiment, oral administration can be in the form of a spray-dried dispersion. In another embodiment, the oral dosage form is a sublingual dosage form, such as a lozenge. In such solid dosage forms, the compounds of formula I are generally combined with one or more adjuvants. Such capsules or tablets can contain controlled-release formulations. In the case of capsules, tablets, and pills, the dosage form can also contain buffering agents or can be prepared with an enteric coating.

[0220] In another embodiment, oral administration can be in liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs, which contain inert diluents commonly used in the art (such as water). Such compositions can also contain adjuvants, such as wetting agents, emulsifying agents, suspending agents, flavoring agents (such as sweetening agents), and / or fragrances.

[0221] In another embodiment, the present invention includes parenteral dosage forms. "Parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intracardiac injection, and infusion. Injectable preparations (such as sterile injectable aqueous or oily suspensions) can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents.

[0222] In another embodiment, the present invention includes topical dosage forms. "Topical administration" includes, for example, transdermal administration, such as by transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. Topical formulations may include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of the present invention are administered by transdermal devices, patches of the reservoir and porous membrane type or patches of the solid matrix variety are used for administration.

[0223] Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, sheets, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical carriers include alcohols, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be added; see, for example, J. Pharm. Sci., 88(10), 955-958, by Finnin and Morgan (October 1999).

[0224] Formulations suitable for topical administration to the eye include, for example, eye drops, in which the compounds of the present invention are dissolved or suspended in a suitable carrier. Typical formulations suitable for ocular or otic administration may be in the form of droplets of a micronized suspension or an isotonic, pH-adjusted sterile saline solution. Other formulations suitable for ocular and otic administration include ointments, biodegradable (e.g., absorbable gelfoam, collagen) and non-biodegradable (e.g., silicone) implants, sheets, lenses, and particulate or vesicular systems, such as niosomes or liposomes. Polymers, such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers, such as (hydroxypropyl)methylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers, such as, for example, gelan gum, may be combined with preservatives (such as benzalkonium chloride). Such formulations may also be delivered by iontophoresis.

[0225] For nasal administration or administration by inhalation, the active compounds of the present invention can be conveniently delivered in the form of a solution or suspension from a pump spray container squeezed or pumped by the patient or as an aerosol spray from a pressurized container or nebulizer using a suitable propellant. Formulations suitable for nasal administration are usually administered from a dry powder inhaler in the form of a dry powder (alone, as a mixture, e.g., a dry mixture with lactose, or mixed component particles, e.g., mixed with phospholipids, such as phosphatidylcholine), or as an aerosol spray, with or without a suitable propellant (e.g., 1,1,1,2 - tetrafluoroethane or 1,1,1,2,3,3,3 - heptafluoropropane), from a pressurized container, pump, nebulizer, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist) or spray device. For nasal use, the powder may contain a bioadhesive, such as chitosan or cyclodextrin.

[0226] In another embodiment, the present invention includes rectal dosage forms. Such rectal dosage forms can be, for example, in the form of suppositories. Cocoa butter is a traditional suppository base, but various alternatives can be used as appropriate.

[0227] Other carrier materials and modes of administration known in the pharmaceutical art can also be used. The pharmaceutical compositions of the present invention can be prepared by any well - known pharmaceutical techniques, such as effective formulation and administration methods. The above considerations regarding effective formulations and administration procedures are well - known in the art and are described in standard textbooks. The formulation of drugs is described, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Lieberman et al., Eds., Pharmaceutical Dosage Forms, Marcel Dekker, New York, N.Y., 1980; and Kibbe et al., Eds., Handbook of Pharmaceutical Excipients (3rd ed.), American Pharmaceutical Association, Washington, 2000.

[0228] The compounds of the present invention can be used alone or in combination with other therapeutic agents in the treatment of various disorders or disease states. The compounds of the present invention and other therapeutic agents can be administered simultaneously (in the same dosage form or different dosage forms) or sequentially.

[0229] Two or more compounds can be administered simultaneously, together, or sequentially. Additionally, simultaneous administration can be achieved by mixing the compounds prior to dosing or by administering the compounds at the same time point but at different anatomical sites or using different routes of administration.

[0230] The phrases "administered together", "co-administered", "administered simultaneously", and "simultaneously administered" refer to the combined administration of the compounds.

[0231] The present invention includes the use of a combination of a CFTR potentiator compound provided by Formula I and one or more additional pharmaceutically active agents. If a combination of active agents is administered, they can be administered sequentially or simultaneously in separate dosage forms or in combination in a single dosage form. Accordingly, the present invention also includes a pharmaceutical composition comprising an amount of: (a) a first agent comprising a compound of Formula I or a pharmaceutically acceptable salt of the compound; (b) a second pharmaceutically active agent; (c) an optional third pharmaceutically active agent; and (d) a pharmaceutically acceptable carrier, vehicle, or diluent.

[0232] Depending on the disease, disorder, or condition to be treated, various pharmaceutically active agents can be selected for use in combination with the compound of Formula I. For example, a pharmaceutical composition for the treatment of cystic fibrosis can comprise a compound of Formula I or a pharmaceutically acceptable salt thereof, and one or more agents, such as a CFTR modulator, such as another CFTR potentiator, a CFTR corrector, including a CAL (CFTR-associated ligand) inhibitor, a CFTR production corrector or read-through agent, a CFTR stabilizer, including a CFTR-Dab2 (disabled homolog 2) inhibitor, or a CFTR amplifier; an epithelial sodium channel (ENaC) inhibitor / blocker; an oligonucleotide patch; an autophagy inducer; a protein stability modulator, including a histone deacetylase (HDAC) inhibitor; or a supportive therapy, such as a mucolytic, a bronchodilator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, an anticholinergic, a mast cell stabilizer, a corticosteroid, a nutritional agent, or an enzyme replacement.

[0233] The combination can include multiple agents from a particular class of agents; for example, a combination of a compound of Formula I and two or more CFTR correctors. Pharmaceutically active agents that can be used in combination with the compound of Formula I and its compositions include, but are not limited to:

[0234] (i) CFTR potentiators, such as VX-770 (ivacaftor), GLPG-1837, GLPG-2451, QBW-251, GLPG-3067, FDL-129, CTP-656, FDL-176, PTI-P271, and CTP-656;

[0235] (ii) CFTR correctors, such as VX-809 (lumacaftor), VX-661 (tezacaftor), VX-983, VX-152, VX-440, VX-659, GLPG-2737, P247-A, FDL-169, FDL-304, GLPG-2222, GLPG-2665, GLPG-2851, PTI-C1811, NU-001, and NU-002;

[0236] (iii) CFTR potentiators, such as PTI-428 and PTI-130;

[0237] (iv) Read-through agents, such as ataluren;

[0238] (v) CFTR stabilizers, such as N91115 (cavosonstat, an S-nitrosoglutathione reductase "GSNOR" inhibitor);

[0239] (vi) Epithelial sodium channel (ENaC) inhibitors, such as SPX-101, QBW-276, and VX-371;

[0240] (vii) Oligonucleotide patches, such as QR-010;

[0241] (viii) Autophagy inducers, such as the combination of CX-4945, cysteamine, and epigallocatechin gallate (EGCG), and cystamine and rapamycin;

[0242] (ix) Protein homeostasis regulators, such as histone deacetylase (HDAC) inhibitors, including 4-phenylbutyrate (4-PBA);

[0243] (x) Supportive therapies, such as albuterol, salmeterol, ciprofloxacin, fluticasone, prednisone, ipratropium bromide, lipase, protease, and amylase.

[0244] The present invention also includes a kit suitable for implementing the above-described treatment methods. In one embodiment, the kit comprises a first dosage form, the first dosage form comprising one or more compounds of the present invention, optionally in combination with one or more additional therapeutic agents; and a container for said dosage, in an amount sufficient to implement the method of the present invention. In another embodiment, the kit of the present invention comprises one or more compounds of the present invention, optionally containing one or more additional therapeutic agents.

[0245] General synthesis scheme

[0246] The compounds of the present invention can be prepared by any method known in the art for preparing compounds of similar structures. In particular, the compounds of the present invention can be prepared by the procedures described in the following schemes, or by the specific methods described in the examples, or by processes similar to either of them.

[0247] Those skilled in the art will understand that the experimental conditions described in the following schemes illustrate suitable conditions for achieving the indicated transformations, and that the exact conditions used to prepare the compounds of formula (I) may need to be or may desirably be changed. It should also be understood that the transformations may need to be or may desirably be carried out in an order different from that described in the schemes, or that one or more of the transformations may be modified to provide the desired compounds of the present invention.

[0248] All derivatives of formula I can be prepared by the procedures described in the general methods given below or by their conventional modification schemes. In addition to any new intermediates used therein, the present invention also includes any one or more of these processes for preparing derivatives of formula I. Those skilled in the art will understand that the following reactions can be heated under heat or under microwave radiation.

[0249] The following procedures, including those mentioned in the Examples and Preparations, illustrate methods for synthesizing the compounds of Formula I. Those skilled in the art will understand that the compounds of the present invention and their intermediates can be prepared by methods other than those specifically described herein, for example, by modified methods described herein, or by methods known in the art. Suitable synthetic guidance, functional group interconversions, use of protecting groups, etc. are described, for example, in "Comprehensive Organic Transformations" by R C Larock, VCH Publishers Inc. (1989); "Advanced Organic Chemistry" by J March, Wiley Interscience (1985); "Designing Organic Synthesis" by S Warren, Wiley Interscience (1978); "Organic Synthesis – The Disconnection Approach" by S Warren, Wiley Interscience (1982); "Guidebook to Organic Synthesis" by R K Mackie and D M Smith, Longman (1982); "Protective Groups in Organic Synthesis" by T W Greene and P G M Wuts, John Wiley and Sons, Inc. (1999); and "Protecting Groups" by P J Kocienski, Georg Thieme Verlag (1994); and any updated versions of the said standard procedures.

[0250] In addition, those skilled in the art will understand that it may be necessary or desirable to protect one or more sensitive groups at any stage in the synthesis of the compounds of the present invention to prevent unwanted side reactions. In particular, it may be necessary or desirable to protect amino or carboxylic acid groups. Protecting groups for use in the preparation of the compounds of the present invention can be used in a conventional manner. See, for example, those described in 'Greene’s Protective Groups in Organic Synthesis' by Theodora W Greene and Peter G M Wuts, fifth edition, (John Wiley and Sons, 2014), which is hereby incorporated by reference and which also describes methods for removing such groups.

[0251] In the general synthetic methods below, substituents are defined as above with reference to the compounds of formula (I) unless otherwise specified. Where solvent ratios are given, the ratios are by volume unless otherwise specified.

[0252] The compounds of the present invention can be prepared by any method known in the art for preparing compounds of similar structures. In particular, the compounds of the present invention can be prepared by the procedures described in the schemes below, or by the specific methods described in the examples, or by methods similar to either.

[0253] Those skilled in the art will understand that the experimental conditions described in the following schemes illustrate suitable conditions for achieving the indicated transformations, and that the exact conditions used to prepare the compounds of formula I may need to be or may desirably be varied.

[0254] According to a first process, a compound of formula (IC) (where R 2 = CN) can be prepared from compounds of formula (IA) and (IB) as shown in Scheme 1.

[0255] Scheme 1

[0256]

[0257] In Scheme 1, at a suitable temperature such as 0 °C, the compound of formula (IA) is converted to the compound of formula (IB) by treatment with a suitable halogenating agent (such as N-(Hal) succinimide, preferably NBS) in a suitable solvent (such as DCM or DMF), where Hal is chlorine, bromine or iodine (preferably bromine). Those skilled in the art also know that alternative methods for specifically introducing a suitable halogen group such as Br can be achieved using alternative reagents, solvents and temperatures. At a suitable temperature, the compound of formula (IB) is converted to the compound of formula (IC) by treatment with a suitable source of organometallic cyanide (such as Zn(CN)2 or CuCN) in the presence of a suitable catalyst, such as Pd(dppf)Cl2 (or Pd2(dba)3 plus dppf) in a suitable solvent (such as DMF or NMP). Those skilled in the art also know that alternative organometallic coupling strategies can be used, which include alternative coupling partners, metals and solvent combinations. Those skilled in the art fully understand that the compound of formula (IB) is prepared and isolated as described above, or the compound of formula (IB) is prepared in situ without isolation in a sequential reaction strategy to obtain the compound of formula (IC). In compounds of formula (IA), (IB) or (IC) where a chiral center is present (where R 1a and R 1b are different groups (for example where R 1a is (C1-C3) alkyl and R 1bIn the case of being H)), those skilled in the art fully understand that suitable separation methods such as SFC chromatography can be used to obtain individual enantiomers to provide both the (+) enantiomer and the (-) enantiomer of the compound of formula (IA), (IB) or (IC). Those skilled in the art fully understand that the individual enantiomers of the compound of (IA), (IB) or (IC) are prepared and separated as described above, or separated using alternative separation techniques such as HPLC, which uses a suitable chiral stationary phase and is eluted with a suitable mobile phase determined to be necessary for separating the desired enantiomer.

[0258] According to the second method, the compound of formula (ID) (wherein R 2 = H, CN, (C1-C3) alkyl) can be prepared from the compounds of formula (II) and (III) as shown in Scheme 2.

[0259] Scheme 2

[0260]

[0261] In Scheme 2, the compound of formula (ID), wherein Hal is chlorine, bromine or iodine, can be prepared from the compounds of formula (II) and (III) using a suitable organometallic cross-coupling reaction, such as the Suzuki cross-coupling reaction, with boronate formation first if necessary. Typical Suzuki cross-coupling conditions include a palladium catalyst containing a suitable phosphine ligand, in the presence of an inorganic base, in aqueous dioxane or methanol, at an elevated temperature, under heat or microwave irradiation. Preferred conditions include Pd(OAc)2, Pd(dppf)Cl2 or Pd(PPh3)4 in aqueous dioxane or methanol with sodium carbonate, cesium carbonate or potassium carbonate, at room temperature to 120 °C. Typical boronate formation conditions include Pd(dppf)Cl2 and potassium acetate with bis(pinacolato)diboron and a compound of formula W-Q (where Q = chlorine, bromine or iodine) refluxed in dioxane. Alternatively, the compound of formula (ID) can be prepared by an alternative cross-coupling strategy, such as the Migita-Kosugi-Stille coupling using the compounds of formula (II) and formula (III) (where Q = SnR y 3 and R y is an alkyl group (e.g., butyl)), with an arylstannane formation reaction first if needed.

[0262] The compound of formula (ID) can also be prepared from the compound of formula (II) using a suitable zinc reagent such as the compound of formula (III) (where Q = ZnBr) with a palladium catalyst such as Pd(OAc)2, in the presence of a suitable phosphine ligand such as s-Phos, in a suitable solvent such as THF, at a suitable temperature such as room temperature.

[0263] The compound of formula (ID) can also be prepared by a suitable CH activation strategy using the compound of formula (II) and the compound of formula (III) (where Q = H) in the presence of a palladium catalyst and in the presence of an inorganic base at a suitable temperature such as 50 °C. Typical conditions include Pd(OAc)2, as well as sodium acetate and Bu4NCl. Those skilled in the art will know that alternative conditions are available and can be selected according to the reactivity of the substrate. The compound of formula (III) can be obtained commercially or by methods similar to those described herein.

[0264] According to the third process, the compound of formula (IE) can be prepared from the compounds of formula (IVa), (V), (VI) and (VII) as shown in Scheme 3.

[0265] Scheme 3

[0266]

[0267] In Scheme 3, the compound of formula (IE) (where R 2 and R 3 = H) can be prepared in a sealed tube by reacting the compound of formula (VII) with aqueous ammonium hydroxide in a suitable solvent such as MeOH at a suitable temperature such as 70 °C for a suitable time such as 18 hours. The compound of formula (VII) can be prepared by a suitable alkylation reaction with the compounds of formula (V) and (VI) (LG is a suitable leaving group, such as a halogen, especially a chlorine atom or a mesylate) in a suitable solvent such as DMF at a suitable temperature such as 80 °C in the presence of a suitable base such as Cs2CO3. The compound of formula (VI) can be obtained commercially or by methods similar to those described herein. The compound of formula (V) can be prepared from the compound of formula (IVa) by reaction with DMF-DMA at a suitable temperature from room temperature to 100 °C, preferably at 50 °C.

[0268] As shown in Scheme 4, the compound of formula (IV) can be prepared from the compounds of formula (III), (VIII), (IX), (X), (XI) and (XII).

[0269] Scheme 4

[0270]

[0271] In Scheme 4, Hal is chlorine, bromine or iodine; PG is a suitable protecting group understood by those skilled in the art; the compound of formula III (W-Q) is as defined in Scheme 2. The compound of formula (IX) can be prepared by halogenating the compound of formula (VIII). The compound of formula (IX) can be prepared by treating the compound of formula (VIII) with a suitable halogenating agent such as N-(Hal)succinimide, preferably NIS, in a suitable solvent such as DCM or DMF, at a suitable temperature such as 0 °C. Those skilled in the art also know that alternative methods for the specific introduction of a suitable halogen group such as iodine can be achieved using alternative reagents, solvents and temperatures. Those skilled in the art also know that alternative halogenation strategies can be used, which include alternative sources of halogen, solvent and temperature combinations. Those skilled in the art fully understand that the compound of formula (IX) is prepared and isolated as described above, or prepared in situ without isolation in a sequential reaction strategy, to give the compound of formula (X). The compound of formula (X) can be prepared from the compound of formula (IX) using a suitable protecting group such as trimethylsilylethoxymethyl (SEM), by reacting SEMCl with the compound of formula (IX) and a suitable base such as NaH in a suitable solvent such as THF and at a suitable temperature such as 0 °C to room temperature. The compound of formula (XI) (where R 3 is H) can be prepared in a sealed tube, at a suitable temperature such as 70 °C, by reacting the compound of formula (X) with aqueous ammonium hydroxide in a suitable solvent such as MeOH for an appropriate time such as 18 hours. Additionally, the compound of formula (XI) (where R 3 is (C1-C3)alkyl) can be prepared in a sealed tube, at an appropriate temperature such as 70 °C, by reacting the compound of formula (X) with a suitable primary amine such as methylamine in a suitable solvent such as THF. The compound of formula (XII) can be prepared from the compounds of formula (XI) and (III) using a suitable organometallic cross-coupling reaction, such as the Suzuki cross-coupling reaction, optionally preceded by a boronate formation reaction, as described in Scheme 2. Typical boronate formation conditions include refluxing Pd(dppf)Cl2 and potassium acetate with bis(pinacolato)diboron and the compound of formula (III) (where Q = Hal) in dioxane. Alternatively, the compound of formula (XII) can be prepared by an alternative cross-coupling strategy, the cross-coupling strategy such as using the compound of formula (XII) and the compound of formula (III) (where Q = SnR y3) The Migita-Kosugi-Stille coupling of (3) can be preceded by an arylstannane formation reaction if desired. The compound of formula (IV) can be prepared from the compound of formula (XII) (where PG = SEM) using a suitable deprotection method (such as neat TFA) or optionally in a suitable solvent (such as DCM) at a suitable temperature (such as 0 °C to room temperature). Those skilled in the art fully understand that alternative deprotection methods, such as TBAF, can be used in a suitable solvent such as THF at a suitable temperature, such as 0 °C to 70 °C.

[0272] The compound of formula (II) can be prepared from the compounds of formula (VI), (IX) and (XIII), where Hal is chlorine, bromine or iodine, as shown in Scheme 5.

[0273] Scheme 5

[0274]

[0275] The compound of formula (XIII) can be prepared from the compounds of formula (IX) and formula (VI) (where LG is a suitable leaving group, such as a halogen, especially a chlorine atom or a mesylate) in a suitable solvent such as DMF in the presence of a suitable base such as Cs2CO3 at a suitable temperature such as 80 °C. Those skilled in the art fully understand that alternative methods for preparing the compound of formula (XIII) can be used, for example, the Mitsonobu reaction of the compounds of formula (IX) and (VI) (where LG = OH) using a suitable alcohol activating reagent DIAD and PPh3 in a suitable solvent such as THF at a suitable temperature such as 0 °C to room temperature. The compound of formula (II) (where R 3 is H) can be prepared by reacting the compound of formula (XIII) with an aqueous ammonium hydroxide solution for an appropriate time such as 18 hours in a sealed tube at a suitable temperature such as 70 °C in a suitable solvent such as MeOH. Additionally, the compound of formula (II) (where R 3 is (C1-C3) alkyl) can be prepared by reacting the compound of formula (XIII) with a suitable primary amine such as methylamine in a sealed tube at a suitable temperature such as 70 °C in a suitable solvent such as THF.

[0276] The compound of formula (IIA) (where Y = 1,2,3-triazole) can be prepared from the compounds of formula (IXa), (XIV), (XV), (XVI) and (XVII), where Hal is chlorine, bromine or iodine, as shown in Scheme 6.

[0277] Scheme 6

[0278]

[0279] The compound of formula (IIA) can be prepared from the compounds of formula (XV) and (XVII) using a suitable 1,3-dipolar cycloaddition reaction, such as a copper-catalyzed click reaction, in a suitable solvent such as toluene and tBuOH and a suitable base such as DIPEA, and at a suitable temperature such as from 0 °C to room temperature, using a catalyst such as CuI. Those skilled in the art fully understand that alternative methods for heterocycle formation are also possible. The compound of formula (XV) (wherein R 3 is H) can be prepared by reacting the compound of formula (XIV) with aqueous ammonium hydroxide for a suitable time such as 18 hours in a suitable solvent such as MeOH in a sealed tube at a suitable temperature such as 70 °C. Additionally, the compound of formula (XV) (wherein R 3 is (C1-C3)alkyl) can be prepared by reacting the compound of formula (XIV) with a suitable primary amine such as methylamine in a sealed tube at a suitable temperature such as 70 °C in a suitable solvent such as THF.

[0280] The compound of formula (XIV) can be prepared from the compounds of formula (IXa) and (XVI) (wherein LG is a suitable leaving group, such as a halogen, especially a chlorine atom or a mesylate) at a suitable temperature such as 80 °C in a suitable solvent such as DMF in the presence of a suitable base such as Cs2CO3, and if necessary, first performing a conversion reaction between suitable functional groups, for example, converting an alcohol (LG = OH) to a chloride (LG = Cl) using methods known to those skilled in the art.

[0281] The compound of formula (Xi) (wherein R 2 =(C1-C3)alkyl, PG = SEM and Hal is chlorine, bromine or iodine) can be prepared from the compound of formula (X) (wherein R 2 =H and Hal is chlorine, bromine or iodine), as shown in Scheme 7.

[0282] Scheme 7

[0283]

[0284] The compound of formula (Xi) (wherein R 2 =(C1-C3)alkyl and PG = SEM) can be prepared from the compound of formula (X) (wherein R 2 =H and PG = SEM) and the compound of formula (XVIII) at a suitable temperature such as -78 °C in a suitable solvent such as THF using a suitable non-nucleophilic base such as LDA. Those skilled in the art fully understand that alternative methods for selective ligand-directed deprotonation-alkylation can be used in combination with alternative PG, bases, and alkylating groups in a suitable solvent and at a suitable temperature.

[0285] The compound of formula (IF) can be prepared from the compounds of formula (III), (XVII), (XIV), (XIX), (XX), (XXI) and (XXII), where Q is Hal and Hal is chlorine, bromine or iodine, as shown in Scheme 8.

[0286] Scheme 8

[0287]

[0288] The compound of formula (IF) can be prepared from the compound of formula (XXI) by appropriate halogen displacement, similarly to Schemes 4, 5 and 6.

[0289] The compound of formula (XXI) can be prepared from the compounds of formula (XX) and formula (III) (where Q = Hal) by an appropriate organometallic cross-coupling reaction, such as the Suzuki cross-coupling reaction described in Scheme 8.

[0290] Typical Suzuki cross-coupling conditions include a palladium catalyst containing a suitable phosphine ligand, in the presence of an inorganic base, in aqueous dioxane or methanol, at an elevated temperature, under heat or microwave irradiation. Preferred conditions include Pd(OAc)2, Pd(dppf)Cl2 or Pd(PPh3)4 in aqueous dioxane or methanol with sodium carbonate, cesium carbonate or potassium carbonate, at room temperature to 120 °C. The compound of formula (XX) can be prepared from the compounds of formula (XIX) and (XXII) by a boronate formation reaction. Typical boronate formation conditions include refluxing Pd(dppf)Cl2 and potassium acetate with bis(pinacolato)diboron in dioxane. The compound of formula (XIX) can be prepared from the compounds of formula (XIV) and (XVII) using a suitable 1,3-dipolar cycloaddition reaction, such as a copper-catalyzed click reaction, in a suitable solvent such as toluene and tBuOH and a suitable base such as DIPEA, and at a suitable temperature such as 0 °C to room temperature, using a catalyst such as CuI. Those skilled in the art fully understand that alternative methods of heterocycle formation are also possible.

[0291] The compound of formula (IIB) can be prepared from the compounds of formula (XV) and (XXIII), and where Hal is chlorine, bromine or iodine, as shown in Scheme 9.

[0292] Scheme 9

[0293]

[0294] The compound of formula (IIB) can be prepared from the compounds of formula (XV) and (XXIII) by an appropriate 1,3-dipolar cycloaddition reaction for an appropriate time such as 16 hours at a suitable temperature such as 0 °C to 60 °C, in a suitable solvent such as toluene, in the presence of a suitable base such as Et3N.

[0295] The compound of formula (VI) can be prepared from the compounds of formula (XXXI), (XXIV), (XXV) and (XXVI) as shown in Scheme 10, where Hal is chlorine, bromine or iodine; M is a suitable metal.

[0296] Scheme 10

[0297]

[0298] The compound of formula (VI) (where LG = Cl) can be prepared by treating the compound of formula (XXVI) with suitable chlorination (such as pure SOCl2 or in a suitable solvent) at a suitable temperature. The compound of formula (XXVI) can be prepared from the compounds of formula (XXIV) and (XXV) by a suitable organometallic addition reaction using a suitable metal (M) such as Mg in a suitable solvent such as THF at a suitable temperature such as from 0 °C to room temperature. The compound of formula (XXIV) can be prepared by appropriately oxidizing the compound of formula (XXXI) using a suitable reagent such as MnO2 in a suitable solvent. Those skilled in the art also know that alternative oxidation strategies including alternative oxidants and solvent combinations can be used.

[0299] Alternatively, as shown in Scheme 11, the compound of formula (XXXI) can be prepared from the compound of formula (XXVII), where Hal is chlorine, bromine or iodine; M is a suitable metal.

[0300] Scheme 11

[0301]

[0302] The compound of formula (XXXI) can be prepared by refluxing the compound of formula (XXVII) and a suitable organometallic compound of formula (XXVIII) in a suitable aprotic solvent such as THF at a suitable temperature such as 0 °C. Those skilled in the art recognize that alternative methods can be used which employ different organometallic nucleophiles to add an alkyl group to an aldehyde.

[0303] As shown in Scheme 12, the compound of formula (XXIV) can alternatively be prepared from the compounds of formula (XXVII), (XXIX) and (XXX), where Hal is chlorine, bromine or iodine; M is a suitable metal.

[0304] Scheme 12

[0305]

[0306] The compound of formula (XXIV) can be prepared from the compounds of formula (XXX) and (XXVIII) using a suitable metal (M) such as Mg in a suitable solvent such as THF at a suitable temperature such as 0 °C to room temperature. The compound of formula (XXX) can be prepared from the compound of formula (XXIX) and N,O-dimethylhydroxylamine in a suitable solvent such as DCM at a suitable temperature such as 0 °C to room temperature in the presence of a suitable peptide coupling reagent such as HATU and in the presence of a suitable base such as DIPEA.

[0307] In the case of compounds described in all of the foregoing general method schemes that result in the presence of chiral centers, where R 1a and R 1b are different groups (e.g., where R 1a is (C1-C3)alkyl and R 1b is H), it is well understood by those skilled in the art that the individual enantiomers can be obtained using suitable separation methods such as SFC chromatography to provide the (+) and (-) enantiomers of these compounds. It is well understood by those skilled in the art that the individual enantiomers of the compounds described in the foregoing general method schemes are prepared and separated as described above, or separated using alternative separation techniques such as HPLC using a suitable chiral stationary phase and eluting with a suitable mobile phase determined to be necessary for separating the desired enantiomer.

[0308] The following non-limiting preparations and examples illustrate the preparation of the compounds and salts of the invention. In the examples and preparations listed below and in the foregoing schemes, reference may be made to the following abbreviations, definitions, and analytical procedures. Other abbreviations common in the art are also used. Standard IUPAC nomenclature has been used.

[0309] The following abbreviations may be used: AcOH is acetic acid; Ar is argon; aq is aqueous solution; Bn is benzyl; Boc is tert-butoxycarbonyl; Boc2O is di-tert-butyl dicarbonate; br is broad peak; tBu is tert-butyl; tBuOH is tert-butanol; n-BuLi is n-butyllithium; Bu4NCl is tetrabutylammonium chloride; °C is degree Celsius; CDCl3 is deuterated chloroform; Cs2CO3 is cesium carbonate; CsF is cesium fluoride; CuCN is copper(I) cyanide; CuI is copper(I) iodide; δ is chemical shift; d is doublet; DCM is dichloromethane or methylene chloride; DIAD is diisopropyl azodicarboxylate; DIPEA is N-ethyl diisopropylamine or N,N-diisopropylethylamine; DMA is N,N-dimethylacetamide; DMAP is 4-dimethylaminopyridine; DMF is N,N-dimethylformamide; DMF-DMA is N,N-dimethylformamide dimethyl acetal; DMSO is dimethyl sulfoxide; DPPA is diphenylphosphoryl azide; Dppf is 1,1'-bis(diphenylphosphino)ferrocene; EDA is ethylenediamine; Et2O is diethyl ether; EtOAc is ethyl acetate; EtOH is ethanol; Et3N is triethylamine; Et3SiH is triethylsilane; g is gram; HATU is 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridin-3-ium hexafluorophosphate; HCl is hydrochloric acid; HCO2H is formic acid; HPLC is high performance liquid chromatography; H2 is hydrogen; H2O is water; Hr is hour, Hrs is hours; K2CO3 is potassium carbonate; KHSO4 is potassium hydrogen sulfate; KOAc is potassium acetate; K3PO4 is potassium phosphate; L is liter; LCMS is liquid chromatography mass spectrometry; LDA is lithium diisopropylamide; LiAlH4 or LAH is lithium aluminum hydride; LiCl is lithium chloride; LiHMDS is lithium bis(trimethylsilyl)amide; LiOH·H2O is lithium hydroxide monohydrate; is lithium tri-sec-butylborohydride; m is multiple; M is molarity; MeCN is acetonitrile; MeMgBr is methylmagnesium bromide; MeOH is methanol; 2-MeTHF is 2-methyltetrahydrofuran; mg is milligram; MgSO4 is magnesium sulfate; MHz is megahertz; min is minute; mL is milliliter; mmol is millimole; MnO2 is manganese dioxide; mol is mole; MS m / z is mass spectrometry peak; MTBE is tert-butyl methyl ether; MsCl is methanesulfonyl chloride; NaCN is sodium cyanide; NaBH4 is sodium borohydride; Na2CO3 is sodium carbonate; NaH is sodium hydride; NaHCO3 is sodium bicarbonate; NaHSO4 is sodium bisulfate; NaHMDS is sodium bis(trimethylsilyl)amide; NaOH is sodium hydroxide; NaOAc is sodium acetate; NaOMe is sodium methoxide; Na2SO4 is sodium sulfate; Na2S2O3 is sodium thiosulfate; NBS is N-bromosuccinimide; NCS is N-chlorosuccinimide; NH3 is ammonia; NH4Cl is ammonium chloride; NH4HCO3 is ammonium bicarbonate; NH2NH2.H2O is hydrazine hydrate; NH2OH·HCl is hydroxylamine hydrochloride; NH4OH is ammonium hydroxide; NH4OAc is ammonium acetate; NiI is nickel iodide; NIS is N-iodosuccinimide; nM is nanomole; NMP is 1-methyl-2-pyrrolidone; NMR is nuclear magnetic resonance; Pd / C is palladium on carbon; Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium(0); Pd(dppf)Cl2 is dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II); Pd(OH)2 is palladium(II) hydroxide; Pd(OAc)2 is palladium(II) acetate; PPh3 is triphenylphosphine; Pd(PPh3)4 is tetrakis(triphenylphosphine)palladium(0); Pet.Ether is petroleum ether; pH is hydrogen ion concentration; ppm is parts per million; PtO2 is platinum(IV) oxide; q is quartet; rt is room temperature; RT is retention time; s is singlet; SCX is strong cation exchange; SEM-Cl is 2-(trimethylsilyl)ethoxymethyl chloride; SFC is supercritical fluid chromatography; S-Phos is 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl; SOCl2 is thionyl chloride; t is triplet; T3P is propylphosphonic anhydride; TBAF is tetrabutylammonium fluoride; TBD is 1,5,7-triazabicyclo[4.4.0]dec-5-ene; TBME is tert-butyl methyl ether; TFA is trifluoroacetic acid; TFP is tris(2-furyl)phosphine; THF is tetrahydrofuran; Ti(OiPR)4 is titanium(IV) isopropoxide; TPTU is 2-(2-pyridin-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate; μL is microliter; μmol is micromole; XPhos is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; Zn(CN)2 is zinc cyanide.

[0310] In all cases,1 The 19 H and 1 F nuclear magnetic resonance (NMR) spectra are consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts per million relative to the low field of tetramethylsilane (for 19 H-NMR) and the high field of trichlorofluoromethane (for

[0311] F NMR), and the following conventional abbreviations are used to denote the main peaks: for example, s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak. The following abbreviations are used for common solvents: CDCl3, deuterochloroform; DMSO-d6, deuterodimethyl sulfoxide; and MeOH-d4, deuteromethanol. Where appropriate, tautomeric forms may be recorded in the NMR data; and some exchangeable protons may not be visible.

[0312] Mass spectra MS (m / z) are recorded using electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI). 19 F, 35 Cl, 79 Br, and 127 I.

[0313] Where preparative TLC or silica gel chromatography has been used, those skilled in the art can select any combination of suitable solvents to purify the desired compounds.

[0314] The following are analytical and preparative chromatographic methods for the analysis and purification of the compounds of the present invention.

[0315] Preparative SFC method

[0316] SFC method A1 : Column: Lux Cellulose-3, 250 mm x 21.2 mm 5u; Mobile phase - Isocratic conditions: CO2 / MeOH, 80 / 20 (v / v); Flow rate: 80.0 mL / min.

[0317] SFC method A3 : Column: Lux Cellulose-3, 250 mm x 21.2 mm 5u; Mobile phase A: CO2; Mobile phase B: MeCN / MeOH, 50 / 50 (v / v); Isocratic conditions: 70% A / 30% B; Flow rate: 80.0 mL / min.

[0318] SFC method A4Column: Lux Cellulose-1, 250 mm x 21.2 mm 5u; Mobile phase A: CO2; Mobile phase B: MeCN / MeOH, 50 / 50 (v / v); Isocratic condition: 75% A / 25% B; Flow rate: 80.0 mL / min.

[0319] SFC method A6 Column: Lux Cellulose-1, 250 mm x 21.2 mm 5u; Mobile phase A: CO2; Mobile phase B: MeCN / MeOH, 50 / 50 (v / v); Isocratic condition: 80% A / 20% B; Flow rate: 80.0 mL / min.

[0320] SFC method A7 Column: Lux Cellulose-3, 500 mm x 21.2 mm 5u; Mobile phase A: CO2; Mobile phase B: MeOH + 0.2% NH4OH; Isocratic condition: 70% A / 30% B; Flow rate: 80.0 mL / min.

[0321] SFC method A9 Column: Lux Cellulose-3, 500 mm x 21.2 mm 5u; Mobile phase A: CO2; Mobile phase B: MeOH + 0.2% NH4OH; Isocratic condition: 90% A / 10% B; Flow rate: 80.0 mL / min.

[0322] SFC method A10 Column: Lux Cellulose-3, 250 mm x 21.2 mm 5u; Mobile phase A: CO2; Mobile phase B: MeOH + 0.2% NH4OH; Isocratic condition: 92.5% A / 7.5% B; Flow rate: 80.0 mL / min.

[0323] SFC method B1 Column: Chiral Tech OJ-H, 250 mm x 21.2 mm 5u; Mobile phase A: CO2; Mobile phase B: MeOH + 0.2% NH4OH; Isocratic condition: 80% A / 20% B; Flow rate: 80.0 mL / min.

[0324] SFC method B3 Column: Chiral Tech OJ-H, 250 mm x 50 mm 5u; Mobile phase A: CO2; Mobile phase B: MeOH + 0.2% NH4OH; Isocratic condition: 85% A / 15% B; Flow rate: 250.0 mL / min.

[0325] SFC method B4:Column: Chiral Tech OJ-H, 500mm x 21.2mm 5u; Mobile phase A: CO2; Mobile phase B: MeOH + 0.2% NH4OH; Isocratic condition: 75% A / 25% B; Flow rate: 80.0 mL / min.

[0326] SFC method C1 : Column: Chiral Tech AS-H, 250mm x 21.2mm 5u; Mobile phase A: CO2; Mobile phase B: MeOH + 0.2% NH4OH; Isocratic condition: 75% A / 25% B; Flow rate: 80.0 mL / min.

[0327] SFC method C3 : Column: Chiral Tech AS-H, 250mm x 21.2mm 5u; Mobile phase A: CO2; Mobile phase B: MeOH + 0.2% NH4OH; Isocratic condition: 80% A / 20% B; Flow rate: 80.0 mL / min.

[0328] SFC method C4 : Column: Chiral Tech AS-H, 250mm x 21.2mm 5u; Mobile phase A: CO2; Mobile phase B: MeOH + 0.2% NH4OH; Isocratic condition: 85% A / 15% B; Flow rate: 80.0 mL / min.

[0329] SFC method C5 : Column: Chiral Tech AS-H, 250mm x 21.2mm 5u; Mobile phase A: CO2; Mobile phase B: MeOH + 0.2% NH4OH; Isocratic condition: 85% A / 15% B; Flow rate: 80.0 mL / min.

[0330] SFC method D1 : Chiral Tech IA 250mm x 21.5mm 5u; Mobile phase A: CO2; Mobile phase B: IPA; Isocratic condition: 60% A / 40% B; Flow rate: 80.0 mL / min.

[0331] SFC method D4 : Chiral Tech IA 250mm x 21.5mm 5u; Mobile phase A: CO2; Mobile phase B: MeOH; Isocratic condition: 60% A / 40% B; Flow rate: 80.0 mL / min.

[0332] SFC method F1: Column: Chiral Tech OD-H, 500mm x 21.5mm, 5u; Mobile phase A: CO2; Mobile phase B: EtOH + 0.2% NH4OH; Isocratic condition: 80% A / 20% B; Flow rate: 80.0 mL / min.

[0333] Analytical SFC method

[0334] SFC method A2 : Column: Lux Cellulose-3, 250mm x 4.6mm, 5u; Mobile phase A: CO2; Mobile phase B: MeOH; Gradient elution (time, %A, %B): (0.00min, 95%A, 5%B), (1.00min, 95%A, 5%B), (9.00min, 40%A, 60%B), (9.50min, 40%A, 60%B), (10.00min, 95%A, 5%B); Flow rate: 3.0 mL / min.

[0335] SFC method A5 : Column: Lux Cellulose-1, 250mm x 4.6mm, 5u; Mobile phase A: CO2; Mobile phase B: MeOH / MeCN, 50 / 50, (v / v); Gradient elution (time, %A, %B): (0.00min, 95%A, 5%B), (1.00min, 95%A, 5%B), (9.00min, 40%A, 60%B), (9.50min, 40%A, 60%B), (10.00min, 95%A, 5%B); Flow rate: 3.0 mL / min.

[0336] SFC method A8 : Column: Lux Cellulose-3, 250mm x 4.6mm, 5u; Mobile phase A: CO2; Mobile phase B: MeOH + 0.2% NH4OH; Gradient elution (time, %A, %B): (0.00min, 95%A, 5%B), (1.00min, 95%A, 5%B), (9.00min, 40%A, 60%B), (9.50min, 40%A, 60%B), (10.00min, 95%A, 5%B); Flow rate: 3.0 mL / min.

[0337] SFC method B2Column: Chiral Tech OJ-H, 250mm x 4.6mm 5u; Mobile phase A: CO2; Mobile phase B: MeOH + 0.2% NH4OH; Gradient elution (time, %A, %B): (0.00min, 95%A, 5%B), (1.00min, 95%A, 5%B), (9.00min, 40%A, 60%B), (9.50min, 40%A, 60%B), (10.00min, 95%A, 5%B); Flow rate: 3.0 mL / min.

[0338] SFC method C2 Column: Chiral Tech AS-H, 250mm x 4.6mm 5u; Mobile phase A: CO2; Mobile phase B: MeOH + 0.2% NH4OH; Gradient elution (time, %A, %B): (0.00min, 95%A, 5%B), (1.00min, 95%A, 5%B), (9.00min, 40%A, 60%B), (9.50min, 40%A, 60%B), (10.00min, 95%A, 5%B); Flow rate: 3.0 mL / min.

[0339] SFC method D2 Column: Chiral Tech IA 250mm x4.6 mm 5u; Mobile phase A: CO2; Mobile phase B: MeOH + 0.2% NH4OH; Gradient elution (time, %A, %B): (0.00min, 95%A, 5%B), (1.00min, 95%A, 5%B), (9.00min, 40%A, 60%B), (9.50min, 40%A, 60%B), (10.00min, 95%A, 5%B); Flow rate: 3.0 mL / min.

[0340] SFC method D3 Column: Chiral Tech IA 250mm x4.6 mm 5u; Mobile phase A: CO2; Mobile phase B: IPA; Gradient elution (time, %A, %B): (0.00min, 95%A, 5%B), (1.00min, 95%A, 5%B), (9.00min, 40%A, 60%B), (9.50min, 40%A, 60%B), (10.00min, 95%A, 5%B); Flow rate: 3.0 mL / min.

[0341] SFC method F2Column: Chiral Tech OD-H 250mm x 4.6mm 5u; Mobile phase A: CO2; Mobile phase B: EtOH + 0.2% NH4OH; Gradient elution (time, %A, %B): (0.00 min, 95% A, 5% B), (1.00 min, 95% A, 5% B), (9.00 min, 40% A, 60% B), (9.50 min, 40% A, 60% B), (10.00 min, 95% A, 5% B); Flow rate: 3.0 mL / min.

[0342] Preparative HPLC method

[0343] HPLC method C20A Column: CHIRALPAK IC, 2.5 cm I.D. x 25 cm length; Isocratic mobile phase: DCM / MeOH, 95 / 5 (v / v); Flow rate: 30 mL / min; Temperature: 35 °C.

[0344] HPLC method C20B Column: CHIRALPAK IC, 5.0 cm I.D. x 25 cm length; Isocratic mobile phase: DCM / MeOH, 95 / 5 (v / v); Flow rate: 60 mL / min; Temperature: 35 °C.

[0345] HPLC method C21 Column: CHIRALPAK IC, 5.0 cm I.D. × 25 cm length; Isocratic mobile phase: DCM / MeOH, 90 / 10 (v / v); Flow rate: 60 mL / min.

[0346] HPLC method C22A Column: CHIRALPAK IC, 2.5 cm I.D. × 25 cm length; Isocratic mobile phase: DCM / MeOH / DEA, 95 / 5 / 0.1 (v / v / v); Flow rate: 30 mL / min; Temperature: 35 °C.

[0347] HPLC method C22B Column: CHIRALPAK IC, 5.0 cm I.D. × 25 cm length; Isocratic mobile phase: DCM / MeOH / DEA, 95 / 5 / 0.1 (v / v / v); Flow rate: 30 mL / min; Temperature: 35 °C.

[0348] HPLC method C23A Column: CHIRALPAK IC, 5.0 cm I.D. × 25 cm length; Isocratic mobile phase: DCM / EtOH, 90 / 10 (v / v); Flow rate: 60 mL / min; Temperature: 35 °C.

[0349] HPLC method C23B: Column: CHIRALPAK IC, 2.5 cm I.D. × 25 cm in length; Isocratic mobile phase: DCM / EtOH, 90 / 10 (v / v); Flow rate: 60 mL / min; Temperature: 35 °C.

[0350] HPLC method C24A : Column: CHIRALPAK IC, 5.0 cm I.D. × 25 cm in length; Isocratic mobile phase: DCM / EtOH, 95 / 5 (v / v); Flow rate: 60 mL / min; Temperature: 35 °C.

[0351] HPLC method C24B : Column: CHIRALPAK IC, 2.5 cm I.D. × 25 cm in length; Isocratic mobile phase: DCM / EtOH, 95 / 5 (v / v); Flow rate: 60 mL / min; Temperature: 35 °C.

[0352] HPLC method C25A : Column: CHIRALPAK IC, 5.0 cm I.D. × 25 cm in length; Isocratic mobile phase: Hex / EtOH, 70 / 30 (v / v); Flow rate: 60 mL / min.

[0353] HPLC method C25B : Column: CHIRALPAK IC, 2.0 cm I.D. × 25 cm in length; Isocratic mobile phase: Hex / EtOH, 70 / 30 (v / v); Flow rate: 9 mL / min.

[0354] HPLC method C26 : Column: CHIRALPAK IC, 5.0 cm I.D. × 25 cm in length; Isocratic mobile phase: Hex / IPA, 70 / 30 (v / v); Flow rate: 60 mL / min.

[0355] HPLC method C27 : Column: CHIRALPAK IC, 5.0 cm I.D. × 25 cm in length; Isocratic mobile phase: Hex / EtOAc / DEA, 60 / 40 / 0.1 (v / v / v); Flow rate: 60 mL / min; Temperature: 35 °C.

[0356] HPLC method C28 : Column: CHIRALPAK IC, 2.5 cm I.D. × 25 cm in length; Isocratic mobile phase: Hex / EtOH, 85 / 15 (v / v); Flow rate: 30 mL / min.

[0357] HPLC method C29 : Column: CHIRALPAK IC, 5.0 cm I.D. × 25 cm in length; Isocratic mobile phase: DCM / EtOH, 80 / 20 (v / v); Flow rate: 60 mL / min.

[0358] HPLC method C30 : Column: CHIRALPAK IC, 5.0 cm I.D. × 25 cm in length; Isocratic mobile phase: DCM / EtOH, 75 / 25 (v / v); Flow rate: 60 mL / min.

[0359] HPLC method C31 : Column: CHIRALPAK IC 5.0 cm I.D. × 25 cm in length; Isocratic mobile phase: DCM / EtOH / DEA, 90 / 10 / 0.1 (v / v / v); Flow rate: 60 mL / min.

[0360] HPLC method C32 : Column: CHIRALPAK IC, 5.0 cm I.D. × 25 cm in length; Isocratic mobile phase: DCM / EtOH / DEA, 85 / 15 / 0.1 (v / v / v); Flow rate: 60 mL / min.

[0361] HPLC method C33 : Column: CHIRALPAK IC, 5.0 cm I.D. × 25 cm in length; Isocratic mobile phase: Hexane / EtOH, 50 / 50 (v / v); Flow rate: 30 mL / min.

[0362] HPLC method C34 : Column: CHIRALPAK IC, 5.0 cm I.D. × 25 cm in length; Isocratic mobile phase: 100% MeOH; Flow rate: 60 mL / min.

[0363] HPLC method B4 : Column: CHIRALCEL OJ, 2.5 cm I.D. × 25 cm in length; Isocratic mobile phase: MeOH / DEA, 90 / 10 (v / v); Flow rate: 30 mL / min; Temperature: 35 °C.

[0364] HPLC method B5 : Column: CHIRALCEL OJ, 2.5 cm I.D. × 25 cm in length; Isocratic mobile phase: MeOH / DEA, 100 / 0.1 (v / v); Flow rate: 30 mL / min; Temperature: 35 °C.

[0365] HPLC method B6 : Column: CHIRALCEL OJ, 2.5 cm I.D. × 25 cm in length; Isocratic mobile phase: EtOH / DEA, 100 / 0.1 (v / v); Flow rate: 30 mL / min; Temperature: 35 °C.

[0366] HPLC method D4: Column: CHIRALPAK AD-H, 25 cm I.D. × 250 cm length; Isocratic mobile phase: EtOH / MeCN, 80 / 20 (v / v); Flow rate: 20 mL / min; Temperature: 35 °C.

[0367] HPLC method D5 : Column: CHIRALPAK AD-H, 2.5 cm I.D. × 25 cm length; Isocratic mobile phase: Hexane / EtOH, 70 / 30 (v / v), Flow rate: 30 mL / min; Temperature: 35 °C.

[0368] HPLC method D6 : Column: CHIRALPAK AD-H, 2.5 cm I.D. × 25 cm length; Isocratic mobile phase: MeOH / MeCN, 90 / 10 (v / v); Flow rate: 30 mL / min.

[0369] HPLC method D7 : Column: CHIRALPAK AD-H, 5.0 cm I.D. × 25 cm length; Isocratic mobile phase: Hexane / IPA, 70 / 30 (v / v); Flow rate: 60 mL / min.

[0370] HPLC method E3 : Column: CHIRALPAK IE, 2.5 cm I.D. × 25 cm length; Isocratic mobile phase: Hexane / EtOH, 70 / 30 (v / v); Flow rate: 60 mL / min; Temperature: 35 °C.

[0371] HPLC method E4 : Column: CHIRALPAK IE, 5.0 cm I.D. × 25 cm length; Isocratic mobile phase: DCM / EtOH, 95 / 5 (v / v); Flow rate: 55 mL / min; Temperature: 35 °C.

[0372] HPLC method E5 : Column: CHIRALPAK IE, 5.0 cm I.D. × 25 cm length; Isocratic mobile phase: Hexane / EtOH, 80 / 20 (v / v); Flow rate: 60 mL / min; Temperature: 35 °C.

[0373] HPLC method E6 : Column: CHIRALPAK IE, 2.5 cm I.D. × 25 cm length; Isocratic mobile phase: Hexane / EtOH / DEA, 50 / 50 / 0.1 (v / v / v); Flow rate: 30 mL / min; Temperature: 35 °C.

[0374] HPLC method E8: Column: CHIRALPAK IE, 5.0 cm I.D. × 25 cm in length; Isocratic mobile phase: hexane / EtOH, 50 / 50 (v / v); Flow rate: 60 mL / min; Temperature: 35 °C.

[0375] HPLC method F1 : Column: CHIRALPAK AS-H, 5.0 cm I.D. × 25 cm in length; Isocratic mobile phase: hexane / EtOH, 85 / 15 (v / v); Flow rate: 60 mL / min; Temperature: 35 °C.

[0376] HPLC method F2 : Column: CHIRALPAK AS-H, 5.0 cm I.D. × 25 cm in length; Isocratic mobile phase: DCM / MeOH, 60 / 40 (v / v); Flow rate: 60 mL / min; Temperature: 35 °C.

[0377] HPLC method F4 : Column: CHIRALPAK AS-H, 5.0 cm I.D. × 25 cm in length; Isocratic mobile phase: EtOH / DEA, 100 / 0.1 (v / v); Flow rate: 60 mL / min; Temperature: 35 °C.

[0378] HPLC method F7 : Column: CHIRALPAK AS-H, 2.0 cm I.D. × 25 cm in length; Isocratic mobile phase: hexane / EtOH / DEA, 50 / 50 / 0.2 (v / v / v); Flow rate: 14 mL / min; Temperature: 25 °C.

[0379] HPLC method F8 : Column: CHIRALPAK AS-H, 2.5 cm I.D. × 25 cm in length; Isocratic mobile phase: DCM / MeOH, 95 / 5 (v / v); Flow rate: 30 mL / min; Temperature: 25 °C.

[0380] HPLC method F9 : Column: CHIRALPAK AS-H, 5.0 cm I.D. × 25 cm in length; Isocratic mobile phase: DCM / EtOH / DEA, 90 / 10 / 0.1 (v / v / v); Flow rate: 60 mL / min; Temperature: 25 °C.

[0381] HPLC method G2 : Column: CHIRALCEL OD-H, 2.5 cm I.D. × 25 cm in length; Isocratic mobile phase: hexane / IPA, 60 / 40 (v / v); Flow rate: 30 mL / min; Temperature: 35 °C.

[0382] HPLC method G3: Column: CHIRALCEL OD-H, 2.0 cm I.D. × 25 cm in length; Isocratic mobile phase: IPA / TFA, 100 / 0.2 (v / v); Flow rate: 40 mL / min; Temperature: 40 °C.

[0383] HPLC method H1 : Column: CHIRALCEL OZ-H, 5.0 cm I.D. × 25 cm in length; Isocratic mobile phase: hexane / EtOH, 50 / 50 (v / v); Flow rate: 30 mL / min; Temperature: 35 °C.

[0384] HPLC method H3 : Column: CHIRALCEL OZ-H, 2.5 cm I.D. × 25 cm in length; Isocratic mobile phase: hexane / EtOH, 80 / 20 (v / v); Flow rate: 30 mL / min; Temperature: 35 °C.

[0385] HPLC method J1 : Column: XterraRP18 (19x250 mm, 10 μ); Mobile phase A: 20 mM (NH4)2CO3 aqueous solution; Mobile phase B: MeCN; Gradient elution (time, %A, %B): (0 min, 90%A, 10%B), (3 min, 75%A, 25%B), (18 min, 40%A, 60%B), (19 min, 5%A, 95%B), (20 min, 5%A, 95%B); Flow rate: 16 mL / min;

[0386] HPLC method K1 : Column: YMC Triart C18 (20x250 mm, 5 μ); Mobile phase A: 20 mM (NH4)2CO3 aqueous solution; Mobile phase B: MeCN; Gradient elution (time, %A, %B): (0 min, 90%A, 10%B), (3 min, 75%A, 25%B), (18 min, 40%A, 60%B), (19 min, 5%A, 95%B), (20 min, 5%A, 95%B); Flow rate: 16 mL / min.

[0387] HPLC method L1 : Column: Reprosil Gold C18 (30x100 mm, 5 μ); Mobile phase A: 10 mM (NH4)2CO3 aqueous solution; Mobile phase B: MeCN; Gradient elution (time, %A, %B): (0 min, 90%A, 10%B), (2 min, 60%A, 40%B), (10 min, 30%A, 70%B), (11 min, 5%A, 95%B), (12 min, 5%A, 95%B); Flow rate: 30 mL / min.

[0388] HPLC method L2Column: Reprosil Gold C18 (250x20mm, 5μ); Mobile phase A: 20mM NH4HCO3 aqueous solution; Mobile phase B: MeCN; Gradient elution (time, %A, %B): (0min, 90%A, 10%B), (3min, 70%A, 30%B), (18min, 40%A, 60%B), (19min, 5%A, 95%B); Flow rate: 20mL / min.

[0389] HPLC method N1 Column: Hydrosphere C18 (250x20mm, 5μ); Mobile phase A: 10mM NH4OAc aqueous solution; Mobile phase B: MeCN; Gradient elution (time, %A, %B): (0min, 90%A, 10%B), (3min, 70%A, 30%B), (18min, 40%A, 60%B), (19min, 5%A, 95%B); Flow rate: 20mL / min.

[0390] HPLC method N2 Column: Hydrosphere C18 (250x20mm, 5μ); Mobile phase A: 0.1% formic acid aqueous solution; Mobile phase B: MeCN; Gradient elution (time, %A, %B): (0min, 90%A, 10%B), (3min, 80%A, 20%B), (18min, 40%A, 60%B), (19min, 5%A, 95%B); Flow rate: 20mL / min.

[0391] HPLC method P1: Column: Gemini C18 (100x30mm, 5μ); Mobile phase A: 20mM NH4HCO3 aqueous solution; Mobile phase B: MeCN; Flow rate: 30mL / min; Gradient elution (time, %A, %B): (0min, 90%A, 10%B), (2min, 70%A, 30%B), (10min, 35%A, 65%B), (12min, 5%A, 95%B).

[0392] HPLC method Q1 Column: CHIRALPAK IB, 2.0cm I.D. × 25cm length; Isocratic mobile phase: Hex / EtOH (50 / 50) (v / v); Flow rate: 14mL / min; Temperature: 25°C.

[0393] Analytical HPLC method

[0394] HPLC method A[Acidic]Column: Acquity BEH C18, 50×2.1 mm, 1.7 μm; Mobile phase: MeCN (0.05% TFA) - water (0.05% TFA); Gradient: 5% - 95% MeCN for 2 min, hold at 95% MeCN for 0.5 min.; Re-equilibrate back to 5% MeCN until 2.7 min.; Flow rate: 0.8 mL / min; Temperature: 45 °C.

[0395] HPLC method B1 Column: CHIRALCEL OJ-H, 0.46 cm I.D. × 15 cm long; Injection: 20.0 μL; Mobile phase: MeOH / MeCN, 90 / 10 (v / v); Flow rate: 1.0 mL / min; Wavelength: UV 254 nm; Temperature: 35 °C.

[0396] HPLC method B2 Column: CHIRALCEL OJ-H, 0.46 cm I.D. × 15 cm long; Injection: 2.0 μL; Mobile phase: MeOH / DEA, 100 / 0.1 (v / v); Flow rate: 1.0 mL / min; Wavelength: UV 214 nm; Temperature: 35 °C.

[0397] HPLC method B3 Column: CHIRALCEL OJ-H, 0.46 cm I.D. × 15 cm long; Injection: 1.0 μL; Mobile phase: EtOH; Flow rate: 1.0 mL / min; Wavelength: UV 214 nm; Temperature: 35 °C.

[0398] HPLC method C1 Column: CHIRALPAK IC, 0.46 cm I.D. × 25 cm long; Mobile phase: DCM / EtOH, 95 / 5 (v / v); Flow rate: 1.0 mL / min; Wavelength: UV 214 nm; Temperature: 25 °C.

[0399] HPLC method C2 Column: CHIRALPAK IC, 0.46 cm I.D. × 15 cm long; Mobile phase: DCM / EtOH, 95 / 5 (v / v); Flow rate: 1.0 mL / min; Wavelength: UV 214 nm; Temperature: 25 °C.

[0400] HPLC method C3 Column: CHIRALPAK IC, 0.46 cm I.D. × 15 cm long, Mobile phase: DCM / EtOH, 98 / 2 (v / v); Flow rate: 1.0 mL / min; Wavelength: UV 254 nm; Temperature: 25 °C.

[0401] HPLC method C4: Column: CHIRALPAK IC, 0.46 cm I.D. × 25 cm length; Mobile phase: DCM / MeOH, 95 / 5 (v / v); Flow rate: 1.0 mL / min; Temperature: 25 °C.

[0402] HPLC method C5 : Column: CHIRALPAK IC, 0.46 cm I.D. × 15 cm length, 5 μm; Mobile phase: DCM / MeOH, 95 / 5 (v / v); Flow rate: 1.0 mL / min; Wavelength: UV 254 nm; Temperature: 35 °C.

[0403] HPLC method C6 : Column: CHIRALPAK IC, 0.46 cm I.D. × 15 cm length; Mobile phase: DCM / EtOH, 90 / 10 (v / v); Flow rate: 1.0 mL / min; Wavelength: UV 254 nm; Temperature: 25 °C.

[0404] HPLC method C7 : Column: CHIRALPAK IC, 0.46 cm I.D. × 15 cm length; Mobile phase: DCM / MeOH / DEA, 95 / 5 / 0.1 (v / v / v); Flow rate: 1.0 mL / min; Wavelength: UV 214 nm; Temperature: 35 °C.

[0405] HPLC method C8 : Column: CHIRALPAK IC, 0.46 cm I.D. × 15 cm length; Mobile phase: MeOH; Flow rate: 1.0 mL / min; Wavelength: UV 214 nm; Temperature: 35 °C.

[0406] HPLC method C9 : Column: CHIRALPAK IC, 0.46 cm I.D. × 15 cm length; Mobile phase: DCM / MeOH, 90 / 10 (v / v); Flow rate: 1.0 mL / min; Wavelength: UV 254 nm; Temperature: 35 °C.

[0407] HPLC method C10 : Column: CHIRALPAK IC, 0.46 cm I.D. × 15 cm length; Mobile phase: DCM / EtOH / DEA, 90 / 10 / 0.1 (v / v); Flow rate: 1.0 mL / min; Wavelength: UV 254 nm; Temperature: 25 °C.

[0408] HPLC method C11 : Column: CHIRALPAK IC, 0.46 cm I.D. × 25 cm length; Mobile phase: hexane / EtOH, 70 / 30 (v / v); Flow rate: 1.0 mL / min; Wavelength: UV 214 nm; Temperature: 35 °C.

[0409] HPLC method C12 : Column: CHIRALPAK IC, 0.46 cm I.D. × 15 cm in length; Mobile phase: hexane / EtOH, 85 / 15 (v / v); Flow rate: 1.0 mL / min; Wavelength: UV 214 nm; Temperature: 35 °C.

[0410] HPLC method C13 : Column: CHIRALPAK IC, 0.46 cm I.D. × 15 cm in length; Mobile phase: hexane / EtOAC / DEA, 60 / 40 / 0.1 (v / v / v); Flow rate: 1.0 mL / min; Wavelength: UV 214 nm; Temperature: 35 °C.

[0411] HPLC method C14 : Column: CHIRALPAK IC, 0.46 cm I.D. × 15 cm in length; Mobile phase: hexane / EtOH, 80 / 20 (v / v / v); Flow rate: 1.0 mL / min; Wavelength: UV 214 nm; Temperature: 35 °C.

[0412] HPLC method C15 : Column: CHIRALPAK IC, 0.46 cm I.D. × 15 cm in length; Mobile phase: hexane / EtOH / DEA, 50 / 50 / 0.1 (v / v / v) ； Flow rate: 1.0 mL / min; Wavelength: UV 214 nm; Temperature: 35 °C.

[0413] HPLC method C16 : Column: CHIRALPAK IC, 0.46 cm I.D. × 15 cm in length; Mobile phase: MeOH / MeCN, 90 / 10 (v / v); Flow rate: 1.0 mL / min; Wavelength: UV 214 nm; Temperature: 35 °C.

[0414] HPLC method C16A : Column: CHIRALPAK IC, 0.46 cm I.D. × 25 cm in length; Mobile phase: DCM / EtOAc / DEA, 85 / 15 / 0.1 (v / v / v); Flow rate: 1.0 mL / min; Wavelength: UV 254 nm; Temperature: 35 °C.

[0415] HPLC method C17 : Column: CHIRALPAK IC, 0.46 cm I.D. × 25 cm in length; Mobile phase: hexane / EtOH, 50 / 50 (v / v); Flow rate: 1.0 mL / min; Wavelength: UV 254 nm; Temperature: 35 °C.

[0416] HPLC method D1: Column: CHIRALPAK AD-H, 0.46 cm I.D. × 15 cm in length; mobile phase: EtOH / MeCN, 80 / 20 (v / v); flow rate: 1.0 mL / min; wavelength: UV 214 nm; temperature: 35 °C.

[0417] HPLC method D2 : Column: CHIRALPAK AD-H, 0.46 cm ID x 15 cm in length; mobile phase: hexane / EtOH, 70 / 30 (v / v); flow rate: 1.0 mL / min; wavelength: UV 214 nm; temperature: 35 °C.

[0418] HPLC method D3 : Column: CHIRALPAK AD-H, 0.46 cm ID x 15 cm in length; mobile phase: hexane / EtOH, 60 / 40 (v / v); flow rate: 1.0 mL / min; wavelength: UV 214 nm; temperature: 25 °C.

[0419] HPLC method E1 : Column: CHIRALPAK IE, 0.46 cm I.D. × 15 cm in length; mobile phase: hexane / EtOH, 70 / 30 (v / v); flow rate: 1.0 mL / min; wavelength: UV 214 nm; temperature: 25 °C.

[0420] HPLC method E2 : Column: CHIRALPAK IE, 0.46 cm I.D. × 15 cm in length; mobile phase: hexane / IPA, 70 / 30 (v / v); flow rate: 1.0 mL / min; wavelength: UV 254 nm; temperature: 35 °C.

[0421] HPLC method E7 : Column: CHIRALPAK IE, 0.46 cm I.D. × 25 cm in length; mobile phase: hexane / EtOH / DEA, 50 / 50 / 0.1 (v / v / v); flow rate: 1.0 mL / min; wavelength: UV 254 nm; temperature: 35 °C.

[0422] HPLC method F3 : Column: CHIRALPAK AS-H, 0.46 cm x 15 cm in length; mobile phase: hexane / EtOH, 85 / 15 (v / v); flow rate: 1.0 mL / min; wavelength: 254 nm; temperature: 35 °C.

[0423] HPLC method F5 : Column: CHIRALPAK AS-H, 0.46 cm x 15 cm in length; mobile phase: MeOH; flow rate: 1.0 mL / min; wavelength: 254 nm; temperature: 35 °C.

[0424] HPLC method G1 Column: CHIRALPAK OD-H, 0.46 cm x 15 cm in length; Mobile phase: hexane / IPA, 60 / 40 (v / v); Flow rate: 1.0 mL / min; Wavelength: 214 nm; Temperature: 25 °C.

[0425] HPLC method H2 Column: CHIRALCEL OZ-H, 0.46 cm x 15 cm in length; Mobile phase: hexane / EtOH, 50 / 50 (v / v); Flow rate: 1.0 mL / min; Wavelength: 214 nm; Temperature: 25 °C.

[0426] HPLC method M1 Column: RESTEK C18 (30x2.1) 3u; Temperature: 50 °C; Flow rate: 1.5 mL / min; Injection volume: 3 ul; Mobile phase A: 0.05% aqueous HCOOH solution; Mobile phase B: MeCN; Gradient elution (time, %A, %B): (0 min, 98% A, 2% B), (0.75 min, 98% A, 2% B), (1.0 min, 90% A, 10% B), (2.0 min, 2% A, 98% B), (2.25 min, 2% A, 98% B).

[0427] Preparation of intermediates

[0428] Preparation 1 : N'-(7-{[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethyl formimidamide

[0429]

[0430] Step 1: At 0 °C, under N2, to a solution of (1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)methanol (Preparation 102, 0.698 g, 3.324 mmol) in DCM (15 mL) was added SOCl2 (0.48 mL, 6.648 mmol). The mixture was stirred at room temperature for 1 hour and evaporated to dryness under vacuum to give 4-(chloromethyl)-1-(2,4-difluorophenyl)-1H-pyrazole as a brown oil (0.74 g, yield 93%). This material was used in the following reaction without further purification.

[0431] Step 2: To a solution of N,N-dimethyl-N'-{5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}methanimidamide (Preparation 17, 0.87 g, 2.591 mmol) in DMF (15 mL) was added Cs2CO3 (1.69 g, 5.182 mmol), and the mixture was stirred at room temperature for 5 minutes. At 0 °C, 4-(chloromethyl)-1-(2,4-difluorophenyl)-1H-pyrazole (Step 1, 0.74 g, 3.109 mmol) was added dropwise to the mixture, and the mixture was stirred at 60 °C for 4 hours. The reaction mixture was evaporated to dryness under vacuum, diluted with EtOAc (150 mL), washed with brine (2 × 100 mL) and dried (Na2SO4). The organic matter was evaporated to dryness under vacuum to give a residue, which was purified by silica gel column chromatography, eluting with a DCM (0%-5%) solution of MeOH to give the title compound as a yellow solid (750 mg, 54%). 1 1H NMR (400 MHz, DMSO-d6): 2.94 (s, 3H), 3.17 (s, 3H), 5.43 (s, 2H), 7.24 (t, 1H), 7.52 (t, 1H), 7.76 (t, 1H), 7.80 (s, 1H), 8.08 (s, 1H), 8.29 (s, 1H), 8.50 (s, 1H), 8.87 (s, 1H), 9.49 (s, 2H). LCMS m / z = 528.1 [M+H] +

[0432] Preparation 2 : N'-(7-{1-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylmethanimidamide

[0433]

[0434] To a solution of 1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethanol (869 mg, 4.2 mmol) in DCM (20 mL) at 0 °C was added SOCl2 (613 μL) and the solution was stirred at 40 °C for 2 h. The reaction mixture was evaporated to dryness, N,N-dimethyl-N'-[5-(2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl)formamidine (Preparation 17, 1.4 g, 4.2 mmol), Cs2CO3 (5.46 g, 16.8 mmol) and DMF (30 mL) were added, and the reaction was stirred at 80 °C for 14 h. The cooled mixture was poured into water (15 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound as an off-white solid (800 mg, 36%). LCMS m / z = 524.1 [MH] +

[0435] Preparation 3 : N'-(7-(1-(1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)ethyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine

[0436]

[0437] To a solution of 4-(1-chloroethyl)-1-(2,4-difluorophenyl)-1H-pyrazole (Preparation 146, 1.08 g, 4.45 mmol) in DMF (30 mL) were added (E)-N-methyl-N'-(5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)formamidine (Preparation 17, 0.99 g, 52.97 mmol) and Cs2CO3 (4.84 g, 14.85 mmol) and the mixture was stirred under N2 at 90 °C for 6 h. The reaction mixture was diluted with water and extracted (EtOAc). The combined extracts were washed (brine), dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by preparative HPLC to give the title compound (400 mg, 25%). LCMS m / z = 542.1 [MH] +

[0438] Preparation 4 : N'-(7-(1-(1-(2-fluorophenyl)-1H-pyrazol-4-yl)propyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine

[0439]

[0440] To a solution of 4-(1-chloropropyl)-1-(2-fluorophenyl)-1H-pyrazole (Preparation 100, 0.58 g, 2.42 mmol) in DMF (30 mL) was added N,N-dimethyl-N'-(5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)formamidine (Preparation 17, 0.54 g, 1.61 mmol) and Cs2CO3 (2.62 g, 8.05 mmol), and the reaction mixture was stirred overnight at 90 °C under nitrogen. The reaction was quenched with H2O, extracted with EtOAc (100 mL × 2), and the combined organic layers were washed with brine, dried and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH = 9:1) to give the title compound (0.3 g, 35%). 1 1H NMR (400 MHz, DMSO-d6): 0.80 (t, 3H), 2.31 (m, 2H), 2.95 (s, 3H), 3.17 (s, 3H), 5.97 (t, 1H), 7.30 - 7.50 (m, 3H), 7.74 (t, 1H), 7.90 (s, 1H), 8.21 (s, 1H), 8.31 (s, 1H), 8.47 (s, 1H), 8.87 (s, 1H), 9.52 (s, 2H). LCMS m / z = 538.1 [M+H] +

[0441] Preparation 5 : N'-(7-(1-(1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)propyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine

[0442]

[0443] Step 1: At 0 °C, SOCl2 (976 mg, 8.4 mmol) was added dropwise to a solution of 1-(1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)propan-1-ol (Preparation 104, 1.0 g, 4.2 mmol) in DCM (40 mL). The reaction mixture was stirred at room temperature for 3 h and evaporated to dryness to give 4-(1-chloropropyl)-1-(2,4-difluorophenyl)-1H-pyrazole (1.1 g, crude), as a brown oil, which was used directly in the next step without further purification. LCMS m / z = 253.2 [M+H] +

[0444] Step 2: To a mixture of N,N-dimethyl-N'-(5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)formamidine (Preparation 17, 1.44 g, 4.28 mmol) in DMF (30 mL) was added Cs2CO3 (6.95 g, 21.4 mmol) and 4-(1-chloropropyl)-1-(2,4-difluorophenyl)-1H-pyrazole (1.1 g, 4.28 mmol), and the mixture was stirred at 80 °C for 16 h. The solvent was evaporated under reduced pressure, and the residue was partitioned between water (50 mL) and EtOAc (30 mL). The layers were separated, and the aqueous phase was extracted with additional EtOAc (30 mL × 3). The combined organic extracts were dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography, eluting from 0 to 10% with methanol in dichloromethane over 20 min to give the title compound as a brown solid (650 mg, 27%, 2 steps). 1 1H NMR (400 MHz, DMSO-d6): 0.83 (t, 3H), 2.33 (q, 2H), 2.95 (s, 3H), 3.17 (s, 3H), 5.96 (q, 1H), 7.22 (t, 1H), 7.52 (m, 1H), 7.75 (m, 1H), 7.80 (s, 1H), 8.20 (s, 1H), 8.28 (s, 1H), 8.46 (s, 1H), 8.87 (s, 1H), 9.52 (s, 2H). LCMS m / z = 556.2 [M+H] +

[0445] Preparation 6 : N'-{5-(4-methoxypyrimidin-5-yl)-7-[1-(1-phenyl-1H-1,2,3-triazol-4-yl)propyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-N,N-dimethylformamidine

[0446]

[0447] To a stirred solution of N'-[5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N,N-dimethylformimidamide (Preparation 19, 1 g, 3.36 mmol) and 4-(1-chloropropyl)-1-phenyl-1H-1,2,3-triazole (Preparation 119, 895 mg, 4.06 mmol) in DMF (20 mL) was added Cs2CO3 (2.74 g, 8.41 mmol)) and the reaction mixture was stirred at 60 °C for 5 h. The cooled reaction mixture was diluted with EtOAc, washed with water and then with brine. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with MeOH:DCM (3:97) to give the title compound as an off-white solid (1 g, 61.7%). 1 1H NMR (400 MHz, DMSO-d6): 0.85 (t, 3H), 2.38 (m, 2H), 2.75 (s, 3H), 3.10 (s, 3H), 3.87 (s, 3H), 6.11 (m, 1H), 7.48 (m, 1H), 7.59 (m, 2H), 7.71 (s, 1H), 7.88 (d, 1H), 8.41 (s, 1H), 8.67 (s 1H), 8.72 (d, 2H), 8.95 (s, 1H). LCMS m / z = 482.8 [M+H] +

[0448] Preparation 7 : N'-(7-(1-(2-(2,4-difluorophenyl)-2H-imidazol-4-yl)propyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine

[0449]

[0450] Step 1: SOCl2 (5 mL) was added dropwise to a solution of 1-(2-(2,4-difluorophenyl)-1H-imidazol-4-yl)propan-1-ol (Preparation 137, 1.4 g, 5.88 mmol) in DCM (50 mL). The reaction mixture was stirred at room temperature for 2 h and evaporated to dryness in vacuo to give 4-(1-chloropropyl)-2-(2,4-difluorophenyl)-1H-imidazole, which was used directly in Step 2 (1.4 g, 92%).

[0451] Step 2: To a solution of N,N-dimethyl-N'-(5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)formamidine (Preparation 17, 1.22 g, 3.64 mmol) in DMF (50 mL) was added 4-(1-chloropropyl)-2-(2,4-difluorophenyl)-1H-imidazole (Step 1, 1.4 g, 5.45 mmol) and Cs2CO3 (5.93 g, 18.2 mmol). The reaction mixture was stirred at 90 °C overnight, cooled and extracted with EtOAc. The organic layer was washed with brine, dried and evaporated. The residue was purified by silica gel column chromatography (DCM:MeOH = 9:1) to give the title compound (450 mg, 22%). LCMS m / z = 556.1 [MH] +

[0452] Preparation 8 : N'-(7-(1-(1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)ethyl)-5-(2-(trifluoromethyl))pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine

[0453]

[0454] To a solution of N,N-dimethyl-N'-(5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)formamidine (Preparation 17, 839 mg, 2.5 mmol) in DMF (30 mL) was added Cs2CO3 (3.25 g, 10 mmol) and 4-(1-chloroethyl)-1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazole (Preparation 114, 600 mg, 2.5 mmol). The mixture was stirred at 80 °C for 16 h, then the cooled reaction mixture was poured into water (20 mL) and extracted with EtOAc (15 mL×3). The combined extracts were washed with brine (10 mL), dried (Na2SO4) and evaporated to dryness in vacuo. The residue was triturated with pet.ether to give the title compound as a brown solid (900 mg, 66%). LCMS m / z = 539.1 [MH +

[0455] Preparation 9 : N'-(7-(1-(1-(2,4-difluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)propyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine

[0456] ​

[0457] To a solution of 4-(1-chloropropyl)-1-(2,4-difluorophenyl)-5-methyl-1H-1,2,3-triazole (Preparation 111, 2.2 g, 8.83 mmol) in DMF (80 mL) was added N,N-dimethyl-N'-(5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)formamidine (Preparation 17, 2.96 g, 8.83 mmol) and Cs2CO3 (11.5 g, 35.32 mmol). The reaction mixture was stirred at 80 °C for 5 h, poured into water (100 mL) and extracted with EtOAc (50 mL × 3). The organic extract was washed (brine, 100 mL), dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by combi-flash, eluting with EtOAc (20 - 80%) in pet. ether to give the title compound as an off-white solid (2.8 g, 55%). 1 1H NMR (400 MHz, MeOD-d4): 0.87 (t, 3H), 2.44 (m, 2H), 2.76 (s, 3H), 2.89 (s, 6H), 6.04 (t, 1H), 7.11 (m, 1H), 7.24 (m, 1H), 7.52 (m, 1H), 7.88 (s, 1H), 8.34 (s, 1H), 8.58 (s, 1H), 9.29 (s, 2H). LCMS m / z = 571 [M+H]+ +

[0458] Preparation 10 : N'-(7-((1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-(6-methoxypyridin-3-yl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine

[0459]

[0460] To a solution of N'-(5-(6-methoxypyridin-3-yl)-6-methyl-7-(prop-2-ynyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine (Preparation 11, 0.23 g, 0.66 mmol) in toluene (20 mL) was added t-BuOH (5 mL), DIPEA (2 mL), 1-azido-2,4-difluorobenzene (0.26 g, 1.65 mmol) and CuI (76 mg, 0.40 mmol) under N2. The reaction mixture was stirred overnight at room temperature, water was added and the mixture was extracted with EtOAc. The organic layer was collected, washed with brine, dried and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH = 9 / 1) to give the title compound as a solid (0.22 g, 66.2%). 1 1H NMR (400 MHz, DMSO-d6): 2.50 (s, 3H), 2.79 (s, 3H), 3.06 (s, 3H), 3.87 (s, 3H), 5.67 (s, 2H), 6.83 (d, 1H), 7.33 (m, 1H), 7.65 (m, 1H), 7.75 - 7.90 (m, 2H), 8.19 (s, 1H), 8.61 (s, 1H), 8.68 (s, 2H).

[0461] Preparation 11 : N'-(5-(6-methoxypyridin-3-yl)-6-methyl-7-(prop-2-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine

[0462]

[0463] To a solution of N'-(5-(6-methoxypyridin-3-yl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine (Preparation 12, 0.42 g, 1.35 mmol) in DMF (25 mL) was added NaH (60%, 81 mg, 2.03 mmol) portionwise and stirred for 10 minutes. 3-Bromoprop-1-yne (0.24 g, 2.03 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction was carefully quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography (EtOAc / MeOH = 10 / 1) to give the title compound (0.23 g, 48.9%) as a grey solid. LCMS m / z = 349.2 [M+H]+ +

[0464] Preparation 12: N'-(5-(6-Methoxypyridin-3-yl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine

[0465]

[0466] A solution of 5-(6-methoxypyridin-3-yl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 23, 0.45 g, 1.7 mmol) in DMF-DMA (30 mL) was stirred at 100 °C for 2 h. The mixture was evaporated to dryness in vacuo and the residue was diluted with EtOAc and NaHCO3 solution. The organic layer was washed with brine, dried and evaporated to dryness to give the title compound (0.42 g, 79.6%) as a solid. LCMS m / z = 311.2 [MH] + ; RT [HPLC Method A] = 1.183 min.

[0467] Preparation 13: N'-[7-(But-3-yn-2-yl)-5-(4-chlorophenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N,N-dimethylimidamide

[0468]

[0469] Sodium ethoxide (66.4 mg, 0.96 mmol) was added to a solution of N'-[7-(but-3-yn-2-yl)-5-(4-chlorophenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N,N-dimethylimidamide (Preparation 14, 200 mg, 0.637 mmol) in anhydrous DMF (4 mL) under ice-cooling and the mixture was stirred for 30 min. 3-Bromo-1-butyne (0.134 mL, 1.27 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with EtOAc:heptane (20:80 to 100:0) to give the title compound as an oil. LCMS m / z = 366.1 [MH] +

[0470] Preparation 14 : N'-(5-(4-Chlorophenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine

[0471]

[0472] A solution of 5-(4-chlorophenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 79, 300 mg, 1.16 mmol) in N,N-dimethylformamide dimethyl acetal (4.8 mL) was stirred at room temperature for 1 hour and then at 50 °C for an additional 16 hours. The cooled mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure to give the title compound as an off-white solid (350 mg, 96.2%). LCMS m / z = 314.1 [MH] +

[0473] Preparation 15 : N'-(7-(but-3-yn-2-yl)-5-(4-chlorophenyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine

[0474]

[0475] At 0 °C, NaH (9.56 mg, 0.24 mmol) was added to a stirred solution of N'-(5-(4-chlorophenyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine (Preparation 16, 50 mg, 0.16 mmol) in DMF (1.5 mL). After 15 minutes, 3-bromo-but-1-yne (0.022 mL, 0.24 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by preparative TLC using 50% EtOAc:hexane to give the title compound as an off-white solid (30 mg, 51.5%). 1 1H NMR (400 MHz, CDCl3): 1.79 (d, 3H), 2.43 (s, 3H), 2.77 (s, 3H), 3.00 (s, 3H), 6.14 (m, 2H), 7.32 (d, 2H), 7.39 (d, 2H), 8.45 (s, 1H), 8.50 (brs, 1H).

[0476] Preparation 16 : N'-(5-(4-chlorophenyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine

[0477]

[0478] At 0 °C, N,N-dimethylformamide dimethyl acetal (2.0 mL) was added to 5-(4-chlorophenyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 24, 100.0 mg, 0.4 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated to dryness, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and evaporated in vacuo to give the title compound as a light brown solid (80.0 mg, 66%). LCMS m / z = 314.2 [MH] +

[0479] Preparation 17 : N,N-dimethyl-N'-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl)formamidine

[0480]

[0481] A solution of 5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 18, 24 g, 85.7 mmol) in DMF-DMA (300 mL) was heated to 100 °C for 3 hours. The cooled mixture was concentrated in vacuo, and the crude product was purified by silica gel column chromatography, eluting with DCM:MeOH = 20:1 to give the title compound (25 g, 87%) as a yellow solid. 1 1H NMR (400 MHz, DMSO-d6): 2.96 (s, 3H), 3.16 (s, 3H), 7.92 (s, 1H), 8.39 (s, 1H), 8.86 (s, 1H), 9.52 (s, 2H). LCMS m / z = 336.1 [MH] +

[0482] Preparation 18 : 5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0483]

[0484] To a solution of 5-[2-(trifluoromethyl)pyrimidin-5-yl]-7-{[(2-trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 25, 38 g, 92.7 mmol) in DCM (200 mL) was slowly added TFA (100 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and the pH was adjusted to 8 with aqueous ammonia. The resulting mixture was stirred for 16 hours and filtered to give the title compound (24 g, 92%) as a yellow solid. 1HNMR(400MHz, DMSO-d6): δ 6.53 (s, 2H), 7.61 (s, 1H), 8.18 (s, 1H), 9.06 (s, 2H). LCMS m / z = 243.4, 245.2 [M+H] +

[0485] Preparation 19 : N'-[5-(4-Methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-N,N-dimethylformimidamide

[0486]

[0487] The stirred solution of 5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 20, 3 g, 12.38 mmol) in DMF-DMA (45 mL) was heated at 60 °C for 12 h. The cooled reaction mixture was concentrated in vacuo, and the product was washed with hexane to give the title compound as a gray solid (3 g, 81.5%). 1 HNMR(400MHz, DMSO-d6): δ 2.77 (s, 3H), 3.10 (s, 3H), 3.90 (s, 3H), 7.48 (s, 1H), 8.30 (s, 1H), 8.66 (s, 1H), 8.73 (s, 1H), 8.74 (s, 1H), 11.98 (s, 1H). LCMS m / z = 298.1 [M+H] +

[0488] Preparation 20 : 5-(4-Methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0489]

[0490] To a stirred solution of 5-(4-methoxypyrimidin-5-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 27, 32 g, 85.90 mmol) in DCM (300 mL) at 0 °C was added TFA (131.5 mL, 1718.1 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo, the residue was diluted with MeOH, and ammonia (150 mL) was added. The resulting solution was stirred at room temperature for 12 h, then the reaction mixture was concentrated and filtered. The resulting solid was washed with water, then with 10% MeOH:DCM, and dried in vacuo to give the title compound as a gray solid (18.2 g, 87.5%). 1HNMR(400MHz, DMSO-d6): 3.94(s, 3H), 6.14(br s, 2H), 7.26(s, 1H), 8.08(s, 1H), 8.41(s, 1H), 8.75(s, 1H), 11.82(s, 1H). LCMS m / z=243.2[MH] +

[0491] Preparation 21 : N'-(5-(2-Methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine

[0492]

[0493] A solution of 5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 22, 1 g, 4.145 mmol) in DMF-DMA (20 mL) was stirred at 60 °C for 6 h. The reaction mixture was evaporated under reduced pressure and the resulting solid was triturated with Et2O to afford the title compound as a light brown solid (900 mg, 73%). 1 HNMR(400MHz, DMSO-d6): 2.74(s, 3H), 3.09(s, 3H), 3.80(s, 3H), 6.98(dd, 1H), 7.39(s, 1H), 7.92(d, 1H), 8.05(d, 1H), 8.31(s, 1H), 8.67(s, 1H), 11.83(s, 1H). LCMS m / z=297.4[MH] +

[0494] Preparation 22 : 5-(2-Methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0495]

[0496] The title compound was obtained as a white solid (11 g, 84.5%) from 5-(2-methoxypyridin-3-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 26, 20 g, 53.77 mmol) according to a procedure similar to that described in Preparation 190. 1HNMR(400MHz, DMSO-d6): 3.87 (s, 3H), 5.91 (br s, 2H), 7.07 (m, 1H), 7.20 (s, 1H), 7.63 (m, 1H), 8.08 (s, 1H), 8.16 (m, 1H), 11.79 (s, 1H). LCMS m / z=242.0 [MH] +

[0497] Preparation 23 : 5-(6-Methoxypyridin-3-yl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0498]

[0499] A 25% TFA in DCM solution (30 mL) of 5-(6-methoxypyridin-3-yl)-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 28, 0.8 g, 2.1 mmol) was stirred overnight at room temperature. The mixture was concentrated and an excess of NaHCO3 solution was added. The mixture was extracted with DCM, and the combined organic layers were washed with brine, dried and evaporated to dryness. The residue was washed with TBME to give the title compound (0.45 g, 83.9%) as a grey solid. LCMS m / z=256.2 [MH] +

[0500] Preparation 24 : 5-(4-Chlorophenyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0501]

[0502] TFA (2.4 mL, 30.7 mmol) was added to a stirred solution of 5-(4-chlorophenyl)-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 29, 400 mg, 1.023 mmol) in DCM (10.0 mL) at 0 °C and the mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness under reduced pressure, the residue was dissolved in methanol (3 mL) and treated with NH4OH (6 mL), and the mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness in vacuo to give the title compound as a brown solid (200 mg, 75%). LCMS m / z=259.0 [MH] +

[0503] Preparation 25: 5-[2-(Trifluoromethyl)pyrimidin-5-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0504]

[0505] At room temperature under N2, a solution of K2CO3 (30 g, 217 mmol) in H2O (40 mL) and PdCl2(dppf) (8.1 g, 11.1 mmol) was added to a solution of 5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 33, 43 g, 110 mmol) and 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (36.2 g, 132 mmol) in 1,4-dioxane (220 mL), and the reaction was stirred at 100 °C for 4 h. The cooled reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using petroleum ether:EtOAc (50:50) to give the title compound (38 g, 84%) as a yellow solid. 1 HNMR (400 MHz, DMSO-d6): 0.00 (s, 9H), 0.93 (t, 2H), 3.64 (t, 2H), 5.64 (s, 2H), 6.73 (br s, 2H), 7.88 (s, 1H), 8.31 (s, 1H), 9.13 (s, 2H). LCMS m / z = 411.1 [MH] +

[0506] Preparation 26 : 5-(2-Methoxypyridin-3-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0507]

[0508] To a stirred solution of 5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 33, 25 g, 64.05 mmol) in EtOH:water (4:1, 750 mL) was added 2-methoxypyridin-3-ylboronic acid (14.69 g, 96.08 mmol), then Na2CO3 (27.15 g, 256.21 mmol), and the mixture was degassed with Ar for 15 minutes. Pd(PPh3)4 (7.39 g, 6.4 mmol) was added and the reaction was heated at 100 °C for 3 hours. The cooled mixture was diluted with water and the solution was extracted with EtOAc. The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the title compound (40 g, 79%, for composite batch) as a white solid. 1 1H NMR (400 MHz, DMSO-d6): -0.08 (s, 9H), 0.84 (t, 2H), 3.56 (t, 2H), 3.87 (s, 3H), 5.52 (s, 2H), 6.06 (br s, 2H), 7.10 (m, 1H), 7.39 (s, 1H), 7.55 - 7.64 (m, 2H), 8.15 (s, 1H). LCMS m / z = 372.4 [M+H]+ +

[0509] Preparation 27 : 5-(4-Methoxypyrimidin-5-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0510]

[0511] To a stirred solution of 5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 33, 35 g, 89.68 mmol) in EtOH:water (1.4 L, 4:1) was added 4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (25.4 g, 107.61 mmol), then Na2CO3 (28.51 g, 269.0 mmol), and the reaction mixture was degassed with Ar for 15 minutes. Pd(PPh3)4 (10.36 g, 8.97 mmol) was added and the reactants were stirred at 100 °C for 5 h. The cooled mixture was diluted with water and extracted with DCM. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with acetone-DCM (30:70) to afford the title compound as an off-white solid (17.81 g, 53.4%). 1 1H NMR (400 MHz, DMSO-d6): 0.07 (s, 9H), 0.84 (t, 2H), 3.58 (t, 2H), 3.94 (s, 3H), 5.52 (s, 2H), 6.34 (br s, 2H), 7.46 (s, 1H), 8.15 (s, 1H), 8.40 (s, 1H), 8.77 (s, 1H). LCMS m / z = 373.0 [M+H]+ +

[0512] Preparation 28 : 5-(6-methoxypyridin-3-yl)-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0513]

[0514] To a solution of 5-iodo-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 34, 1.5 g, 3.7 mmol) in dioxane (60 mL) was added 6-methoxypyridin-3-ylboronic acid (0.85 g, 5.6 mmol), NaHCO3 solution (15 mL) and Pd(PPh3)4 (0.21 g, 0.185 mmol), and the reactants were stirred overnight at 100 °C in N2. The cooled reaction mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried and evaporated to dryness. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 3:1) to afford the title compound as a yellow solid (0.8 g, 56.1%). 1HNMR (400 MHz, CDCl3): δ 0.00 (s, 9H), 0.98 (t, 2H), 2.42 (s, 3H), 3.64 (t, 2H), 4.05 (s, 3H), 5.68 (s, 2H), 6.92 (d, 1H), 7.45 - 7.75 (m, 3H), 8.26 (s, 1H), 8.33 (s, 1H). LCMS m / z = 256.2 [M+H] +

[0515] Preparation 29 : 5-(4-Chlorophenyl)-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0516]

[0517] To a degassed solution of 5-iodo-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 34, 800 mg, 1.97 mmol), 4-chlorophenylboronic acid (433.2 mg, 2.77 mmol) and Na2CO3 (838.8 mg, 7.92 mmol) in EtOH - water (4:1, 20 mL) under N2 was added Pd(PPh3)4 (71.5 mg, 0.062 mmol) and the reaction mixture was degassed with Ar for 15 minutes. The reaction was heated at 90 °C for 5 hours, filtered through a plug and washed with EtOAc (2 × 30 mL). The combined filtrates were washed with water, dried (Na2SO4), and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography (hexane solution of 20 - 25% EtOAc) to give the title compound as a pale yellow solid (400 mg, 51.98%). 1 HNMR (400 MHz, DMSO-d6): δ -0.09 (s, 9H), 0.84 (t, 2H), 2.31 (s, 3H), 3.52 (t, 2H), 5.58 (s, 2H), 5.80 (br s, 2H), 7.36 (d, 2H), 7.54 (d, 2H), 8.13 (s, 1H). LCMS m / z = 389.0 [M+H] +

[0518] Preparation 30 : N'-(7-((5-(2-Fluorophenyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)methyl)-5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine

[0519]

[0520] To a solution of stirred N'-(5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine (Preparation 21, 100 mg, 0.337 mmol) in DMF was added Cs2CO3 (220.02 mg, 0.675 mmol), then 3-(chloromethyl)-5-(2-fluorophenyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole (Preparation 121, 172.6 mg, 0.506 mmol, isomer mixture), and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ice water and extracted with EtOAc (30 mL × 2). The combined extracts were washed with water, brine, dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography to give the title compound as a viscous yellow solid (160 mg, 78%, a mixture of two isomers). The isomer mixture can be used without further purification. LCMS m / z = 602 [MH]+ +

[0521] Preparation 31 : N'-(5-(2-methoxypyridin-3-yl)-7-((5-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazol-3-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine

[0522]

[0523] The title compound (140 mg, 71%) as a mixture of isomers was prepared in a similar manner to Preparation 30 using 3-(chloromethyl)-5-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole (Preparation 122, 163.5 mg, 0.506 mmol) and N'-(5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine (Preparation 21, 100 mg, 0.337 mmol). 1HNMR(400MHz, DMSO-d6): -0.09(s, 6H), 0.79(t, 2H), 3.08(s, 3H), 3.57(t, 2H), 3.80(s, 3H), 5.75(s, 2H), 6.98(m, 1H), 7.41 - 7.46(m, 3H), 7.60(s, 1H), 7.95(m, 3H), 8.05(m, 1H), 8.37(s, 1H), 8.71(s, 1H). LCMS m / z=584.2[MH] +

[0524] Preparation 32 : N'-(7-((1-(2-Fluorophenyl)-1H-pyrazol-4-yl)methyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine

[0525]

[0526] A mixture of 7-((1-(2-Fluorophenyl)-1H-pyrazol-4-yl)methyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 57, 160 mg, 0.352 mmol) in DMF-DMA (8 mL) was stirred at 90 °C for 0.5 h. The mixture was concentrated to give the crude product, which was purified by combi-flash on a silica column, eluting with a DCM solution of MeOH (0%-5%) to give the title compound as an orange solid (110 mg, 61%). 1 HNMR(400MHz, DMSO-d6): -0.09(s, 9H), 0.84(t, 2H), 2.31(s, 3H), 3.52(t, 2H), 5.58(s, 2H), 5.80(br s, 2H), 7.36(d, 2H), 7.54(d, 2H), 8.13(s, 1H). LCMS m / z=510.1[MH] +

[0527] Preparation 33 : 5-Iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0528]

[0529] To a stirred solution of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (Preparation 72, 40 g, 97.8 mmol) in dioxane:MeOH (110 mL, 5:1) was added NH4OH (aq) (570 mL) and the resulting suspension was stirred in an autoclave at 70 °C for 2 h and then at 90 °C for 16 h. The cooled reaction mixture was diluted with DCM, the layers were separated, the organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude product was triturated with ether and dried under reduced pressure to give the title compound as an off-white solid (32 g, 83.84 %). 1 1H NMR (400 MHz, DMSO-d6): 0.09 (s, 9H), 0.82 (t, 2H), 3.48 (t, 2H), 5.44 (s, 2H), 6.66 (br s, 2H), 7.56 (s, 1H), 8.12 (s, 1H). LCMS m / z = 391.0 [M+H] +

[0530] Preparation 34 : 5-Iodo-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0531]

[0532] NH4OH was added to a stirred solution of 4-chloro-5-iodo-6-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Preparation 73, 1 g, 2.36 mmol) in dioxane (25.0 mL) (75 mL), and the mixture was heated to 120 °C for 16 h. The reaction was evaporated to dryness in vacuo, extracted with EtOAc (3 × 25 mL), washed with water and brine, dried (Na2SO4) and evaporated to dryness. The residue was purified by column chromatography to give the title compound as an off-white solid (400 mg, 42.11 %). 1 1H NMR (400 MHz, DMSO-d6): -0.10 (s, 9H), 0.82 (t, 2H), 2.38 (s, 3H), 3.45 (t, 2H), 5.54 (s, 2H), 6.58 (br s, 2H), 8.09 (s, 1H). LCMS m / z = 405.2 [M+H] +

[0533] Preparation 35: 4-Chloro-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0534]

[0535] Suspend (4-chloro-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)boronic acid (Preparation 61, 340 mg, 0.88 mmol), powdered NiI (40 mg, 0.12 mmol), and trans-2-aminocyclohexanol (20 mg, 0.12 mmol) in anhydrous iPrOH (1.25 mL) and DMSO (1.75 mL). Add NaHMDS (1 M solution in THF, 0.97 mL, 0.97 mmol), degas the suspension under N2, add a solution of iodo-oxetane (70 μL, 0.79 mmol) in anhydrous iPrOH (0.5 mL), and heat the reaction mixture under microwave irradiation at 80 °C for 30 minutes. Partition the mixture between water and EtOAc, separate the layers, extract the aqueous layer with EtOAc, dry the combined organics (MgSO4), filter, and concentrate in vacuo. Purify the crude yellow oil by silica gel column chromatography, eluting with EtOAc:heptane (50:50 to 100:0) to afford the title compound as a yellow oil (77.4 mg, 14%). 1 1H NMR (400 MHz, DMSO-d6): 1.98 (d, 3H), 4.50 - 4.60 (m, 3H), 5.04 (m, 2H), 6.38 (q, 1H), 7.45 (m, 1H), 7.54 - 7.62 (m, 2H), 7.73 (m, 1H), 8.17 (s, 1H), 8.70 (s, 2H). LCMS m / z = 399.0 [M+H] +

[0536] Preparation 36 : 4-Chloro-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[4-methoxy-2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine

[0537]

[0538] A suspension of (4-chloro-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)boronic acid (Preparation 61, 35 mg, 0.074 mmol), 5-bromo-4-methoxy-2-(trifluoromethyl)pyrimidine (Preparation 141, 19 mg, 0.074 mmol) and Na2CO3 (32 mg, 0.3 mmol) in EtOH (4.5 mL) and H2O (0.5 mL) was degassed with N2. Pd(PPh3)4 (8 mg) was added and the reaction mixture was stirred at about 90 °C for 2 h. The solvent was blown off under a stream of N2, the residue was partitioned between water and EtOAc, the layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo to give the title compound in quantitative yield. The product was used without further purification. LCMS m / z = 519.0 [MH] +

[0539] Preparation 37 : 4-chloro-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(3-methoxypyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0540]

[0541] A suspension of 4-chloro-7-(1-(1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)propyl)-5-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (Preparation 63, 827 mg, 1.71 mmol), 2-chloro-3-methoxypyrazine (521 mg, 3.61 mmol) and Na2CO3 (726 mg, 6.85 mmol) in EtOH (9 mL) and H2O (1.5 mL) was degassed under N2. Pd(PPh3)4 (198 mg, 0.17 mmol) was added and the reaction mixture was stirred at 90 °C. The cooled reaction mixture was partitioned between water and EtOAc, the layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated to give a yellow oil. It was purified by silica gel column chromatography, eluting with EtOAc:DCM (40:60 to 100:0) to give the title compound as an off-white foam (370 mg, 46.6 %). 1HNMR(400MHz, DMSO-d6): 0.86(t, 3H), 2.48(m, 2H), 3.90(s, 3H), 6.25(m, 1H), 7.45(m, 1H), 7.52 - 7.62(m, 2H), 7.84(m, 1H), 8.22 - 8.30(m, 3H), 8.78(s, 1H), 8.82(d, 1H). LCMS m / z=465.1[MH] +

[0542] Preparation 38 : 5-(4-Chlorophenyl)-7-(1H-pyrazol-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0543]

[0544] To a solution of 5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 80, 5.43 g, 22.2 mmol) in DMF (120 mL) was added Cs2CO3 (14.5 g, 44.4 mmol) and 4-(chloromethyl)-1H-pyrazole hydrochloride (5.1 g, 33.3 mmol), and the reaction mixture was heated at 60 °C for 12 h. The cooled mixture was diluted with water, extracted with EtOAc, and the organic phase was washed with brine and dried (Na2SO4). The residue was purified by silica gel column chromatography, eluting with DCM:MeOH (15:1) to give the title compound as a white solid (1.1 g, 15% yield). 1 HNMR(400MHz, DMSO-d6): 5.24(s, 2H), 6.17(br s, 2H), 7.40 - 7.76(m, 7H), 8.19(s, 1H), 12.81(s, 1H). LCMS m / z=325.2[MH] +

[0545] Preparation 39 : 5-(2-Methoxypyridin-3-yl)-7-(1H-pyrazol-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0546]

[0547] To a stirred solution of 5-(2-methoxypyridin-3-yl)-7-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 40, 22 g, 48.78 mmol) in DCM (300 mL) at 0 °C was added TFA (37.35 mL, 487.8 mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and diluted with cold water. Ammonia water was added and the solution was stirred at room temperature for 24 h. The resulting mixture was filtered, the solid was washed with water, then with ether and dried in vacuo. The solid was suspended in DCM / MeOH and purified by passing through a bed of neutral alumina to afford the title compound as a white solid (10 g, 67.7%). 1 HNMR(400MHz,DMSO-d6):3.85(s,3H),5.21(s,2H),5.98(br s,2H),7.06(m,1H),7.32(s,1H),7.43-7.77(m,3H),8.16(s,2H),12.76(s,1H).LCMS m / z=323[MH] +

[0548] Preparation 40 : 5-(2-methoxypyridin-3-yl)-7-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0549]

[0550] To a stirred solution of 5-iodo-7-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 74, 35 g, 74.4 mmol) in EtOH: water (4:1, 875 mL) was added 2-methoxypyridin-3-ylboronic acid (17.07 g, 111.61 mmol), then Na2CO3 (31.54 g, 297.62 mmol), and the mixture was degassed with Ar for 15 min. Pd(PPh3)4 (8.59 g, 7.44 mmol) was added and the reaction mixture was heated at 100 °C for 3 h. The cooled reaction mixture was diluted with water, the solution was extracted with EtOAc, the combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford the title compound (22 g, 65.5%) as an off-white solid. 1HNMR(400MHz, DMSO-d6): -0.12(s, 9H), 0.78(t, 2H), 3.47(t, 2H), 3.85(s, 3H), 5.23(s, 2H), 5.33(s, 2H), 6.00(br s, 2H), 7.06(m, 1H), 7.32(s, 1H), 7.56(s, 1H), 7.61(m, 1H), 7.89(s, 1H), 8.16(s, 2H). LCMS m / z=452.0[MH] +

[0551] Preparation 41 : 7-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0552]

[0553] A mixture of 5-iodo-7-(prop-2-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 85, 60 g, 0.201 mol), CuI (21.08 g, 0.11 mol), DIPEA (347.4 mL, 2.01 mol) and 1-azido-2-fluorobenzene (56.92 g, 0.362 mol) in toluene (1.9 L) and t-BuOH (480 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with hexane (500 mL) and the mixture was filtered under reduced pressure. The resulting solid was suspended in saturated methanol NH3:DCM (1:5, 2 L) and filtered, washed with saturated methanol NH3:DCM (1:5, 5×500 mL). The filtrate was concentrated under reduced pressure, the residue was triturated with ether (200 mL), filtered and dried to give the title compound as a pale yellow solid (40 g, 45.9%). filtered, washed with saturated methanol NH3:DCM (1:5, 5×500 mL). The filtrate was concentrated under reduced pressure, the residue was triturated with ether (200 mL), filtered and dried to give the title compound as a pale yellow solid (40 g, 45.9%). 1 HNMR(400MHz, DMSO-d6): 5.50(s, 2H), 6.64(br s, 2H), 7.41(m, 1H), 7.53 - 7.63(m, 3H), 7.79(m, 1H), 8.14(s, 1H), 8.57(s, 1H). LCMS m / z=436.0[MH] +

[0554] Preparation 42 : 7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0555]

[0556] To a stirred solution of 7-(but-3-yn-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 86, 19 g, 60.88 mmol) in toluene (37.5 mL) at room temperature was added t-BuOH (12.5 mL), CuI (5.80 g, 30.44 mmol) and DIPEA (99.75 mL, 547.88 mmol). The mixture was cooled to 0 °C, 1-azido-2-fluorobenzene (14.39 g, 103.49 mmol) was added and the reaction was stirred at room temperature for 16 h. The mixture was filtered and the resulting solid was suspended in hot THF, the mixture was filtered to give the crude. The material was washed with Et2O and dried in vacuo to give the title compound as a brown solid (22.2 g, 81.17%). 1 HNMR (400 MHz, DMSO-d6): 1.87 (d, 3H), 6.21 - 6.26 (m, 1H), 6.62 - 6.76 (brs, 2H), 7.43 (m, 1H), 7.54 - 7.63 (m, 3H), 7.80 - 7.84 (m, 1H), 8.17 - 8.29 (m, 1H), 8.64 (s, 1H). LCMS m / z = 450.0 [MH] +

[0557] Preparation 43 : 7-{1-[1-(3-fluoropyridin-2-yl)-1H-1,2,3-triazol-4-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0558]

[0559] Under N2 at 0 °C, 2-azido-3-fluoropyridine (Preparation 144, 624.16 mg, 4.49 mmol), DIPEA (4.02 mL, 22.44 mmol) and CuI (235 mg, 1.23 mmol)) were added successively to a stirred solution of 7-(but-3-yn-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 86, 700 mg, 2.24 mmol) in a mixture of toluene:tBuOH (3:1) (70 mL), and the reaction was stirred at room temperature for 24 h. The mixture was diluted with EtOAc, washed with water and then with brine. The organic layer was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with MeOH:DCM (4:96) to give the title compound as an off-white solid (250 mg, 24.75%). 1HNMR(400MHz, DMSO-d6): 1.88(d, 3H), 6.22 - 6.27(m, 1H), 6.63(br s, 2H), 7.60(s, 1H), 7.69 - 7.73(m, 1H), 8.13 - 8.17(m, 2H), 8.48(m, 1H), 8.72(s, 1H). LCMS m / z=450.8[MH] +

[0560] Preparation 44 : 7-{1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0561]

[0562] Following a procedure similar to that described in Preparation 43, the title compound was obtained as a white solid (2.7 g, 72%) from 7-(but-3-yn-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 86) and 1-azido-2,4-difluorobenzene 1 HNMR(400MHz, DMSO-d6): 1.89(d, 3H), 6.24(m, 1H), 6.70 - 6.90(br s, 2H), 7.33(m, 1H), 7.59(s, 1H), 7.68(m, 1H), 7.88(m, 1H), 8.40(s, 1H), 8.64(s, 1H). LCMS m / z=468.0[MH] +

[0563] Preparation 45 : 7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0564]

[0565] At 0 °C, DIPEA (15 mL, 82.8 mmol) and CuI (876 mg, 4.6 mmol) were added to a solution of 5-iodo-7-(pent-1-yn-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 87, 3 g, 9.2 mmol) in toluene:t-BuOH (100 mL, 4:1), then 1-azido-2-fluorobenzene (2.2 g, 16.06 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The mixture was filtered, washed with ether:hexane (1:4), and the filtrate was evaporated under reduced pressure to give the title compound as a light brown solid (3 g, 96.15%). 1HNMR(400MHz, DMSO-d6): 0.80(t, 3H), 2.32(m, 2H), 6.04(m, 1H), 6.64(br s, 2H), 7.44(m, 1H), 7.55 - 7.67(m, 4H), 7.85(m, 1H), 8.15(s, 1H), 8.48(s, 1H). LCMS m / z=463.9[MH] +

[0566] Preparation 46 : 7-{1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0567]

[0568] To a solution of 5-iodo-7-(pent-1-yn-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 87, 70 g, 214.85 mmol) in toluene (100 ml) was added 1-azido-2,4-difluorobenzene (50 g, 322.25 mmol), and CuI (24.55 g, 128.9 mmol), DIPEA (177.5 ml, 1.07 mol) and t-BuOH (750 ml) were added under N2, and the reaction mixture was stirred at room temperature for 16 h. The mixture was filtered, concentrated in vacuo, and the residue was purified by flash chromatography (eluting with DCM:MeOH = 20:1) to give the title compound as a white solid (70 g, 67.8%). 1 HNMR(400MHz, DMSO-d6): 0.79(t, 3H), 2.31(m, 2H), 6.00(m, 1H), 6.65(br s, 2H), 7.35(m, 1H), 7.61(s, 1H), 7.69(m, 1H), 7.90(m, 1H), 8.14(s, 1H), 8.67(d, 1H). LCMS m / z=482.0[MH] +

[0569] Preparation 47 to 53

[0570] Following the procedure described in Preparation 46, the following compounds were prepared from 5-iodo-7-(pent-1-yn-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 87) and the appropriate commercially available azides.

[0571]

[0572]

[0573] Preparation 54 : 7-((1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-iodo-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0574]

[0575] At 0 °C, to a solution of 5-iodo-2-methyl-7-prop-2-ynyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (Preparation 89, 3.8 g, 12.18 mmol) in toluene:t-BuOH (60 mL, 4:1) was added DIPEA (16.84 mL, 97.45 mmol), copper(I) iodide (1.16 g, 6.09 mmol) and 1-azido-2-fluorobenzene (Preparation 145, 2.87 g, 20.71 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction was evaporated to dryness in vacuo, water was added, then ammonium hydroxide solution was added, and the resulting mixture was stirred for 30 min and filtered (the process was repeated until the filtrate was colorless). The solid was washed with a hexane solution of 5% EtOAc and dried. The residue was purified by column chromatography (DCM solution of 0.5% MeOH) to give the title compound as an off-white solid (3.35 g, 61.4%). 1 HNMR (400 MHz, DMSO-d6): 2.56 (s, 3H), 5.51 (s, 4H), 7.19 (s, 1H), 7.25 - 7.44 (m, 3H), 7.93 (t, 1H), 8.08 (d, 1H). LCMS m / z = 450.0 [M+H] +

[0576] Preparation 55 : 7-((1-(2-Fluorophenyl)-1H-pyrazol-4-yl)methyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0577]

[0578] A mixture of 4-chloro-7-((1-(2-fluorophenyl)-1H-pyrazol-4-yl)methyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 67, 20 g, 44.2 mmol) and NH4OH (100 mL) in 1,4-dioxane (50 mL) was stirred in an autoclave at 100 °C for 8 h. The reaction mixture was cooled to room temperature, the solid was filtered off and washed with water to give the title compound as a white solid (17 g, 89%). 1HNMR(400MHz, DMSO-d6): δ 5.27 (s, 2H), 6.63 (brs, 2H), 7.31 - 7.48 (m, 3H), 7.56 (s, 1H), 7.74 - 7.79 (m, 2H), 8.16 (s, 1H), 8.25 (d, 1H). LCMS m / z = 434.9 [M+H] +

[0579] Preparation 56 : 7-(1-(1-(2-Fluorophenyl)-1H-pyrazol-4-yl)ethyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0580]

[0581] In a sealed tube, at 100 °C, a solution of 4-chloro-7-(1-(1-(2-fluorophenyl)-1H-pyrazol-4-yl)ethyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 69, 0.5 g, 1.07 mmol) in dioxane (10 mL) and NH3·H2O (30 mL) was stirred for 18 h. The reaction mixture was diluted with EtOAc (100 mL), the organic layer was collected, washed with brine, dried and evaporated in vacuo to give the title compound (360 mg, 75%). 1 HNMR(400MHz, DMSO-d6): δ 1.81 (d, 3H), 6.04 (q, 1H), 6.50 - 6.75 (br s, 2H), 7.30 - 7.48 (m, 3H), 7.60 (s, 1H), 7.75 (m, 2H), 8.18 (s, 1H), 8.22 (s, 1H). LCMS m / z = 449.1 [M+H] +

[0582] Preparation 57 : 7-(1-(2-(2-Fluorophenyl)-1H-imidazol-5-yl)ethyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0583]

[0584] The following reaction was carried out in parallel 4 times. An aqueous NH3 solution (75 mL) was added to a stirred solution of 4-chloro-7-(1-(2-(2-fluorophenyl)-1H-imidazol-5-yl)ethyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (prepared 70.2 g, 4.277 mmol) in 1,4-dioxane (35 mL) in a sealed tube, and the resulting suspension was heated to 130 °C for 16 hours. The reaction mixture was evaporated to dryness in vacuo, the residue was dissolved in H2O, and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na2SO4), and concentrated under reduced pressure to give an impure sample of the title compound as a brown solid (2.02 g). The products of all four reactions were combined and purified by flash chromatography to give the title compound as an off-white solid (4.8 g, 62.6%). 1 1H NMR (400 MHz, DMSO-d6): 1.74 (d, 3H), 5.98 (q, 1H), 6.59 (br s, 2H), 7.20 - 7.43 (m, 5H), 7.94 (t, 1H), 8.13 (s, 1H), 12.19 (s, 1H). LCMS m / z = 449 [M+H]+ +

[0585] Preparation 58 : 7-((2-(2-Fluorophenyl)-1H-imidazol-5-yl)methyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0586]

[0587] NH4OH (75.0 mL) was added to a stirred solution of 4-chloro-7-[2-(2-fluorophenyl)-3H-imidazol-4-ylmethyl]-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (prepared 68.8 g, 17.63 mmol) in dioxane (25.0 mL), and the reaction mixture was heated at 120 °C for 16 hours. The reaction mixture was evaporated to dryness in vacuo, and the residue was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with water and then with brine, dried (Na2SO4), and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography to give the title compound as an off-white solid (4 g, 52%). 1 1H NMR (400 MHz, DMSO-d6): 2.14 (s, 2H), 6.60 (br s, 2H), 7.15 (s, 1H), 7.26 - 7.35 (m, 2H), 7.40 (m, 1H), 7.50 (s, 1H), 7.94 (t, 1H), 8.14 (s, 1H). LCMS m / z = 435 [M+H]+ +

[0588] Preparation 59 : 7-(1-(3-(2-Fluorophenyl)isoxazol-5-yl)ethyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0589]

[0590] At 0 °C, Et3N (11.32 mL, 81.70 mmol) was added to a stirred solution of 7-(but-3-yn-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 85, 15 g, 48.06 mmol) and 2-fluoro-N-hydroxybenzimidoyl chloride (Preparation 130, 12.51 g, 72.09 mmol) in toluene (600 mL). The reaction mixture was stirred at 60 °C for 16 h. The solid was removed by filtration and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography, eluting with 50% EtOAc:hexane to give the title compound as an off-white solid (11 g, 51%). 1 1H NMR (400 MHz, DMSO-d6): 1.90 (d, 3H), 6.24 (q, 1H), 6.69 (brs, 2H), 6.89 (s, 1H), 7.33 - 7.42 (m, 2H), 7.55 (m, 1H), 7.66 (s, 1H), 7.86 (t, 1H), 8.13 (s, 1H). LCMS m / z = 450 [M+H] +

[0591] Preparation 60 : N'-(7-((1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine

[0592]

[0593] A solution of 7-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 41, 1.0 g, 2.99 mmol) in DMF-DMA (15 mL) was stirred at 80 °C overnight. The reaction mixture was evaporated to dryness in vacuo to give the title compound (1.1 g, 98%) as a yellow solid. 1HNMR(400MHz, DMSO-d6): 3.20 (s, 3H), 3.25 (s, 3H), 5.58 (s, 2H), 7.43 (m, 1H), 7.54 - 7.62 (m, 3H), 7.83 (m, 1H), 8.36 (s, 1H), 8.59 (s, 1H), 8.87 (s, 1H). LCMS m / z=491 [MH] +

[0594] Preparation 61 : (4-Chloro-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)boronic acid

[0595]

[0596] Sodium periodate (2.24 g, 10.5 mmol) was added to a solution of 4-chloro-7-{1-[1-[(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (Preparation 62, 2.46 g, 5.25 mmol) in THF (30 mL) and water (40 mL), and the reaction mixture was stirred at room temperature for 18 h. The mixture was acidified to pH 2 with 1N HCl, then poured into water and extracted with DCM (3x). The combined organic layers were dried (MgSO4), filtered and concentrated. The crude product was purified by silica gel column chromatography, eluting with MeOH:EtOAc (0:100 to 5:95) to give the title compound as an off-white foam (741 mg, 36.6%). 1 HNMR(400MHz, DMSO-d6): 1.98 (d, 3H), 4.08 (br s, 1H), 6.38 (m, 1H), 6.73 (d, 1H), 7.43 (m, 1H), 7.54 - 7.65 (m, 2H), 7.82 (m, 1H), 7.92 (s, 1H), 8.67 (s, 1H). LCMS m / z=386.9 [MH] +

[0597] Preparation 62 : 4-Chloro-7-{1-[1-[(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0598]

[0599] A solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane in THF (9.2 mL, 1 M, 9.2 mmol) was added to a suspension of 4-chloro-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 65, 3.44 g, 7.3 mmol), Et3N (1.3 mL, 9.2 mmol), Pd2(dba)3 (400 mg, 0.37 mmol) and XPhos (361 mg, 0.73 mmol) in dioxane (37 mL), and the reaction mixture was stirred at 75 °C for 18 h. The cooled reaction mixture was diluted with EtOAc, filtered through a filter, and the filtrate was evaporated under reduced pressure. The crude dark orange oil was purified by silica gel column chromatography, eluting with EtOAc:heptane (20:80 to 80:20), to give the title compound as a yellow foam (2.46 g, 72%). 1 1H NMR (400 MHz, CDCl3): 1.26 (s, 3H), 1.29 (s, 1H), 1.39 (2xs, 6H), 2.10 (d, 3H), 6.43 (m, 1H), 7.26 - 7.37 (m, 2H), 7.45 (m, 1H), 7.92 - 8.01 (m, 3H), 8.76 (s, 1H). LCMS m / z = 469.1 [M+H] +

[0600] Preparation 63

[0601]

[0602] 4-chloro-7-(1-(1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)propyl)-5-(4,4,5,5-tetramethyl)-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine Following a procedure similar to that described in Preparation 62, the title compound (827 mg, 69%) was obtained from 4-chloro-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 66). 1 1H NMR (400 MHz, DMSO-d6): 0.86 (t, 3H), 1.32 (s, 12H), 2.48 (m, 2H), 6.15 (m, 1H), 7.45 (m, 1H), 7.52 - 7.62 (m, 2H), 7.84 (m, 1H), 8.15 (s, 1H), 8.70 (s, 1H), 8.82 (d, 1H). LCMS m / z = 483.1 [M+H] +

[0603] Preparation 64 : 4-Chloro-7-[1-(2-fluorophenyl)-1H-[1,2,3]triazol-4-ylmethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0604]

[0605] To a stirred solution of 4-chloro-7-[1-(2-fluorophenyl)-1H-[1,2,3]triazol-4-ylmethyl]-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 95, 2.5 g, 5.507 mmol) in degassed dioxane (50 mL) was added X-Phos (449 mg, 0.551 mmol), Pd2(dba)3 (226 mg, 0.275 mmol), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (22.03 mL, 22.03 mmol, 1 M solution in THF). The mixture was stirred at room temperature for 10 minutes. Et3N (3.07 mL, 22.026 mmol) was added and the mixture was stirred at 75 °C for 2 hours. The reaction mixture was passed through filtration and evaporated to dryness in vacuo. The residue was purified by flash column chromatography (100% DCM) to give the title compound as a pale yellow solid (2.2 g, 88%). 1 1H NMR (400 MHz, CDCl3): 1.35 (s, 12H), 5.65 (s, 2H), 7.25 - 7.32 (m, 2H), 7.42 (m, 1H), 7.87 - 7.90 (m, 2H), 8.07 (d, 1H), 8.66 (s, 1H). LCMS m / z = 455.0 [M+H] +

[0606] Preparation 65 : 4-Chloro-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

[0607]

[0608] 7-(But-3-yn-2-yl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 91, 3.0 g, 9.0 mmol) was suspended in toluene (40 mL) and tBuOH (10 mL) under N2, 1-azido-2-fluorobenzene (1.96 g, 13.6 mmol), CuI (0.95 mg, 5.0 mmol) and Hunig's base (16 mL, 90 mmol) were added, and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between EtOAc and water, and the mixture was filtered and separated into layers. The aqueous phase was extracted with EtOAc, the combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The light brown solid was triturated with Et2O to remove residual azide. The crude product was purified by silica gel column chromatography, eluting with EtOAc:DCM (0:100 to 10:90) to afford the title compound as a pale yellow solid (3.44 g, 81.7%). The aqueous phase was extracted with EtOAc, the combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The light brown solid was triturated with Et2O to remove residual azide. The crude product was purified by silica gel column chromatography, eluting with EtOAc:DCM (0:100 to 10:90) to afford the title compound as a pale yellow solid (3.44 g, 81.7%). 1 1H NMR (400 MHz, DMSO-d6): 1.98 (d, 3H), 6.35 (q, 1H), 7.45 (m, 1H), 7.54 - 7.61 (m, 2H), 7.84 (m, 1H), 8.18 (s, 1H), 8.70 (m, 2H). LCMS m / z = 469.1 [M+H] +

[0609] Preparation 66 : 4-Chloro-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

[0610]

[0611] Step 1: 2-Fluorophenyl azide (2.26 g, 16.5 mmol), copper(I) iodide (1.25 g, 6.5 mmol) and Hunig's base (10 equiv, 118 mmol, 21 mL) were added under N2 to a solution of 1-pentyn-3-ol (1 g, 12 mmol) in toluene (40 mL) and tBuOH (10 mL). The suspension was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and 15% NH4OH. The aqueous layer was extracted with EtOAc (2×), and the combined organics were shaken vigorously with 15% NH4OH (2×) until the solution was essentially colorless. The organics were dried (MgSO4) and evaporated to dryness in vacuo. The residue was purified using Biotage 50 g flash column, eluting with a 50 - 80 - 100% EtOAc / heptane gradient to afford 1-(1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)propan-1-ol (2.29 g, 86.3%).1 HNMR (400 MHz, CDCl3): 1.05 (t, 3H), 1.90 - 2.20 (m, 3H), 4.95 (m, 1H), 7.30 - 7.50 (m, 2H), 8.00 (m, 2H), 8.10 (s, 1H). LCMS m / z = 222.2 [MH] +

[0612] Step 2: Dissolve 1-(1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)propan-1-ol (Step 1, 1 g, 4.5 mmol) in DCM (24 mL). Slowly add SOCl2 (5.0 mL, 67.8 mmol) and stir the reactants at room temperature for 2.5 h. Evaporate the reaction mixture to dryness in vacuo, and co-distill the resulting brown oil with toluene several times to remove the last traces of SOCl2, to give 4-(1-chloropropyl)-1-(2-fluorophenyl)-1H-1,2,3-triazole (1.1 g, 100%), which is used without further purification. LCMS m / z = 242.1 [MH] +

[0613] Step 3: Dissolve 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 71, 898 mg, 3.21 mmol) in DMF (20 mL), add Cs2CO3 (2.09 g, 6.43 mmol), and stir the reactants at room temperature for 30 min, then cool in an ice / water bath. Add dropwise a solution of 4-(1-chloropropyl)-1-(2-fluorophenyl)-1H-1,2,3-triazole (Step 2, 1.54 g, 6.43 mmol) in DMF (7 mL), allow the reactants to warm to room temperature, and then stir at 50 °C for 24 h. Partition the mixture between water and EtOAc, separate the layers. Evaporate the organic layer under reduced pressure, and purify the residual oil by silica gel column chromatography, eluting with EtOAc:heptane (10:90 to 50:50), to give the title compound (1.24 g, 44%). 1 HNMR (400 MHz, CDCl3): 0.95 (t, 3H), 2.42 - 2.60 (m, 2H), 6.15 (m, 1H), 7.24 - 7.39 (m, 2H), 7.45 (m, 1H), 7.82 (s, 1H), 7.94 (m, 1H), 8.10 (s, 1H), 8.64 (s, 1H). LCMS m / z = 483.0 [MH] +

[0614] Preparation 67 : 4-chloro-7-((1-(2-fluorophenyl)-1H-pyrazol-4-yl)methyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

[0615]

[0616] To a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 71, 20 g, 71.7 mmol) in DMF (200 mL) was added K2CO3 (49.5 g, 358.5 mmol) and the mixture was stirred at room temperature for 10 minutes, then 4-(chloromethyl)-1-(2-fluorophenyl)-1H-pyrazole (Preparation 98, 20 g, 95.2 mmol) was added. The resulting mixture was stirred at 60 °C for 6 hours, filtered and concentrated under reduced pressure to give a crude product, which was washed with EtOAc and water to give the title compound (20 g, 62.5%) as a yellow solid. 1 HNMR (400 MHz, CDCl3): 5.41 (s, 2H), 7.20 - 7.32 (m, 3H), 7.42 (s, 1H), 7.72 (s, 1H), 7.84 - 7.87 (m, 1H), 8.05 (d, 1H), 8.68 (s, 1H). LCMS m / z = 453.9 [MH] +

[0617] Preparation 68 : 4-chloro-7-((2-(2-fluorophenyl)-1H-imidazol-5-yl)methyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

[0618]

[0619] At 0 °C, cesium carbonate (42.43 g, 130.55 mmol) was added to a stirred solution of 5-chloromethyl-2-(2-fluorophenyl)-1H-imidazole (Preparation 108, 11 g, 52.22 mmol) in DMF (100 mL), then at the same temperature, a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 71, 14.6 g, 52.22 mmol) in DMF (50 mL) was added. The reaction mixture was stirred at room temperature for 16 hours and diluted with EtOAc. The combined organics were washed with H2O, brine, and dried (Na2SO4), and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography to give the title compound as a yellow solid (8 g, 33.77%). 1 HNMR (400 MHz, MeOD-d4): 5.48 (s, 2H), 7.20 - 7.26 (m, 3H), 7.41 (m, 1H), 7.79 (s, 1H), 7.92 (t, 1H), 8.60 (s, 1H). LCMS m / z = 453.8 [MH] +

[0620] Preparation 69: 4-chloro-7-(1-(1-(2-fluorophenyl)-1H-pyrazol-4-yl)ethyl)-5-iodo-7H-pyrrolo[2,3- d]pyrimidine

[0621]

[0622] To a solution of 4-(1-chloroethyl)-1-(2-fluorophenyl)-1H-pyrazole (WO2013 / 071232 compound 32, 2.17 g, 9.7 mmol) in DMF (50 mL) was added 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 71, 2.46 g, 8.8 mmol) and Cs2CO3 (14.3 g, 44.0 mmol), and the reaction mixture was stirred at 60 °C for 18 h. After cooling, water was added and the mixture was extracted with EtOAc (60 mL × 2). The organic extracts were collected, washed with brine, dried and evaporated to give a residue, which was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 9) to give the title compound (0.5 g, 12%). 1 1H NMR (400 MHz, DMSO-d6): 1.89 (d, 3H), 6.20 (q, 1H), 7.30 - 7.50 (m, 3H), 7.72 (t, 1H), 7.76 (s, 1H), 8.16 (s, 1H), 8.27 (s, 1H), 8.69 (s, 1H). LCMS m / z = 468.0 [M+H]+ +

[0623] Preparation 70 : 4-chloro-7-(1-(2-(2-fluorophenyl)-1H-imidazol-5-yl)ethyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

[0624]

[0625] At 0 °C, DIAD (3.90 mL, 19.68 mmol) was added to a stirred solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 71, 5 g, 17.89 mmol) in THF (150 mL), then PPh3 (5.25 g, 20.038 mmol) was added and the mixture was stirred at 0 °C for 10 minutes. A solution of 1-(2-(2-fluorophenyl)-1H-imidazol-5-yl)ethan-1-ol (Preparation 135, 3.68 mg, 17.89 mmol) in THF (100 mL) was added to the mixture at 0 °C, and the reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with H2O and extracted with EtOAc. The combined extracts were washed with water and brine, dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by flash chromatography in 20% EtOAc:hexanes to afford the title compound as an off-white solid (4 g, 48%). LCMS m / z = 468.8 [MH] +

[0626] Preparation 71: 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

[0627]

[0628] A mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (500 g, 3255.84 mmol) and NIS (805.74 g, 3581.43 mmol) in DMF (3.3 L) was stirred at room temperature for 3 hours. The mixture was poured into ice water (20 L), the resulting solid was filtered, washed with saturated sodium thiosulfate solution (4 × 2.5 L), water (4 × 2.5 L), and dried in vacuo to afford the title compound as an off-white solid (780 g, 85.8%). 1 1H NMR (400 MHz, DMSO-d6): 7.94 (s, 1H), 8.59 (s, 1H). LCMS m / z = 279.6 [MH] +

[0629] Preparation 72 : 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0630]

[0631] NaH (60%, 15.74 g, 393.60 mmol) was added portionwise to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 71, 100 g, 357.82 mmol) in THF (2.5 L) cooled in ice. The resulting suspension was stirred at 0 °C for 1 h. SEM-Cl (69.81 mL, 393.60 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 16 h. The reaction was cooled to 0 °C and quenched with aqueous brine solution, and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with EtOAc:hexane (7:93) to afford the title compound as a white solid (85 g, 58.0%). 1 1H NMR (400 MHz, DMSO-d6): 0.10 (s, 9H), 0.82 (t, J = 7.2 Hz, 2H), 3.51 (t, J = 7.2 Hz, 2H), 5.60 (s, 2H), 8.13 (s, 1H), 8.69 (s, 1H). LCMS m / z = 410.0 [M+H]+ +

[0632] Preparation 73 : 4-chloro-5-iodo-6-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0633]

[0634] At -78 °C under N2, LDA (79.26 mL, 158.52 mmol) was added to a solution of 4-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Preparation 72, 43 g, 105.68 mmol) in THF (500 mL). The mixture was stirred at -20 °C for 2 h, cooled again to -78 °C, and MeI (8 mL, 126.82 mmol) was added. The reaction mixture was stirred at -20 °C for 2 h. The reaction was quenched with saturated NH4Cl solution and extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried (Na2SO4), and evaporated to dryness in vacuo. The residue was purified by column chromatography (petroleum ether / EtOAc 10:1) to afford the title compound as a yellow solid (10 g, 65%). 1 1H NMR (400 MHz, DMSO-d6): 0.11 (s, 9H), 0.83 (t, J = 7.2 Hz, 2H), 2.54 (s, 3H), 3.47 (t, J = 7.2 Hz, 2H), 5.70 (s, 2H), 8.62 (s, 1H). LCMS m / z = 424, 426 [M+H]++

[0635] Preparation 74 : 5-Iodo-7-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0636]

[0637] To a stirred solution of 4-chloro-5-iodo-7-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Prepared 75, 5 g, 10.2 mmol) in dioxane (30 mL) was added NH4OH (100 mL) and the reaction mixture was stirred at 120 °C in a sealed tube for 16 h. The cooled reaction mixture was diluted with ice-cold water, the resulting solid was filtered off, washed with water and then with hexane, and dried under reduced pressure to give the title compound (12 g, 83.3%, for composite batch) as a white solid. 1 1H NMR (400 MHz, DMSO-d6): 0.10 (s, 9H), 0.76 (m, 2H), 3.46 (t, 2H), 5.17 (s, 2H), 5.34 (s, 2H), 6.58 (brs, 2H), 7.45 (s, 1H), 7.52 (s, 1H), 7.84 (s, 1H), 8.13 (s, 1H).

[0638] Preparation 75 : 4-Chloro-5-iodo-7-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine

[0639]

[0640] NaH (60% in oil, 3.4 g, 85.87 mmol) was added to a stirred solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Prepared 71, 20 g, 71.56 mmol) in DMF (400 mL), then 4-(chloromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (26.49 g, 107.34 mmol) was added and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and EtOAc (250 mL each), the layers were separated, the organic layer was washed with water and then with brine solution, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by silica gel column chromatography to give the title compound (15.2 g, 43.3%) as a colorless gum. 1HNMR(400MHz, DMSO-d6): 0.11(s, 9H), 0.73(m, 2H), 3.43(t, 2H), 5.32(m, 4H), 7.57(s, 1H), 7.89(s, 1H), 8.03(s, 1H), 8.67(s, 1H). LCMS m / z=489.6[MH] +

[0641] Preparation 76 : 6-Bromo-5-(4-chlorophenyl)-7-(prop-2-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0642]

[0643] Propargyl bromide (73.8 mg, 0.5 mmol) was added to a solution of 6-bromo-5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 78, 107 mg, 0.331) in DMF (6 mL), and the mixture was cooled to 0 °C. NaOEt (27 mg, 0.4 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with aqueous NH4Cl solution and extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with 20% LiCl solution, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with EtOAc:heptane (0:100 to 100:0) to give the title compound as a beige solid (67 mg, 55.9%). 1 HNMR(400MHz, CDCl3): 2.98(s, 1H), 5.04(br s, 2H), 5.15(s, 2H), 7.45 - 7.53(m, 4H), 8.36(s, 1H). LCMS m / z=363.0[MH]

[0644] Preparation 77 : 7-(But-3-yn-2-yl)-5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0645]

[0646] To a stirred solution of 7-(but-3-yn-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 86, 5 g, 16.02 mmol) in EtOH:water (125 mL, 9:1) was added 4-chlorophenylboronic acid (3.50 g, 22.43 mmol), then Na2CO3 (6.79 g, 64.08 mmol), and the resulting reaction mixture was degassed with Ar(g) for 15 minutes. Pd(PPh3)4 (1.11 g, 0.96 mmol) was added and the reaction was stirred at 90 °C for 5 h. The cooled mixture was filtered and the filtrate was concentrated in vacuo. The residue was diluted with water, extracted with DCM, the combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with EtOAc:hexane (50:50) to give the title compound as an off-white solid (2.7 g, 56.84%). 1 1H NMR (400 MHz, DMSO-d6): 1.70 (d, 3H), 3.62 (s, 1H), 5.70 (m, 1H), 6.22 (brs, 2H), 7.48 - 7.53 (m, 5H), 8.17 (s, 1H). LCMS m / z = 297.0 [M+H]+ +

[0647] Preparation 78 : 6-Bromo-5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0648]

[0649] A solution of a mixture of 6-bromo-5-(4-chlorophenyl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 82, 150 mg, 0.331 mmol) and TBAF (343 mg, 1.24 mmol) in THF (3.3 mL) was heated at 70 °C for 18 h. 1 M HCl (2 mL) and water (2 mL) were added, and then the cooled mixture was basified by addition of saturated sodium bicarbonate. The mixture was extracted with DCM (3 × 50 mL), the combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to give the title compound which was used without further purification. LCMS m / z = 324.9 [M+H]+ +

[0650] Preparation 79 : 5-(4-Chlorophenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0651]

[0652] A solution of 5-(4-chlorophenyl)-2-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 81, 500 mg, 1.28 mmol) in TFA (3 mL) was stirred at room temperature for 30 minutes. The solution was diluted with heptane and concentrated in vacuo to remove TFA. The residue was dissolved in MeCN (12 mL), 35% aqueous NH4OH (ca. 6 mL) was added to adjust the pH to ca. 10, the mixture was diluted with additional MeCN and water, and the resulting solid was filtered off and dried in vacuo to give the title compound as an off-white solid, which was used without further purification. LCMS m / z = 289.0 [MNa] +

[0653] Preparation 80 : 5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0654]

[0655] TFA (73.52 mL, 960.13 mmol) was added to a stirred solution of 5-(4-chlorophenyl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 83, 18 g, 48.0 mmol) in DCM (180 mL) at ice-cooled temperature, and the resulting suspension was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, diluted with MeOH (80 mL), treated with EDA (57.75 mL, 480.06 mmol), and the solution was stirred for 16 hours. The reaction mixture was concentrated and filtered, and the resulting solid was washed with water and dried in vacuo to give the title compound as a white solid (10 g, 85.11%). 1 HNMR (400 MHz, DMSO-d6): 6.06 (br s, 2H), 7.28 (s, 1H), 7.46 - 7.51 (m, 4H), 8.11 (s, 1H), 11.84 (br s, 1H). LCMS m / z = 245.0 [MH] +

[0656] Preparation 81 : 5-(4-chlorophenyl)-2-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0657]

[0658] 4-Chloro-5-iodo-2-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (Preparation 84, 1.1 g, 2.60 mmol) was suspended in NH4OH (3 mL) and dioxane (1 mL), and the reaction mixture was heated at 130 °C under microwave irradiation for 60 minutes. The cooled mixture was concentrated, and the residue was suspended in water and stirred for 1 hour. The mixture was filtered and dried to give a brown solid. A mixture of this solid (680 mg, 1.68 mmol), 4-chlorophenylboronic acid (312 mg, 1.93 mmol), and Na2CO3 (713 mg, 6.73 mmol) was suspended in EtOH (9 mL) and water (1 mL) and degassed for 5 minutes. Pd(PPh3)4 (97.1 mg, 0.084 mmol) was added and the reaction mixture was heated to 90 °C for 18 hours. The cooled reaction mixture was diluted with water, extracted with EtOAc, the organic phase was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with 50 - 100% EtOAc:heptane to give the title compound as a solid (500 mg, 49.4%). LCMS m / z = 390.1 [MH] +

[0659] Preparation 82 : 6-Bromo-5-(4-chlorophenyl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0660]

[0661] To a stirred solution of 5-(4-chlorophenyl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 83, 500 mg, 1.334 mmol) in DMF (20 mL) was added NBS (284.8 mg, 1.6 mmol), and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with water, extracted with EtOAc, the combined organic extracts were washed with water and then with brine, dried (Na2SO4), and concentrated under reduced pressure to give the title compound as an off-white solid (500 mg, 82.62%). 1 HNMR (400 MHz, DMSO-d6): 0.08 (s, 9H), 0.85 (t, 2H), 3.58 (t, 2H), 5.60 (s, 2H), 6.09 (br s, 2H), 7.42 (d, 2H), 7.58 (d, 2H), 8.18 (s, 1H). LCMS m / z = 454.8 [MH] +

[0662] Preparation 83 : 5-(4-Chlorophenyl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0663]

[0664] To a stirred solution of 5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 33, 25 g, 64.05 mmol) in EtOH:water (620 mL, 9:1) was added 4-chlorophenylboronic acid (14.02 g, 89.68 mmol), then Na2CO3 (27.15 g, 256.21 mmol), and the mixture was degassed with Ar for 15 minutes. Pd(PPh3)4 (4.44 g, 3.84 mmol) was added and the reaction was stirred at 90 °C for 5 h. The cooled mixture was filtered, the filtrate was concentrated, the residue was diluted with water and extracted with DCM. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with EtOAc:hexane (40:60) to give the title compound as an off-white solid (18 g, 74.94%). 1 1H NMR (400 MHz, DMSO-d6) δ 0.08 (s, 9H), 0.84 (t, J = 7.0 Hz, 2H), 3.55 (t, J = 7.0 Hz, 2H), 5.53 (s, 2H), 6.21 (br s, 2H), 7.46 - 7.53 (m, 5H), 8.18 (s, 1H). LCMS m / z = 451.0 [M+H]+ +

[0665] Preparation 84 : 4-Chloro-5-iodo-2-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0666]

[0667] To a mixture of 4-chloro-5-iodo-2-methyl-7H-pyrrolo[2,3-d]pyrimidine (1.7 g, 5.79 mmol) in DMF (25 mL) was slowly added a 60% dispersion of NaH (0.290 g, 7.2 mmol), and the mixture was stirred under Ar for 15 minutes. SEM-Cl (1.28 mL, 7.24 mmol) was added in portions over 5 minutes and the reaction was stirred at room temperature for 18 h. Saturated aqueous sodium bicarbonate (25 mL) was added and the mixture was extracted with EtOAc. The organic extract was dried (MgSO4) and concentrated under reduced pressure to give the title compound as an oil (1.1 g, 44.9%) which was used without further purification.1 HNMR (400 MHz, MeOD-d4): -0.05 (s, 9H), 0.89 (t, 2H), 2.71 (s, 3H), 3.59 (t, 2H), 5.63 (s, 2H), 7.78 (s, 1H). LCMS m / z = 423.9 [MH] +

[0668] Preparation 85 : 5-Iodo-7-(prop-2-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0669]

[0670] A solution of 4-chloro-5-iodo-7-(prop-2-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (Preparation 90, 8 g, 0.025 mol) in 1,4-dioxane (45 mL) and an aqueous solution of NH4OH (30%, 100 mL) were heated to 90 °C and maintained for 4 h, then maintained at room temperature for an additional 16 h. The reaction mixture was filtered and washed with EtOAc (15 mL) to give the title compound (6.8 g, 90%). 1 HNMR (400 MHz, DMSO-d6) 3.57 (s, 1H), 4.95 (s, 2H), 6.66 (br s, 2H), 7.52 (s, 1H), 8.13 (s, 1H). LCMS m / z = 299.0 [MH] +

[0671] Preparation 86 : 7-(But-3-yn-2-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0672]

[0673] To a stirred solution of 7-(but-3-yn-2-yl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 91, 28 g, 84.45 mmol) in dioxane (120 mL) was added NH4OH (400 mL) and the reaction was stirred in a sealed tube at 120 °C for 16 h. The cooled mixture was filtered, the solid washed with water and then with 50% EtOAc-hexane, and dried in vacuo to give the title compound as an off-white solid (20 g, 75.87%). 1 HNMR (400 MHz, DMSO-d6) 1.63 (d, 3H), 3.51 (d, 1H), 5.61 (m, 1H), 6.67 (br s, 2H), 7.60 (s, 1H), 8.12 (s, 1H). LCMS m / z = 312.8 [MH]+

[0674] Preparation 87 : 5-Iodo-7-(pent-1-yn-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0675]

[0676] A mixture of 4-chloro-5-iodo-7-(pent-1-yn-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (Preparation 92, 350.0 g, 1.012 mol) in dioxane (1.75 L) was added to NH3.H2O (5.0 L) and the reaction mixture was stirred in an autoclave (10 L) at 80 °C for 10 h. The cooled reaction mixture was filtered and dissolved in EtOAc (7.0 L). The solution was washed with brine (2 × 5.0 L), dried (Na2SO4), and concentrated in vacuo. The crude solid was triturated (petroleum ether:EtOAc = 3.0 L:300.0 mL) for 24 h, filtered, and dried to give the title compound as a brown solid (200.0 g, 60.61%). 1 1H NMR (400 MHz, CDCl3): 0.97 (t, 3H), 1.96 - 2.02 (m, 2H), 2.50 (d, 1H), 5.55 (m, 1H), 5.76 (brs, 2H), 7.33 (s, 1H), 8.26 (s, 1H).

[0677] Preparation 88 : 5-Iodo-7-(1-cyclopropylprop-2-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0678]

[0679] Following the procedure described in Preparation 85, the title compound was obtained from 4-chloro-7-(1-cyclopropylprop-2-yn-1-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 93) as a pale yellow solid (1.8 g, 65%). 1 1H NMR (400 MHz, DMSO-d6) 0.38 (m, 1H), 0.48 (m, 1H), 0.61 - 0.66 (m, 2H), 1.54 (m, 1H), 3.53 (s, 1H), 5.17 (m, 1H), 7.60 (s, 1H), 8.10 (s, 1H). LCMS m / z = 338.8 [M+H] +

[0680] Preparation 89 : 5-Iodo-2-methyl-7-(prop-2-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0681]

[0682] To a solution of 4-chloro-5-iodo-2-methyl-7-prop-2-ynyl-7H-pyrrolo[2,3-d]pyrimidine (Preparation 94, 10 g, 30.21 mmol) in 1,4-dioxane (40 mL) was added ammonium hydroxide solution (75 mL) in a sealed tube, and the reaction mixture was stirred at 110 °C for 10 h. The reaction volume was reduced to half of its original volume and cooled. The solid was precipitated and collected by filtration, washed with Et2O and dried to give the title compound as an off-white solid (4.8 g, 50.9%). 1 HNMR (400 MHz, DMSO-d6) 2.39 (s, 3H), 3.38 (s, 1H), 4.92 (s, 2H), 6.57 (br s, 2H), 7.39 (s, 1H). LCMS m / z = 312.9 [MH] +

[0683] Preparation 90 : 4-Chloro-5-iodo-7-(prop-2-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0684]

[0685] To a stirred solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (155 g, 0.554 mol) in DMF (750 mL) was added NaOEt (21% in EtOH, 215.7 g, 0.665 mol), and the mixture was stirred at room temperature for 10 min and then cooled to 0 °C. Propargyl bromide (80% toluene solution, 123.7 g, 0.831 mol) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with cold water (1 L), the resulting suspension was filtered, washed with water and then with hexane (2 × 200 mL), and dried under reduced pressure to give the title compound as a pale yellow solid (162 g, 92.5%). 1 HNMR (400 MHz, DMSO-d6) 3.49 (s, 1H), 5.14 (s, 2H), 8.05 (s, 1H), 8.69 (s, 1H). LCMS m / z = 318.0 [MH] +

[0686] Preparation 91 : 7-(But-3-yn-2-yl)-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

[0687]

[0688] To a stirred solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (80 g, 286.26 mmol) in DMF (1 L) was added K2CO3 (79.12 g, 572.51 mmol), then but-3-yn-2-yl methanesulfonate (63.62 g, 429.38 mmol) was added, and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled to 0 °C and diluted with water. The resulting solid was filtered off, washed with diethyl ether and dried in vacuo to give the title compound as a yellow solid (49 g, 51.63%). 1 1H NMR (400 MHz, CDCl3) 1.70 (d, 3H), 2.54 (d, 1H), 5.78 (m, 1H), 7.69 (s, 1H), 8.61 (s, 1H). LCMS m / z = 331.6 [M+H] +

[0689] Preparation 92 : 4-Chloro-5-iodo-7-(pent-1-yn-3-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0690]

[0691] K2CO3 (296.72 g, 2146.92 mmol) and pent-1-yn-3-yl methanesulfonate (Preparation 138, 313.4 g, 1932.22 mmol) were added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 71, 300 g, 1073.46 mmol) in DMF (2500 mL), cooled to 5 °C, and the reaction mixture was stirred at 80 °C for 5 h. Water (4 L) was added to the cooled mixture and stirred at room temperature for 2 h. The resulting solid material was filtered off, washed with water (3 L), 10% EtOAc:hexane, diethyl ether (500 mL) and dried to give the title compound as an off-white solid (190 g, 57.2%). 1 1H NMR (400 MHz, CDCl3) 0.97 (t, 3H), 1.96 - 2.09 (m, 2H), 2.55 (s, 1H), 5.61 (m, 1H), 7.66 (s, 1H), 8.60 (s, 1H). LCMS m / z = 345.9 [M+H] +

[0692] Preparation 93 : 4-Chloro-7-(1-cyclopropylprop-2-yn-1-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

[0693]

[0694] To a stirred solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (9.0 g, 34.61 mmol) in DMF (75 mL) at 0 - 5 °C was added Cs2CO3 (33.75 g, 103.8 mmol), followed by the addition of (1-chloroprop-2-yn-1-yl)cyclopropane (9.91 g, 86.53 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water, extracted with EtOAc, and the combined organic phases were washed with water, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the title compound as an off-white solid (6.5 g, 38%). 1 HNMR(400MHz,DMSO-d6)0.38(m,1H),0.53(m,1H),0.65 - 0.76(m,2H),1.62 - 1.69(m,1H),3.62(s,1H),5.31(m,1H),8.18(s,1H),8.67(s,1H).LCMS m / z=357.8[MH] +

[0695] Preparation 94 : 4-chloro-5-iodo-2-methyl-7-(prop-2-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0696]

[0697] To a solution of 4-chloro-5-iodo-2-methyl-7H-pyrrolo[2,3-d]pyrimidine (10 g, 34.13 mmol) in DMF (55 mL) was added sodium ethoxide solution (19.177 mL, 51.195 mmol, 2.67 M in ethanol), then propargyl bromide (4.56 mL, 51.19 mmol) was added at 0 °C, and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by column chromatography (hexane solution of 2% EtOAc) to give the title compound as an off-white solid (4 g, 35.34%). 1 HNMR(400MHz,CDCl3)2.73 9s,3H),5.00(s,2H),7.50(s,1H).LCMS m / z=332[MH] +

[0698] Preparation 95 : 4-chloro-7-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

[0699]

[0700] To a stirred solution of 4-chloro-5-iodo-7-(prop-2-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (Preparation 90, 48 g, 151.17 mmol) in toluene:t-BuOH (1000 mL, 4:1) was added CuI (15.83 g, 83.14 mmol) and DIPEA (263.3 mL, 1511.72 mmol), and the reaction mixture was stirred at room temperature for 10 minutes. 1-Azido-2-fluorobenzene (Preparation 145, 31.09 g, 226.76 mmol) was added at 0 °C, and the resulting mixture was stirred at room temperature for 48 hours. The reaction mixture was diluted with water and ammonia, and extracted with EtOAc. The combined extracts were washed with water, brine, dried (Na2SO4) and evaporated to dryness in vacuo. The residue was triturated with 20% EtOAc-hexane to give the title compound as an off-white solid (38 g, 55.3%). 1 HNMR (400 MHz, DMSO-d6) δ 5.68 (s, 2H), 7.42 (t, 1H), 7.57 (m, 2H), 7.80 (t, 1H), 8.11 (s, 1H), 8.63 (s, 1H), 8.69 (s, 1H). LCMS m / z = 455 [M+H] +

[0701] Preparation 96 : 2-Amino-4-(4-chlorophenyl)-1-{2-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]prop-2-yl}-1H-pyrrole-3-carbonitrile

[0702]

[0703] 1-Azido-2-fluorobenzene (Preparation 145, 38 mg, 0.26 mmol), CuI (19 mg, 0.10 mmol) and Hünig's base (0.31 mL, 1.8 mmol) were added under N2 to a solution of 2-amino-4-(4-chlorophenyl)-1-[2-methylbut-3-yn-2-yl]-1H-pyrrole-3-carbonitrile (Preparation 97, 50 mg, 0.18 mmol) in toluene (2.5 mL) and tBuOH (0.6 mL), and the reaction was stirred at room temperature for 4 hours. The mixture was poured into water and extracted twice with EtOAc. The combined organic extracts were dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with EtOAc:heptane (20:80 to 80:20) to give the title compound as a dark green oil (78.4 mg, 71.7%). LCMS m / z = 421.4 [M+H] +

[0704] Preparation 97 : 2-Amino-4-(4-chlorophenyl)-1-[2-methylbut-3-yn-2-yl]-1H-pyrrole-3-carbonitrile

[0705]

[0706] Malononitrile (187 mg, 2.8 mmol) was added to a solution of 4-chloro-N-(2-methylbut-3-yn-2-yl)benzamide (587 mg, 2.1 mmol) in MeOH (10 mL), and the solution was degassed under N2 while cooling in an ice / water bath. A solution of KOH (336 mg, 5.93 mmol) in water (1.5 mL) was added dropwise, and then the reaction mixture was stirred at 65 °C for 1 h. The cooled mixture was poured into water and extracted with EtOAc (3×). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The resulting brown oil was purified by silica gel column chromatography, eluting with EtOAc:heptane (20:80 to 80:20), to give the title compound as a dark yellow oil (288 mg, 48.4%). 1 1H NMR (400 MHz, CDCl3) 1.85 (s, 6H), 2.68 (s, 1H), 4.72 (s, 2H), 6.46 (s, 1H), 7.32 (d, 2H), 7.52 (d, 2H). LCMS m / z = 284.3 [M+H] +

[0707] Preparation 98 : 4-(Chloromethyl)-1-(2-fluorophenyl)-1H-pyrazole

[0708]

[0709] At 0 °C, SOCl2 (45.3 mL, 625 mmol) was added dropwise to a solution of (1-(2-fluorophenyl)-1H-pyrazol-4-yl)methanol (Preparation 99, 20 g, 130.2 mmol) in DCM (200 mL). After addition, the reaction mixture was stirred at room temperature for 4 h. The mixture was concentrated in vacuo to give the title product (20 g, 99%) as a dark brown oil, which was used directly in the next step without further purification. 1 1H NMR (400 MHz, CDCl3) 4.62 (s, 2H), 7.22 - 7.36 (m, 3H), 7.83 (s, 1H), 7.88 - 7.92 (m, 1H), 8.05 (d, 1H).

[0710] Preparation 99 : (1-(2-Fluorophenyl)-1H-pyrazol-4-yl)methanol

[0711]

[0712] At 0 °C, NaBH4 (12 g, 315.6 mmol) was added in several portions to a mixture of 1-(2-fluorophenyl)-1H-pyrazole-4-carbaldehyde (20.0 g, 131.6 mmol) and MeOH (200 mL). After the addition was complete, the mixture was stirred at room temperature for 2 h. The reaction was carefully quenched with water (100 mL) at 0 °C. The mixture was extracted with EtOAc (200 mL × 3), dried (Na2SO4), and concentrated in vacuo to give the title compound (20 g, 99%) as a brown solid. 1 HNMR (400 MHz, CDCl3) 2.02 (brs, 1H), 4.68 (s, 2H), 7.20 - 7.31 (m, 3H), 7.75 (s, 1H), 7.87 (m, 1H), 8.00 (d, 1H). LCMS m / z = 193.1 [MH] +

[0713] Preparation 100: 4-(1-chloropropyl)-1-(2-fluorophenyl)-1H-pyrazole

[0714]

[0715] SOCl2 (2 mL) was slowly added to a solution of 1-(1-(2-fluorophenyl)-1H-pyrazol-4-yl)propan-1-ol (Preparation 101, 0.5 g, 2.42 mmol) in DCM (20 mL), and the mixture was stirred at room temperature for 3 h. The reaction mixture was evaporated to dryness in vacuo to give the title compound (0.58 g, 100%). 1 HNMR (400 MHz, CDCl3) 1.09 (t, 3H), 2.15 (m, 2H), 4.95 (t, 1H), 7.20 - 7.30 (m, 3H), 7.74 (s, 1H), 7.87 (m, 1H), 8.00 (s, 1H). LCMS m / z = 235.1 [MH] +

[0716] Preparation 101 : 1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propan-1-ol

[0717]

[0718] At 0 °C, EtMgBr (31.6 mL, 31.6 mmol) was added dropwise to a solution of 1-(2-fluorophenyl)-1H-pyrazole-4-carbaldehyde (3 g, 15.8 mmol) in THF (50 mL), and the reaction mixture was stirred at room temperature for 2 h. Water was added to quench the reaction, and the mixture was extracted with EtOAc. The organic layer was collected, washed with brine, dried, and evaporated. The crude product was purified by silica gel column chromatography, eluting with DCM:MeOH (95:5) to give the title compound (3 g, 86%). 1 HNMR (400 MHz, CDCl3) 1.00 (t, 3H), 1.88 (m, 2H), 4.71 (m, 1H), 7.19 - 7.27 (m, 3H), 7.71 (s, 1H), 7.87 (m, 1H), 7.95 (s, 1H). LCMS m / z = 221.2 [MH] +

[0719] Preparation 102 :(1-(2,4-Difluorophenyl)-1H-pyrazol-4-yl)methanol

[0720]

[0721] At 0 °C, NaBH4 (0.32 g, 8.43 mmol) was added dropwise to a solution of 1-(2,4-difluorophenyl)-1H-pyrazole-4-carbaldehyde (0.7 g, 3.365 mmol) in MeOH (20 mL). The cooling was removed and the reaction mixture was stirred at room temperature for 30 min. The mixture was quenched with water and extracted with EtOAc (150 mL × 2). The combined extracts were washed with brine (2 × 100 mL), dried (Na2SO4), and evaporated in vacuo to give the title compound (0.70 g, 99%) as an oil. 1 HNMR (400 MHz, DMSO-d6) 4.45 (d, 2H), 5.02 (t, 1H), 7.24 (t, 1H), 7.53 (t, 1H), 7.72 (s, 1H), 7.80 (m, 1H), 8.04 (s, 1H). LCMS m / z = 211.1 [MH] +

[0722] Preparation 103 :1-(1-(2,4-Difluorophenyl)-1H-pyrazol-4-yl)propan-1-ol

[0723]

[0724] To a solution of 1-(1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)propan-1-one (1.5 g, 6.35 mmol) in MeOH (60 mL) at 0 °C was added NaBH4 (360 mg, 9.52 mmol), and the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with 1 N HCl (2 mL), the solvent was evaporated under reduced pressure, and the residue was partitioned between EtOAc (20 mL) and water (30 mL). The aqueous phase was extracted with EtOAc (20 mL × 2), the combined extracts were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography, eluting with a DCM solution of MeOH from 0% to 15% in 20 min to give the title compound (1.0 g, 66%) as a red oil. 1 1H NMR (400 MHz, DMSO-d6) δ 0.88 (t, 3H), 1.67 (q, 2H), 4.50 (q, 1H), 5.04 (d, 1H), 7.24 (m, 1H), 7.53 (m, 1H), 7.58 (s, 1H), 7.80 (m, 1H), 7.99 (s, 1H). LCMS m / z = 239.2 [M+H]+ +

[0725] Preparation 104 : 1-(1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)propan-1-one

[0726]

[0727] Step 1: A degassed mixture of (E)-2-(ethoxymethylene)-3-oxopentanenitrile (Australian J. Chem. 44(9) 1263 - 73; 1991; 6 g, 39.17 mmol), Et3N (11.89 g, 117.5 mmol) and (2,4-difluorophenyl)hydrazine hydrochloride (10.61 g, 58.75 mmol) in EtOH (200 mL) was heated under reflux in a N2 atmosphere for 2 h. The reaction was cooled to room temperature and the solvent was removed under reduced pressure to give a residue. The crude product was purified by silica gel column chromatography, eluting with petroleum ether:EtOAc (10:1 to 1:1) to give 1-(5-amino-1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)propan-1-one as a yellow oil (5 g, 50.8%). LCMS m / z = 252.1 [M+H]+ +

[0728] Step 2: At room temperature, tert-butyl nitrite (4.1 g, 39.8 mmol) was added dropwise to a mixture of 1-(5-amino-1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)propan-1-one (5 g, 19.9 mmol) in THF (150 mL), and the reaction mixture was stirred at 65 °C for 4 h. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with petroleum ether:EtOAc (10:1 to 1:1), to give the title compound as a yellow oil (2 g, 42.54%). 1 HNMR(400MHz,MeOD-d4)1.19(t,3H),2.92(q,2H),7.18(m,1H),7.27(m,1H),7.84(m,1H),8.20(s,1H),8.65(s,1H).LCMS m / z=237.1[MH] +

[0729] Preparation 105 : 5-(Chloromethyl)-2-(2-fluorophenyl)-1H-imidazole

[0730]

[0731] (2-(2-Fluorophenyl)-1H-imidazol-5-yl)methanol (Preparation 110, 100 mg, 0.52 mmol) was heated with SOCl2 (0.075 mL, 1.041 mmol) at 80 °C for 3 h. The reaction mixture was evaporated to dryness in vacuo, and the residue was dissolved in CHCl3 and evaporated to dryness to give the title compound as a brown solid (80 mg, 73%). 1 HNMR(400MHz,DMSO-d6)4.90(s,2H),7.42-7.57(m,2H),7.68(m,1H),7.80(s,1H),8.02(m,1H).LCMS m / z=175[M-Cl] +

[0732] Preparation 106 : 5-(Chloromethyl)-2-phenyl-1H-imidazole

[0733]

[0734] The title compound was prepared from (2-phenyl-1H-imidazol-5-yl)methanol (Preparation 107) in a similar manner to Preparation 105 as an off-white solid (312 mg, 93%). 1 HNMR(400MHz,DMSO-d6)4.93(s,2H),7.64-7.66(m,3H),7.86(s,1H),8.18-8.21(m,2H).

[0735] Preparation 107 : (2-Phenyl-1H-imidazol-5-yl)methanol

[0736]

[0737] In a similar manner to the preparation of 110, the title compound was prepared from benzamidine hydrochloride as an off-white solid (3.6 g, 43%). This compound was used in the preparation of 106 without purification. 1 HNMR(400MHz, DMSO-d6) 4.43(s, 2H), 4.87 - 5.06(m, 1H), 6.91 - 7.04(m, 1H), 7.32(m, 1H), 7.40(m, 2H), 7.91(m, 2H), 12.31 - 12.44(m, 1H). LCMS m / z = 175.0 [MH] +

[0738] Preparation 108 : 4-(Chloromethyl)-1-(2-fluorophenyl)-1H-imidazole

[0739]

[0740] At 0 °C, SOCl2 (0.06 mL, 0.833 mmol) was added to a stirred solution of (1-(2-fluorophenyl)-1H-imidazol-4-yl)methanol (Preparation 109, 80 mg, 0.416 mmol) in DCM (1 mL). The resulting solution was heated to reflux for 16 h. The reaction mixture was concentrated under reduced pressure to give the title compound (80 mg, 91.24%) as an off-white solid. 1 HNMR(400MHz, DMSO-d6) 4.83(s, 2H), 7.40 - 7.78(m, 5H), 7.93(s, 1H).

[0741] Preparation 109 : (1-(2-fluorophenyl)-1H-imidazol-4-yl)methanol

[0742]

[0743] The borane-THF complex (1 M solution) was added dropwise to a stirred solution of 1-(2-fluorophenyl)-1H-imidazole-4-carboxylic acid (300 mg, 1.46 mmol) in THF (2 mL) at room temperature and the mixture was heated under reflux for 2 hours and then stirred at room temperature for 16 hours. The reaction mixture was cooled to 0 °C and MeOH (1.5 mL) was added dropwise and the mixture was evaporated to dryness. The residue was dissolved in 1.5 mL of 2 N HCl solution and refluxed for 2 hours, cooled to 0 °C and treated dropwise with 2 mL of 2 N NaOH solution. The solid was removed by filtration and dried to give the title compound as an off-white solid (250 mg, 89%). 1 HNMR (400 MHz, DMSO-d6) 4.21 (d, 2H), 4.99 (t, 1H), 7.32 - 7.52 (m, 4H), 7.63 (t, 1H), 7.96 (s, 1H). LCMS m / z = 193 [MH] +

[0744] Preparation 110: (2-(2-Fluorophenyl)-1H-imidazol-5-yl)methanol

[0745]

[0746] A suspension of 2-fluoro-benzamidine hydrochloride (3 g, 17.18 mmol), 1,3-dihydroxy-propan-2-one (3.17 g, 35.22 mmol) and NH4Cl (4.2 g) in NH4Cl (30 mL) was heated at 80 °C for 1 hour. The reaction mixture was extracted with EtOAc (50 mL × 3), washed with brine, dried (Na2SO4) and evaporated in vacuo to give a solid which was purified by silica gel column chromatography eluting with a DCM solution of 2% methanol to give the title compound as an off-white solid (2.2 g, 66.6%). 1 HNMR (400 MHz, DMSO-d6, 100 °C) 4.50 (s, 2H), 7.01 (s, 1H), 7.25 (m, 2H), 7.38 (m, 1H), 7.99 (m, 1H). LCMS m / z = 175 [M-Cl] +

[0747] Preparation 111 : 4-(1-Chloropropyl)-1-(2,4-difluorophenyl)-5-methyl-1H-1,2,3-triazole

[0748]

[0749] At 0 °C, SOCl2 (2.64 g, 22.2 mmol) was added to a solution of 1-(1-(2,4-difluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)propan-1-ol (Preparation 112, 2.8 g, 11.1 mmol) in DCM (80 mL), and the reaction mixture was stirred at 40 °C for 5 h. The reaction mixture was evaporated to dryness to give the title compound as a yellow solid (2.4 g, 80%). 1 HNMR (400 MHz, CDCl3) 1.11 (t, 3H), 2.30 (s, 3H), 2.38 (m, 2H), 5.07 (t, 1H), 7.08 (m, 2H), 7.53 (m, 1H). LCMS m / z = 272.1 [MH] +

[0750] Preparation 112 : 1-(1-(2,4-difluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)propan-1-ol

[0751]

[0752] At 0 °C, NaBH4 (374 mg, 9.88 mmol) was added to a solution of 1-(1-(2,4-difluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)propan-1-one (Preparation 113, 1.24 g, 4.94 mmol) in MeOH (25 mL), and the reaction mixture was stirred at room temperature for 3 h. The mixture was quenched with 1 N HCl and concentrated in vacuo. The residue was diluted with EtOAc (50 mL), washed with brine (30 mL), dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by combi-flash, eluting with EtOAc (10 - 70%) in petroleum ether to give the title compound as a white solid (1.1 g, 88%). 1 HNMR (400 MHz, MeOD-d4) 1.01 (t, 3H), 2.02 (m, 2H), 2.31 (s, 3H), 4.81 (t, 1H), 7.29 (m, 1H), 7.40 (m, 1H), 7.65 (m, 1H). LCMS m / z = 254.1 [MH] +

[0753] Preparation 113 : 1-(1-(2,4-difluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)propan-1-one

[0754]

[0755] Step 1: At 0 - 5 °C, under N2, to a stirred solution of 1-(2,4-difluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (7 g, 29.3 mmol) in DCM (150 mL), HATU (22.3 g, 58.6 mmol) and DIPEA (11.34 g, 87.9 mmol) were added simultaneously, and the solution was stirred for 15 minutes. N,O-Dimethylhydroxylamine (3.7 g, 38 mmol) was added and the reactants were stirred at room temperature for 16 hours. The reaction mixture was diluted with water (150 mL) and extracted with DCM (150 mL × 2). The combined organic layers were washed with brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc (20 - 70%) in petroleum ether to give 1-(2,4-difluorophenyl)-N-methoxy-N,5-dimethyl-1H-1,2,3-triazole-4-carboxamide (7.6 g) as a light-colored solid.

[0756] Step 2: At 0 °C, under N2, to a solution of 1-(2,4-difluorophenyl)-N-methoxy-N,5-dimethyl-1H-1,2,3-triazole-4-carboxamide (from Step 1, 2 g, 7.09 mmol) in THF (25 mL), EtMgBr (1.42 mL, 14.2 mmol, 1 M) was added and the mixture was stirred at room temperature for 3 hours. The reaction was quenched with NH4Cl solution (20 mL) and extracted with EtOAc (100 mL × 2). The combined organic matter was washed with brine (50 mL), dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography, eluting with EtOAc (10 - 70%) in petroleum ether to give the title compound as a white solid (1.24 g, 69%). 1 HNMR (400 MHz, CDCl3) 1.19 (t, 3H), 2.44 (s, 3H), 3.16 (q, 2H), 7.06 (m, 2H), 7.42 (m, 1H). LCMS m / z = 252.2 [MH] +

[0757] Preparation 114 : 4-(1-chloroethyl)-1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazole

[0758]

[0759] At 0 °C, SOCl2 (699 mg, 5.88 mmol) was added to a solution of 1-(1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)ethanol (Preparation 115, 650 mg, 2.94 mmol) in DCM (10 mL). The reaction mixture was then stirred at room temperature for 3 hours. Evaporation to dryness gave the title compound as a yellow solid (600 mg, 85%). LCMS m / z = 240.1 [MH] +

[0760] Preparation 115 : 1-(1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)ethan-1-ol

[0761]

[0762] Step 1: At 0 °C, CH3MgBr (2.3 mL, 6.8 mmol) was added to a solution of 1-(2-fluorophenyl)-N-methoxy-N,5-dimethyl-1H-1,2,3-triazole-4-carboxamide (Preparation 116, 900 mg, 3.4 mmol) in THF (30 mL) and the reactants were stirred at room temperature for 2 hours. The reaction mixture was quenched with ammonium chloride solution (20 mL) and extracted with EtOAc (30 mL × 2). The combined organics were washed with brine (50 mL), dried (Na2SO4) and evaporated to dryness in vacuo to give 1-(1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl]ethan-1-one (700 mg, 94%), which was used in Step 2 without further purification. LCMS m / z = 220.1 [MH] +

[0763] Step 2: To a solution of 1-(1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)ethanone (700 mg, 3.2 mmol) in MeOH (20 mL) at 0 °C was added NaBH4 (182 mg, 4.8 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with 1N HCl and the solvent was removed in vacuo. The residue was extracted with EtOAc (20 mL), washed with brine (10 mL), dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by combi-flash, eluting with a petroleum ether solution of 10 - 50% EtOAc to give the title compound as an off-white solid (650 mg, 91%). LCMS m / z = 222.1 [MH] +

[0764] Preparation 116: 1-(2-Fluorophenyl)-N-methoxy-N,5-dimethyl-1H-1,2,3-triazole-4-carboxamide

[0765]

[0766] At 0 - 5 °C, under N2, to a solution of 1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (Preparation 117, 5 g, 22.6 mmol) in DCM (80 mL) were added HATU (12.88 g, 33.9 mmol) and DIPEA (12 mL, 67.8 mmol) simultaneously and the mixture was stirred for 20 minutes. N,O-Dimethylhydroxylamine (3.3 g, 33.9 mmol) was added and the reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with water (50 mL) and extracted with DCM (100 mL × 2). The combined organic extracts were washed with brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc (20 - 60%) in petroleum ether to give the title compound as a white solid (4.8 g, 80%). LCMS m / z = 265.1 [MH] +

[0767] Preparation 117 : 1-(2-Fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid

[0768]

[0769] LiOH (1.68 g, 70.2 mmol) was added to a solution of methyl 1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylate (Preparation 118, 5.5 g, 23.4 mmol) in MeOH / H2O (30 mL / 10 mL) and the reaction mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue was treated with 1N HCl. The resulting solid was collected by filtration, washed with water (20 mL) and dried to give the title compound as a white solid (5 g, 96%). 1 HNMR (400 MHz, DMSO-d6) 2.41 (s, 3H), 7.50 (m, 1H), 7.61 (m, 1H), 7.71 - 7.76 (m, 2H), 13.25 (brs, 1H). LCMS m / z = 222.1 [MH] +

[0770] Preparation 118 : Methyl 1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylate

[0771]

[0772] 1-Azido-2-fluorobenzene (Preparation 145, 7.13 g, 52 mmol) and methyl 3-oxobutanoate (6 g, 52 mmol) were added to a suspension of ground K2CO3 (14.35 g, 104 mmol) in DMSO (100 mL). The reaction mixture was stirred at room temperature for 14 h. The reaction mixture was poured into water (50 mL), and the solid was collected and washed with water (50 mL) and ether (20 mL) to give the title compound as an off-white solid (5.5 g, 44.7%). 1 HNMR (400 MHz, DMSO-d6) 2.42 (s, 3H), 3.89 (s, 3H), 7.50 (m, 1H), 7.61 (m, 1H), 7.71 - 7.77 (m, 2H). LCMS m / z = 236.1 [MH] +

[0773] Preparation 119 : 4-(1-Chloropropyl)-1-phenyl-1H-1,2,3-triazole

[0774]

[0775] SOCl2 (0.23 mL, 3.171 mmol) was added to a solution of 1-(1-phenyl-1H-1,2,3-triazol-4-yl)propan-1-ol (Preparation 120, 200 mg, 1.057 mmol) in DCM (10 mL) at 0 °C, and the reaction mixture was heated to reflux for 3 h. The reaction mixture was evaporated to dryness to give the title compound (200 mg, 85.4%), which was used without further purification. 1 HNMR (400 MHz, DMSO-d6) 1.03 (t, 3H), 2.15 - 2.30 (m, 2H), 5.31 (t, 1H), 7.50 (t, 1H), 7.61 (t, 2H), 7.91 (d, 2H).

[0776] Preparation 120 : 1-(1-Phenyl-1H-1,2,3-triazol-4-yl)propan-1-ol

[0777]

[0778] To a stirred solution of 1-pentyn-3-ol (1 g, 11.89 mmol) in toluene: t-BuOH (4:1, 28 mL) was added CuI (1.24 g, 6.538 mmol) and DIPEA (20.7 mL, 118.88 mmol). The reaction mixture was stirred at room temperature for 10 minutes, then phenyl azide (Preparation 143, 2.61 g, 21.40 mmol) was added at 0 °C, and the resulting reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with aqueous NH4OH and extracted with EtOAc. The combined organics were washed with water, brine, dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography to give the title compound as an off-white solid (1.3 g, 53.7%). 1 1H NMR (400 MHz, DMSO-d6) 0.91 (t, 3H), 1.73 - 1.89 (m, 2H), 4.67 (m, 1H), 5.34 (d, 1H), 7.47 (t, 1H), 7.58 (t, 2H), 7.91 (d, 2H), 8.63 (s, 1H). LCMS m / z = 204.4 [M+H] +

[0779] Preparation 121 : 3-(Chloromethyl)-5-(2-fluorophenyl)-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole

[0780]

[0781] To a stirred solution of 3-(chloromethyl)-5-(2-fluorophenyl)-4H-1,2,4-triazole (Preparation 123, 400 mg, 1.896 mmol) in DCM (40 mL) at 0 °C was added dropwise SEM-Cl (1.009 mL, 5.687 mmol). The reaction was stirred for 10 minutes and Et3N (1.056 mL, 7.583 mmol) was added dropwise at 0 °C and the reaction was stirred at room temperature for 8 hours. The reaction was quenched with ice-cold water and basified with aqueous NaHCO3. The two layers were separated and the aqueous layer was extracted with DCM (40 mL). The combined organics were dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a hexane solution of 10 - 15% EtOAc to give the title compound as a colorless oil (180 mg, 27.77%, a mixture of two isomers). LCMS m / z = 342 [M+H] +

[0782] Preparation 122: 3-(Chloromethyl)-5-phenyl-4-((2-(trimethylsilyl)ethoxy)methyl)-4H-1,2,4-triazole

[0783]

[0784] Using 3-(chloromethyl)-5-phenyl-4H-1,2,4-triazole (300 mg, 1.554 mmol), the title compound was prepared in a similar manner to Preparation 121 to give the title compound (160 mg, 31.78%, a mixture of two isomers). LCMS m / z = 324 [MH] +

[0785] Preparation 123 : 3-(Chloromethyl)-5-(2-fluorophenyl)-4H-1,2,4-triazole hydrochloride

[0786]

[0787] Step 1: A solution of ethyl (Z)-2-amino-2-(2-(2-fluorobenzoyl)hydrazono)acetate (Preparation 143, 6.2 g, 24.484 mmol) in n-butanol (50 mL) was stirred at 180 °C for 24 hours. The reaction mixture was evaporated to dryness in vacuo and the residue was purified by flash chromatography (silica gel, hexane solution of 10 - 20% EtOAc) to give a mixture of ethyl 5-(2-fluorophenyl)-4H-1,2,4-triazole-3-carboxylate and butyl 5-(2-fluorophenyl)-4H-1,2,4-triazole-3-carboxylate as an off-white solid (2.5 g, 43%), which was used in Step 2. LCMS m / z = 236.0, 264.0 [MH] +

[0788] Step 2: A solution of the compound from Step 1 (6 g, 22.79 mmol) in anhydrous THF (20 mL) was added dropwise to a stirred suspension of LAH (1.297 g, 34.185 mmol) in anhydrous THF (140 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour and at room temperature for 1 hour. The reaction mixture was cooled to 0 °C and quenched by Fischer workup (1.3 mL H2O + 1.3 mL 15% NaOH + 2.6 mL H2O), and the solid was filtered through a bed. The combined filtrates were concentrated under reduced pressure and the residue was purified by silica gel column chromatography using a DCM solution of 3 - 5% MeOH to give (5-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)methanol as a yellow solid (1.07 g, 24%). 1HNMR(400MHz,DMSO-d6,100℃)4.64(s,2H),5.20(br s,1H),7.29(br s,2H),7.45(br s,1H),7.97(t,1H),13.70(brs,1H).LCMS m / z=194[MH] +

[0789] Step 3: (5-(2-Fluorophenyl)-4H-1,2,4-triazol-3-yl)methanol (step 2, 350 mg, 1.81 mmol) was dissolved in SOCl2 (48 mmol, 3 mL) and heated to ~80 °C for 1.5 h. The cooled reaction mixture was evaporated to dryness in vacuo, and the residue was azeotroped with toluene several times to afford the title compound as a pale yellow solid (450 mg, 100%). 1 HNMR(400MHz,DMSO-d6)4.82(s,2H),7.33-7.43(m,2H),7.54(m,1H),7.99(m,1H).LCMS m / z=212.2[MH] +

[0790] Preparation 124 : 5-(1-Chloroethyl)-3-(2-methoxyphenyl)isoxazole

[0791]

[0792] SOCl2 (0.11 mL, 1.60 mmol) was added to a stirred solution of 1-(3-(2-methoxyphenyl)isoxazol-5-yl)ethan-1-ol (Preparation 125, 100 mg, 0.46 mmol) in DCM (3 mL), and the mixture was heated at reflux for 4 h. The reaction mixture was evaporated to dryness in vacuo under N2 to afford the title compound (107 mg), which was used without further purification. 1 HNMR(400MHz,MeOD-d4)1.87(d,3H),3.88(s,3H),5.59(m,1H),6.96-7.75(m,5H).LCMS m / z=237.6[MH] +

[0793] Preparation 125 : 1-(3-(2-Methoxyphenyl)isoxazol-5-yl)ethan-1-ol

[0794]

[0795] Step 1: NH2OH·HCl (612 mg, 8.814 mmol) was added to a stirred aqueous solution (5 mL) of 2-methoxybenzaldehyde (1 g, 7.35 mmol) and KOH (989 mg, 17.63 mmol), and the reaction mixture was heated to 70 °C and maintained for 2 h. At 0 °C, the reaction mixture was acidified to pH 3 with 2 N HCl and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with water (20 mL × 2), brine, dried (Na2SO4), and evaporated to dryness in vacuo to give 2-methoxybenzaldoxime as an off-white solid (1.1 g), which was used in Part 2 without further purification. 1 1H NMR (400 MHz, DMSO-d6) δ 2.50 (s, 3H), 3.82 (s, 3H), 6.95 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 8.28 (s, 1H), 11.20 (s, 1H).

[0796] Step 2: NCS (530 mg, 3.974 mmol) was added to a stirred solution of 2-methoxybenzaldoxime (Step 1, 500 mg, 3.311 mmol) in DMF (5 mL), and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with MTBE (2 ×). The combined extracts were washed with water, brine, dried (Na2SO4), and evaporated to dryness in vacuo to give (Z)-N-hydroxy-2-methoxybenzimidoyl chloride (400 mg, 65.08%) as an off-white solid, which was used without further purification.

[0797] Step 3: At 0 °C, Et3N (0.51 mL, 3.696 mmol) was added to a stirred solution of (Z)-N-hydroxy-2-methoxybenzimidoyl chloride (300 mg, 2.117 mmol) in toluene (7 mL) and a solution of methyl propargyl alcohol (167 mg, 2.39 mmol) in toluene (3 mL). The reaction mixture was heated to 80 °C and maintained for 3 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Combi Flash using a 10 - 20% EtOAc in hexanes solution to give the title compound as a light brown liquid (325 mg, 68.19%). 1 1H NMR (400 MHz, DMSO-d6) δ 1.44 (d, J = 6.8 Hz, 3H), 3.87 (d, J = 1.6 Hz, 3H), 4.89 (m, 1H), 5.75 (m, 1H), 6.67 - 6.74 (m, 1H), 7.01 - 7.25 (m, 2H), 7.45 - 7.54 (m, 1H), 7.71 - 7.75 (m, 1H).

[0798] Preparation 126: 5-(1-chloroethyl)-3-(3-methoxyphenyl)isoxazole

[0799]

[0800] The title compound (Preparation 127) was prepared from 1-(3-(3-methoxyphenyl)isoxazol-5-yl)ethan-1-ol in a manner similar to that of Preparation 124. 1 HNMR (400 MHz, DMSO-d6) 1.88 (d, 3H), 3.81 (s, 3H), 5.57 (m, 1H), 7.08 (m, 1H), 7.25 (s, 1H), 7.38 - 7.48 (m, 3H).

[0801] Preparation 127 : 1-(3-(3-methoxyphenyl)isoxazol-5-yl)ethan-1-ol

[0802]

[0803] Starting from 3-methoxybenzaldehyde, the title compound was prepared in a manner similar to that of Preparation 124 as a light yellow solid in 44% yield (210 mg). 1 HNMR (400 MHz, DMSO-d6) 1.45 (d, 3H), 3.81 (s, 3H), 4.88 (m, 1H), 5.78 (d, 1H), 7.06 (m, 1H), 7.38 - 7.47 (m, 3H). LCMS m / z = 220.4 [MH] +

[0804] Preparation 128 : 5-(1-chloroethyl)-3-(2-fluorophenyl)isoxazole

[0805]

[0806] At 0 - 5 °C, SOCl2 (1.225 mL, 16.891 mmol) was added to a stirred solution of 1-(3-(2-fluorophenyl)isoxazol-5-yl)ethan-1-ol (Preparation 129, 1.0 g, 4.826 mmol) in DCM. The reaction was heated to reflux for 5 h, evaporated to dryness in vacuo, the residue was diluted with EtOAc, washed with water and brine, dried (Na2SO4), and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography, eluting with 13% EtOAc / hexane to give the title compound as a brown liquid (600 mg, 55%). 1HNMR(400MHz, DMSO-d6) 1.89 (d, 3H), 5.61 (q, 1H), 7.04 (s, 1H), 7.32 - 7.46 (m, 2H), 7.58 (m, 1H), 7.90 (m, 1H). LCMS m / z=225 [M] +

[0807] Preparation 129 : 1-(3-(2-Fluorophenyl)isoxazol-5-yl)ethan-1-ol

[0808]

[0809] At 0 - 5 °C, Et3N (38.202 mL, 274.225 mmol) was added to a stirred toluene solution of 2-fluoro-N-hydroxybenzimidoyl chloride (Preparation 130, 28 g, 161.3 mmol) and but-3-yn-2-ol (13.53 mL, 177.4 mmol). The reaction mixture was stirred at 60 °C for 4 hours, then cooled and the solid was removed by filtration. The filtrate was concentrated under reduced pressure. The residue obtained was purified by column chromatography using 15% EtOAc / hexane to give the title compound as a brown liquid (15 g, 45%). 1 HNMR(400MHz,DMSO-d6) 1.46 (d, 3H), 4.92 (m, 1H), 5.83 (d, 1H), 6.73 (d, 1H), 7.32 - 7.42 (m, 2H), 7.58 (m, 1H), 7.89 (m, 1H). LCMS m / z=208.2 [MH] +

[0810] Preparation 130 : 2-Fluoro-N-hydroxybenzimidoyl chloride

[0811]

[0812] At 10 - 20 °C, NCS (26.39 g, 197.66 mmol) was added portionwise to a stirred solution of (E)-2-fluorobenzaldoxime (Preparation 131, 25.0 g, 179.69 mmol) in DMF (50 mL). The reaction mixture was stirred at room temperature for 4 hours, diluted with water and extracted with Et2O. The combined organic extracts were washed with water, then with brine, dried (Na2SO4) and evaporated to dryness in vacuo to give the title compound (28 g, 90%) as a white gummy liquid. 1 HNMR(400MHz,DMSO-d6) 7.32 (m, 2H), 7.54 (m, 1H), 7.64 (m, 1H), 12.61 (s, 1H).

[0813] Preparation 131 :(E)-2-Fluorobenzaldoxime

[0814]

[0815] At a temperature below 10 °C, water was added to a suspension of 2-fluorobenzaldehyde (48 g, 386.75 mmol) and hydroxylamine hydrochloride (29.56 g, 425.42 mmol) in EtOH. An aqueous NaOH solution was added dropwise at 10 °C and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was acidified to pH 4 with HCl (5 N) and extracted with DCM. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 4% EtOAc / hexane to give the title compound as a white solid (32 g, 59.47%). 1 1H NMR (400 MHz, DMSO-d6) δ 7.21 - 7.28 (m, 2H), 7.44 (m, 1H), 7.74 (m, 1H), 8.23 (s, 1H). LCMS m / z = 139 [M] +

[0816] Preparation 132 :5-(1-Chloroethyl)-3-(o-tolyl)isoxazole

[0817]

[0818] SOCl2 (0.1 mL, 1.476 mmol) was added to a solution of 1-[3-(o-tolyl)isoxazol-5-yl]ethan-1-ol (Preparation 133, 100 mg, 0.49 mmol) in DCM (5 mL) and the reaction mixture was heated to reflux for 6 h. The cooled reaction mixture was concentrated under reduced pressure and co-evaporated with DCM to give the title compound (104 mg, crude) as a brown oil. 1 1H NMR (400 MHz, DMSO-d6) δ 1.88 (d, 3H), 2.43 (s, 3H), 5.59 (q, 1H), 7.02 (s, 1H), 7.30 - 7.43 (m, 3H), 7.55 (d, 1H). LCMS m / z = 222.0 [M + H] +

[0819] Preparation 133 :1-[3-(o-tolyl)isoxazol-5-yl]ethan-1-ol

[0820]

[0821] To a stirred solution of N-hydroxy-2-methylbenzohydroximoyl chloride (400 mg, 2.358 mmol) in toluene (10 mL) was added but-3-yn-2-ol (181 mg, 2.594 mmol), then Et3N (0.55 mL, 4.01 mmol) was added and the reaction mixture was stirred at 80 °C for 3 h. The cooled reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a brown liquid. It was purified by silica gel column chromatography to give the title compound (250 mg, 52.16%) as a pale yellow liquid. 1 1H NMR (400 MHz, DMSO-d6) δ 2.43 (s, 3H), 2.50 (s, 3H), 4.90 (m, 1H), 5.77 (d, 1H), 6.67 (s, 1H), 7.29 - 7.40 (m, 3H), 7.51 (d, 1H). LCMS m / z = 204.2 [M+H]+ +

[0822] Preparation 134 : 5-(1-chloroethyl)-3-(3-fluorophenyl)isoxazole

[0823]

[0824] To a stirred solution of 1-[3-(3-fluorophenyl)isoxazol-5-yl]ethanol (100 mg, 0.483 mmol) in DCM (5 mL) was added SOCl2 (0.12 mL, 1.69 mmol) and the reaction mixture was stirred under reflux for 5 h. The cooled reaction mixture was concentrated under reduced pressure; the resulting crude product was triturated with hexane, filtered and dried under reduced pressure to give the title compound (108 mg, quantitative) as a pale yellow solid. 1 1H NMR (400 MHz, CDCl3) δ 1.93 (d, 3H), 5.15 (m, 1H), 6.57 (s, 1H), 7.13 (m, 1H), 7.40 - 7.57 (m, 3H).

[0825] Preparation 135 : 1-(2-(2-fluorophenyl)-1H-imidazol-5-yl)ethan-1-ol

[0826]

[0827] At 0 °C, CH3MgBr (90.2 mL, 126.32 mmol, 1.4 M) was slowly added to a stirred anhydrous THF solution (250 mL) of 2-(2-fluorophenyl)-1H-imidazole-5-carbaldehyde (Preparation 136, 8 g, 42.105 mmol). The resulting mixture was stirred at 0 °C for 30 minutes and then at room temperature for 3 hours. The reaction mixture was cooled to 0 °C and quenched with saturated ammonium chloride solution and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure to give the title compound as a pale yellow solid (6.3 g, 72.6%). LCMS m / z = 207.2 [MH] +

[0828] Preparation 136 : 2-(2-fluorophenyl)-1H-imidazole-5-carbaldehyde

[0829]

[0830] At 0 °C, MnO2 (45.28 g, 520.83 mmol) was added to a stirred DCM (320 mL) solution of (2-(2-fluorophenyl)-1H-imidazol-5-yl)methanol (Preparation 110, 10 g, 52.08 mmol) and the reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was filtered through a filter and the bed was washed with DCM. The combined filtrates were evaporated to dryness in vacuo and the residue was triturated with hexanes to afford the title compound as an off-white solid (7.8 g, 79%). 1 1H NMR (400 MHz, DMSO-d6) δ 7.36 (m, 2H), 7.52 (m, 1H), 8.00 (m, 1H), 8.13 (s, 1H), 9.80 (s, 1H), 13.2 (brs, 1H). LCMS m / z = 191 [MH] +

[0831] Preparation 137 : 1-(2-(2,4-difluorophenyl)-1H-imidazol-4-yl)propan-1-ol

[0832]

[0833] Step 1: A solution of 2,4-difluorobenzonitrile (20 g, 143.8 mmol) in THF (100 mL) was added dropwise to a solution of LiHMDS (360 mL, 359.5 mmol) in THF (200 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 4 h. c.HCl (100 mL) was added dropwise to keep the temperature below 30 °C. EtOAc was added and the aqueous layer was collected. The pH was adjusted to 10 by careful addition of 6N NaOH, the organic layer was collected, dried and evaporated to dryness to give 2,4-difluorobenzimidamide (10 g, 44%), which was used in Step 2 without further purification.

[0834] Step 2: 1,3-Dihydroxypropan-2-one (11.5 g, 128.0 mmol) and NH4Cl (13.7 g) were added to a solution of 2,4-difluorobenzimidamide (10 g, 64.0 mmol) in NH3·H2O (250 mL). The reaction mixture was stirred at 80 °C for 2 h, cooled, diluted with water, extracted with EtOAc, dried and evaporated to dryness. The residue was purified by silica gel column chromatography (DCM / MeOH = 9 / 1) to give (2-(2,4-difluorophenyl)-1H-imidazol-4-yl)methanol (2 g, 15%), which was used in Step 3 without further purification.

[0835] Step 3: MnO2 (22.6 g, 66.6 mmol) was added to a solution of (2-(2,4-difluorophenyl)-1H-imidazol-4-yl)methanol (from Step 2, 2 g, 8.09 mmol) in DCM (100 mL). The reaction mixture was stirred at room temperature for 4 h and the mixture was filtered. The filtrate was collected and evaporated in vacuo to give 2-(2,4-difluorophenyl)-1H-imidazole-4-carbaldehyde (1.5 g, 75%), which was used in Step 4 without further purification.

[0836] Step 4: EtMgBr (21.6 mL, 21.6 mmol) was added dropwise to a solution of 2-(2,4-difluorophenyl)-1H-imidazole-4-carbaldehyde (from Step 3, 1.5 g, 7.2 mmol) in THF (50 mL) at 0 °C. After addition, the reaction mixture was warmed to room temperature and stirred for 2 h. The reaction was quenched (with c.NH4Cl solution) and extracted with EtOAc. The combined extracts were washed (with brine), dried and evaporated to give the title compound (1 g, 58%). LCMS m / z = 239.2 [MH] +

[0837] Preparation 138 : pent-1-yn-3-yl methanesulfonate

[0838]

[0839] Et3N (745.6 mL, 5349.48 mmol) and DMAP (43.56 g, 356.61 mmol) were added to a solution of ice-cooled pent-1-yn-3-ol (300 g, 3566.33 mmol) in DCM (2400 ml), and the solution was stirred for 15 minutes. Methanesulfonyl chloride (333.48 ml, 4279.59 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water (1200 mL) at 0 °C, the organic layer was separated, washed with water (1200 mL), dried (Na2SO4) and concentrated in vacuo to give the title compound as a brown liquid (580 g, quantitative). 1 HNMR (400 MHz, DMSO-d6) 0.98 (t, 3H), 1.82 (m, 2H), 3.23 (s, 3H), 3.86 (d, 1H), 5.21 (m, 1H).

[0840] Preparation 139 : 2-(Difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine

[0841]

[0842] A mixture of 2-(difluoromethyl)-5-bromopyrimidine (500 mg, 2.23 mmol), bis(pinacolato)diboron (623 mg, 2.5 mmol) and KOAc (657 mg, 6.7 mmol) in DMF (11 mL) was degassed under N2. Pd(dppf)Cl2.DCM (82 mg, 0.11 mmol) was added and the reaction mixture was stirred at 90 °C for 2.5 hours. The cooled reaction mixture was poured into water and extracted with EtOAc (2×), the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography, eluting with EtOAc:heptane (0:100 to 20:80) to give the title compound (388.8 mg, 68%). 1 HNMR (400 MHz, CDCl3) 1.38 (s, 12H), 6.86 - 7.13 (dd, 1H), 8.52 (s, 2H). LCMS m / z = 175.0 [M - C6H 10 +

[0843] Preparation 140 : 5-Fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0844] ​

[0845] 3-Bromo-5-fluoro-2-methoxypyridine (250 mg, 1.21 mmol) was added to a stirred solution of KOAc (238.2 mg, 2.42 mmol) in dioxane (10 mL), and then bis(pinacolato)diboron (308.1 mg, 1.21 mmol) was added. The reaction mixture was degassed with N2 for 10 minutes and PdCl2(dppf).DCM (99.02 mg, 0.12 mmol) was added and degassed for another 10 minutes. The reaction mixture was heated at 100 °C for 45 minutes and evaporated to dryness under reduced pressure. The residue was dissolved in a hexane solution of 50% EtOAc, filtered, and evaporated to dryness in vacuo to give the title compound (250 mg, 81.4%), which was used without further purification. LCMS m / z = 254 [MH] :5-Bromo-4-methoxy-2-(trifluoromethyl)pyrimidine +

[0846] Preparation 141

[0847]

[0848] 5-Bromo-4-chloro-2-(trifluoromethyl)pyrimidine (740 mg, 2.83 mmol) was dissolved in MeOH (5.5 mL) and cooled in an ice / water bath. NaOMe (156 mg, 2.83 mmol) was dissolved in 2.5 mL of MeOH and added dropwise to the cooled solution. The reactants were warmed to room temperature and stirred overnight. Additional NaOMe (60 mg) was added to the cooled reactants and stirred at room temperature for an additional 1 hour. The reactants were quenched with water and extracted with DCM (2x). The combined organics were dried (MgSO4) and evaporated to dryness to give the title compound as an orange oil (638.7 mg, 98%), which was used without further purification. 1 1H NMR (400 MHz, CDCl3) 4.08 (s, 3H), 8.62 (s, 1H).

[0849] Preparation 142 :Ethyl (Z)-2-amino-2-(2-(2-fluorobenzoyl)hydrazono)acetate

[0850]

[0851] ​A solution of ethyl 2-ethoxy-2-iminoacetate (19 g, 123.26 mmol) and 2-fluorobenzohydrazide (19.68 g, 135.59 mmol) in DCM (350 mL) was stirred under reflux for 12 h. The resulting solid was collected by filtration and washed with DCM (200 mL) to give the title compound as an off-white solid (24.5 g, 80%). 1 HNMR (400 MHz, DMSO-d6) 1.28 (t, 3H), 4.25 (q, 2H), 6.66 (s, 2H), 7.29 (m, 2H), 7.57 (m, 2H), 10.18 (s, 1H). LCMS m / z = 254 [MH] +

[0852] Preparation 143 : Phenyl azide compound

[0853]

[0854] HCl (10 mL) was added to a stirred aqueous solution (20 mL) of aniline (2 g, 21.475 mmol), and then a solution of NaNO2 (1.92 g, 27.918 mmol) in water (10 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, and a solution of NaN3 (1.67 g, 25.77 mmol) in water (10 mL) was added thereto at the same temperature. The resulting reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was extracted with MTBE, and the combined organic layers were washed with water, NaHCO3, and brine, dried (Na2SO4), and concentrated under reduced pressure (bath temperature maintained at 10 °C) to give the title compound as a yellow liquid (2.61 g). 1 HNMR (400 MHz, DMSO-d6) 7.11 (d, 2H), 7.19 (t, 1H), 7.42 (t, 2H).

[0855] Preparation 144 : 2-Azido-3-fluoropyridine

[0856]

[0857] At 0 °C, ethylenediamine (0.056 mL, 0.57 mmol), ascorbic acid (Na-salt) (112.6 mg, 0.57 mmol), CuI (54.11 mg, 0.3 mmol) and NaN3 (277.0 mg, 4.3 mmol) were added to a stirred solution of 2-bromo-3-fluoropyridine (500 mg, 2.84 mmol) in EtOH:H2O (20 mL), and the reaction mixture was stirred at 80 °C for 16 h. The cooled mixture was concentrated in vacuo, the residue was diluted with EtOAc, washed with water and then with brine, and dried (Na2SO4). The organic layer was then filtered and evaporated under reduced pressure to give the title compound as a yellow solid (300 mg, 75.91%). 1 1H NMR (400 MHz, DMSO-d6) δ 7.47 (m, 1H), 7.81 (dd, 1H), 9.44 (d, 1H). LCMS m / z = 138 [M+H]+ + , 110 [M-N2]+ +

[0858] Preparation 145 : 1-azido-2-fluorobenzene

[0859]

[0860] A solution of NaNO2 (6.52 g, 94.5 mmol) in H2O (10 mL) was added dropwise to a solution of 2-fluoroaniline (10 g, 90 mmol) in TFA (50 mL) and H2SO4 (20 mL) while maintaining the internal temperature between 0 - 10 °C. After addition, the mixture was kept at 0 - 10 °C for 1 h, and a solution of NaN3 (6.44 g, 99 mmol) in H2O (10 mL) was added dropwise while maintaining the internal temperature between 0 - 10 °C. Stirring was continued for another hour. The reaction mixture was extracted with DCM (50 mL), and the combined extracts were washed with saturated aqueous NaHCO3 (20 mL × 2), brine (20 mL) and dried (Na2SO4). The solvent was removed in vacuo to give the title compound (10 g, 81%) as a yellow oil. 1 1H NMR (400 MHz, CDCl3) δ 7.05 - 7.12 (m, 5H).

[0861] Preparation 146 : 4-(1-chloroethyl)-1-(2,4-difluorophenyl)-1H-pyrazole

[0862]

[0863] At 0 °C, under N2, SOCl2 (4.83 mL, 66.67 mmol) was added to a solution of 1-(1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)ethanol (Preparation 147, 6.0 g, 26.67 mmol) in DCM (15 mL), and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give the title compound as a brown oil (6.46 g, 99%). 1 1H NMR (400 MHz, CDCl3) 1.90 (d, 3H), 5.21 (q, 1H), 7.01 (m, 2H), 7.78 - 7.85 (m, 2H), 7.93 (s, 1H).

[0864] Preparation 147 : 1-(1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)ethan-1-ol

[0865]

[0866] At 0 °C, CH3MgBr (32 mL, 96.154 mmol) was added dropwise rapidly to a solution of 1-(2,4-difluorophenyl)-1H-pyrazole-4-carbaldehyde (8 g, 38.462 mmol) in THF (50 mL). After the addition, the mixture was warmed to room temperature and stirred for an additional 30 minutes. The mixture was quenched with NH4Cl solution, then diluted with EtOAc (50 mL) and washed with brine (150 mL × 2). The organic solution was dried (Na2SO4) and concentrated to give the desired product as an orange oil (6 g, 65%). 1 1H NMR (400 MHz, DMSO-d6) 1.38 (d, 3H), 4.77 (m, 1H), 5.08 (d, 1H), 7.24 (m, 1H), 7.52 (m, 1H), 7.70 (s, 1H), 7.80 (m, 1H), 7.98 (d, 1H). LCMS m / z = 225.1 [M+H] +

[0867] Examples 1 and 2: 4-Amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomers 1 and 2

[0868]

[0869] To a solution of 6-bromo-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 46, 160 mg, 0.30 mmol) in NMP (5 mL) were added Zn(CN)2 (106 mg, 0.91 mmol), Pd2(dba)3 (27 mg, 0.03 mmol) and dppf (33 mg, 0.06 mmol), and the reaction mixture was stirred at 155 °C under microwave irradiation for 3 h. The cooled reaction mixture was diluted with water and the mixture was extracted with EtOAc (30 mL × 2). The organic layer was collected, washed with brine, dried and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with petroleum ether:EtOAc (20:80) to give 4-amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (80 mg, 56%). The product was further purified by preparative HPLC method E6 to give Example 1, enantiomer 1. 1 HNMR (400 MHz, DMSO-d6): 2.01 (d, 3H), 6.36 (m, 1H), 7.00 - 7.25 (br s, 2H), 7.10 (t, 1H), 7.33 (m, 1H), 7.42 (m, 2H), 7.74 (t, 2H), 8.25 (d, 1H), 8.38 (s, 1H), 9.09 (s, 2H). LCMS m / z = 476.2 [MH] + ; RT [HPLC method E7] = 9.845 min.

[0870] Further elution afforded Example 2, enantiomer 2. 1 HNMR (400 MHz, DMSO-d6): 2.01 (d, 3H), 6.36 (m, 1H), 7.00 - 7.25 (br s, 2H), 7.10 (t, 1H), 7.33 (m, 1H), 7.42 (m, 2H), 7.74 (t, 2H), 8.25 (d, 1H), 8.38 (s, 1H), 9.09 (s, 2H). LCMS m / z = 476.2 [MH] + ; RT [HPLC method E7] = 10.941 min.

[0871] Examples 3 and 4: 4-Amino-7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomers 1 and 2

[0872]

[0873] 4-Amino-7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile was prepared from 6-bromo-7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 50) according to the procedure described in Example 1 / 2, with a yield of 66%. Further purification by preparative HPLC method H3 gave Example 3, Enantiomer 1. 1 HNMR(400MHz,DMSO-d6):0.86(t,3H),2.50(d,2H),6.10(t,1H),7.19(br s,2H),7.30-7.48(m,3H),7.75-7.80(m,2H),8.26(s,1H),8.39(s,1H),9.21(s,2H).LCMS m / z=508.2[MH] + ; RT [HPLC method C16] = 4.128 min.

[0874] Further elution provided Example 4, Enantiomer 2. 1 HNMR(400MHz,DMSO-d6):0.86(t,3H),2.53(m,2H),6.10(m,1H),7.18(br s,2H),7.35-7.46(m,3H),7.74-7.79(m,2H),8.26(s,1H),8.39(s,1H),9.21(s,2H).LCMS m / z=508.1[MH] + ; RT [HPLC method C16] = 7.540 min.

[0875] Examples 5 to 19

[0876] The following examples were obtained from the appropriate racemic compounds using suitable chiral HPLC or SFC conditions.

[0877]

[0878]

[0879]

[0880]

[0881]

[0882]

[0883] Examples 20 and 21 : 4-Amino-7-{1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomers 1 and 2

[0884]

[0885] Under N2, to a mixture of 6-bromo-7-{1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 51, 150 mg, 0.25 mmol) in NMP (2 mL) was added Zn(CN)2 (59 mg, 0.5 mmol), dppf (14 mg, 0.025 mmol) and Pd2(dba)3 (23 mg, 0.025 mmol), and the reaction mixture was heated at 155 °C for 1.5 h under microwave irradiation. The cooled mixture was diluted with water (25 mL), and the mixture was extracted with DCM (15 mL×4). The combined organic layers were dried (Na2SO4), filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by preparative HPLC, eluting with a solution of water (0.1% TFA) in MeCN from 55% to 65% to give 4-amino-7-{1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (90 mg, 68%) as a yellow solid. This solid was further purified by chiral HPLC method E8 to give Example 20, enantiomer 1. 1 1H NMR (400 MHz, DMSO-d6): 0.86 (t, 3H), 2.53 (m, 2H), 6.10 (m, 1H), 7.17 (brs, 2H), 7.24 (t, 1H), 7.53 (t, 1H), 7.76 (m, 2H), 8.24 (s, 1H), 8.38 (s, 1H), 9.21 (s, 2H). LCMS m / z = 526.2 [M+H] + ; RT [HPLC method C17] = 3.301 min.

[0886] Further elution gave Example 21, enantiomer 2. 1HNMR (400 MHz, DMSO-d6): 0.86 (t, 3H), 2.53 (m, 2H), 6.10 (m, 1H), 7.17 (br s, 2H), 7.24 (t, 1H), 7.53 (t, 1H), 7.76 (m, 2H), 8.24 (s, 1H), 8.38 (s, 1H), 9.21 (s, 2H). LCMS m / z = 526.2 [MH] + ; RT [HPLC method C17] = 7.568 min.

[0887] Examples 22 and 23: 4-Amino-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, enantiomers 1 and 2

[0888]

[0889] To a solution of 6-bromo-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 52, 3.3 g, 6.238 mmol) in DMF (30 mL) was added Zn(CN)2 (1.04 g, 8.82 mmol), dppf (0.65 g, 1.176 mmol) and Pd2(dba)3 (0.57 g, 0.624 mmol) and the reaction mixture was stirred in a microwave reactor under N2 at 140 °C for 2 h. The cooled mixture was concentrated and diluted with EtOAc (150 mL). The organic solution was washed with brine (2 × 100 ml), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by preparative HPLC to give 4-amino-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (1.7 g, 56%) as a white solid. The compound was further purified by chiral HPLC method C20B to give Example 23, enantiomer 1. 1 HNMR (400 MHz, DMSO-d6): 0.92 (t, 3H), 2.57 - 2.62 (m, 2H), 6.30 (t, 1H), 7.20 (br s, 2H), 7.42 (m, 1H), 7.52 - 7.60 (m, 2H), 7.80 (m, 1H), 8.38 (s, 1H), 8.78 (s, 1H), 9.22 (s, 2H). LCMS m / z = 509.2 [MH] +; RT[HPLC method C5] = 2.143 min.

[0890] Further elution gave Example 23, Enantiomer 2. 1 HNMR(400 MHz, DMSO-d6): 0.92 (t, 3H), 2.57 - 2.62 (m, 2H), 6.30 (t, 1H), 7.22 (brs, 2H), 7.42 (m, 1H), 7.52 - 7.60 (m, 2H), 7.80 (m, 1H), 8.38 (s, 1H), 8.78 (s, 1H), 9.22 (s, 2H). LCMS m / z = 509.2 [MH] + ; RT[HPLC method C5] = 2.585 min.

[0891] Example 24: 4-Amino-5-[6-(difluoromethoxy)pyridin-3-yl]-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile, single enantiomer

[0892]

[0893] Copper cyanide (32 mg, 0.35 mmol) was added to a solution of 6-bromo-5-[6-(difluoromethoxy)pyridin-3-yl]-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, single enantiomer (Example 55, 66 mg, 0.12 mmol) in DMF (1 mL), and the reaction was degassed with N2 and heated at 165 °C for 1 hour under microwave irradiation. The cooled reaction mixture was diluted with DCM (30 mL), 30% NH4OH was added and the mixture was stirred vigorously for 45 minutes. The phases were separated, the aqueous phase was extracted with DCM, the combined organic extracts were washed with 30% NH4OH (30 mL), then dried (MgSO4), filtered and concentrated in vacuo. The orange oil was suspended in DCM / heptane and evaporated under reduced pressure to give an orange solid. It was purified by HPLC to give the title compound (27 mg, 44%). 1 HNMR(400 MHz, DMSO-d6): 0.92 (t, 3H), 2.56 - 2.62 (m, 2H), 6.25 (m, 1H), 7.26 (m, 2H), 7.42 - 7.47 (m, 1H), 7.55 - 7.65 (m, 2H), 7.80 (m, 1H), 8.18 (m, 1H), 8.34 (s, 1H), 8.42 (s, 1H), 8.75 (s, 1H). LCMS m / z = 506.3 [MH] +

[0894] Example 25: 4-Amino-5-(4-chlorophenyl)-7-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile

[0895]

[0896] To a solution of 6-bromo-5-(4-chlorophenyl)-7-{[1-(propan-2-yl)-1H-pyrazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 43, 0.15 g, 0.34 mmol) in DMF (3 mL) was added Zn(CN)2 (40 mg, 0.50 mmol), Pd2(dba)3 (31 mg, 0.034 mmol) and dppf (38 mg, 0.068 mmol), and the reaction mixture was stirred at 140 °C for 3 h. The cooled mixture was diluted with water and then extracted with EtOAc. The organic layer was washed with brine, dried and evaporated. The crude product was purified by preparative HPLC to give the title compound (25.6 mg, 19%). 1 1H NMR (400 MHz, DMSO-d6): 1.35 (d, 6H), 4.46 (m, 1H), 5.34 (s, 2H), 7.42 (s, 1H), 7.54 (d, 2H), 7.62 (d, 2H), 7.76 (s, 1H), 8.35 (s, 1H). LCMS m / z = 392.2 [M+H]+ +

[0897] Example 26: 4-Amino-5-(4-chlorophenyl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile

[0898]

[0899] A mixture of 6-bromo-5-(4-chlorophenyl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 56, 20 mg, 0.04 mmol), Zn(CN)2 (4.71 mg, 0.04 mmol), Pd2(dba)3 (1.84 mg, 0.002 mmol) and TFP (1.40 mg, 0.006 mmol) in DMF (0.4 mL) was purged with Ar in a microwave vial. The reaction mixture was then heated at 90 °C for 18 h under microwave irradiation. The cooled mixture was passed through Filtration, the filtrate was purified by silica gel column chromatography, eluted with MeOH:DCM (0:100 to 5:95), to give the title compound (4.6 mg, 26%). 1 HNMR (400 MHz, CDCl3): 5.10 (s, 2H), 5.45 (br s, 2H), 7.28 - 7.58 (m, 7H), 7.92 (m, 1H), 8.28 (s, 1H), 8.50 (s, 1H). LCMS m / z = 445.1 [MH] +

[0900] Example 27: 4-Amino-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile

[0901]

[0902] Under microwave irradiation, at 140 °C, a mixture of 6-bromo-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 40, 1.5 g, 2.81 mmol), Zn(CN)2 (660 mg, 5.63 mmol), Pd2(dba)3 (258 mg, 0.281 mmol), dppf (306 mg, 0.563 mmol) and DMF (15 mL) was stirred under N2 for 1 h. The cooled mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column (eluted with DCM:MeOH = 10:1), to give the title compound (500 mg, yield: 37.1%) as a brown solid. 1 HNMR (400 MHz, DMSO-d6): 5.54 (s, 2H), 7.18 (br s, 2H), 7.32 - 7.47 (m, 3H), 7.76 (m, 1H), 7.79 (s, 1H), 8.26 (d, 1H), 8.41 (s, 1H), 9.21 (s, 2H). LCMS m / z = 480.0 [MH] +

[0903] The solid material was further purified by silica gel column (gradient elution with 50 - 100% EtOAc / CH2Cl2) to give the desired product as a light yellow solid, which was slurried in ethanol. The slurry was cooled for 1 h and collected by vacuum filtration, washed with a minimal amount of cold ethanol. After drying overnight under high vacuum, the title compound was obtained as a crystalline solid (415 mg, 30.8%). 1HNMR(400MHz, DMSO-d6): 5.55(s, 2H), 7.19(br s, 2H), 7.34 - 7.38(m, 1H), 7.41 - 7.50(m, 2H), 7.78(m, 1H), 7.80(s, 1H), 8.27(s, 1H), 8.43(s, 1H), 9.22(s, 2H). LCMS m / z=480.0[MH] +

[0904] Example 28: 4-Amino-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile

[0905]

[0906] Under N2, to a solution of 6-bromo-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 44, 0.2 g, 0.36 mmol) in DMF (6 mL) was added Zn(CN)2 (64 mg, 0.55 mmol), Pd2(dba)3 (33 mg, 0.036 mmol) and dppf (40 mg, 0.072 mmol) and the reaction mixture was stirred at 140 °C for 1.5 h under microwave irradiation. The cooled mixture was partitioned between water and EtOAc, the layers were separated, the organic phase was washed with brine, dried and evaporated under reduced pressure. The crude product was purified by preparative HPLC to give the title compound (110 mg, 61.8%). LCMS m / z=495.1[MH] +

[0907] Examples 29 to 36

[0908] Following a procedure similar to that described in Example 28, the following examples were prepared from the appropriate bromo starting materials.

[0909]

[0910]

[0911]

[0912] Use a NMP instead of DMF as the reaction solvent.

[0913] Example 37: 4-Amino-7-{[1-(2-difluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile

[0914]

[0915] Step 1: To a solution of N'-(7-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine (Preparation 60, 500 mg, 1.02 mmol) in dioxane (10 mL) were added H2O (2 mL), 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (391 mg, 2.04 mmol), PdCl2(dppf) (75 mg, 0.102 mmol) and K2CO3 (282 mg, 2.04 mmol), and the reaction mixture was stirred at 100 °C under N2 for 5 h. The cooled mixture was filtered and the filtrate was concentrated. The residue was diluted with EtOAc (150 mL), the solution was washed with brine (2 x 150 mL), dried (Na2SO4) and concentrated. The crude product was purified by silica gel column chromatography, eluting with MeOH:DCM (1:20) to give N'-(7-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine as a yellow solid (300 mg, 57%). LCMS m / z = 511.2 [M+H] +

[0916] Step 2: To a solution of N'-(7-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine (Step 1, 300 mg, 0.588 mmol) in MeOH (5 mL) was added NH3.H2O (5 mL), and the reaction mixture was stirred at 70 °C in a sealed tube for 18 h. The cooled mixture was concentrated to give a brown solid (240 mg, 90%).

[0917] Step 3: NBS (103 mg, 0.578 mmol) was added portionwise to a solution of the solid from Step 2 in DMF (4 mL) cooled in ice over 1 minute. The mixture was then warmed to room temperature and stirred for 18 h. The mixture was concentrated in vacuo and the crude product was purified by silica gel column chromatography, eluting with MeOH:DCM (1:20) to give the title compound as a yellow solid (140 mg, 50%). LCMS m / z = 511.2 [MH]+

[0918] Step 4: In a microwave vial, CuCN (71 mg, 0.787 mmol) was added to a solution of the compound from Step 3 (140 mg, 0.262 mmol) in DMF (4 mL). The solution was degassed with N2 for 2 minutes and then the reaction mixture was heated at 160 °C for 2 h under microwave irradiation. The cooled reaction mixture was filtered and concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound as a white solid (9.4 mg, 7%). 1 1H NMR (400 MHz, MeOD-d4): δ 5.83 (s, 2H), 7.33 - 7.49 (m, 2H), 7.52 - 7.62 (m, 1H), 7.82 (m, 1H), 8.38 (s, 1H), 8.51 (d, 1H), 9.19 (s, 2H). LCMS m / z = 481.1 [MH]+ +

[0919] Example 38: 4-Amino-7-{1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile

[0920]

[0921] At 145 °C, a solution of 6-bromo-7-{1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 53, 170 mg, 0.29 mmol), Zn(CN)2 (137 mg, 1.17 mmol), Pd2(dba)3 (40 mg, 0.044 mmol) and dppf (48 mg, 0.087 mmol) in DMF (3 mL) was stirred under microwave irradiation for 2 h. The cooled mixture was evaporated under reduced pressure to give a residue which was purified by silica gel column chromatography, eluting with MeOH:DCM (0:100 to 10:90) to give the required compound as a brown solid (80 mg, 52.44%). LCMS m / z = 527.0 [MH]+ +

[0922] Example 39 : 4-Amino-7-{(1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-(2-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile

[0923]

[0924] Step 1: To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 71, 1.2 g, 4.285 mmol) in DMF (8 mL) were added 18-crown-6 (1.13 g, 4.285 mmol), K2CO3 (1.18 g, 8.571 mmol) and 5-(1-chloroethyl)-3-(2-fluorophenyl)isoxazole (Preparation 128, 1.34 g, 4.714 mmol). The mixture was stirred at 60 °C for 2 h, evaporated to dryness in vacuo, diluted with EtOAc (80 mL) and washed with brine (2 × 100 mL), dried (Na2SO4) and concentrated. The residue was purified on a 20 g silica gel column, eluting with MeOH:DCM (1:30) to give 5-[1-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl]ethyl-3-(2-fluorophenyl)isoxazole (1.42 g, 71%) as an orange solid. LCMS m / z = 468.9 [M+H] +

[0925] Step 2: To a solution of the compound from Step 1 (1.42 g, 3.04 mmol) in dioxane (15 mL) was added NH3·H2O (5 mL). The mixture was stirred overnight at 90 °C in a sealed tube and then evaporated to dryness to give 1-{1-[3-(2-fluorophenyl)isoxazol-5-yl]ethyl}-3-iodo-1H-pyrrolo[2,3-d]pyridin-4-amine as a white solid (1.3 g, 97.0%), which was used in Step 3. LCMS m / z = 450.0 [M+H] +

[0926] Step 3: To a solution of the compound from Step 2 (1.3 g, 2.895 mmol) in dioxane (16 mL) was added H2O (4 mL), 2-methoxypyrimidin-5-ylboronic acid (0.54 g, 3.474 mmol), PdCl2(pddf)·DCM (0.21 g, 0.289 mmol), and K2CO3 (0.8 g, 5.790 mmol), and the mixture was stirred at 90 °C under N2 for 3 h. The reaction mixture was filtered and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography, eluting with MeOH:DCM (1:20), to give 7-{1-[3-(2-fluorophenyl)isoxazol-5-yl]ethyl}-5-(2-methoxypyrimidin)-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a brown solid (0.77 g, 61% yield), which was used in Step 4. LCMS m / z = 432.1 [MH] +

[0927] Step 4: NBS (0.35 g, 1.965 mmol) was added portionwise to a solution of the compound from Step 3 (0.77 g, 1.786 mmol) in DMF (15 mL). The mixture was stirred at 0 °C overnight, concentrated, and diluted with EtOAc (80 mL). The organic layer was washed with brine (2 × 70 mL), dried (Na2SO4), and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography, eluting with MeOH:DCM (1:20), to give 5-(4-amino-6-bromo-7-{1-[3-(2-fluorophenyl)isoxazol-5-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidin-2-ol as a brown solid (0.56 g, 62%), which was used in Step 5. LCMS m / z = 510.0, 512.0 [MH] +

[0928] Step 5: To a solution of the compound from Step 4 (560 mg, 1.1 mmol) in DMF (15 mL) in a microwave vial was added Zn(CN)2 (193 mg, 1.65 mmol), dppf (123 mg, 0.22 mmol), and Pd2(dba)3 (100 mg, 0.11 mmol). The mixture was stirred in a microwave reactor at 140 °C under a N2 atmosphere for 2 h. The mixture was concentrated, diluted with EtOAc (100 mL), washed with brine (2 × 100 mL), dried (Na2SO4), and concentrated. The residue was purified by preparative HPLC to give the title compound (92.9 mg, 18%) as a yellow solid. 1HNMR(400MHz, DMSO-d6): 2.06(s, 3H), 4.00(s, 3H), 6.51(m, 1H), 6.98 - 7.17(m, 3H), 7.32 - 7.45(m, 2H), 7.60(m, 1H), 7.89(m, 1H), 8.34(s, 1H), 8.74(s, 2H). LCMS m / z=457.2[MH] +

[0929] Example 40 : 6-Bromo-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0930]

[0931] At 0 °C, NBS (5.09 g, 28.6 mmol) was added in several portions to a mixture of 7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 57, 13 g, 28.6 mmol) and DCM (130 mL), and the mixture was stirred at 0 °C for 60 minutes. The reaction was quenched (5% NaHCO3 solution), extracted with DCM (150 mL × 3), washed (brine, 100 mL × 1), dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by silica gel column (eluted with DCM:MeOH = 20:1) to give the title compound (13 g, 86%) as a yellow solid. 1 HNMR(400MHz, CDCl3): 5.54(s, 2H), 5.65(br s, 2H), 7.19 - 7.29(m, 3H), 7.81 - 7.82(m, 2H), 8.16(m, 1H), 8.44(s, 1H), 9.06(s, 2H). LCMS m / z=532.9[MH] +

[0932] Examples 41 to 55

[0933] Following a procedure similar to that described in Example 40, the following examples were prepared from the appropriate pyrrolo[2,3-d]pyrimidin-4-amine starting materials.

[0934]

[0935]

[0936]

[0937]

[0938]

[0939] Example 56 : 6-Bromo-5-(4-chlorophenyl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0940]

[0941] CuI (19.6 mg, 0.102 mmol), Hünig's base (0.33 mL, 1.85 mmol), and 2-fluorophenyl azide (35.6 mg, 0.259 mmol) were added to a suspension of 6-bromo-5-(4-chlorophenyl)-7-(prop-2-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 76, 67 mg, 0.19 mmol) in t-BuOH (0.5 mL) and toluene (2 mL), and the reaction mixture was stirred at room temperature for 18 h. NH4OH (20 mL) was added and the mixture was extracted with EtOAc (3 × 50 mL). The combined organic extracts were dried (Na2SO4), filtered, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to give the title compound (26 mg, 28%). 1 1H NMR (400 MHz, CDCl3): 5.20 (br s, 2H), 5.78 (s, 2H), 7.28 - 7.34 (m, 2H), 7.44 - 7.51 (m, 5H), 7.94 (m, 1H), 8.13 (s, 1H), 8.36 (m, 1H). LCMS m / z = 499.9 [M+H] +

[0942] Example 57 : 7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0943]

[0944] At 85 °C, a mixture of 7-((1-(2-fluorophenyl)-1H-pyrazol-4-yl)methyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 55, 17 g, 39.2 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine (16 g, 58.8 mmol), Pd(dppf)Cl2 (1.43 g, 1.96 mmol) and K2CO3 (13.5 g, 98 mmol) in DMF (170 mL) and water (17 mL) was stirred under N2 for 6 h. The resulting mixture was filtered and concentrated to give a black solid, which was purified by silica gel column chromatography, eluting with petroleum ether:EtOAc (2:1) to give the title compound (13 g, 73%) as a pale yellow solid. 1 1H NMR (400 MHz, CDCl3): δ 5.25 (br s, 2H), 5.45 (s, 2H), 7.20 - 7.30 (m, 3H), 7.76 (s, 1H), 7.86 (m, 1H), 8.00 (s, 1H), 8.10 (d, 1H); 8.48 (s, 1H), 9.03 (s, 2H). LCMS m / z = 455.1 [M+H]+ +

[0945] Example 58 : 5-(4-chlorophenyl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0946]

[0947] To a stirred solution of 7-(but-3-yn-2-yl)-5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 77, 800 mg, 2.70 mmol) in toluene (24 mL) and tBuOH (8 mL) was added CuI (283 mg, 1.49 mmol), DIPEA (0.29 mL, 1.69 mmol), and the mixture was then cooled in ice. 1-Azido-2-fluorobenzene (676 mg, 4.87 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The mixture was filtered, washed with EtOAc, and the filtrate was concentrated in vacuo. The solid was diluted with water, extracted with EtOAc, the combined organic extracts were washed with water and then with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with EtOAc:hexane (60:40) to give the title compound as a pale yellow solid (550 mg, 46.9%). filtered, washed with EtOAc, and the filtrate was concentrated in vacuo. The solid was diluted with water, extracted with EtOAc, the combined organic extracts were washed with water and then with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, eluting with EtOAc:hexane (60:40) to give the title compound as a pale yellow solid (550 mg, 46.9%). 1HNMR(400MHz, DMSO-d6): 1.91(d, 3H), 6.12 - 6.22(br s, 2H), 6.31(m, 1H), 7.42 - 7.59(m, 8H), 7.80(m, 1H), 8.19(s, 1H), 8.66(s, 1H). LCMS m / z=434.0[MH] +

[0948] Examples 59 to 71

[0949] Using the following nine-step reaction scheme, Example 59 - 71 was prepared by palladium-catalyzed borylation of 7-{1-[2-(2-fluorophenyl)-1H-imidazol-5-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 57) with 13 different boric acids or esters.

[0950]

[0951] 1. Prepare a solution of 0.3 M boric acid or ester monomer in a degassed mixture of dioxane:EtOH:H2O (7:3:2) (Solution B).

[0952] 2. Prepare a solution of 0.2 M 7-{1-[2-(2-fluorophenyl)-1H-imidazol-5-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 57) in a degassed mixture of dioxane:EtOH:H2O (7:3:2) (Solution A).

[0953] 3. Prepare a 10 mL 2 M Na2CO3 solution in degassed distilled water (Solution C).

[0954] 4. Under argon purge, add 500 μL of Solution A (1.5 eq, 150 μmol) to each reaction vial, followed by 500 μL of Solution B (1 eq, 100 μmol).

[0955] 5. Add 150 μL (3 eq, 300 μmol) of Solution C to each vial.

[0956] 6. Dispense Pd(PPh3)4 (0.1 eq, 10 μmol, 12 mg) as a solid under an argon stream.

[0957] 7. Stir each reaction vial at 100 °C for 16 hours.

[0958] 8. Filter the reactants and evaporate the solvent in a heat detector (1 hour, 5 Torr, and 45 °C).

[0959] 9. Add 1 mL of DMSO to the crude product. Dilute 10 μL of the DMSO solution to 200 μL with DMSO for QC analysis and use the remaining amount for preparative HPLC to obtain the title compound.

[0960]

[0961]

[0962]

[0963]

[0964] Examples 72 to 86

[0965] Prepare Examples 72 - 86 using the following eight - step reaction scheme by palladium - catalyzed boric acid cross - coupling of 7 - {[1 - (2 - fluorophenyl)-1H - 1,2,3 - triazol - 4 - yl]methyl}-5 - iodo - 7H - pyrrolo[2,3 - d]pyrimidin - 4 - amine (Preparation 41) with 15 different boric acids or esters.

[0966]

[0967] 1. Prepare a solution (Solution A) of 0.2 M boric acid or ester monomer in a degassed mixture of DMF:H2O (4:1).

[0968] 2. Prepare a solution (Solution B) of 0.2 M 7 - {[1 - (2 - fluorophenyl)-1H - 1,2,3 - triazol - 4 - yl]methyl}-5 - iodo - 7H - pyrrolo[2,3 - d]pyrimidin - 4 - amine (Preparation 41) in a degassed mixture of DMF:H2O (4:1).

[0969] 3. Under argon purge, add 500 μL of Solution A (1 equivalent, 100 μmol) to each reaction vial, followed by 500 μL of Solution B (1 equivalent, 100 μmol).

[0970] 4. Add 98 mg (3 equivalents, 300 μmol) of anhydrous Cs2CO3 to each vial.

[0971] 5. Dispense PdCl2(dppf)·DCM (0.17 equivalent, 17 μmol, ~15 mg) under an argon stream.

[0972] 6. Stir each reaction vial at 100 °C for 16 hours.

[0973] 7. Filter the reaction mixture and evaporate the solvent in a heat detector (1 hour, 5 Torr, and 45 °C).

[0974] 8. Add 1 mL of DMSO to the crude product. Dilute 10 μL of the DMSO solution to 200 μL with DMSO for QC analysis, and purify the remaining amount by preparative HPLC to obtain the title compound.

[0975]

[0976]

[0977]

[0978] Examples 87 to 100

[0979] Prepare compounds of the following general structure according to the following procedure:.

[0980]

[0981] 1. Prepare a solution of the appropriate boric acid (0.2 M) in a degassed mixture of DMF:H2O (4:1) (Solution A).

[0982] 2. Prepare a solution of 0.2 M 7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 42) in a degassed mixture of DMF:H2O (4:1) (Solution B).

[0983] 3. Under Ar, add 500 μL of Solution A (1 equivalent, 100 μmol) to each reaction vial, then add 500 μL of Solution B (1 equivalent, 100 μmol).

[0984] 4. Add 98 mg (3 equivalents, 300 μmol) of anhydrous Cs2CO3 to each vial.

[0985] 5. Dispense PdCl2(dppf)·DCM (0.17 equivalent, 17 μmol, ~15 mg) under Ar.

[0986] 6. Stir each reaction vial at 100 °C for 16 hours.

[0987] 7. Filter the reactants and evaporate the solvent in vacuo.

[0988] 8. Add DMSO (1 mL) to the crude product and purify the solution by preparative HPLC to obtain the desired compound.

[0989]

[0990]

[0991] a Replace boric acid with boronic ester. The bond with an arrow indicates the attachment point of group W.

[0992] Examples 101 to 107

[0993] Using the following reaction scheme, the following examples were prepared by palladium-catalyzed cross-linking of 7-{1-[3-(2-fluorophenyl)isoxazol-5-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 59) with 7 different boric acids or boronic esters.

[0994]

[0995] 1. Prepare a solution of 0.2 M boronic acid or ester monomer in a degassed mixture of DMF:H2O (4:1) (Solution A).

[0996] 2. Prepare a solution of 0.2 M 7-{1-[3-(2-fluorophenyl)isoxazol-5-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 59) in a degassed mixture of DMF:H2O (4:1) (Solution B).

[0997] 3. Under argon purge, add 500 μL of Solution A (1 equivalent, 100 μmol) to each reaction vial, and then add 500 μL of Solution B (1 equivalent, 100 μmol).

[0998] 4. Add 98 mg (3 equivalents, 300 μmol) of anhydrous Cs2CO3 to each vial.

[0999] 5. Dispense PdCl2(dppf)·DCM (0.17 equivalent, 17 μmol, about 15 mg) under an argon stream.

[1000] 6. Stir each reaction vial at 100 °C for 16 hours.

[1001] 7. Filter the reactants and evaporate the solvent in a heat detector (1 hour, 5 Torr, 45 °C).

[1002] 8. Add 1 mL of DMSO to the crude product. Dilute 10 μL of the DMSO solution to 200 μL with DMSO for QC analysis, and purify the remaining amount by preparative HPLC to obtain the title compound.

[1003]

[1004]

[1005] Examples 108 to 182

[1006] The following examples were obtained from suitable racemic compounds using the chiral HPLC or SFC conditions described above.

[1007]

[1008]

[1009]

[1010]

[1011]

[1012]

[1013]

[1014]

[1015]

[1016]

[1017]

[1018]

[1019]

[1020]

[1021]

[1022]

[1023]

[1024]

[1025]

[1026]

[1027]

[1028]

[1029]

[1030]

[1031] Examples 183 and 184 : 7-{1-[3-(2-Fluorophenyl)isoxazol-5-yl]ethyl}-5-(2-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomers 1 and 2

[1032]

[1033] To a stirred solution of 7-{1-[3-(2-fluorophenyl)isoxazol-5-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 59, 1 g, 2.226 mmol) in EtOH:H2O (30 mL, 4:1) was added 2-methoxypyrimidin-5-ylboronic acid (0.514 g, 3.34 mmol) and Na2CO3 (0.944 g, 8.904 mmol). The reaction mixture was degassed with Ar for 15 minutes and Pd(PPh3)4 (0.154 g, 0.134 mmol) was added, and the reaction was heated at 90 °C for 6 hours. The cooled mixture was concentrated to dryness in vacuo, diluted with H2O and extracted with EtOAc. The combined extracts were dried (Na2SO4), evaporated to dryness, and the residue was purified by flash chromatography to give the title compound (530 mg, 55%) as an off-white solid. It was combined with the product from the parallel reaction (210 mg).

[1034] The product was purified by chiral SFC method A7 to give Example 183, i.e., enantiomer 1, (-)7-{1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-(2-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (238.5 mg). 1 1H NMR (400 MHz, DMSO-d6): 1.95 (d, 3H), 3.96 (s, 3H), 6.32 (q, 1H), 6.46 (brs, 2H), 6.92 (s, 1H), 7.35 (m, 1H), 7.41 (m, 1H), 7.57 (m, 1H), 7.64 (s, 1H), 7.85 (m, 1H), 8.22 (s, 1H), 8.63 (s, 2H). LCMS m / z = 432.3 [M+H] + ; RT [SFC method A8] = 7.434 min; [α] D MeOH = -11.7°.

[1035] Further elution provided Example 184, i.e., enantiomer 2, (+)7-{1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-(2-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (323.8 mg). 1HNMR (400 MHz, DMSO-d6): 1.95 (d, 3H), 3.96 (s, 3H), 6.32 (q, 1H), 6.46 (brs, 2H), 6.92 (s, 1H), 7.35 (m, 1H), 7.41 (m, 1H), 7.57 (m, 1H), 7.64 (s, 1H), 7.85 (m, 1H), 8.22 (s, 1H), 8.63 (s, 2H). LCMS m / z = 432.3 [MH] + ; RT [SFC method A8] = 8.212 min; [α] D MeOH = +12.6°.

[1036] Examples 185 and 186 : 7-{1-[1-(2,5-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomers 1 and 2

[1037]

[1038] Step 1: Under N2, to a solution of 7-{1-[1-(2,5-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 49, 400 mg, 0.83 mmol) in dioxane (20 mL) and water (5 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine (250 mg, 0.91 mmol), Pd(dppf)Cl2 (61 mg, 0.08 mmol), K2CO3 (344 mg, 2.49 mmol), and the reaction mixture was heated at 85 °C for 6 h. The cooled mixture was evaporated under reduced pressure and the residue was purified by HPLC to give 7-{1-[1-(2,5-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (125 mg, 30%).

[1039] Step 2: The racemic product was further purified by chiral HPLC using Method C31 to give 7-{1-[1-(2,5-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, i.e., enantiomer 1, Example 185, as a white solid (77 mg). 1HNMR(400MHz, DMSO-d6): 0.86(t, 3H), 2.39(m, 2H), 6.13(m, 1H), 6.78(br s, 2H), 7.49(m, 1H), 7.65(m, 1H), 7.79(m, 1H), 7.92(s, 1H), 8.27(s, 1H), 8.68(s, 1H), 9.07(s, 2H). LCMS m / z=502.1[MH] + RT[HPLC method C10] = 2.318 min.

[1040] Further elution gave enantiomer 2, i.e., Example 186, as a white solid (46 mg). 1 HNMR(400MHz, DMSO-d6): 0.86(t, 3H), 2.39(m, 2H), 6.13(m, 1H), 6.84(br s, 2H), 7.49(m, 1H), 7.65(m, 1H), 7.80(m, 1H), 7.91(s, 1H), 8.26(s, 1H), 8.75(s, 1H), 9.07(s, 2H). LCMS m / z=502.1[MH] + RT[HPLC method C10] = 2.871 min.

[1041] Examples 187 and 188 : 7-{1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomers 1 and 2

[1042]

[1043] Step 1: In a procedure similar to that described in Step 1 of Examples 185 / 186, 7-{1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine was prepared from 7-{1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 50) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine.

[1044] Step 2: Purify the compound from Step 1 by chiral HPLC method F9 to obtain 7-{1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, namely enantiomer 1, 1 HNMR (400 MHz, DMSO-d6): 0.86 (t, 3H), 2.39 (m, 2H), 6.14 (m, 1H), 6.72 (brs, 2H), 7.46 (m, 1H), 7.64 (m, 2H), 7.92 (s, 1H), 8.26 (s, 1H), 8.77 (s, 1H), 9.07 (s, 2H). LCMS m / z = 502.1 [MH] + ; RT [HPLC method C10] = 2.311 min. and enantiomer 2; 1 HNMR (400 MHz, DMSO-d6): 0.86 (t, 3H), 2.39 (m, 2H), 6.14 (m, 1H), 6.72 (brs, 2H), 7.46 (m, 1H), 7.64 (m, 2H), 7.92 (s, 1H), 8.26 (s, 1H), 8.77 (s, 1H), 9.07 (s, 2H). LCMS m / z = 502.1 [MH] + ; RT [HPLC method C10] = 2.843 min

[1045] Examples 189 and 190 : 7-{1-[1-(2,4-difluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine, enantiomers 1 and 2

[1046]

[1047] To a solution of N'-(7-(1-(1-(2,4-difluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)propyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformamidine (Preparation 9, 2.8 g, 4.92 mmol) in dioxane was added NH4OH (25 mL), and the sealed tube was heated at 100 °C for 18 h. The solvent was evaporated and the residue was diluted with EtOAc (150 mL) and water. The organic extract was washed with brine, dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by preparative HPLC to give 7-{1-[1-(2,4-difluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a white solid (1.9 g, 75%). The solid was separated by HPLC using a CHIRALPAK IC column to give Enantiomer 1 (700 mg, 36%). 1 1H NMR (400 MHz, MeOD-d4): 0.87 (t, 3H), 2.15 (s, 3H), 2.42 (m, 2H), 6.01 (t, 1H), 7.11 (m, 1H), 7.26 (m, 1H), 7.48 (m, 1H), 7.72 (s, 1H), 8.17 (s, 1H), 8.98 (s, 2H). LCMS m / z = 516.2 [M+H] + ; RT [HPLC Method C13] = 2.297 min;

[1048] Further elution gave Enantiomer 2 (725 mg, 38%). 1 1H NMR (400 MHz, MeOD-d4): 0.87 (t, 3H), 2.15 (s, 3H), 2.42 (m, 2H), 6.01 (t, 1H), 7.11 (m, 1H), 7.26 (m, 1H), 7.48 (m, 1H), 7.72 (s, 1H), 8.17 (s, 1H), 8.98 (s, 2H). LCMS m / z = 516.2 [M+H] + ; RT [HPLC Method C13] = 3.405 min.

[1049] Example 191 : 7-{1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-(5-methoxypyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[1050]

[1051] A stirred solution of 7-{1-[3-(2-fluorophenyl)isoxazol-5-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 59, 100 mg, 0.226 mmol), 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine (105 mg, 0.445 mmol) and K3PO4 (189 mg, 0.89) in dioxane:water (2.5 mL, 4:1) was degassed with N2 for 30 minutes. Pd2(dba)3 (20.38 mg, 0.022 mmol) was added thereto, then SPhos (18.25 mg, 0.045 mmol) was added, the mixture was degassed for a further 5 minutes and heated to 110 °C for 16 hours. The reaction mixture was partitioned between water and EtOAc, and the water was further extracted with EtOAc. The combined organics were washed with water, brine, dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography, eluting with MeOH:DCM (0:100 - 1:10), then by preparative TLC to give the title compound as an off-white solid (18.5 mg, 19.3%). 1 1H NMR (400 MHz, DMSO-d6): 1.98 (d, 3H), 3.94 (s, 3H), 6.33 (q, 1H), 6.90 (m, 1H), 7.30 - 7.45 (m, 3H), 7.56 (q, 1H), 7.86 (m, 1H), 8.13 (br s, 1H), 8.27 (s, 1H), 8.33 (m, 1H), 8.89 (s, 1H). LCMS m / z = 432.2 [M+H] +

[1052] Example 192 : 4-(4-amino-7-{[2-(2-fluorophenyl)-1H-imidazol-5-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorobenzonitrile

[1053]

[1054] A stirred solution of 7-{[2-(2-fluorophenyl)-1H-imidazol-5-yl]methyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 58, 100 mg, 0.23 mmol), (4-cyano-3-fluorophenyl)boronic acid (76.76 mg, 0.46 mmol) and Na2CO3 (97.47 mg, 0.92 mmol) in EtOH:water (4:1, 5 mL) was degassed with N2 for 30 minutes. Pd(PPh3)4 (15.9 mg, 0.014 mmol) was added thereto and the resulting brown suspension was heated to 110 °C and maintained for 6 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (2X). The combined extracts were washed with water, brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with MeOH:DCM (0:100 - 1:10) to give the title compound as an off-white solid (24 mg, 24.4%). 1 1H NMR (400 MHz, MeOH-d4): δ 5.58 (s, 2H), 7.32 - 7.44 (m, 3H), 7.56 (m, 1H), 7.60 - 7.67 (m, 3H), 7.93 (t, 1H), 8.09 (m, 1H), 8.40 (s, 1H). LCMS m / z = 428 [M+H]+ +

[1055] Example 193 : 7-{[2-(2-fluorophenyl)-1H-imidazol-5-yl]methyl}-5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[1056]

[1057] Using 7-{[2-(2-fluorophenyl)-1H-imidazol-5-yl]methyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 68, 500 mg, 1.15 mmol) and (2-methoxypyridin-3-yl)boronic acid (352 mg, 2.3 mmol), the title compound was prepared in a manner similar to that of Example 192 as a white solid (235 mg, 41%). 1 1H NMR (400 MHz, MeOD-d4): δ 3.92 (s, 3H), 5.40 (s, 2H), 7.03 (dd, 1H), 7.12 - 7.30 (m, 4H), 7.40 (q, 1H), 7.67 (dd, 1H), 7.95 (t, 1H), 8.12 - 8.22 (m, 3H). LCMS m / z = 416 [M+H]+ +

[1058] Example 194 : 7-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(2-methoxy-6-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[1059]

[1060] A stirred solution of 7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 95, 150 mg, 0.345 mmol) in EtOH:water (4:1, 3 mL), (2-methoxy-6-methylpyridin-3-yl)boronic acid (86.32 mg, 0.517 mmol) and Na2CO3 (146.14 mg, 1.37 mmol) was degassed with Ar for 15 minutes. Pd(PPh3)4 (39.8 mg, 0.034 mmol) was added and the reaction mixture was heated at 100 °C for 16 hours. The reaction was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organics were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by flash chromatography and preparative TLC to give the title compound as an off-white solid (26 mg, 15%). 1 1H NMR (400 MHz, DMSO-d6): 2.44 (s, 3H), 3.84 (s, 3H), 5.55 (s, 2H), 6.00 (br s, 2H), 6.92 (d, 1H), 7.36 (s, 1H), 7.42 (t, 1H), 7.51 - 7.61 (m, 3H), 7.82 (t, 1H), 8.16 (s, 1H), 8.61 (s, 1H). LCMS m / z = 431 [M+H] +

[1061] Example 195 : 5-(5-Fluoro-2-methoxypyridin-3-yl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[1062]

[1063] The title compound was prepared in a similar manner to Example 194 using 7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 95) and 5-fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Preparation 140) and obtained as a white solid (25 mg, 20.8%). 1 HNMR(400MHz,DMSO-d6):3.85(s,3H),5.56(s,2H),6.23(br s,2H),7.42(t,1H),7.47-7.63(m,4H),7.81(t,1H),8.11(d,1H),8.17(s,1H),8.62(s,1H).LCMS m / z=435[MH] +

[1064] Example 196 : 5-[2-(Difluoromethoxy)pyridin-3-yl]-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[1065]

[1066] A stirred solution of 7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 95, 100 mg, 0.23 mmol), 2-(difluoromethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (155 mg, 0.575 mmol) and Cs2CO3 (299.7 mg, 0.92 mmol) in DMF:water (4:1, 10 mL) was degassed with Ar for 15 minutes. PdCl2(dppf).DCM (37.5 mg, 0.046 mmol) was added and the reaction mixture was heated at 100 °C for 6 hours. The reaction was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organics were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by flash chromatography and preparative TLC to give the title compound as an off-white solid (12.5 mg, 12.02%). 1 HNMR(400MHz,DMSO-d6):5.59(s,2H),6.22(br s,2H),7.32-7.90(m,8H),8.19(s,1H),8.22(m,1H),8.61(m,1H).LCMS m / z=453[MH] +

[1067] Example 197 : 7-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(1,3-oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[1068]

[1069] Using 7-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 95, 150 mg, 0.345 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (168.1 mg, 0.862 mmol), the title compound was prepared in a manner similar to that of Example 196 as a white solid (15 mg, 11.6%). 1 HNMR (400 MHz, DMSO-d6): 5.62 (s, 2H), 7.32 - 7.43 (m, 3H), 7.54 (m, 1H), 7.74 (s, 1H), 7.81 (t, 1H), 8.21 (s, 1H), 8.26 (s, 1H). 8.40 (d, 1H). LCMS m / z = 377.0 [MH] +

[1070] Example 198 : 7-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(tetrahydrofuran-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[1071]

[1072] To a stirred solution of 5-(2,5-dihydrofuran-2-yl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 199, 40 mg, 0.106 mmol) in MeOH (2.0 mL) was added 50% wet Pd / C (20.0 mg) and the reaction mixture was stirred under H2 at room temperature for 16 hours. The reaction mixture was passed through filtration, and the solvent was evaporated to dryness in vacuo. The residue was purified by preparative TLC to give the title compound as an off-white solid (10 mg, 32%). 1HNMR(400MHz,DMSO-d6): 1.24(s,1H), 1.87 - 2.23(m,3H), 3.83(m,1H), 3.94(m,1H), 4.96(m,1H), 5.47(s,2H), 6.79(br s,2H), 7.24(s,1H), 7.42(t,1H), 7.53 - 7.62(m,2H), 7.81(t,1H), 8.11(s,1H), 8.55(s,1H). LCMS m / z=380[MH] +

[1073] Example 199 : 5-(2,5-Dihydrofuran-2-yl)-7-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[1074]

[1075] To a degassed solution of 7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 95, 2.0 g, 4.59 mmol) were added Bu4NCl (1.59 g, 5.74 mmol), NaOAc (1.31 g, 13.78 mmol), 2,3-dihydrofuran (3.47 mL, 45.95 mmol) and Pd(OAc)2 (1.03 g, 4.59 mmol). After stopping the degassing for 15 minutes, the resulting reaction mixture was heated to 50 °C and maintained for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography and then by preparative HPLC to give the title compound as an off-white solid (80 mg, 4.6%). 1 HNMR(400MHz,DMSO-d6) 4.67(s,2H), 5.47(s,2H), 6.02(br s,1H), 6.22(m,2H), 6.67(br s,2H), 7.42(t,1H), 7.51 - 7.64(m,2H), 7.81(t,1H), 8.12(s,1H), 8.56(s,1H). LCMS m / z=378[MH] +

[1076] Example 200 : 7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[1077]

[1078] To a degassed solution of 7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 95, 2 g, 4.56 mmol) in MeCN:H2O (80 mL, 4:1) was added (4-methoxypyrimidin-5-yl)boronic acid (1.19 g, 5.055 mmol), followed by CsF (3.49 g, 23.0 mmol). The resulting mixture was degassed with Ar for 15 minutes, Pd(PPh3)4 (0.69 g, 0.597 mmol) was added, and the reaction mixture was heated at 70 °C for 6 hours. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography and then triturated with DCM-ether to afford the title compound as an off-white solid (1.5 g, 78%). 1 HNMR (400 MHz, DMSO-d6) 3.93 (s, 3H), 5.57 (s, 2H), 6.33 (s, 2H), 7.42 (t, 1H), 7.48 (s, 1H), 7.52 - 7.62 (m, 2H), 7.81 (t, 1H), 8.17 (s, 1H), 8.41 (s, 1H), 8.62 (d, 1H), 8.75 (s, 1H). LCMS m / z = 418 [MH] +

[1079] Example 201 : Example 201 was not prepared.

[1080] Example 202 : 7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(2-methoxypyridin-3-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[1081]

[1082] To a stirred solution of 7-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-ylmethyl]-5-iodo-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 54, 150.0 mg, 0.334 mmol) in EtOH-water (4:1) (8.0 mL) was added 2-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (153.2 mg, 1.002 mmol) and Na2CO3 (106.16 mg, 1.002 mmol). The reaction mixture was degassed with Ar for 15 min, Pd(PPh3)4 (38.6 mg, 0.033 mmol) was added, degassed with Ar for 5 min, and heated to 90 °C for 6 h. The reaction mixture was filtered through filter paper and washed with 5% MeOH / DCM. The combined organics were evaporated to dryness under reduced pressure and the residue was azeotroped with toluene. The solid was triturated with Et2O and purified by preparative TLC (3% MeOH:DCM) to afford the title compound as an off-white solid (45.0 mg, 31.31%). 1 1H NMR (400 MHz, MeOD-d4) 2.53 (s, 3H), 3.92 (s, 3H), 5.59 (s, 2H), 7.03 (dd, 1H), 7.24 (s, 1H), 7.38 (m, 2H), 7.54 (m, 1H), 7.67 (dd, 1H), 7.81 (t, 1H), 8.14 (dd, 1H), 8.37 (d, 1H). LCMS m / z = 431 [M+H]+ +

[1083] Example 203 : 7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(4-methoxypyrimidin-5-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[1084]

[1085] Using 7-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-ylmethyl]-5-iodo-2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 54, 200.0 mg, 0.445 mmol) and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine (94 mg, 0.49 mmol), the title compound was prepared in a similar manner to that described in Example 202 as an off-white solid (32.19 mg, 16.8%). 1HNMR (400 MHz, CDCl3): 2.60 (s, 3H), 4.04 (s, 3H), 4.91 (s, 2H), 5.60 (s, 2H), 7.25 - 7.32 (m, 3H), 7.44 (m, 1H), 7.92 (m, 1H), 8.16 (d, 1H), 8.46 (s, 1H), 8.75 (s, 1H). LCMS m / z = 432 [M+H] +

[1086] Example 204 : 5-(2-(Difluoromethyl)pyrimidin-5-yl)-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[1087]

[1088] Under N2, to a solution of 7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 55, 375 mg, 0.86 mmol) in DMF (20 mL) was added 2-(difluoromethyl)pyrimidin-5-ylboronic acid (0.3 g, 1.73 mmol), Na2CO3 solution (5 mL), and Pd(dppf)Cl2 (63 mg, 0.086 mmol). The reaction was stirred at 100 °C for 6 hours, then water was added to the cooled mixture. The reaction mixture was extracted with EtOAc (40 mL × 2), and the combined organic layers were washed with brine, dried, and evaporated to dryness under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 9:1) to give the title compound (200 mg, 58%). 1 HNMR (400 MHz, DMSO-d6): 5.38 (s, 2H), 6.59 (br s, 2H), 7.05 (t, 1H), 7.33 - 7.50 (m, 3H), 7.74 (m, 2H), 7.77 (s, 1H), 8.30 (s, 2H), 8.98 (s, 2H). LCMS m / z = 437.1 [M+H

[1089] Example 205: 5-[2-(Difluoromethyl)pyrimidin-5-yl]-7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[1090]

[1091] To a solution of 7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 56, 360 mg, 0.80 mmol) in DMF (30 mL) was added 2-(difluoromethyl)pyrimidin-5-ylboronic acid (279 mg, 1.60 mmol), Na2CO3 solution (8 mL). Pd(dppf)Cl2 (59 mg, 0.08 mmol) was added under N2. The reaction mixture was stirred overnight at 100 °C, cooled and water was added. The mixture was extracted with EtOAc (50 mL × 2), and the combined extracts were washed with brine, dried and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the title compound (300 mg, 70%). 1 1H NMR (400 MHz, DMSO-d6) ...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, wherein W is selected from phenyl, optionally fused to a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl, said heterocycloalkyl containing one, two, three or four heteroatoms independently selected, each occurrence, from N, O and S(O) n ; a five- to ten-membered heteroaryl containing one, two, three or four heteroatoms independently selected from N, O and S(O) each time it appears n ; a 4- to 7-membered heterocycloalkyl containing one, two, three or four heteroatoms independently selected from N, O and S(O) each time it appears n ; and C3-C7 cycloalkyl; Among them, The phenyl, 5- to 10-membered heteroaryl, 4- to 7-membered heterocycloalkyl, and C3-C7 cycloalkyl are each optionally substituted with one, two, three, four, or five R 5 substituents; Y is a five-membered heteroaryl containing one, two, three or four heteroatoms independently selected from N, O and S(O) each time it appears n ; wherein said five-membered heteroaryl is optionally substituted with one, two or three substituents independently selected from halogen, C 1- 6 alkyl and C 1- 6 haloalkyl Z is selected from phenyl, C3-C7 cycloalkyl, five- or six-membered heteroaryl containing one, two or three heteroatoms each independently selected from N, O and S(O) n and four- to seven-membered heterocycloalkyl containing one, two or three heteroatoms each independently selected from N, O and S(O) n ; wherein said phenyl, C3-C7 cycloalkyl, five- to six-membered heteroaryl and four- to seven-membered heterocycloalkyl are each independently optionally substituted by one, two, three, four or five R 6 substituents; R 1a and R 1b each independently selected from -H or C 1- C6 alkyl; wherein said C 1- C6 alkyl is optionally substituted with one, two or three substituents, each independently selected from halogen, -OH, C1-C3 alkoxy, C3-C7 cycloalkyl and a four- to seven-membered heterocycloalkyl containing one, two or three heteroatoms each independently selected from N, O and S(O) n ; and wherein said C3-C7 cycloalkyl and four- to seven-membered heterocycloalkyl are each optionally substituted, each time it appears, independently with one, two or three substituents selected from -OH, halogen and C 1- C6 alkyl; R 2 selected from -H, halogen, -CN, C 1- 6-alkyl and C 1- 6-haloalkyl; R 3 and R 4 each independently selected from -H, C 1- C6 alkyl, and C 1- C6 haloalkyl; R 5 is independently selected from halogen, -CN, C 1- 6-alkyl, C 1- 6-haloalkyl, -OR 7 , -N(R 7 )2, -N(R 7 )C(O)R 7 , -SR 7 , oxo, C2-C7 alkoxyC 1- 6-alkyl, -S(O)2C 1- 6-alkyl, -C(O)R 7 and a five-membered heteroaryl containing one, two, three or four heteroatoms independently selected from N, O and S(O) n each time it appears, wherein the five-membered heteroaryl is optionally substituted by one, two or three substituents independently selected from halogen, -CN, C 1- 6-alkyl, C 1- 6-haloalkyl, -OR 7 , -N(R 7 )2 and -SR 7 each time it appears; R 6 independently selected from halogen, C 1- 6-alkyl, and C 1- 6-haloalkyl, -OR 7 , -N(R 7 )2, and -SR 7 ; R 7 independently selected from -H, C 1- C6 alkyl, C 1- C6 haloalkyl, C 3- C7 cycloalkyl and C 1- C6 alkyl C 3- C7 cycloalkyl; and n is independently 0, 1 or 2 each time it appears.

2. The compound according to claim 1, wherein R 3 and R 4 are both -H; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2, wherein Y is selected from pyrazolyl, triazolyl, imidazolyl and isoxazolyl, each of which is optionally substituted by C 1- C6 alkyl; or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 2, wherein the moiety Y-Z is selected from: or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 3, wherein W is phenyl, which is optionally substituted by one, two or three Rs 5 substituted; or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 3, wherein W is selected from pyrimidinyl, pyridinyl, pyrazinyl and pyrazolyl, each of which is optionally substituted with one, two or three R 5 substituted; or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 3, wherein W is C 3- a C7 cycloalkyl group, optionally substituted by one, two or three R 5 substituents; or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 6, wherein W is Optionally, it is substituted by one, two or three R 5 groups; R 5 independently selected from -OCH3, -CHF2, -CF3 and -N(CH3)2 each time it appears; or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 3, wherein Z is selected from phenyl and C 3- 7-cycloalkyl, each of which is optionally substituted by one, two or three R 6 substituents; or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 9, wherein Z is phenyl, which is optionally substituted by one or two fluorine or chlorine; or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 9, wherein Z is C 3- C7 cycloalkyl; or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 2, wherein R 2 Selected from: -H, -CN, and -Br; or a pharmaceutically acceptable salt thereof.

13. A compound selected from: 4-Amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{ (1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{ (1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-7-{ (1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-7-{ (1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-7-{ (1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-7-{ (1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-7-{ (1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-7-{ (1R)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-7-{ (1R)-1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-(2-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-7-{ (1S)-1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-(2-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-7-{ (1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-7-{ (1S)-1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-7-{ (1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-7-{ (1R)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-7-{ (1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-7-{ [1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{ [1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-7-{ [1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 6-Bromo-7-{ [1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-[4-(Cyclopropoxy)phenyl]-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-Cyclobutyl-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(4-Chlorophenyl)-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-[6-(Cyclopropoxy)pyridin-3-yl]-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(6-Methoxypyridin-3-yl)-7-[(1S)-1-(1-phenyl-1H-1,2,3-triazol-4-yl)propyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-[(1S)-1-(1-Phenyl-1H-1,2,3-triazol-4-yl)propyl]-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(4-Chlorophenyl)-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(3-methoxypyrazin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(5-Fluoro-2-methoxypyridin-3-yl)-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-[6-(Difluoromethoxy)pyridin-3-yl]-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{(1S)-1-[1-(3,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{(1S)-1-[1-(3,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-6-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{(1S)-1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{(1S)-1-[1-(2,5-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{(1S)-1-[2-(2,4-difluorophenyl)-1H-imidazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{(1S)-1-[1-(2,5-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{(1S)-1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{(1S)-1-[1-(2,4-difluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-(2-methoxy-6-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-[2-methoxy-6-(trifluoromethyl)pyridin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-7-{ (1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-7-{ (1S)-1-[1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-7-{ (1R)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-7-{ (1R)-1-[1-(2,3-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-7-{ (1R)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-5-[2-(difluoromethoxy)pyrimidin-5-yl]-7-{ (1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-5-(4-chlorophenyl)-7-{ [1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 5-(2-Fluoro-4-methoxyphenyl)-7-{ 1-[2-(2-fluorophenyl)-1H-imidazol-5-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(3-Fluoro-4-methylphenyl)-7-{ 1-[2-(2-fluorophenyl)-1H-imidazol-5-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{ 1-[2-(2-fluorophenyl)-1H-imidazol-5-yl]ethyl}-5-[4-(2H-1,2,3-triazol-2-yl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(4-Ethoxy-3-fluorophenyl)-7-{ [1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(4-Chloro-2-methoxyphenyl)-7-{ [1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-[4-(Difluoromethoxy)phenyl]-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[4-(methylthio)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-[4-(Difluoromethoxy)phenyl]-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-[2-Fluoro-4-(methylthio)phenyl]-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(4-Chloro-3-fluorophenyl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(3-Chloro-5-fluorophenyl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-Cyclopropyl-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 4-(4-Amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorobenzonitrile; 5-[4-(Cyclopropoxy)phenyl]-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(4-Methoxypyrimidin-5-yl)-7-[(1S)-1-(1-phenyl-1H-1,2,3-triazol-4-yl)propyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-[2-(Difluoromethyl)pyrimidin-5-yl]-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-[2-(Dimethylamino)pyrimidin-5-yl]-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{(1R)-1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(1H-pyrazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{(1S)-1-[1-(4-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{(1S)-1-[1-(3,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{(1R)-1-[1-(3,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-6-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{(1S)-1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{(1R)-1-[1-(2,3-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(5-fluoro-2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-Cyclopropyl-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{(1S)-1-[1-(2-Fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(4-Chlorophenyl)-7-{(1S)-1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{(1S)-1-[3-(2-Fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-(2-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(5-Fluoro-2-methoxypyridin-3-yl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-[2-(Difluoromethoxy)pyridin-3-yl]-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[4-methoxy-2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-[4-methoxy-2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(4-Chlorophenyl)-7-{2-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propan-2-yl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(4-Chlorophenyl)-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(4-Chlorophenyl)-7-{[2-(2-fluorophenyl)-1H-imidazol-5-yl]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(4-Chlorophenyl)-7-[(2-phenyl-1H-imidazol-5-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(4-Chlorophenyl)-7-[(3-cyclohexyl-1,2-oxazol-5-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-({1-[4-(Difluoromethyl)phenyl]-1H-pyrazol-4-yl}methyl)-5-(2-methoxypyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 7-{(1S)-1-[1-(2,3-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 4-Amino-5-[6-(cyclopropoxy)pyridin-3-yl]-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; and 4-Amino-7-{(1S)-1-[1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.

14. A compound selected from: 4-Amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-7-{ (1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-7-{ (1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-7-{ (1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-7-{ (1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 4-Amino-7-{ (1R)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; and 4-Amino-7-{ [1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.

15. The compound 4-Amino-7-{ (1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically acceptable salt thereof.

16. The compound 4-Amino-7-{ (1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically acceptable salt thereof.

17. The compound 4-Amino-7-{ (1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile or a pharmaceutically acceptable salt thereof.

18. Use of a compound according to any one of claims 1-17 or a pharmaceutically acceptable salt of said compound in the manufacture of a medicament for the treatment of cystic fibrosis, asthma, bronchiectasis, chronic obstructive pulmonary disease (COPD), constipation, diabetes, dry eye disease, pancreatitis, sinusitis or Sjogren's syndrome in a patient in need thereof.

19. Use of a compound according to any one of claims 1-17 or a pharmaceutically acceptable salt of said compound in the manufacture of a medicament for the treatment of cystic fibrosis.

20. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds according to any one of claims 1-17 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

21. The pharmaceutical composition according to claim 20, further comprising one or more additional therapeutic agents.

22. The pharmaceutical composition according to claim 21, wherein the one or more additional therapeutic agents are independently selected from CFTR potentiators, CFTR corrector agents, epithelial sodium channel (ENaC) inhibitors, CFTR amplifiers, CFTR stabilizers, read-through agents, oligonucleotide patches, autophagy inducers, and protein stability modulators.

23. The pharmaceutical composition according to claim 22, wherein the CFTR potentiator is, each time it appears, selected from VX-770 (Ivacaftor), GLPG-1837, GLPG-2451, QBW-251, FDL-176, FDL-129, CTP-656, and PTI-P271.

24. The pharmaceutical composition according to claim 22, wherein the CFTR corrector agent is, each time it appears, selected from VX-809 (lumacaftor), VX-661 (tezacaftor), VX-983, VX-152, VX-440, VX-659, GLPG-2737, P247-A, GLPG-2222, GLPG-2665, GLPG-2851, FDL-169, and PTI-C1811.

25. The pharmaceutical composition according to claim 22, wherein the epithelial sodium channel (ENaC) inhibitor is, each time it appears, selected from SPX-101, QBW-276, and VX-371.

26. The pharmaceutical composition according to claim 22, wherein the CFTR amplifier is, each time it appears, selected from PTI-428 and PTI-130.

27. The pharmaceutical composition according to claim 22, wherein the CFTR stabilizer is N-91115 (Cavosonstat).

28. The pharmaceutical composition according to claim 22, wherein the read-through agent is ataluren.

29. The pharmaceutical composition according to claim 22, wherein the oligonucleotide patch is QR-010.

30. The pharmaceutical composition according to claim 22, wherein the autophagy inducer is, each time it appears, selected from the combination of cysteamine and epigallocatechin gallate (EGCG) and CX-4945.

31. Use of the pharmaceutical composition according to any one of claims 21-30 in the manufacture of a medicament for treating cystic fibrosis in a patient in need thereof.

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