BR122024011694A2 - BICYCLIC HETEROARYL DERIVATIVE COMPOUNDS AS CFTR ENHANCERS, PHARMACEUTICAL COMPOSITION COMPRISING THE SAME AND USE OF SAID COMPOUNDS TO TREAT CYSTIC FIBROSIS, ASTHMA, BRONCHIECTASIA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CONSTIPATION, DIABETES MELLITUS, DRY EYE DISEASE, PANCREATITIS, RHINO-SINUSITIS OR SJOGREN'S SYNDROME - Google Patents

Abstract

“BICYCLIC HETEROARYL DERIVATIVE COMPOUNDS AS CFTR ENHANCERS, PHARMACEUTICAL COMPOSITION COMPRISING THE SAME AND USE OF SAID COMPOUNDS FOR TREATING CYSTIC FIBROSIS, ASTHMA, BRONCHIECTASIA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CONSTIPATION, DIABETES MELLITUS, DRY EYE DISEASE, PANCREATITIS, RHINO-SINUSITIS OR SJOGREN'S SYNDROME” The present invention relates to derivatives of 1,3-disubstituted-1H-pyrazolo[3,4-d]pyrimidin-4-amine, derivatives of 5,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazin-4-amine or derivatives of 5,7-disubstituted-imidazo[5,1-f][1,2,4]triazine-4-amine, and pharmaceutically acceptable salts thereof. The compounds are potentiators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). The invention also discloses pharmaceutical compositions comprising the compounds, optionally in combination with additional therapeutic agents, and methods of potentiating, in mammals, including humans, CFTR by administration of the compounds. These compounds are useful for the treatment of cystic fibrosis (CF), asthma, bronchiectasis, chronic obstructive pulmonary disease (COPD), constipation, diabetes mellitus, dry eye disease, pancreatitis, rhinosinusitis, Sjogren's syndrome, and other CFTR-associated disorders.

Description

[001] Divided from BR 11 2019 012335 0, filed on 12/14/2017.

Field of Invention

[002] The present invention relates to small molecule potentiators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). This invention also relates to pharmaceutical compositions comprising the potentiators, optionally in combination with additional therapeutic agents, and methods of potentiating, in mammals, including humans, CFTR by administration of the small molecule CFTR potentiators. The present invention also relates to the treatment of cystic fibrosis and other disorders in mammals, including humans, with the CFTR potentiators. More particularly, this invention relates to derivatives of 1,3-disubstituted-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 5,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazin-4-amine or 5,7-disubstituted-imidazo[5,1-f][1,2,4]triazine-4-amine useful for the treatment of cystic fibrosis (CF), asthma, bronchiectasis, chronic obstructive pulmonary disease (COPD), constipation, diabetes mellitus, dry eye disease, pancreatitis, rhinosinusitis, Sjogren's syndrome and other CFTR associated disorders.

Background of the Invention

[003] Cystic fibrosis (CF) is the most common lethal genetic disease affecting Caucasians. CF is an autosomal recessive disease with an incidence of between 1 in 2,000 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). There are over 70,000 people affected worldwide, of whom approximately 33,000 are in the United States. (www.cff.org/What-is-CF/About-Cystic-Fibrosis/). The hallmarks of CF are excessive mucus secretion and defective mucus clearance, resulting in airway obstruction, infection, and inflammation; pancreatic insufficiency; and elevated sweat chloride concentration. CF is a multisystem disease that affects the lungs, pancreas, and the 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, pages 59–68).

[004] For most patients, there is a high burden of care for supportive therapies that do not address the root cause of the disease. 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 in the fourth decade of life.

[005] Cystic fibrosis is caused by mutations in the gene for CFTR (Cystic Fibrosis Transmembrane Conductance Regulator), an ion channel found in epithelia and other tissues. CFTR is found in the apical membrane of epithelial cells of 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). CFTR mutations have been 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 by deletion, nonsense or frameshift mutations, 2) defective endoplasmic reticulum trafficking due to improper folding, 3) improper gating, 4) reduced conductance due to alterations in the channel pore, 5) reduced channel production due to altered splicing, and 6) increased plasma membrane endocytosis.

[006] Nearly 2,000 different mutations in CFTR are known to cause CF. The Phe508 deletion of 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 F508del homozygous and approximately 40% are heterozygous, so that 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).

[007] The F508del mutation causes loss of CFTR function due to reduced channel density and impaired channel gating. Channel density at the apical membrane is reduced due to unfolding of the protein. The unfolded CFTR is recognized by cellular quality control mechanisms and degraded (Ward, C. L. and Kopito, R. R., J. Biol. Chem., 1994, 269, 25710-25718). F508del function is further reduced because it has a significantly reduced channel probability (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, C833C839).

[008] Small molecules called "correctors" have been shown to reverse the F508del CFTR folding/trafficking defect and increase the density of CFTR channels at 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, Van Goor, F. et al., Proc. Nat. Acad. Sci. USA, 2011, 108, 18843- 18848). "Enhancers" are small molecules that increase the probability of mutant CFTR channel opening, reversing the gating defect. Pharmacological repair of F508del may require at least a corrector and an enhancer to resolve folding and gating defects, while G551D may benefit from only an enhancer.

[009] Kalydeco® (ivacaftor, VX-770) is a marketed potentiator that improves the gating characteristics of G551D. In patients with G551D, it substantially improved lung function (predicted percent increase in FEV1 was 10 to 13%), allowed weight gain, and reduced 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). Kalydeco® is also approved for people with G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, and S549R mutations and other mutations, including those with partial function that are being investigated.

[010] Although Kalydeco® monotherapy did not lead to any significant improvement in F508del homozygous patients (Flume, P. A. et al., Chest, 2012, 142, 718-724), a combination of a corrector (VX-809, Lumacaftor or VX661, tezacaftor) with Kalydeco® resulted in a modest improvement in lung function (percent predicted FEV1 increased by 3 to 4%) (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). The combination VX-809 plus Kalydeco® (called Orkambi®) is a marketed therapy for homozygous F508del patients.

[011] For both the G551D and F508del patient populations, improved therapies are expected to provide additional benefit to patients. The majority of G551D patients are heterozygous for the G551D/F508del compound, and treatment with the combination of the corrector VX-661 with Kalydeco® resulted in an additional increase in lung function with Kalydeco® alone (Pilewski, J. M. et al., J. Cystic Fibrosis, 2015, 14, Suppl. 1, S1).

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

[013] Modulation of CFTR activity may also be beneficial for other diseases not directly caused by CFTR mutations, such as secretory diseases and other CFTR-mediated protein misfolding disorders. CFTR regulates the flow of chloride and bicarbonate across the epithelia of many cells to control fluid movement, protein solubilization, mucus viscosity, and enzyme activity. Defects in CFTR can cause obstruction of the airways or ducts in many organs, including the liver and pancreas. Enhancers are compounds that increase the activation activity of CFTR present on the cell membrane. Any disease involving mucus thickening, impaired fluid regulation, impaired mucus clearance, or blocked ducts leading to inflammation and tissue destruction may be candidates for enhancers. Therefore, there is a significant therapeutic need for novel small molecules that act as CFTR enhancers.

[014] In addition to cystic fibrosis, CFTR-related 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 mellitus, dry eye disease, pancreatitis, rhinosinusitis, and Sjogren's syndrome.

Summary of the Invention

[015] A first embodiment of a first aspect of the present invention is a compound of Formula I or a pharmaceutically acceptable salt thereof; wherein Y is a five-membered heteroaryl comprising one to four heteroatoms, each of which is independently selected from the group consisting of N, O and S(O)n; wherein the heteroaryl is optionally substituted by one to three substituents, each of which is independently selected from the group consisting of halo, C1-C6alkyl and C1-C6haloalkyl; Z is phenyl, optionally substituted by one to three halo; R1a and R1b are each independently selected from the group consisting of -H, -OH, halo, C1-C6alkyl optionally substituted with one to three substituents, each of which is independently selected from the group consisting of halo, -OH, C1-C3alkoxy, C3-C7cycloalkyl, and a four- to seven-membered heterocycloalkyl comprising one to three heteroatoms, each of which is independently selected from the group consisting of N, O, and S(O)n, C3-C7cycloalkyl optionally substituted with one to three substituents, each of which is independently selected from the group consisting of -OH, halo, and C1-C6alkyl, and four- to seven-membered heterocycloalkyl comprising one to three heteroatoms, each of which is independently selected from the group consisting of N, O, and S(O)n; and wherein the four- to seven-membered heterocycloalkyl is optionally substituted by one to three substituents, each of which is independently selected from the group consisting of -OH, halo, and C1-C6alkyl; or R1a and R1b taken together with the carbon to which they are attached form a C3-C7cycloalkyl or a four- to seven-membered heterocycloalkyl comprising one to three heteroatoms, each of which is independently selected from the group consisting of N, O, and S(O)n; and wherein the C3-C7cycloalkyl or four- to seven-membered heterocycloalkyl is optionally substituted by one to three substituents, each of which is independently selected from the group consisting of -OH, halo, and C1-C6alkyl; and n at each occurrence is independently 0, 1, or 2.

[016] A second embodiment of the first aspect of the present invention is the compound of the first embodiment, wherein one of R1a and R1b is C1-C6alkyl and the other is -H; or a pharmaceutically acceptable salt thereof.

[017] A third embodiment of the first aspect of the present invention is the compound of the second embodiment, wherein the YZ moiety is selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[018] A fourth embodiment of the first aspect of the present invention is the compound of the third embodiment wherein Z is phenyl optionally substituted by one or two fluoros or chloros; or a pharmaceutically acceptable salt thereof.

[019] A first embodiment of a second aspect of the present invention is a compound of Formula II or a pharmaceutically acceptable salt thereof; wherein W is a five- to six-membered heteroaryl comprising one to three heteroatoms, each of which is independently selected from the group consisting of N, O, and S(O)n; and wherein the heteroaryl is optionally substituted by one to three R3; Y is a five-membered heteroaryl comprising one to four heteroatoms, each of which is independently selected from the group consisting of N, O, and S(O)n; wherein the heteroaryl is optionally substituted by one to three substituents, each of which is independently selected from the group consisting of halo, C1-C6alkyl, and C1-C6haloalkyl; Z is C1-C6alkyl or phenyl; wherein the phenyl is optionally substituted by one to three halo; R1a and R1b are each independently selected from the group consisting of -H, -OH, halo, C1-C6alkyl optionally substituted with one to three substituents, each of which is independently selected from the group consisting of halo, -OH, C1-C3alkyloxy, C3-C7cycloalkyl and a four- to seven-membered heterocycloalkyl comprising one to three heteroatoms, each of which is independently selected from the group consisting of N, O and S(O)n, C3-C7cycloalkyl optionally substituted with one to three substituents, each of which is independently selected from the group consisting of -OH, halo and C1-C6alkyl; and four- to seven-membered heterocycloalkyl optionally substituted with one to three substituents, each of which is independently selected from the group consisting of -OH, halo and C1-C6alkyl; or R1a and R1b taken together with the carbon to which they are attached form a four- to seven-membered C3-C7cycloalkyl or heterocycloalkyl comprising one to three heteroatoms, each of which is independently selected from the group consisting of N, O, and S(O)n; and wherein the four- to seven-membered C3-C7cycloalkyl or heterocycloalkyl is optionally substituted by one to three substituents, each of which is independently selected from the group consisting of -OH, halo, and C1-C6alkyl; R2 is selected from the group consisting of -H, -CN, halo, and C1-C3alkyl; R3 at each occurrence is independently selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, halo, and C1-C6haloalkyl; and n at each occurrence is independently 0, 1, or 2.

[020] A second embodiment of the second aspect of the present invention is a compound of the first embodiment of the second aspect of the invention, wherein W is pyrimidinyl or pyrazinyl, and wherein the pyrimidinyl or pyrazinyl is optionally substituted by one, two or three R3.

[021] A third embodiment of the second aspect of the present invention is a compound of the first embodiment of the second aspect of the invention, wherein the chemical moiety YZ is selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[022] A first embodiment of a third aspect of the present invention is a compound of Formula III or a pharmaceutically acceptable salt thereof; wherein W is selected from the group consisting of phenyl and a five- to six-membered heteroaryl comprising one to three heteroatoms, each of which is independently selected from the group consisting of N, O, and S(O)n; wherein the phenyl and heteroaryl are optionally substituted by one to three R3; Y is a five-membered heteroaryl comprising one to four heteroatoms, each of which is independently selected from the group consisting of N, O, and S(O)n; wherein the heteroaryl is optionally substituted by one to three substituents, each of which is independently selected from the group consisting of halo, C1-C6alkyl, and C1-C6haloalkyl; Z is C1-C6alkyl or phenyl; wherein the phenyl is optionally substituted by one to three halo; R1a and R1b are each independently selected from the group consisting of -H, -OH, halo, C1-C6alkyl optionally substituted by one to three substituents, each of which is independently selected from the group consisting of halo, -OH, C1-C3alkyloxy, C3-C7cycloalkyl, and a four- to seven-membered heterocycloalkyl comprising one to three heteroatoms, each of which is independently selected from the group consisting of N, O, and S(O)n, C3-C7cycloalkyl optionally substituted by one to three substituents, each of which is independently selected from the group consisting of -OH, halo, and C1-C6alkyl, and four- to seven-membered heterocycloalkyl optionally substituted by one to three substituents, each of which is independently selected from the group consisting of -OH, halo, and C1-C6alkyl, or R1a and R1b taken together with the carbon to which they are attached form a C3-C7cycloalkyl or a heterocycloalkyl of four- to seven-membered heteroatoms comprising one to three heteroatoms, each of which is independently selected from the group consisting of N, O, and S(O)n; and wherein the four- to seven-membered C3-C7cycloalkyl or heterocycloalkyl is optionally substituted by one to three substituents, each of which is independently selected from the group consisting of -OH, halo, and C1-C6alkyl; R3 at each occurrence is independently selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, halo, and C1-C6haloalkyl; and n at each occurrence is independently 0, 1, or 2.

[023] A second embodiment of the third aspect of the present invention is a compound of the first embodiment of the third aspect of the present invention, wherein W is phenyl that is optionally substituted by one or two halos; or a pharmaceutically acceptable salt thereof.

[024] A third embodiment of the third aspect of the present invention is a compound of the second embodiment of the third aspect of the present invention wherein the compound is 5-(4-chlorophenyl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}imidazo[5,1-f][1,2,4]triazin-4-amine; or a pharmaceutically acceptable salt thereof.

[025] A fifth embodiment of the first aspect of the present invention is a compound of the first embodiment of the first aspect of the present invention, wherein the compound is selected from the group consisting of 1-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 1-{(1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine; and 1-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine; or a pharmaceutically acceptable salt thereof.

[026] A fourth embodiment of the second aspect of the present invention is a compound of the first embodiment of the second aspect of the invention wherein the compound is selected from the group consisting of 7-{(1R)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine; 7-{(1R)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 4-amino-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 7-{(1R)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 7-{(1R)-1-[1-(2,5-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 7-{(1S)-1-[1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 4-amino-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2,5-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-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]pyrrolo[2,1-f][1,2,4]triazine-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]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 4-amino-7-{(1S)-1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{[3-(2-fluorophenyl)-1,2-oxazol-5-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(propan-2-yl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1S)-1-[1-(propan-2-yl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; and 4-amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.

[027] A fifth embodiment of the second aspect of the present invention is a compound of the first embodiment of the second aspect of the invention wherein the compound is selected from the group consisting of 7-{(1R)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine; 7-{(1R)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 4-amino-7-{(1R)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 7-{(1R)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 4-amino-7-{(1R)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 7-{(1R)-1-[1-(2,5-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 7-{(1S)-1-[1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 4-amino-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2,5-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-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]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 4-amino-7-{(1S)-1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{[3-(2-fluorophenyl)-1,2-oxazol-5-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1S)-1-[1-(propan-2-yl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; and 4-amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.

[028] A sixth embodiment of the first aspect of the present invention is the compound 1-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine or a pharmaceutically acceptable salt thereof.

[029] A sixth embodiment of the second aspect of the present invention is the compound 4-amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile or a pharmaceutically acceptable salt thereof.

[030] A seventh embodiment of the second 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]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile or a pharmaceutically acceptable salt thereof.

[031] An eighth embodiment of the second 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]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile or a pharmaceutically acceptable salt thereof.

[032] A ninth embodiment of the second 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]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile or a pharmaceutically acceptable salt thereof.

[033] A first embodiment of a fourth aspect of the present invention is a method of treating cystic fibrosis, asthma, bronchiectasis, chronic obstructive pulmonary disease (COPD), constipation, diabetes mellitus, dry eye disease, pancreatitis, rhinosinusitis or Sjogren's syndrome in a patient in need of treatment, the method comprising administering a therapeutically effective amount of a compound, or pharmaceutically acceptable salt of said compound, according to any one of the first to sixth embodiments of the first aspect, or any one of the first to ninth embodiments of the second aspect, or any one of the first to third embodiments of the third aspect, to a patient in need of treatment thereof.

[034] A second embodiment of the fourth aspect of the present invention is a method of treating cystic fibrosis in a patient in need of treatment thereof, the method comprising administering a therapeutically effective amount of a compound, or pharmaceutically acceptable salt of said compound, according to any one of the first to sixth embodiments of the first aspect, or any one of the first to ninth embodiments of the second aspect, or any one of the first to third embodiments of the third aspect, to a patient in need of treatment thereof.

[035] A first embodiment of a fifth aspect of the present invention is the compound or pharmaceutically acceptable salt thereof according to any one of the first to sixth embodiments of the first aspect, or any one of the first to ninth embodiments of the second aspect, or any one of the first to third embodiments of the third aspect, for use in the treatment of cystic fibrosis.

[036] A first embodiment of a sixth 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 sixth embodiments of the first aspect, or any one of the first to ninth embodiments of the second aspect, or any one of the first to third embodiments of the third aspect, or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.

[037] A second embodiment of the sixth aspect of the present invention is the pharmaceutical composition of the first embodiment of the sixth aspect, further comprising one or more additional therapeutic agents.

[038] A third embodiment of the sixth aspect of the present invention is the pharmaceutical composition of the second embodiment of the sixth aspect; wherein the one or more additional therapeutic agents are selected from the group consisting of a CFTR potentiator, a CFTR corrector, an epithelial sodium channel (ENaC) inhibitor, a CFTR amplifier, a CFTR stabilizer, a reader agent, an oligonucleotide patch, an autophagy inducer, and a protease modulator.

[039] A fourth embodiment of the sixth aspect of the present invention is a pharmaceutical composition of the third embodiment of the sixth aspect; wherein the CFTR potentiator in each occurrence is selected from the group consisting of VX770 (Ivacaftor), GLPG-1837, GLPG-2451, QBW-251, FDL-176, FDL-129, CTP656, and PTI-P271.

[040] A fifth embodiment of the sixth aspect of the present invention is a pharmaceutical composition of the third embodiment of the sixth aspect; wherein the CFTR corrector in each occurrence is selected from the group consisting of VX809 (lumacaftor), VX-661 (tezacaftor), VX-983, VX-152, VX-440, VX-659, GLPG2737, P247-A, GLPG-2222, GLPG-2665, GLPG-2851, FDL-169, and PTIC1811.

[041] A sixth embodiment of the sixth aspect of the present invention is a pharmaceutical composition of the third embodiment of the sixth aspect; wherein the epithelial sodium channel (ENaC) inhibitor in each occurrence is selected from the group consisting of SPX-101, QBW-276, and VX-371.

[042] A seventh embodiment of the sixth aspect of the present invention is a pharmaceutical composition of the third embodiment of the sixth aspect; wherein the CFTR amplifier in each occurrence is selected from the group consisting of PTI428 and PTI-130.

[043] An eighth embodiment of the sixth aspect of the present invention is a pharmaceutical composition of the third embodiment of the sixth aspect; wherein the CFTR stabilizer is N-91115 (Cavosonstat).

[044] A ninth embodiment of the sixth aspect of the present invention is a pharmaceutical composition of the third embodiment of the sixth aspect; wherein the reading agent is ataluren (PTC124).

[045] A tenth embodiment of the sixth aspect of the present invention is a pharmaceutical composition of the third embodiment of the sixth aspect; wherein the autophagy inducer in each occurrence is selected from the group consisting of CX-4945 and the combination of cysteamine and epigallocatechin gallate (EGCG).

[046] A first embodiment of a seventh aspect of the present invention is a method of treating cystic fibrosis in a patient in need of treatment thereof, the method comprising administering the pharmaceutical composition according to any one of the first to tenth embodiments of the sixth aspect to the patient in need of treatment thereof.

[047] A first embodiment of an eighth aspect of the present invention is the pharmaceutical composition according to any one of the first to tenth embodiments of the sixth aspect for use in the treatment of cystic fibrosis.

DEFINITIONS

[048] The term “alkyl” refers to a straight or branched chain saturated hydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbon by the removal of one hydrogen); in one embodiment of one to six carbon atoms (i.e., C1-C6alkyl). Examples of such substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, and tert-butyl), pentyl, isoamyl, hexyl, and the like.

[049] The term “haloalkyl” refers to an alkyl in which at least one hydrogen in the alkyl is replaced by a halogen atom. The term “C1-C6 haloalkyl” refers to a C1-C6 alkyl group, as defined herein, in which one, two, three, four, five, or six hydrogen atoms are replaced by 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 all the same as each other. Examples of haloalkyls include: chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2-chloro-3-fluoropentyl, and the like.

[050] The term “alkoxy” refers to a straight or branched chain saturated hydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbon by the removal of a hydrogen) that is in turn attached to an oxygen atom; in one embodiment of one to six carbon atoms (i.e., C1-C6alkoxy). Examples of such substituents include methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy), pentoxy, and the like.

[051] The term "cycloalkyl" refers to a carbocyclic substituent obtained by removing a hydrogen atom from a saturated carbocyclic molecule and having the specified number of carbon atoms. In one embodiment, a cycloalkyl substituent has three to seven carbon atoms (i.e., C3-C7cycloalkyl). Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "cycloalkyl" includes saturated mono-, bi-, and tricyclic carbocycles, as well as bridged and fused ring carbocycles, as well as spiro-fused ring systems.

[052] As used herein, the term "heterocycloalkyl" refers to a monocyclic ring system containing the heteroatoms N, O or S(O)n as specified. The term "heterocycloalkyl" refers to a substituent obtained by removing one hydrogen from a saturated or partially saturated ring structure containing the specified number of ring atoms; wherein at least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen and sulfur. If the heterocycloalkyl substituent is in turn substituted by a group or substituent, the group or substituent may be attached to a nitrogen heteroatom, or may be attached to a ring carbon atom, as appropriate. In some cases, the number of atoms in a cyclic substituent containing one or more heteroatoms (i.e., heteroaryl or heterocycloalkyl) is indicated by the prefix "x to y members"; where x is the minimum number and y is the maximum number of atoms forming the cyclic chemical portion of the substituent. Thus, for example, "four- to seven-membered heterocycloalkyl" refers to a heterocycloalkyl containing four to seven atoms, including one or more heteroatoms, in the cyclic chemical portion of the heterocycloalkyl. Examples of single-ring heterocycloalkyls include azetidinyl, oxetanyl, thietanyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, hydropyranyl, piperidinyl, morpholinyl, piperazinyl, azepinil, oxepinil and diazepinil.

[053] The term "heteroaryl" refers to an aromatic ring structure containing the specified number of ring atoms in which at least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. A five- to six-membered heteroaryl is an aromatic ring system that has five or six ring atoms with at least one of the ring atoms being N, O, or S(O)n.

[054] Examples of heteroaryl substituents include six-membered ring substituents such as pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl; five-membered ring substituents such as pyrrolyl, theinyl, furanyl, triazolyl, imidazolyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl, and isothiazolyl. In a group having a heteroaryl substituent, the ring atom of the heteroaryl substituent that is attached to the group may be the at least one heteroatom, or may be a ring carbon atom, wherein the ring carbon atom may be in the same ring as the at least one heteroatom or the ring carbon atom may be in a different ring than the at least one heteroatom. Similarly, if the heteroaryl substituent is in turn substituted by a group or substituent, the group or substituent may be attached to at least one heteroatom, or may be attached to a ring carbon atom, wherein the ring carbon atom may be in the same ring as the at least one heteroatom or wherein the ring carbon atom may be in a different ring than the at least one heteroatom. The term "heteroaryl" also includes pyridinyl N-oxides and groups containing a pyridine N-oxide ring. The groups mentioned above, as derivatives of the groups listed above, may be C-linked or N-linked, where this is possible. For example, a group derived from pyrrole may be pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). Also, a group derived from imidazole may be imidazol-1-yl (N-linked) or imidazol-2-yl (C-linked).

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

[056] The term "hydrogen" refers to a hydrogen substituent, and can be represented as -H.

[057] The term “hydroxy” or “hydroxyl” refers to -OH. Compounds bearing a carbon to which one or more hydroxyl substituents are attached include, for example, alcohols, enols, and phenol.

[058] The term “phenyl” refers to an aromatic ring having the radical —C6H5, derived from benzene by removal of a hydrogen atom. Phenyl, if so specified, may be optionally fused to a five- or six-membered cycloalkyl or heterocycloalkyl ring to form bicyclic compounds. 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.

[059] If substituents are described as being "independently selected" from a group, each example of a substituent is selected independently of the other. Each substituent, therefore, may be identical to or different from the other substituent (or substituents).

[060] As used herein, the term "formula I", “formula (I)”, “Formula (I)” or "Formula I"; "formula II", “formula (II)”, “Formula (II)” or "Formula III"; or "formula III", “formula (III)”, “Formula (III)” or "Formula III" may refer to a "compound(s) of the invention". Such terms are also defined to include all forms of the compound of formula I, including hydrates, solvates, isomers, crystalline and non-crystalline forms, isomorphs, polymorphs, and metabolites thereof. For example, the compounds of the invention, or pharmaceutically acceptable salts thereof, may exist in solvated and unsolvated forms. When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry, independent of moisture. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will depend on the wetting and drying conditions. In such cases, nonstoichiometry will be the norm.

[061] The compounds of the invention may exist as clathrates or other complexes. Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes in which the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the compounds of the invention containing two or more organic and/or inorganic components which may be 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).

[062] Compounds of the invention may have asymmetric carbon atoms. The carbon-carbon bonds of compounds of the invention may be depicted herein using a solid line ( ), a solid wedge ( and ), or a dotted wedge ( ). The use of a solid line to represent bonds to asymmetric carbon atoms means that all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of a solid or dotted wedge to represent bonds to asymmetric carbon atoms meant that only the stereoisomer shown should be included. It is possible that compounds of Formula I, II, or III may contain more than one asymmetric carbon atom. In such compounds, the use of a solid line to represent bonds to asymmetric carbon atoms meant that all possible stereoisomers should be included. For example, unless otherwise indicated, it is intended that compounds of Formula I, II, or III may exist as enantiomers and diastereomers or as racemates and mixtures thereof. The use of a solid line to represent bonds to one or more carbon atoms in a compound of Formula I, II, or III and the use of a solid or dotted wedge to represent bonds to other asymmetric carbon atoms in the same compound are intended to indicate that a mixture of diastereomers is present.

[063] Stereoisomers of Formulas I, II or III 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 invention, including compounds that exhibit more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs). Also included are acid addition or base addition salts in which the counterion is optically active, e.g., D-lactate or L-lysine, or racemic, e.g., DL-tartrate or DL-arginine.

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

[065] The present invention encompasses tautomeric forms of compounds of the invention. Where structural isomers are interconvertible across a low energy barrier, tautomeric isomerism (“tautomerism”) may occur. This may take the form of proton tautomerism in compounds of the invention containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds containing an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism. The various ratios of tautomers in solid and liquid form are dependent on the various substituents in the molecule as well as the particular crystallization technique used to isolate a compound.

[066] Examples of types of potential tautomerisms exhibited by the compounds of the invention include hydroxypyridine or pyridone; amide or hydroxyl-imine and keto or enol tautomerisms:

[067] The compounds of this invention may be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, a salt of the compound may be advantageous due to one or more of the physical properties of the salt, such as increased pharmaceutical stability at different temperatures and humidities, or a desirable solubility in water or oil. In some cases, a salt of a compound may also be used as an aid in the isolation, purification, and/or resolution of the compound. When a salt is intended to be administered to a patient (as opposed to, for example, being used in an in vitro context), the salt is preferably pharmaceutically acceptable. The term "pharmaceutically acceptable salt" refers to a salt prepared by combining a compound of Formulas I, II, or III with an acid whose anion, or a base whose cation, is generally considered suitable for human consumption. Pharmaceutically acceptable salts are particularly useful as products of the processes of the present invention due to their increased aqueous solubility relative to the parent compound. For use in medicine, the salts of the compounds of this invention are non-toxic "pharmaceutically acceptable salts." Salts encompassed by the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention that are generally prepared by reacting the free base with a suitable organic or inorganic acid.

[068] Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention where possible include those derived from inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and sulfuric acid, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids. Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids. Specific examples of suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, p-hydroxybutyrate, galactarate, galacturonate, adipate, alginate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate, 2-naphtha-sulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, thiocyanate and undecanoate.

[069] Furthermore, when the compounds of the invention contain an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, i.e., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. In another embodiment, the base salts are formed from bases that form non-toxic salts, including aluminum, arginine, benzathine, choline, diethylamine, diamine, glycine, lysine, meglumine, olamine, tromethamine, and zinc salts.

[070] 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 agents such as lower (C1-C6) alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (i.e., dimethyl, diethyl, dibutyl, and diamyl sulfates), long-chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), and others.

[071] In one embodiment, hemisals of acids and bases may also be formed, for example, hemisulfate and hemical salts.

[072] Also within the scope of the present invention are so-called "prodrugs" of the compound of the invention. Thus, certain derivatives of the compound of the invention, which may have little or no pharmacological activity, may, when administered into the body, be converted to compounds of the invention having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as "prodrugs". Further information on the use of prodrugs can be found in "Prodrugs as Novel Delivery Systems”, Volume 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 invention can, for example, be produced by substituting appropriate functionalities present in compounds of any of Formulas I, II or III with certain moieties known to those skilled in the art as "chemical promoieties" as described, for example, in Bundgaard, H. 1985. Design of Prodrugs. New York: Elsevier.

[073] The present invention also includes isotopically labeled compounds, which are identical to those cited in formula I, but with the fact that one or more atoms are replaced by an atom with an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 11C, 14C, 15N, 180, 170, 32P, 35S, 18F and 36Cl, respectively. The compounds of the present invention, their prodrugs and said compounds of said prodrugs that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds of the present invention, e.g., those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. In addition, substitution with heavier isotopes such as deuterium, i.e., 2H, may provide certain therapeutic advantages resulting from increased metabolic stability, e.g., increased in vivo half-life, or reduced dosage requirements, and therefore may be preferred in some circumstances. The compounds of Formulas I, II, III of this invention and their isotopically labeled prodrugs can generally be prepared by performing the procedures disclosed in the Schemes and/or the Examples and Preparations below, substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

DETAILED DESCRIPTION OF THE INVENTION

[074] Typically, a compound of the invention is administered in an amount effective to treat a condition as described herein. The compounds of the invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such route, and in a dose effective for the intended treatment. Therapeutically effective doses of the compounds required to treat the progress of the medical condition are readily determined by one of skill in the art using preclinical clinical approaches and familiar medical techniques.

[075] The term "treat", as used herein, unless otherwise indicated, means to reverse, alleviate, inhibit the progress of, or prevent the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above. The term "treat" also includes adjuvant and neo-adjuvant treatment of an individual. The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, buccal or sublingual administration may be employed, whereby the compound enters the bloodstream directly from the mouth.

[076] In another embodiment, the compounds of the invention may also be administered directly into the bloodstream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle injectors (including microneedles), needleless injectors, and infusion techniques. In another embodiment, the compounds of the invention may also be administered topically to the skin or mucosa, i.e., dermally or transdermally. In another embodiment, the compounds of the invention may also be administered intranasally or by inhalation. In another embodiment, the compounds of the invention may also be administered rectally or vaginally. In another embodiment, the compounds of the invention may also be administered directly into the eye or ear.

[077] The dosage regimen for the compounds and/or 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 condition; the route of administration; and the activity of the particular compound employed. 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 are useful in treating the above-listed conditions. In one embodiment, the total daily dose of a compound of the invention (administered in single or divided doses) is typically about 0.01 to about 100 mg/kg. In another embodiment, the total daily dose of the compound of the invention is about 0.1 to about 50 mg/kg, and in another embodiment, about 0.5 to about 30 mg/kg (i.e., mg compound of the invention per kg of body weight). In one embodiment, the dosage is 0.01 to 10 mg/kg/day. In another embodiment, the dosage is 0.1 to 1.0 mg/kg/day. Dosage unit compositions may contain such amounts or submultiples thereof to make up the daily dose. In many cases, administration of the compound will be repeated multiple times in a day (typically not more than 4 times). Multiple doses per day typically may be used to increase the total daily dose, if desired.

[078] For oral administration, the compositions may be provided in the form of tablets containing from about 0.01 mg to about 500 mg of active ingredient, or in another embodiment, from about 1 mg to about 100 mg of active ingredient. Intravenously, doses may range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion.

[079] Suitable subjects according to the present invention include mammalian subjects. Mammals according to the present invention include, but are not limited to, canines, felines, bovines, caprines, equines, ovines, swine, rodents, lagomorphs, primates, and the like, and encompass mammals in utero. In one embodiment, humans are suitable subjects. Human subjects can be of any gender and at any stage of development.

[080] In another embodiment, the invention comprises the use of one or more compounds of the invention for the preparation of a medicament for the treatment of the conditions cited herein.

[081] For the treatment of the conditions referred to above, the compound of the invention may be administered as the compound per se. Alternatively, pharmaceutically acceptable salts are suitable for medical applications due to their greater aqueous solubility relative to the parent compound.

[082] In another embodiment, the present invention comprises pharmaceutical compositions. Such pharmaceutical compositions comprise a compound of the invention presented with a pharmaceutically acceptable carrier. The carrier may be a solid, a liquid, or both, and may be formulated with the compound as a unit dose composition, e.g., a tablet, which may contain from 0.05% to 95% by weight of the active compounds. A compound of the invention may be coupled with suitable polymers as targetable drug carriers. Other pharmacologically active substances may also be present.

[083] The compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmacological protein adapted to that route, and in a dose effective for the intended treatment. The active compounds and compositions, for example, may be administered orally, rectally, parenterally or topically.

[084] Oral administration of a solid dosage form may be, for example, presented in discrete units, such as hard or soft capsules, pills, dragees, lozenges, or tablets, each containing a predetermined amount of at least one present invention.

[085] In another embodiment, the oral administration may be in powder or granule form. In another embodiment, the oral administration may be in a spray-dried dispersion. In another embodiment, the oral dosage form is sublingual, such as a lozenge. In such solid dosage forms, the compounds of Formulas I, II, or III are typically combined with one or more adjuvants. Such capsules or tablets may contain a controlled-release formulation. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents or may be prepared with enteric coatings.

[086] In another embodiment, the oral administration may be in a liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents customarily used in the art (e.g., water). Such compositions may also comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening) and/or perfuming agents.

[087] In another embodiment, the present invention comprises a parenteral dosage form. "Parenteral administration" includes, for example, subcutaneous injections, intravenous injections, intraperitoneal injections, intramuscular injections, intrasternal injections, and infusion. Injectable preparations (e.g., sterile injectable aqueous oleaginous suspensions) may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.

[088] In another embodiment, the present invention comprises a topical dosage form. "Topical administration" includes, for example, transdermal administration, such as via transdermal patches, iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. A topical formulation may include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of this invention are administered by a transdermal device, the administration will be accomplished using an adhesive of the reservoir and porous membrane type or of a solid matrix variety.

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

[090] Formulations suitable for topical administration to the eye include, for example, eye drops in which the compound of this invention is dissolved or suspended in a suitable carrier. A typical formulation suitable for external ocular administration may be in the form of drops of a micronized suspension or solution in pH-adjusted, sterile, isotonic saline. Other formulations suitable for intraocular oral administration include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, wafers, lenses, and particulate vesicular systems such as niosomes or liposomes. A polymer such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, e.g., (hydroxypropyl)methyl cellulose, hydroxyethyl cellulose, or methyl cellulose, or heteropolysaccharide polymer, e.g., gellan gum, may be incorporated with a preservative such as benzalkonium chloride. These formulations can also be administered by iontophoresis.

[091] For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container which is compressed or pumped by the patient or as an aerosol spray, delivered from a pressurized container or a nebulizer with the use of a suitable propellant. Formulations suitable for intranasal administration are typically administered as a dry powder (either alone, as a mixture, e.g. in a dry mix with lactose, or as a mixed component particle, e.g. mixed with phospholipids such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised canister, pump, nozzle, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, e.g. chitosan or cyclodextrin.

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

[093] Other carrier materials and modes of administration known in the art of pharmacy may also be used. The pharmaceutical compositions of the invention may be prepared by any of the well-known techniques of pharmacy, such as effective compounding and handling procedures. The above considerations with respect to effective compounding and handling procedures are well known in the art and are described in standard textbooks. Drug formulation is discussed in, for example, 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.

[094] The compounds of the present invention may be used alone or in combination with other therapeutic agents in the treatment of various conditions or disease states. The compound(s) of the present invention and another therapeutic agent(s) may be administered simultaneously (in the same dosage form or in separate dosage forms) or sequentially.

[095] Two or more compounds may be administered simultaneously, concurrently, or sequentially. Additionally, simultaneous administration may be accomplished by mixing the compounds prior to administration or by administering the compounds at the same point in time but at different anatomical sites or using different routes of administration.

[096] The phrases "concurrent administration", "co-administration", "simultaneous administration" and "simultaneously administered" mean that the compounds are administered in combination.

[097] The present invention includes the use of a combination of a CFTR potentiating compound as provided in Formulas I, II or III and one or more additional pharmaceutically active agents. If a combination of active agents is to be administered, then they may be administered sequentially or simultaneously, in separate dosage forms or combined in a single dosage form. Accordingly, the present invention also includes pharmaceutical compositions comprising an amount of: (a) a first agent comprising a compound of Formulas I, II or III or a pharmaceutically acceptable salt of the compound; (b) a second pharmaceutically active agent; (c) optionally, a third pharmaceutically active agent; and (d) a pharmaceutically acceptable carrier, vehicle or diluent.

[098] Various pharmaceutically active agents may be selected for use in conjunction with the compounds of Formulas I, II, or III, depending on the disease, disorder, or condition to be treated. For example, a pharmaceutical composition for use in the treatment of cystic fibrosis may comprise a compound of Formulas I, II, or III, or a pharmaceutically acceptable salt thereof, together with one or more agents such as a CFTR modulator, e.g., 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 enhancer; an epithelial sodium channel (ENaC) inhibitor/blocker; an oligonucleotide patch; an autophagy inducer; a protease modulator, including a histone deacetylase (HDAC) inhibitor; or supportive therapies, such as a mucolytic agent, 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.

[099] A combination may include more than one agent from a particular class of agents; for example, a combination of a compound of Formulas I, II, or III with two or more CFTR correctors. Pharmaceutically active agents that may be used in combination with compounds of Formulas I, II, or III and compositions thereof include, without limitation: (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; (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 (iii) CFTR amplifiers such as PTI-428 and PTI-130 (iv) reader-activated agents such as ataluren (v) CFTR stabilizers such as N91115 (cavosonstat, an S-nitrosoglutathione reductase “GSNOR” inhibitor) (vi) epithelial sodium channel blocker (ENaC) inhibitors such as SPX-101, QBW-276 and VX-371; (vii) oligonucleotide patches such as QR-010 (viii) autophagy inducers such as CX-4945, the combination of cysteamine and epigallocatechin gallate (EGCG), cystamine and rapamycin (ix) protease modulators such as histone deacetylase (HDAC) inhibitors including 4-phenylbutyrate (4-PBA) (x) supportive therapies such as albuterol, salmeterol, ciprofloxacin, fluticasone, prednisone, ipratropium bromide, lipase, protease and amylase.

[0100] The present invention further comprises kits that are suitable for use in carrying out the treatment methods described above. In one embodiment, the kit contains a first dosage form comprising one or more of the compounds of the present invention optionally in combination with one or more additional therapeutic agents and a container for the dosage, in an amount sufficient to carry out the methods of the present invention. In another embodiment, the kit of the present invention comprises one or more compounds of the invention optionally with one or more additional therapeutic agents.

General Synthetic Schemes

[0101] The compounds of the invention may be prepared by any method known in the art for the preparation of compounds of analogous structure. In particular, the compounds of the invention may be prepared by the procedures described by reference to the Schemes that follow, by the specific methods described in the Examples, or by processes similar to both.

[0102] The skilled person will appreciate that the experimental conditions set forth in the following schemes are illustrative of suitable conditions for effecting the transformations shown, and that it may be necessary or desirable to vary the precise conditions used for the preparation of compounds of Formula (I). It will further be appreciated that it may be necessary or desirable to carry out the transformations in an order different from that described in the schemes, to modify one or more of the transformations, to provide the desired compound of the invention.

[0103] All derivatives of Formulas I, II and III can be prepared by the procedures described in the general methods presented below or by routine modifications thereof. The present invention also encompasses any of these processes for preparing the derivatives of Formulas I, II and III, in addition to any novel intermediates utilized. One skilled in the art will appreciate that the following reactions can be heated thermally or under microwave irradiation.

[0104] The routes below, including those mentioned in the Examples and Preparations, illustrate methods of synthesizing compounds of Formulas I, II, and III. The skilled person will appreciate that the compounds of the invention, and their intermediates, can be made by methods other than those specifically described herein, for example, by adaptation of the methods described herein, for example, by methods known in the art. Suitable guides to synthesis, interconversions of functional groups, use of protecting groups, etc., are, for example: “Comprehensive Organic Transformations” by RC 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 RK Mackie and DM 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 such standard works.

[0105] Furthermore, the skilled artisan will appreciate that it may be necessary or desirable at any stage of the synthesis of compounds of the invention to protect one or more sensitive groups in order to prevent undesirable side reactions. In particular, it may be necessary or desirable to protect groups of amino acids or carboxylic acids. The protecting groups used in the preparation of compounds of the invention may 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 GM Wuts, fifth edition, (John Wiley and Sons, 2014), incorporated herein by reference, which also describes methods for removing such groups.

[0106] In the general synthetic methods below, unless otherwise specified, substituents are as defined above with reference to compounds of Formula (I) above. Where solvent proportions are given, the proportions are by volume unless otherwise indicated.

[0107] The compounds of the invention may be prepared by any method known in the art for the preparation of compounds of analogous structure. In particular, the compounds of the invention may be prepared by the procedures described by reference to the Schemes that follow, by the specific methods described in the Examples, or by processes similar to both.

[0108] The skilled person will appreciate that the experimental conditions set forth in the following schemes are illustrative of conditions suitable for effecting the transformations shown, and that it may be necessary or desirable to vary the precise conditions used for the preparation of compounds of Formula I.

[0109] The following general methods describe the preparation of compounds of Formulas (I) and (II) and (III) as shown below.

[0110] According to a first process, compounds of formula (IIC), (a compound of Formula II wherein R2 is CN) can be prepared from compounds of formulae (IIA) and (IIB, a compound of Formula II wherein R2 is Hal) as illustrated by Scheme 1 wherein Hal is chlorine, bromine or iodine, preferably bromine.

[0111] In Scheme 1, the compound of formula (IIA) is converted to a compound of formula (IIB) by treatment with a suitable halogenating agent such as N-(Hal)succinimide, preferably NBS (where Hal is bromine), in a suitable solvent such as DCM or DMF at a suitable temperature such as 0 °C. One of skill in the art will also recognize that alternative methods for specifically introducing a suitable halogen group such as Br are achievable using alternative reagents, solvents, and temperatures. A compound of formula (IIB) is converted to a compound of formula (IIC) by treatment with a suitable organometallic source of 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 at a suitable temperature. A skilled individual also knows that alternative organometallic coupling strategies can be used to involve coupling partners and alternative metal and solvent combinations. It is well understood by a skilled individual that a compound of formula (IIB) is prepared and isolated as described above or prepared in situ without isolation in a sequential reaction strategy leading to a compound of formula (IIC).

[0112] According to a second process, compounds of Formula (II) can be prepared from compounds of Formulas (IID), (IIE) and (V), as illustrated by Scheme 2, wherein Hal is chlorine, bromine or iodine.

[0113] In Scheme 2, compounds of Formula (II) can be prepared from compounds of Formulas (IIE) and (V) using a suitable organometallic cross-coupling reaction such as a Suzuki cross-coupling reaction preceded, if necessary, by a boronic acid or ester formation. Typical Suzuki cross-coupling conditions include a palladium catalyst containing suitable phosphine ligands, in the presence of an inorganic base, in aqueous dioxane, at elevated temperatures, or under thermal irradiation or under microwave irradiation. Preferred conditions comprise Pd(OAc)2, Pd(dppf)Cl2 or Pd(PPh3)4 with sodium, cesium or potassium carbonate in aqueous dioxane or methanol from room temperature to 120 °C. If required, compounds of Formula (V) can be prepared using typical boronic ester formation conditions comprising Pd(dppf)Cl2 and potassium acetate with bispinacholatediboron with compounds of Formula (XXXIII) (where Hal is Cl, Br or I) in dioxane under reflux. Compounds of Formula (IIE) can be prepared from compounds of Formula (IID) using a suitable halogenation reaction such as NBS (when Hal is bromine) in a suitable solvent such as DCM at a suitable temperature such as 0 °C to room temperature. Compounds of Formula (V) can be obtained commercially or by analogy to the methods described herein.

[0114] According to a third process, compounds of Formula (III) may be prepared from compounds of Formula (IIIA) as illustrated by Scheme 3, wherein LG is a suitable leaving group such as OH or Hal (wherein Hal is chlorine, bromine or iodine). Scheme 3

[0115] In Scheme 3, compounds of Formula (III) can be prepared from compounds of Formula (IIIA) (where LG is OH) using a suitable functional group interconversion reaction as a two-step process using a suitable halogenation reaction followed by a suitable amination reaction. Preferable chlorination conditions comprise treating a compound of Formula (IIIA) with triazole, phosphorus oxychloride and a suitable base such as Et3N in a suitable solvent such as DCM at a suitable temperature of 0 °C to 70 °C, preferably in DCM at 70 °C, in a sealed tube. The intermediate compounds of Formula (IIIB) (where LG=Hal) can be converted to compounds of Formula (III) by treatment with ammonia in dioxane and/or aqueous ammonium hydroxide solution in a suitable solvent at a suitable temperature such as 120 °C for a suitable time such as 1 to 18 hours in a sealed tube in the presence or absence of microwave irradiation. The reaction steps depicted in Scheme 3 can be performed individually or combined in a single preparation.

[0116] According to a fourth process, compounds of Formula (I) can be prepared from compounds of Formulas (IA), (IB), and (IX) and as illustrated by Scheme 4 wherein Hal is chlorine, bromine, or iodine.

[0117] In Scheme 4, compounds of Formula (I) can be prepared from compounds of Formula (IB) and the 2-trifluoromethylpyrimidinyl boronate shown using a suitable organometallic cross-coupling reaction such as the Suzuki cross-coupling reaction. Typical Suzuki cross-coupling conditions include a palladium catalyst containing suitable phosphine ligands, in the presence of an inorganic base, in aqueous dioxane, at elevated temperatures, or under thermal irradiation or under microwave irradiation. Preferred conditions comprise Pd(OAc)2, Pd(dppf)Cl2 or Pd(PPh3)4 with sodium, cesium or potassium carbonate in aqueous dioxane or methanol from room temperature to 120 °C. Compounds of Formula (IB) can be prepared by a suitable alkylation reaction using compounds of Formula (IA) and (IX) in the presence of a suitable base such as Cs2CO3 in a suitable solvent such as DMF at a suitable temperature from room temperature to 100 oC. Compounds of Formula (IA) can be obtained commercially or by analogy to the methods described herein.

[0118] According to a fifth process, compounds of Formula (IIA') can be prepared from compounds of Formulas (IIG), (IIF), (IID''), (IID'), (IIE'), (V) and (XII) and as illustrated by Scheme 5 wherein Hal is chlorine, bromine or iodine.

[0119] In Scheme 5, compounds of Formula (IIA’) can be prepared from compounds of Formulas (IID’), (IIE’) and (V) using a suitable organometallic and halogenation cross-coupling reaction such as a Suzuki cross-coupling reaction preceded, if necessary, by a boronic acid or ester formation in a manner analogous to that described in Scheme 2. Compounds of Formula (IID’) can be prepared from compounds of Formula (IID’’) using a suitable reagent such as an Et3SiH in the presence of TFA in a suitable solvent such as DCM at a suitable temperature such as 0 °C to room temperature for a suitable time of 1 to 18 hours. Alternatively, compounds of Formula (IID’’) can be prepared from compounds of Formula (IIF) and a suitable aldehyde (XII) (where R1a=H). Compounds of Formula (IID’’) can be prepared from a compound of Formula (XI) and an aldehyde of (XII) using a suitable alkylation reaction. Compounds of Formula (IIF) can undergo a suitable halogen-metal exchange reaction using a suitable organometallic reagent such as a Grignard reagent such as isopropylmagnesium chloride-lithium chloride complex in a suitable solvent such as THF at a suitable temperature from -30 oC to room temperature followed by the addition of a suitable carbonyl compound of Formula (XII). Compounds of Formula (IIF) can be prepared from compounds of Formula (IIG) and excess dimethylformamide dimethylacetal at a suitable temperature such as 90 oC for a suitable time such as 2 to 18 hours. Compounds of Formula (IIG) can be obtained commercially or by analogy with the methods described herein.

[0120] According to a sixth process, compounds of Formula (IXA) and (XII) can be prepared from compounds of Formulas (XIII) and (XIV) and as illustrated by Scheme 6.

[0121] In Scheme 6, compounds of Formula (XIV) can be prepared from compounds of Formula (XIII) using a suitable nucleophilic carbon compound of Formula (XV) as a suitable Grignard reagent (where M is Mg, L is Hal) in a suitable solvent such as THF at a suitable temperature such as 0 °C to room temperature. Compounds of Formula (XII) can be prepared from compounds of Formula (XIV) by oxidation using a suitable reagent such as MnO2 in a suitable solvent such as DCM at a suitable temperature such as room temperature to reflux. Compounds of Formula (IXA) can be prepared from compounds of Formula (XIV) using a suitable halogenating reagent such as thionyl chloride (Hal=Cl) in a suitable solvent such as DCM at a suitable temperature such as room temperature. Compounds of Formula (XII) can be obtained commercially or by analogy to the methods described herein.

[0122] According to a seventh process, compounds of Formula (IIA'') (a compound of Formula (II) where R1b=OH) can be prepared from compounds of Formulae (IID''), (IIE'') and (V) and as illustrated in Scheme 7, wherein Hal is chlorine, bromine or iodine.

[0123] In Scheme 7, compounds of Formula (IIA’’) can be prepared from compounds of Formulas (IID’’), (IIE’’) and (V) using a suitable organometallic and halogenation cross-coupling reaction such as a Suzuki cross-coupling reaction preceded, if necessary, by a boronic acid or ester formation in a manner analogous to the methods in Scheme 2.

[0124] According to an eighth process, compounds of Formula (IIIA') can be prepared from compounds of Formulas (XVI), (XVII), (XVIII), (XIX), (XX), (XXI) and (XXII) as illustrated in Scheme 8, wherein Hal is chlorine, bromine or iodine and Rx is a suitable alkyl group such as methyl or ethyl. Scheme 8

[0125] In Scheme 8, compounds of Formula (IIIA’) can be prepared by heating compounds of Formula (XXII), formamide and formamidine acetate in a sealed tube at a suitable temperature such as 130°C under microwave irradiation for a suitable time such as 2 hours. One skilled in the art will appreciate that there are alternative suitable methods for eliciting the formation of heterocycles. Compounds of Formula (XXII) can be prepared from compounds of Formula (XXI) and O-(diphenylphosphinyl)hydroxylamine in the presence of a suitable base such as LiHMDS in a suitable solvent such as DMF at a suitable temperature such as 0°C to room temperature for a suitable time such as 18 hours. Compounds of Formula (XXI) can be prepared by heating compounds of Formula (XX) and ammonium acetate in acetic acid in a sealed tube under microwave irradiation at a suitable temperature such as 130°C. Compounds of Formula (XX) can be prepared from compounds of Formula (XVIII) and (XIX) using an amide bond forming step mediated by a suitable combination of amide bond coupling agent and organic base. Preferred conditions comprise HATU with NMM in a suitable solvent such as DMF at room temperature or elevated temperatures. Compounds of Formula (XVIII) can be prepared from compounds of Formula (XVI) and (XVII) in the presence of a suitable base such as KOtBu in a suitable solvent such as THF at a suitable temperature such as -70 °C to -50 °C followed by treatment with concentrated HCl. Compounds of Formulas (XVI), (XVII) and (XIX) can be obtained commercially or by analogy to the methods described herein.

[0126] According to a ninth process, compounds of Formula (IID''') can be prepared from compounds of Formulas (XV), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII) and (XXIX) and as illustrated in Scheme 9, wherein PG is a suitable nitrogen protecting group (e.g., tBoc).

[0127] In Scheme 9, compounds of Formula (IID’’’) can be prepared from compounds of Formula (XXIX) using a suitable reagent such as Et3SiH in the presence of TFA in a suitable solvent such as DCM at a suitable temperature such as 0 °C to room temperature for a suitable time of 1 to 18 hours. Compounds of Formula (XXIX) can be prepared from compounds of Formula (XXVIII) using a suitable nucleophilic carbon compound of Formula (XV) such as a suitable Grignard reagent (where M is Mg, L is Hal) in a suitable solvent such as THF at a suitable temperature such as 0 °C to room temperature. Compounds of Formula (XXVIII) can be prepared from compounds of Formula (XXVII) using a suitable oxidation with the use of a suitable reagent such as MnO2 in a suitable solvent such as DCM at a suitable temperature such as room temperature to reflux. Compounds of Formula (XXVII) can be prepared from compounds of Formulas (XXV) and (XXVI) in the presence of a suitable base such as DIPEA in a suitable solvent such as toluene and tBuOH at a suitable temperature such as room temperature. Compounds of Formula (XXV) can be prepared from compounds of Formula (XXIV) and ethynylmagnesium bromide in a suitable aprotic solvent such as THF at a suitable temperature such as 0 °C to room temperature. Compounds of Formula (XXIV) can be prepared from compounds of Formula (XXIII) and (Boc)2O in the presence of DMAP in a suitable solvent such as DCM at a suitable temperature such as room temperature. Compounds of Formulas (XV), (XXIII) and (XXVI) can be obtained commercially or by analogy to the methods described herein.

[0128] According to a tenth process, compounds of Formula (I') can be prepared from compounds of Formulas (IA), (XXX), (XXXI), and (IB') and 2-trifluoromethyl pyrimidinyl boronate as illustrated in Scheme 10 wherein Hal is chlorine, bromine, or iodine. Scheme 10

[0129] In Scheme 10, compounds of Formula (I’) can be prepared from compounds of Formula (IB’) and a suitable 2-trifluoromethyl pyrimidinyl boronate using a suitable organometallic cross-coupling reaction such as a Suzuki cross-coupling reaction. Typical Suzuki cross-coupling conditions include a palladium catalyst containing suitable phosphine ligands, in the presence of an inorganic base, in aqueous dioxane, at elevated temperatures, or under thermal irradiation or under microwave irradiation. Preferred conditions comprise Pd(OAc)2, Pd(dppf)Cl2 or Pd(PPh3)4 with sodium, cesium or potassium carbonate in aqueous dioxane or methanol from room temperature to 120 °C. Compounds of Formula (IB’) can be prepared from compounds of Formulas (XXXI) and (XXVI) in the presence of a suitable base such as DIPEA in a suitable solvent such as toluene and tBuOH at a suitable temperature such as room temperature. Compounds of Formula (XXXI) can be prepared from compounds of Formulas (XXX) and (IA) in the presence of a suitable base such as Cs2CO3 in a suitable solvent such as DMF at a suitable temperature such as room temperature. Compounds of Formulas (IA) and (XXVI) can be obtained commercially or by analogy to the methods described herein.

[0130] In the case of compounds described in all of the foregoing general method schemes where R1a and R1b are different groups (e.g., where R1a is (C1-C3)alkyl and R1b is H) leading to the presence of a chiral center, it is well understood by one of skill in the art that the individual enantiomers can be obtained using a suitable separation method such as SFC chromatography to provide both the (+) and (-) enantiomers of these compounds. It is well understood by one of skill in the art that an individual enantiomer of a compound described in the foregoing general method schemes is prepared and isolated as described above, or isolated using an alternative separation technique such as HPLC using a suitable chiral stationary phase eluting with a phase determined to be necessary to isolate the required enantiomers.

[0131] The following non-limiting Preparations and Examples illustrate the preparation of compounds and salts of the present invention. In the Examples and Preparations that are presented below, and in the Schemes mentioned above, the following abbreviations, definitions and analytical procedures may be referred to. Other abbreviations common in the art are also used. Standard IUPAC nomenclature has been used.

[0132] The following abbreviations may be used: AcOH is acetic acid; Ar is argon; aq is aqueous; Bn is benzyl; Boc is tert-butoxycarbonyl; Boc2O is di-tert-butyl dicarbonate; br is broad; tBu is tert-butyl; tBuOH is tert-butanol; n-BuLi is n-butyllithium; Bu4NCl is tetrabutyl ammonium chloride; °C is degrees Celsius; CDCl3 is deuterochloroform; Cs2CO3 is cesium carbonate; CsF is cesium fluoride; CuCN is copper cyanide; CuI is copper iodide; δ is chemical shift; d is doublet; DCM is dichloromethane or methylene chloride; DIAD is diisopropyl azodicarboxylate; DIPEA is N-ethyldiisopropylamine or N,N-diisopropylethylamine; DMA is N,N-dimethyl acetamide; DMAP is 4-dimethyl aminopyridine; DMF is N,N-dimethylformamide; DMF-DMA is N,N-dimethylformamide dimethyl acetal; DMSO is dimethyl sulfoxide; DPPA is diphenyl phosphoryl 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]pyridinium 3-oxide hexafluorophosphate; HCl is hydrochloric acid; HCO2H is formic acid; HPLC is high-pressure liquid chromatography; H2 is hydrogen; H2O is water; H is hour, hs 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; Li- Selectride® is lithium tri-sec-butylborohydride; m is multiplet; M is molar; MeCN is acetonitrile; MeMgBr is methyl magnesium bromide; MeOH is methanol; 2-MeTHF is 2-methyltetrahydrofuran; mg is milligram; MgSO4 is magnesium sulfate; MHz is mega Hertz; min is minutes; ml is milliliter; mmol is millimole; MnO2 is manganese dioxide; mol is mol; MS m/z is mass spectrum peak; MTBE is tert-butyl methyl ether; MsCl is mesyl chloride; NaCN is sodium cyanide; NaBH4 is sodium borohydride; Na2CO3 is sodium carbonate; NaH is sodium hydride; NaHCO3 is sodium hydrogen carbonate; NaHSO4 is sodium hydrogen sulfate; 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-bromo succinimide; NCS is N-chlorosuccinimide; NH3 is ammonia; NH4Cl is ammonium chloride; NH4HCO3 is ammonium hydrogen carbonate; 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 nanomolar; NMP is 1-methyl-2-pyrrolidinone; NMR is nuclear magnetic resonance; Pd/C is palladium on carbon; Pd2(dba)3 is Tris(dibenzylideneacetone)dipalladium; Pd(dppf)Cl2 is [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(OH)2 is palladium hydroxide; Pd(OAc)2 is palladium acetate; PPh3 is triphenylphosphine; Pd(PPh3)4 is tetrakis(triphenylphosphine)palladium (0); Pet. Ether is petroleum ether; pH is power of hydrogen; 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; SM is starting material; S-Phos is 2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl; SOCl2 is thionyl chloride; t is triplet; T3P is propylphosphonic anhydride; TBAF is tert-butyl ammonium fluoride; TBD is 1,5,7-triazabicyclo[4.4.0]dec-5-ene; TBME is tert-butyl dimethyl ether; TFA is trifluoroacetic acid; TFP is tri(2-furyl)phosphine; THF is tetrahydrofuran; Ti(OiPr)4 is titanium(IV) isopropoxide; TPTU is 2-(2-pyridon-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate; μl is microliter; μmol is micromole; XPhos is 2-dicyclohexyl phosphino-2´,4´,6´-triisopropylbiphenyl; and Zn(CN)2 is zinc cyanide.

[0133] 1H and 19F nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts per million from tetramethylsilane (for 1H-NMR) and from trichlorofluoromethane (for 19F-NMR) using conventional abbreviations for designation of major peaks: e.g., s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The following abbreviations have been used for common solvents: CDCl3, deuterochloroform; DMSO-d6, deuterodimethylsulfoxide; and MeOH-d4, deuteromethanol. Where appropriate, tautomers may be recorded within the NMR data; and some exchangeable protons may not be visible.

[0134] Mass spectra, MS (m/z), were recorded using electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI).

[0135] Where relevant and unless otherwise stated, m/z data given are for 19F, 35Cl, 79Br and 127I isotopes.

[0136] In cases where preparative TLC or silica gel chromatography has been used, one skilled in the art can choose any combination of appropriate solvents to purify the desired compound.

[0137] The following analytical and preparative chromatography methods are used for the analysis and purification of intermediates and compounds of the invention. Preparative SFC Methods SFC Method F1: Column: CHIRALPAK ID, 5.0 cm I.D. x 25 cm length; Isocratic Mobile Phase: Hexane/EtOAc/DEA, 60/40/0.1 (v/v/v); Flow Rate: 60 ml/min; Temperature: 35 °C.

Analytical SFC Methods

[0138] SFC Method F2: Column: CHIRALPAK ID, 0.46 cm I.D. x 15 cm 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.

Preparative HPLC Methods

[0139] HPLC Method B2: Column: CHIRALCEL OJ-H 2.5 cm I.D. x 25 cm length; Isocratic Mobile Phase: MeOH/DEA, 100/0.1 (v/v); Flow Rate: 30 ml/min; Temperature: 35 °C.

[0140] 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.

[0141] 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.

[0142] HPLC Method C22A: Column: CHIRALPAK IC, 2.5 cm I.D. x 25 cm length; Isocratic Mobile Phase: DCM/MeOH/DEA, 95/5/0.1 (v/v/v); Flow Rate: 30 ml/min; Temperature: 35 °C.

[0143] HPLC Method C22B: Column: CHIRALPAK IC, 5.0 cm I.D. x 25 cm length; Isocratic Mobile Phase: DCM/MeOH/DEA, 95/5/0.1 (v/v/v); Flow Rate: 30 ml/min; Temperature: 35 °C.

[0144] HPLC Method C23A: Column: CHIRALPAK IC, 5.0 cm I.D. x 25 cm length; Isocratic Mobile Phase: DCM/EtOH, 90/10 (v/v); Flow Rate: 60 ml/min; Temperature: 35 °C.

[0145] HPLC Method C23B: Column: CHIRALPAK IC, 2.5 cm I.D. x 25 cm length; Isocratic Mobile Phase: DCM/EtOH, 90/10 (v/v); Flow Rate: 60 ml/min; Temperature: 35 °C.

[0146] HPLC Method C24A: Column: CHIRALPAK IC, 5.0 cm I.D. x 25 cm length; Isocratic Mobile Phase: DCM/EtOH, 95/5 (v/v); Flow Rate: 60 ml/min; Temperature: 35 °C.

[0147] HPLC Method C24B: Column: CHIRALPAK IC, 2.5 cm I.D. x 25 cm length; Isocratic Mobile Phase: DCM/EtOH, 95/5 (v/v); Flow Rate: 60 ml/min; Temperature: 35 °C.

[0148] HPLC Method C27: Column: CHIRALPAK IC, 5.0 cm I.D. x 25 cm length; Isocratic Mobile Phase: Hexane/EtOAc/DEA, 60/40/0.1 (v/v/v); Flow Rate: 60 ml/min; Temperature: 35 °C.

[0149] HPLC Method C28: Column: CHIRALPAK IC, 2.5 cm I.D. x 25 cm length; Isocratic Mobile Phase: Hexane/EtOH, 85/15 (v/v); Flow Rate: 30 ml/min.

[0150] HPLC Method D4: Column: CHIRALPAK AD-H, 25 cm I.D. x 250 cm length; Isocratic Mobile Phase: EtOH/MeCN, 80/20 (v/v); Flow Rate: 20 ml/min; Temperature: 35 °C.

[0151] HPLC Method D5: Column: CHIRALPAK AD-H, 2.5 cm I.D. x 25 cm length; Isocratic Mobile Phase: Hexane/EtOH, 70/30 (v/v); Flow Rate: 30 ml/min; Temperature: 35 °C.

[0152] HPLC Method D6: Column: CHIRALPAK AD-H, 2.5 cm I.D. x 25 cm length; Isocratic Mobile Phase: MeOH/MeCN, 90/10 (v/v); Flow Rate: 30 ml/min.

[0153] HPLC Method D7: Column: CHIRALPAK AD-H, 5.0 cm I.D. x 25 cm length; Isocratic Mobile Phase: Hexane/IPA, 70/30 (v/v); Flow Rate: 60 ml/min.

[0154] HPLC Method E3: Column: CHIRALPAK IE, 2.5 cm I.D. x 25 cm length; Isocratic Mobile Phase: Hexane/EtOH, 70/30, (v/v); Flow Rate: 60 ml/min; Temperature: 35 °C.

[0155] HPLC Method E4: Column: CHIRALPAK IE, 5.0 cm I.D. x 25 cm length; Isocratic Mobile Phase: DCM/EtOH, 95/5 (v/v); Flow Rate: 55 ml/min; Temperature: 35 °C.

[0156] HPLC Method E5: Column: CHIRALPAK IE 5.0 cm I.D. x 25 cm length; Isocratic Mobile Phase: Hexane/EtOH, 80/20 (v/v); Flow Rate: 60 ml/min; Temperature: 35 °C.

[0157] HPLC Method G1: Column: Waters Sunfire C18 (19 x 100 mm, 5μ); Mobile phase: MeCN(0.05% TFA)-Water (0.5% TFA); Gradient: 20% to 60% MeCN over 8.5 min, 60% to 100% MeCN over 0.5 min, hold at 100% MeCN for 1 min; Flow rate: 25 ml/min.

Analytical HPLC Methods

[0158] HPLC Method A: Column: Acquity BEH C18 50x2.1 mm, 1.7 μ; Mobile phase: MeCN(0.05% TFA)-Water(0.5% TFA); Gradient: 5% to 95% MeCN over 2 min, hold at 95% MeCN for 0.5 min; re-equilibrate back to 5% MeCN within 2.7 min; Flow rate: 0.8 ml/min; Temperature: 45 °C.

[0159] HPLC Method B1: Column: CHIRALCEL OJ-H 0.46 cm I.D. x 15 cm length; Injection: 20.0 ul; Mobile phase: MeOH/MeCN, 90/10(v/v); Flow rate: 1.0 ml/min; Wavelength: UV 254 nm; Temperature: 35 °C.

[0160] HPLC Method C1: Column: CHIRALPAK IC, 0.46 cm I.D. x 25 cm length; Mobile phase: DCM/EtOH, 95/5(v/v); Flow rate: 1.0 ml/min; Wavelength: UV 214 nm; Temperature: 25 °C.

[0161] HPLC Method C2: Column: CHIRALPAK IC, 0.46 cm I.D. x 15 cm length; Mobile phase: DCM/EtOH, 95/5 (v/v); Flow rate: 1.0 ml/min; Wavelength: UV 214 nm; Temperature: 25 °C.

[0162] HPLC Method C4: Column: CHIRALPAK IC, 0.46 cm I.D. x 25 cm length; Mobile phase: DCM/MeOH, 95/5 (v/v); Flow rate: 1.0 ml/min; Temperature: 25°C.

[0163] HPLC Method C5: Column: CHIRALPAK IC, 0.46 cm I.D. x 15 cm length, 5 μ; Mobile phase: DCM/MeOH, 95/5(v/v); Flow rate: 1.0 ml/min; Wavelength: UV 254 nm; Temperature: 35 °C.

[0164] HPLC Method C10: Column: CHIRALPAK IC, 0.46 cm I.D. x 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.

[0165] HPLC Method C12: Column: CHIRALPAK IC, 0.46 cm I.D. x 15 cm length; Mobile phase: Hexane/EtOH, 85/15 (v/v); Flow rate: 1.0 ml/min; Wavelength: UV 214 nm; Temperature: 35 °C.

[0166] HPLC Method C13: Column: CHIRALPAK IC, 0.46 cm I.D. x 15 cm 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.

[0167] HPLC Method C14: Column: CHIRALPAK IC, 0.46 cm I.D. x 15 cm length; Mobile phase: Hexane/EtOH, 80/20 (v/v); Flow rate: 1.0 ml/min; Wavelength: UV 214 nm; Temperature: 35 °C.

[0168] Method D1: Column: CHIRALPAK AD-H, 0.46 cm I.D. x 15 cm length; Mobile phase: EtOH/MeCN, 80/20 (v/v); Flow rate: 1.0 ml/min; Wavelength: UV 214 nm; Temperature: 35 °C.

[0169] Method D2: Column: CHIRALPAK AD-H, 0.46 cm ID x 15 cm length; Mobile phase: Hexane/EtOH, 70/30 (v/v); Flow rate: 1.0 ml/min; Wavelength: UV 214 nm; Temperature: 35 °C.

[0170] Method E1: Column: CHIRALPAK IE, 0.46 cm I.D. x 15 cm length; Mobile phase: Hexane/EtOH, 70/30 (v/v); Flow rate: 1.0 ml/min; Wavelength: UV 214 nm; Temperature: 25°C.

[0171] HPLC Method G2: Column: Waters Atlantis dC18 (4.6 x 50 mm, 5 μ); Mobile phase: MeCN(0.05% TFA)-Water(0.5% TFA); Gradient: 5% to 95% MeCN over 4 min, hold at 95% MeCN for 1 min.; Flow rate: 2 ml/min. Preparation of Intermediates Preparation 1: 5-Bromo-7-{[1-(2-fluorophenyl)-1 H -1,2,3-triazol-4-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0172] To a solution of 7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine (Preparation 45, 1.2 g, 3.88 mmol) in DCM (35 mL) was added portionwise NBS (0.76 g, 4.27 mmol) at 0 °C and the reaction mixture was stirred at 0 °C for 1 h. The mixture was poured into water and the resulting white solid was filtered and dried in vacuo to afford the title product as a white solid (1.3 g, 86%). 1HRMN (400 MHz, CDCl3): 4.47 (s, 2H), 6.19 (br s, 2H), 6.64 (s, 1H), 7.27-7.33 (m, 2H), 7.43 (m, 1H), 7.92-7.98 (m, 3H). LCMS m/z = 388.0 [MH]+ yl]ethyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0173] To a stirred solution of 7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine (Preparation 17, 220 mg, 0.68 mmol) in DMF (2 mL) and DCM (10 mL) was added NBS (115 mg, 0.64 mmol) portionwise at 0 °C and the resulting reaction was stirred at 0 °C for 20 min. The mixture was quenched with 5% aqueous Na2S2O3 solution (10 mL), the layers separated, and the aqueous portion extracted with DCM (10 mL x 2). The combined organic extracts were dried (Na2SO4), filtered, and the filtrate concentrated in vacuo. The residue was purified by preparative HPLC eluting with MeCN:H2O (0.1% TFA) (40:60 to 50:50) to afford the title compound as a white solid (260 mg, 98%). 1HNMR (400 MHz, DMSO-d6): 1.69 (d, 3H), 4.88 (q, 1H), 6.68 (s, 1H), 6.70-6.80 (br s, 1H), 7.40 (m, 1H), 7.52-7.62 (m, 2H), 7.78 (m, 1H), 7.95 (s, 1H), 7.98-8.15 (br s, 1H), 8.41 (s, 1H). LCMS m/z = 402.1, 404.1 [MH]+ Preparation 3: 5-Bromo-7-{1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0174] The title compound was obtained as a white solid (310 mg, 52%) from 7-{1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine (Preparation 20) following a procedure analogous to that described in Preparation 2. 1HNMR (400 MHz, DMSO-d6): 0.87 (t, 3H), 2.10 (m, 2H), 4.72 (m, 1H), 6.81 (br s, 1H), 7.31 (m, 1H), 7.64 (m, 1H), 7.85-7.95 (m, 2H), 8.46 (s, 1H). LCMS m/z = 434.1, 436.1 [MH]+ Preparations 4 to 16

[0175] NBS (0.9-1.0 eq) was added dropwise portionwise to an ice-cooled solution of the appropriate starting material (1 eq) in DCM and the resulting mixture stirred at 0°C for 15 to 60 min until all starting material had been consumed. The mixture was quenched by the addition of 5% Na2S2O3 solution and extracted with DCM (3x). The combined organic extracts were dried (Na2SO4), filtered and the filtrate evaporated under reduced pressure. The residue was purified by column chromatography eluting with EtOAc:pet. ether or DCM:MeOH in a suitable gradient to afford the desired compound. a DMF was used as the reaction solvent instead of DCM, b THF was used as the reaction solvent. Preparation 17: 7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0176] A mixture of 1-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethanol (Preparation 31, 400 mg, 1.2 mmol) in Et3SiH (2 mL) and TFA (6 mL) was stirred at rt for 16 h. The mixture was concentrated in vacuo, aqueous NaHCO3 solution (25 mL) was added, and the mixture extracted with EtOAc (20 mL x 3). The combined organic extracts were dried (Na2SO4), filtered, and the filtrate concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with EtOAc:pet. ether (0:100 to 70:30) to provide the title compound as a white solid (220 mg, 57%). 1HRMN (400 MHz, DMSO- d6): 1.72 (d, 3H), 4.88 (q, 1H), 6.58 (d, 1H), 7.05 (s, 1H), 7.40 (m, 1H), 7.54-7.58 (m, 2H), 7.75 (m, 1H), 7.97 (s, 1H), -8.25 (br s, 2H), 8.37 (s, 1H). LCMS m/z = 324.1 [MH]+. Preparation 18: 7-{1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0177] To a solution of 1-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]ethanol (Preparation 32, 1.5 g, 4.2 mmol) in DCM (10 mL), Et3SiH (5 mL) was slowly added and TFA (5 mL) at 0 °C. The reaction was stirred at rt for 16 h and then concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with pet. ether:EtOAc (34:66) to afford the title compound as a yellow solid (1.2 g, 84%). LCMS m/z = 342.1 [MH]+; RT [HPLC Method A] = 1.445 min. Preparation 19: 7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}pyrrolo[2,1- f][1,2,4]triazin-4-amine

[0178] TFA (3 mL) was slowly added at 0 °C to a solution of tert-butyl(7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]-1-hydroxypropyl}pyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate (Preparation 44, 1.3 g, 2.87 mmol) in DCM (5 mL). Et3SiH (3 mL) was slowly added and the reaction mixture was stirred for 16 h, and then concentrated in vacuo. The residue was dissolved in DCM (15 mL) and the pH adjusted to 8 by the addition of aqueous NaHCO3 solution. The organic phase was dried (Na2SO4), the solvents removed under reduced pressure and the crude product purified by column chromatography on silica gel eluting with DCM:MeOH (91:9) to afford the title compound as a yellow solid (0.6 g, 80%). LCMS m/z = 338.1, 339.1 [MH]+; RT [HPLC Method A] = 1.364 min.

Preparations 20 to 29

[0179] The following compounds were prepared from the appropriate alcohol starting material following a procedure analogous to that described in Preparation 19. Preparation 30: 7-{1-[1-(2-Fluorophenyl)-1H-pyrazol-4-yl]ethyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0180] A mixture of 1-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethanol (Preparation 38, 6.5 g, 19.2 mmol) in Et3SiH (15 mL) and TFA (45 mL) was stirred at rt for 14 h. The solvent was removed under reduced pressure, aqueous NaHCO3 solution (100 mL) added, and the mixture extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine (50 mL), dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc:pet. ether (0:100 to 60:40) to afford the title compound, contaminated with 7-(1-(1-(2-fluorophenyl)-1H-pyrazol-4-yl)vinyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine, as an oil. The oil was dissolved in MeOH (20 mL), Pd/C (500 mg) added, and the mixture degassed under N2, then purged with H2. The reaction was stirred at rt for 2 h, then filtered through Celite®, washing with MeOH. The combined filtrates were evaporated under reduced pressure to afford the title compound as an off-white solid (5 g, 83%). LCMS m/z = 323.1 [MH]+. Preparation 31: 1-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-1-[1-(2-fluorophenyl)- 1H-1,2,3-triazol-4-yl]ethanol

[0181] To a stirred solution of N'-(7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-N,N-dimethylimidoformamide (Preparation 50, 1 g, 3.73 mmol) in THF (30 mL) was added iPrMgCl (LiCl complex) (1.3 M in THF) (11.5 mL, 14.9 mmol) under N2 at -30 °C and the mixture stirred at rt for 4 h. The reaction was cooled with ice, an ice-cooled solution of 1-(1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)ethanone (918 mg, 4.5 mmol) in THF (20 mL) was added and the reaction stirred at rt for 2 h. The mixture was quenched using aqueous NH4Cl (10 ml) and the solvent removed under reduced pressure. The residue was partitioned between H2O (50 ml) and EtOAc (40 ml), the layers separated and the aqueous phase extracted with EtOAc (40 ml x 2). The combined organic extracts were dried (Na2SO4), filtered and the filtrate concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with EtOAc:pet. ether (0:100 to 90:10) to afford the title compound as a yellow solid (400 mg, 31%). 1HRMN (400 MHz, DMSO-d6): 2.05 (s, 3H), 6.09 (s, 1H), 6.64 (d, 1H), 6.85 (d, 1H), 7.40 (m, 1H), 7.50-7.70 (m, 5H), 7.78 (m, 1H), 8.31 (s, 1H). LCMS m/z = 340.1 [MH]+; RT [HPLC Method A] = 1.224 min. Preparations 32 to 44

[0182] The following compounds were prepared from N'-(7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-N,N-dimethylimidoformamide (Preparation 50), and the appropriate ketone or aldehyde, following a method analogous to that described in Preparation 31. Preparation 44: tert-Butyl (7-{1 -[1 -(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]-1 - hydroxypropyl}pyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate

[0183] Ethylmagnesium bromide (8.84 mmol, 8.84 mL) was added to a solution of tert-butyl(7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]carbonyl}pyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate (Preparation 46, 1.5 g, 3.53 mmol) in THF (30 mL) at 0 °C, and upon complete addition, the reaction was stirred at 0 °C for 30 min. NH4Cl solution was slowly added and the mixture extracted with EtOAc (100 mL x 2). The combined organic extracts were concentrated in vacuo to afford the title compound which was used without further purification (1.7 g, quant.). LCMS m/z = 454.1 [MH]+; RT [HPLC Method A] = 1.712 min. Preparation 45: 7-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}pyrrolo[2,1- f][1,2,4]triazin-4-amine

[0184] To an ice-cooled solution of tert-butyl(7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]carbonyl}pyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate (Preparation 46, 5.01 g, 11.79 mmol) in DCM (40 mL) was added Et3SiH (10 mL) and TFA (10 mL) and the reaction stirred at rt for 18 h. The mixture was concentrated in vacuo and the residue suspended in EtOAc (100 mL), washed with saturated NaHCO3 solution and brine (2 x 100 mL), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with MeOH:DCM (5:95 to 9:91) to afford the title compound as a yellow solid (1.2 g, 25%). 1HNMR (400 MHz, MeOD-d4): 4.55 (s, 2H), 6.81 (m, 1H), 7.38-7.44 (m, 3H), 7.60 (m, 1H), 7.85 (m, 1H), 8.04 (s, 1H), 8.31 (s, 1H). LCMS m/z = 310.1 [MH]+ Preparation 46: tert-Butyl (7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]carbonyl} pyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate

[0185] MnO2 (4.09 g, 47 mmol) was added to a solution of tert-butyl(7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl](hydroxyl)methyl}pyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate (Preparation 47, 4.0 g, 9.4 mmol) in DCM (50 mL) and the mixture heated under reflux for 32 h. The cooled mixture was filtered, the filtrate washed with DCM (100 mL x 3) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with pet. ether:EtOAc (50:50) to afford the title compound as a yellow solid (1.5 g, 37%). LCMS m/z = 426.1 [MH]+; RT [HPLC Method A] = 1.684 min. Preparation 47: tert-Butyl (7-{[1 -(2-fluorophenyl)-1H-1,2,3-triazol-4-yl](hydroxyl) methyl}pyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate

[0186] 1-Azido-2-fluorobenzene (2.28 g, 16.67 mmol), CuI (1.5 g, 8.33 mmol), and DIPEA (3.22 g, 24.99 mmol) were added to a solution of tert-butyl[7-(1-hydroxyprop-2-yn-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]carbamate (Preparation 48, 2.4 g, 8.33 mmol) in toluene (30 mL) and t-BuOH (15 mL) and the reaction stirred at rt under N2 for 16 h. The mixture was concentrated in vacuo and the crude product purified by column chromatography on silica gel eluting with DCM:MeOH (97:3) to afford the title compound as a yellow solid (2.6 g, 73.4%). LCMS m/z = 426.1 [MH] + ; RT [HPLC Method A] = 1.604 min. Preparation 48: tert-Butyl[7-(1-hydroxyprop-2-yn-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]carbamate

[0187] Ethynylmagnesium bromide (42 mL, 0.5 M in THF, 21 mmol) was slowly added to an ice-cooled solution of tert-butyl(7-formylpyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate (Preparation 49, 2.5 g, 9.54 mmol) in THF (40 mL) and the reaction stirred at rt for 2 h. Saturated aqueous NH4Cl was slowly added to the reaction, and the mixture extracted with EtOAc (50 mL x 2), the combined organic extracts dried (Na2SO4), and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with pet.ether:EtOAc (50:50) to afford the title compound as a yellow solid (2.4 g, 87%). LCMS m/z = 233.1 [M-(C3HO)]+. Preparation 49: tert-Butyl(7-formylpyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate

[0188](Boc)2O (12 g, 56 mmol) followed by DMAP (4.5 g, 37 mmol) was slowly added to a solution of 4-aminopyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde (WO2007064931, 6.0 g, 37 mmol) in DCM (100 mL) and the reaction stirred for 30 min. The reaction was diluted with water and the mixture extracted with DCM (100 mL x 2), the organic extracts combined, dried (Na2SO4), and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with pet. ether:EtOAc (77:23) to afford the title compound as a yellow solid (2.5 g, 25%). LCMS m/z = 285.1 [MNa]+ Preparation 50: Dimethylimidoformamide

[0189] A mixture of 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (40 g, 0.19 mmol) and N,N-dimethylformamide dimethyl acetal (2 L) was heated at 90 °C for 2 h. The cooled mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with DCM:EtOAc (91:9) to afford the title compound (100 g, 69%). 1HNMR (400 MHz, DMSO-d6): 3.19 (s, 3H), 3.25 (s, 3H), 6.90 (m, 2H), 8.16 (s, 1H), 8.95 (s, 1H). LCMS m/z = 268.0 [MH]+; RT [HPLC Method A] = 0.934 min. Preparation 51: 1 -[-(2,4-Difluorophenyl)-1 H-1,2,3-triazol-4-yl]propan-1 –one

[0190] To a solution of pent-1-yn-3-one (1.3 g, 15.84 mmol) in MeOH/H2O (30 mL/5 mL) was added 1-azido-2,4-difluorobenzene (2.95 g, 19 mmol), sodium L-ascorbate (1.57 g, 7.92 mmol), and CuSO4 (1.27 g, 7.92 mmol) and the reaction stirred at rt for 12 h. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with EtOAc:pet. ether (0:100 to 20:80) to afford the title compound as an off-white solid (2.5 g, 67%). 1HRMN (400 MHz, CDCl3): 1.27 (t, 3H), 3.22 (q, 2H), 7.12 (m, 2H), 7.94 (m, 1H), 8.53 (s, 1H). LCMS m/z = 238.1 [MH]+; RT [HPLC Method A] = 1.605 min. Preparation 52: 1 -[-(2,5-Difluorophenyl)-1 H-1,2,3-triazol-4-yl]propan-1 –one

[0191] The title compound was obtained as an off-white solid (1.75 g, 61%) from pent-1-yn-3-one and 2-azido-1,4-difluorobenzene following the procedure described in Preparation 51. 1HNMR (400 MHz, CDCl3): 1.25 (t, 3H), 3.21 (q, 2H), 7.20 (m, 1H), 723-7.33 (m, 1H), 7.79 (m, 1H), 8.64 (s, 1H). LCMS m/z = 238.1 [MH]+ Preparation 53: 1-[-(3,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propan-1-one

[0192] The title compound was obtained as an off-white solid (1.70 g, 59%) from pent-1-yn-3-one and 4-azido-1,2-difluorobenzene following the procedure described in Preparation 51. 1HNMR (400 MHz, CDCl3): 1.27 (t, 3H), 3.22 (q, 2H), 7.26-7.39 (m, 1H), 7.51 (m, 1H), 7.70 (m, 1H), 8.45 (s, 1H). LCMS m/z = 238.1 [MH]+ Preparation 54: 1-[1-(2-Fluorophenyl)-1H-pyrazol-4-yl]propan-1-one

[0193] To a mixture of 1-[5-amino-1-(2-fluorophenyl)-1H-pyrazol-4-yl]propan-1-one (Preparation 56.5 g, 21.44 mmol) in THF (150 mL) was added dropwise tert-butyl nitrite (4.1 g, 39.8 mmol) at rt and the reaction stirred at 65 °C for 4 h. The solvent was evaporated under reduced pressure and purified by column chromatography on silica gel eluting with pet. ether:EtOAc (10:1 to 1:1) to afford the title compound as a yellow oil (2 g, 42.75%). 1HRMN (400 MHz, MeOD-d4): 1.08 (t, 3H), 2.82 (q, 2H), 7.24-7.31 (m, 2H), 7.36-7.40 (m, 1H), 7.71 (m, 1H), 8.09 (s, 1H), 8.57 (d, 1H). LCMS m/z = 219.1 [MH]+ Preparation 55: 1 -[1 -(2,4-Difluorophenyl)-1 H-pyrazol-4-yl]propan-1 –one

[0194] The title compound was obtained (2 g, 42%) from 1-[5-amino-1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propan-1-one (Preparation 57) following the procedure described in Preparation 54.1HRMN (400 MHz, MeOD-d4): 1.19 (t, 3H), 2.92 (q, 2H), 7.17 (m, 1H), 7.27 (m, 1H), 7.84 (m, 1H), 8.22 (s, 1H), 8.65 (d, 1H). LCMS m/z = 237.1 [MH]+ Preparation 56: 1-[5-Amino-1-(2-fluorophenyl)-1H-pyrazol-4-yl]propan-1-one

[0195] A degassed mixture of (E)-2-(ethoxymethylene)-3-oxopentannitrile (6 g, 39.17 mmol), Et3N (11.89 g, 117.5 mmol) and (2-fluorophenyl)hydrazine hydrochloride (9.55 g, 58.75 mmol) in EtOH (200 mL) was stirred at reflux for 2 h under an atmosphere of N2. The cooled reaction was concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with pet. ether:EtOAc (10:1 to 1:1) to afford the title compound as a yellow oil (5 g, 54.74%). LCMS m/z = 234.1 [MH]+ Preparation 57: 1 -[5-Amino-1 -(2,4-difluorophenyl)-1 H-pyrazol-4-yl]propan-1 –one

[0196] The title compound was obtained as a yellow oil (5 g, 51%) from (E)-2-(ethoxymethylene)-3-oxopentanonitrile and (2,4-difluorophenyl)hydrazine hydrochloride following the procedure described in Preparation 56. LCMS m/z = 252.1 [MH]+ Preparation 58: 1-{1-[1-(2-Fluorophenyl)-1H-pyrazol-4-yl]propyl}-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0197] To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.9 g, 3.78 mmol) in DMF (30 mL) was added 4-(1-chloropropyl)-1-(2-fluorophenyl)-1H-pyrazole (Preparation 61, 1.08 g, 4.54 mmol) and Cs2CO3 (6.16 g, 18.9 mmol) and the reaction stirred at 90 °C under N2 for 18 h. The cooled mixture was diluted with water, then extracted with EtOAc, the organic layer washed with brine, dried, and evaporated. The crude product was purified by column chromatography on silica gel eluting with DCM:MeOH (95:5) to yield the title compound (0.5 g, 28%). 1HRMN (400 MHz, DMSO-d6): 0.75 (t, 3H), 2.18-2.29 (m, 1H), 2.33-2.39 (m, 1H), 5.84 (m, 1H), 7.32 (m, 1H), 7.40-7.48 (m, 2H), 7.74 (m, 2H), 8.19 (s , 1H), 8.26 (s, 1H). LCMS m/z = 463.9 [MH]+ Preparation 59: 1 -{1 -[1 -(2-Fluorophenyl)-1 H-1,2,3-triazol-4-yl]propyl}-3-iodo-1 H- pyrazolo[3,4-d]pyrimidin-4-amine

[0198] To a stirred solution of 3-iodo-1-(pent-1-yn-3-yl)-1H-pyrazolo[3,4- d ]pyrimidin-4-amine (Preparation 60, 7 g, 21.40 mmol) in toluene (25 mL) was added 1-azido-2-fluorobenzene (5.87 g, 42.80 mmol), DIPEA (13.8 g, 107.0 mmol), and t-BuOH (100 mL). CuI (2.45 g, 12.84 mmol) was added and the reaction stirred at rt under N2 for 16 h. The mixture was concentrated under reduced pressure and purified by column chromatography on silica gel eluting with DCM:MeOH (97:3) to afford the title compound (5.4 g, 54%). 1HRMN (400 MHz, DMSO-d6): 0.79 (t, 3H), 2.46 (m, 2H), 6.03 (m, 1H), 7.41 (m, 1H), 7.45-7.60 (m, 2H), 7.83 (m, 1H), 8.28 (s, 1H), 8.61 (s, 1H). LCMS m/z = 464.9 [MH]+ Preparation 60: 3-Iodo-1-(pent-1-yn-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0199] 3-Bromopent-1-yne (8.6 g, 58.5 mmol) was added to a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (10.2 g, 39 mmol) and Cs2CO3 (38 g, 117 mmol) in DMF (200 mL) and the reaction stirred at rt for 16 h. The mixture was concentrated in vacuo, the residue diluted with water and extracted with EtOAc (300 mL × 3). The combined organic phases were washed with brine (300 mL × 2), dried (Na2SO4) and concentrated to afford the title compound as a brown solid (7 g, 55%). LCMS m/z = 327.9 [MH]+ Preparation 61: 4-(1-Chloropropyl)-1-(2-fluorophenyl)-1H-pyrazole

[0200] To a solution of 1-(1-(2-fluorophenyl)-1H-pyrazol-4-yl)propan-1-ol (Preparation 62, 1 g, 4.54 mmol) in DCM (30 mL) was added SOCl2 (5 mL) dropwise and the reaction stirred at rt for 2 h. The mixture was evaporated under reduced pressure to afford the title compound (1.08 g, quant.). Preparation 62: 1-[1-(2-Fluorophenyl)-1H-pyrazol-4-yl]propan-1-ol

[0201] To a solution of 1-(2-fluorophenyl)-1H-pyrazole-4-carbaldehyde (3 g, 15.8 mmol) in THF (50 mL) was added EtMgBr (31.6 mL, 31.6 mmol) dropwise at 0 °C and the reaction stirred at rt for 2 h. Water was added to quench the reaction and the mixture extracted with EtOAc. The organic layer was collected, washed with brine, dried, and evaporated. The crude product was purified by column chromatography on silica gel eluting with DCM:MeOH (95:5) to afford the title compound (3 g, 86%). 1HRMN (400 MHz, CDCl3): 1.00 (t, 3H), 1.74 (br s, 1H), 1.88 (m, 2H), 4.71 (t, 1H), 7.19-7.27 (m, 3H), 7.71 (s, 1H), 7.88 (m, 1H), 7.96 (d, 1H). LCMS m/z = 221.2 [MH]+ Preparation 63: 5-(4-Chlorophenyl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}imidazo[5,1-f][1,2,4]triazin-4-ol

[0202] A mixture of ethyl 1-amino-4-(4-chlorophenyl)-2-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-1H-imidazole-5-carboxylate (Preparation 64, 72 mg, 0.16 mmol), formamide (1.63 mL, 0.6 M), and formamidine acetate (42.5 mg, 0.408 mmol) was degassed for 2 min, then heated at 130 °C under microwave irradiation for 2 h. Additional formamidine acetate (50 mg, 0.48 mmol) was added and the reaction heated at 150 °C for an additional 2 h. The cooled mixture was filtered and dried to afford the title compound as a brown solid (42 mg, 62%). 1HRMN (400 MHz, DMSO-d6): 4.53 (s, 2H), 7.40-7.63 (m, 5H), 7.80 (m, 1H), 7.98 (s, 1H), 8.38 (d, 2H), 8.50 (s, 1H), 11.95 (br s, 1H), LCMS m/z = 422.2 MH]+ Preparation 64: Ethyl 1-amino-4-(4-chlorophenyl)-2-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-1H-imidazol-5-carboxylate

[0203] LiHMDS (1.0 M in THF, 0.181 mL, 0.181 mmol) was added dropwise to an ice-cooled solution of ethyl 4-(4-chlorophenyl)-2-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-1H-imidazole-5-carboxylate (Preparation 65, 70 mg, 0.16 mmol) in DMF (1.1 mL). o-(Diphenylphosphinyl)-hydroxylamine (53.7 mg, 0.23 mmol) was added in two portions while maintaining the internal temperature at 0 °C. The resulting white suspension was diluted with DMF (5 mL) and the solution stirred at rt for 18 h. The reaction was diluted with water and extracted with DCM (4 × 50 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with EtOAc:heptane (0:100 to 100:0) to afford the title compound (35 mg, 50%). 1HNMR (400 MHz, CDCl3): 1.26 (t, 3H), 4.32 (q, 2H), 4.50 (s, 2H), 6.18 (br s, 2H), 7.25-8.23 (m, 9H). LCMS m/z = 441.2 [MH]+ Preparation 65: Ethyl 4-(4-chlorophenyl)-2-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-1H-imidazol-5-carboxylate

[0204] A mixture of ethyl 3-(4-chlorophenyl)-2-{2-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]acetamido}-3-oxopropanoate (Preparation 66, 281 mg, 0.632 mmol) and ammonium acetate (300 mg, 3.89 mmol) in acetic acid (3.16 mL) was heated at 150 °C for 2 h under microwave irradiation. The cooled mixture was concentrated under reduced pressure and the residue purified by column chromatography on silica gel eluting with EtOAc:heptanes (0:100 to 100:0) to afford the title compound (72 mg, 27%). LCMS m/z = 426.3 [MH]+ Preparation 66: Ethyl 3-(4-chlorophenyl)-2-{2-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]acetamido}-3-oxopropanoate

[0205] A mixture of ethyl 2-amino-3-(4-chlorophenyl)-3-oxopropanoate (Preparation 67, 246 mg, 1.02 mmol), 2-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]acetic acid (150 mg 0.678 mmol), NMM (0.261 mL, 2.37 mmol), HATU (387 mg, 1.02 mmol) in DMF (4.52 mL) was stirred at rt for 18 h. The mixture was diluted with NH4Cl, extracted with 3x 100 mL EtOAc, and the combined organic solutions washed with saturated LiCl solution, dried (Na2SO4), and filtered. The filtrate was evaporated under reduced pressure, the residue purified by column chromatography on silica gel eluting with MeOH:DCM (0:100 to 20:80) to afford the title compound (311 mg, x%). LCMS m/z = 445.3 [MH]+ Preparation 67: Ethyl 2-amino-3-(4-chlorophenyl)-3-oxopropanoate

[0206] A solution of ethyl 2-(diphenylmethyleneamino)acetate (5 g, 18.7 mmol) in THF (35 mL) was added via cannula over 30 min to a solution of potassium t-butoxide (15 mL in THF) at -78 °C and the solution stirred for 35 min. 4-Chlorobenzoyl chloride (2.57 mL, 20 mmol) in THF (10 mL) was added dropwise, the reaction stirred at -78 °C for 25 min, then allowed to warm to -50 °C, and stirred for 40 min. The reaction was quenched with a solution of concentrated HCl (2.15 mL, 25.2 moles) in 1 mL of water and the mixture allowed to warm to rt. The aqueous reaction slurry was filtered to remove inorganic salts, the filtrate evaporated and azeotroped to remove residual water. The crude product was purified by column chromatography on silica gel eluting with MeOH:DCM (0:100 to 10:90) to afford the title compound as a white solid (1.01 g, 22%). 1HNMR (400 MHz, DMSO- d6 ): 1.07 (t, 3H), 4.15 (q, 2H), 6.28 (s, 1H), 7.72 (9d, 2H), 8.20 (d, 2H), 9.05 (br s, 2H). LCMS m/z = 242.3 [MH]+

EXAMPLES Examples 1 to 19

[0207] The following compounds were obtained by chiral separation of the corresponding racemic starting material using the HPLC methods previously described. Example 20 and Example 21: 4-Amino-7-{1 -[1 -(2,4-difluorophenyl)-1 H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile, enantiomers 1 and 2.

[0208] To a mixture of 6-bromo-7-{1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (Example 47, 250 mg, 0.442 mmol), Pd2(dba)3 (202.4 mg, 0.22 mmol), and dppf (245 mg, 0.44 mmol) in NMP (10 mL) was added Zn(CN)2 (208 mg, 1.768 mmol) and the reaction stirred at 160 °C for 3 h under microwave irradiation under N2. The cooled mixture was filtered, washed with EtOAc, the filtrate poured into water and extracted with EtOAc (30 ml x 3). The combined organic extracts were dried (Na2SO4), filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with EtOAc:pet. ether (30:70 to 100:0) to afford a yellow solid (75 mg, 33.18%). This solid was further purified by HPLC Method D5 to afford Example 20, enantiomer 1. 1HNMR (400 MHz, MeOD-d4): 1.91 (d, 3H), 5.14 (q, 1H), 7.10 (m, 1H), 7.17 (m, 1H), 7.72 (m, 2H), 8.05 (s, 1H), 8.09 (s, 1H), 9.10 (s, 2H). LCMS m/z = 512.0 [MH]+; RT [HPLC Method D2] = 9.308 min.

[0209] Additional elution provided Example 21, enantiomer 2. 1HRMN (400 MHz, MeOD-d4): 1.91 (d, 3H), 5.14 (q, 1H), 7.10 (m, 1H), 7 .17 (m, 1H), 7.72 (m, 2H), 8.05 (s, 1H), 8.09 (s, 1H), 9.10 (s, 2H). LCMS m/z = 512.0 [MH]+; RT [HPLC Method D2] = 12.255 min.

Examples 22 to 31

[0210] To a solution of the suitable bromide starting material (1 eq) in DMF (10 ml/mmol SM), Zn(CN)2 (1.5-3 eq), dppf (0.1-0.2 eq), and Pd2(dba)3 (0.1 eq) were slowly added and the reaction stirred at 140 to 150 °C for 1.5 to 2 h under microwave irradiation. The reaction was filtered, the residue partitioned between EtOAc and H2O, the layers separated, the aqueous phase extracted with EtOAc, and the combined organics dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with EtOAc:pet. ether in a suitable gradient to afford the desired compound. a DCM:MeOH was used as the column solvent, b NMP was used as the reaction solvent, c Pd(dppf)Cl2 was used instead of Pd2(dba)3. Example 32: 4-Amino-7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile

[0211] To a solution of 6-bromo-7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (Example 46, 270 mg, 0.49 mmol) in NMP (15 mL) in a microwave vial was added Zn(CN)2 (173 mg, 1.47 mmol), dppf (56 mg, 0.1 mmol), and Pd2(dba)3 (46 mg, 0.05 mmol). The sealed vial was microwave irradiated at 140 °C for 2 h. The cooled mixture was diluted with water (10 mL), and extracted with DCM (15 mL × 2). The combined organic extracts were washed with brine (60 ml), dried (Na2SO4), filtered, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc:pet. ether (10:90 to 90:10) to afford the title compound as a white solid (170 mg, 70% yield). LCMS m/z = 494.1 [MH]+ Example 33: 4-Amino-7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile

[0212] The title compound was prepared as a yellow solid (50 mg, 66% yield) from 6-bromo-7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (Example 48) following a procedure similar to that described in Example 32. LCMS m/z = 508.1 [MH]+. Example 34: 4-Amino-7-{1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile

[0213] To a mixture of 6-bromo-7-{1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (Example 49, 250 mg, 0.43 mmol), Pd2(dba)3 (197 mg, 0.215 mmol), and dppf (238 mg, 0.43 mmol) in NMP (10 mL) was added Zn(CN)2 (202 mg, 1.72 mmol) and the reaction stirred at 160 °C for 3 h under microwave irradiation under N2. The cooled mixture was filtered, washed with EtOAc, the filtrate poured into water and extracted with EtOAc (30 ml x 3). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with EtOAc:Pet. ether (30:70 to 0:100) to afford the desired compound as a yellow solid (90 mg, 39.83%). 1HRMN (400 MHz, MeOD-d4):1.02 (t, 3H), 2.34-2.41 (m, 1H), 2.43-2.52 (m, 1H), 4.90 (m, 1H), 7.10 (m, 1H), 7.21 (m, 1H), 7.707.77 (m, 2H), 8.07 (d, 2H), 9.12 (s, 2H). LCMS m/z = 526.1 [MH]+ Example 35: 4-Amino-7-{[3-(2-fluorophenyl)-1,2-oxazol-5-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile

[0214] To a solution of 6-bromo-7-{[3-(2-fluorophenyl)-1,2-oxazol-5-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (Example 51, 120 mg, 0.225 mmol) in DMF (5 mL) was slowly added CuCN (20 mg, 0.45 mmol) and the reaction stirred at 160 °C for 4 h under microwave irradiation. EtOAc (100 mL) was added to the cooled mixture and the solution washed with aqueous NH3 (50 mL), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with DCM:MeOH (91:9) to afford the title compound as a white solid (11.2 mg, 10%). 1HNMR (400 MHz, DMSO-d6): 4.79 (s, 2H), 6.82 (s, 1H), 7.32-7.42 (m, 2H), 7.54 (m, 1H), 7.84 (m, 1H), 8.20 (s, 1H), 9.20 (s, 2H). LCMS m/z = 481.0 [MH]+. Example 36: 4-Amino-7-{1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile

[0215] To a solution of 6-bromo-7-{1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (Example 52, 1.0 g, 1.83 mmol) in NMP (15 mL) was added Zn(CN)2 (0.32 g, 2.74 mmol) and Pd(PPh3)4 (0.2 g, 0.183 mmol) and the reaction stirred at 160 °C for 2 h under microwave irradiation. The cooled mixture was filtered, water and EtOAc (100 mL) added, the layers separated, and the organic phase washed with brine, dried (Na2SO4), and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with Pet. Ether:EtOAc (34:66) to afford the title compound as a yellow solid (135 mg, 15%). LCMS m/z = 495.0 [MH]+.

Examples 37 to 52

[0216] To a solution of the appropriate triazine-4-amine starting material (1 eq) in DCM was added NBS (1.05-2.0 eq) dropwise at 0 °C and the mixture allowed to warm to rt and stirred until all the starting material was consumed. The mixture was quenched with aqueous Na2S2O3 solution and extracted with EtOAc. The organic layer was washed with brine (2x), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with suitable solvents to afford the title compound. a DMF was used as the reaction solvent, b DMF/DCM was used as the reaction solvent, c THF was used as the reaction solvent.

Examples 53 to 68

[0217] The following compounds were obtained by chiral separation of the corresponding racemic starting material using the HPLC methods previously described a further purified by preparative HPLC using a Gemini-C18 150*21.2 mm, 5 μm column; eluting with MeCN:H2O (0.1% TFA); Example 69: 7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0218] To a mixture of 5-bromo-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine (Preparation 2, 260 mg, 0.65 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine (266 mg, 0.97 mmol) in 1,4-dioxane (9 mL) and H2O (3 mL) were added PdCl2(dppf) (48 mg, 0.065 mmol) and Na2CO3 (138 mg, 1.3 mmol), and the reaction stirred under N2 at 95 °C for 2 h. The cooled mixture was concentrated under reduced pressure and the residue partitioned between H2O (30 ml) and EtOAc (30 ml). The layers were separated, the aqueous phase extracted with EtOAc (30 ml x 3), the combined organic extracts were dried (Na2SO4), filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC eluting with MeCN:H2O (0.1% TFA) (45:55 to 55:45) to afford the title compound as a white solid (130 mg, 42%). 1HRMN (400 MHz, DMSO-d6): 1,77 (d, 3H), 4,97 (q, 1H), 6,90 (s, 1H), 7,15-7,25 (m, 2H), 7,48-7,62 (m, 4H), 8,05 (s, 1H), 8,45 (s, 1H), 9,05 (s, 2H). LCMS m/z = 470.2 [MH]+; RT [HPLC Method A] = 1.658 min.

Examples 70 to 79

[0219] The following Examples were prepared from the appropriate bromide and boronate ether starting material following a procedure analogous to that described in Example 69 and purified using silica gel column chromatography eluting with suitable solvents. a purified by column chromatography on silica gel eluting with pet. ether:EtOAc, b DMF was used as the column solvent instead of dioxane, c K2CO3 was used as the base Example 80: 7-{[3-(2-Fluorophenyl)-1,2-oxazol-5-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0220] To a solution of 5-bromo-7-{[3-(2-fluorophenyl)-1,2-oxazol-5-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine (Preparation 14, 250 mg, 0.644 mmol) in 1,4-dioxane (10 mL) was slowly added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine (1.3 g, 4.86 mmol), Pd(dppf)Cl2 (0.26 g, 0.324 mmol), and Na2CO3 (0.69 g, 6.48 mmol) in H2O (2 mL) and the reaction stirred at 100 °C for 16 h under N2. The cooled mixture was concentrated in vacuo and the crude product purified by column chromatography on silica gel eluting with DCM:MeOH (91:9) to afford the title compound as a yellow solid (150 mg, 51%). LCMS m/z = 456.0 [MH]+ Example 81: 7-{[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0221] To a solution of 5-bromo-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine (Preparation 1, 500 mg, 1.27 mmol) in 1,4-dioxane (10 mL) was slowly added 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (867 mg, 4.52 mmol), K2CO3 (356 mg, 2.58 mmol) in H2O (5 mL), and Pd(dppf)Cl2 (105 mg, 0.129 mmol) and the reaction stirred at 105 °C for 2 h under N2. The cooled mixture was concentrated in vacuo and the crude product purified by column chromatography on silica gel eluting with DCM:MeOH (91:9) to afford the title compound as a yellow solid (260 mg, 44%). LCMS m/z = 456.1 [MH] + ; RT [HPLC Method A] = 1.717 min. Example 82: 7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0222] The title compound was obtained as a white solid (7.5 g, 72%) from 5-bromo-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine (Preparation 5) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine following the procedure described in Example 80. 1HNMR (400 MHz, DMSO-d6): 0.93 (t, 3H), 2.20 (m, 2H), 4.82 (m, 1H), 6.97 (s, 1H), 7.15-7.30 (br s, 2H), 7.44 (m, 1H), 7.55 (m, 2H), 7.82 (m, 1H), 8.04 (s, 1H), 8.50 (s, 1H), 9.05 (s, 2H). LCMS m/z = 484.1 [MH]+; RT [HPLC Method A] = 1.743 min. Example 83: 7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0223] The title compound was obtained as a yellow solid (160 mg, 50%) from 5-bromo-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine (Preparation 5) and 4-methoxypyrimidin-5-ylboronic acid following the procedure described in Example 81. 1HNMR (400 MHz, MeOD-d4): 1.05 (t, 3H), 2.35 (m, 2H), 4.08 (s, 3H), 4.91 (q, 1H), 7.00 (s, 1H), 7.38-7.45 (m, 2H), 7.60 (m, 1H), 7.82 (m, 1H), 8.09 (s, 1H), 8.40 (d, 1H), 8.58 (s, 1H), 8.87 (s, 1H). RT [HPLC Method A] = 1.288 min. Example 84: 7-{1-[1-(2,4-Difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0224] To a suspension of 5-bromo-7-{1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine (Preparation 13, 250 mg, 0.58 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine (238 mg, 0.87 mmol), and Na2CO3 (123 mg, 1.16 mmol) in DMF:H2O (12 mL:3 mL) was added Pd(PPh3)4 (70 mg, 0.06 mmol) under N2 and the reaction was stirred at 100 °C for 12 h. The cooled mixture was poured into ice-cold water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc:pet. ether (0:100 to 80:20) to afford the title compound as an off-white solid (100 mg, 35%). LCMS m/z = 502.2 [MH] + ; RT [HPLC Method A] = 1.718 min. Example 85: 7-{1-[1-(2,4-Difluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0225] The title compound was obtained as a light yellow solid (0.5 g, 43%) from 5-bromo-7-{1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine (Preparation 11) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine following the procedure described in Example 84, except dioxane/H2O was used as the reaction solvent. LCMS m/z = 487.1 [MH]+; RT [HPLC Method A] = 1.867 min. Example 86: 7-{1-[1-(2,4-Difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine

[0226] The title compound was obtained as a light yellow solid (1.5 g, 5%) from 5-bromo-7-{1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine (Preparation 13) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine following the procedure described in Example 84, except dioxane/H2O was used as the reaction solvent. LCMS m/z = 501.1 [MH]+; RT [HPLC Method A] = 1.912 min. Examples 87 and 88: -{1-[1-(2-Fluorophenyl)-1H-pyrazol-4-yl]propyl}-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine, enantiomers 1 and 2

[0227] 1-{1-[1-(2-Fluorophenyl)-1H-pyrazol-4-yl]propyl}-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Example 91, 0.17 g) was purified using HPLC Method E5, to afford Example 87, enantiomer 1 (52.7 mg). 1HRMN (400 MHz, DMSO-d6): 0.81 (t, 3H), 2.24-2.30 (m, 1H), 2.41-2.50 (m, 1H), 6.01 (m, 1H), 7.31-7.43 (m, 5H), 7.73 (m, 1H), 7.89 (s, 1H), 8.28 (s , 1H), 8.35 (s, 1H), 9.29 (s, 2H). LCMS m/z = 484.2 [MH]+; RT [HPLC Method C14] = 4.799 min.

[0228] Further elution provided Example 88, enantiomer 2 (47.6 mg). 1HRMN (400 MHz, DMSO-d6): 0.81 (t, 3H), 2.24-2.30 (m, 1H), 2.41-2.50 (m, 1H), 6.01 (m , 1H), 7.31-7.43 (m, 5H), 7.73 (m, 1H), 7.89 (s, 1H), 8.28 (s, 1H), 8.35 (s, 1H), 9.29 (s, 2H). LCMS m/z = 484.2 [MH]+; RT [HPLC Method C14] = 6.068 min. Examples 89 and 90: 1-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-3-[2-(trifluoromethyl)pyrimidin-5-yl ]-1H-pyrazolo[3,4-d]pyrimidin-4-amine, enantiomers 1 and 2

[0229] 1-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Example 92, 1.6 g) was purified using HPLC Method C23A to afford Example 89, enantiomer 1 (504 mg). 1HRMN (400 MHz, DMSO-d6): 0.85 (t, 3H), 2.43-2.50 (m, 2H), 6.19 (m, 1H), 7.35-7.45 (m, 3H), 7.55-7.65 (m, 2H), 7.80 (m, 1H), 8.36 (s, 1H), 8.66 (s , 1H), 9.28 (s, 2H). LCMS m/z = 485.1 [MH]+; RT [HPLC Method C5] = 2.437 min.

[0230] Further elution provided Example 90, enantiomer 2 (508 mg). 1HRMN (400 MHz, DMSO-d6): 0.85 (t, 3H), 2.43-2.50 (m, 2H), 6.19 (m, 1H), 7.35-7.45 (m , 3H), 7.55-7.65 (m, 2H), 7.80 (m, 1H), 8.36 (s, 1H), 8.66 (s, 1H), 9.28 (s, 2H). LCMS m/z = 485.1 [MH]+; RT [HPLC Method C5] = 3.489 min. Example 91: 1 -{1 -[1 -(2-Fluorophenyl)-1H-pyrazol-4-yl]propyl}-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1H-pyrazolo[3, 4-d]pyrimidin-4-amine

[0231] To a solution of 1-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-3-iodo- 1H-pyrazolo[3,4-d]pyrimidin-4-amine (Preparation 58, 0.3 g, 0.45 mmol) in DMF (25 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine (355 mg, 0.90 mmol) and Na2CO3 solution (7 mL). Pd(PPh3)4 (52 mg, 0.045 mmol) was added and the reaction stirred at 100 °C for 18 h. The cooled mixture was partitioned between EtOAc and water and the layers separated. The organic layer was washed with brine, dried and evaporated in vacuo. The crude product was purified by column chromatography on silica gel eluting with DCM:MeOH (95:5) to afford the title compound (170 mg, 78%). LCMS m/z = 484.1 [MH]+ Example 92: 1-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0232] A stirred solution of 1-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Preparation 59, 3 g, 6.46 mmol) in dioxan/H2O (100 mL/25 mL) was added 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (1.86 g, 9.69 mmol), K2CO3 (2.67 g, 19.38 mmol), and Pd(dppf)Cl2 (236 mg, 0.323 mmol) under N2 and the reaction stirred at 90 °C for 2 h. The cooled mixture was filtered, the filtrate concentrated under reduced pressure, and the residue diluted with water and extracted with EtOAc (3 × 100 mL). The combined organic extracts were concentrated in vacuo and purified by prep. HPLC to yield the title compound as a yellow solid (1.6 g, 51%). 1HNMR (400 MHz, DMSO-d6): 0.85 (t, 3H), 2.44 (m, 2H), 6.18 (m, 1H), 7.40 (m, 3H), 7.59 (m, 2H), 7.77 (m, 1H), 8.35 (s, 1H), 8.65 (s, 1H), 9.27 (s, 2H). LCMS m/z = 484.7 [MH]+ Example 93: 5-(4-Chlorophenyl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}imidazo[5,1-f][1,2,4]triazin-4-amine trifluoroacetate

[0233] To a solution of triazole (62.2 mg, 0.90 mmol) in MeCN (5 mL) at 0 °C was added POCl3 (0.033 mL, 0.36 mmol). Et3N (0.126 mL, 0.90 mmol) was added dropwise over 20 min, the solution allowed to warm to rt and stirred for 30 min. 5-(4-Chlorophenyl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}imidazo[5,1-f][1,2,4]triazin-4-ol (Preparation 63, 38 mg, 0.09 mmol) was added dropwise portionwise, the solution diluted with DCM (2 mL), then stirred at 70 °C for 18 h. 0.5 M NH3 in dioxane (7 ml) and NH4OH (1 ml) were added and the reaction stirred under microwave irradiation for 1 h at 120 °C. The mixture was cooled, the resulting precipitate filtered, and the filtrate evaporated under reduced pressure. The residue was purified using HPLC Method G1 to afford the title compound as a solid (12.1 mg, 32%). LCMS m/z = 421.2 [MH]+.

[0234] The following examples were prepared by analogy to previously described routes. Example 94: 1-[1-(1-phenyl-1H-1,2,3-triazol-4-yl)propyl]-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine, enantiomer 1; Separated using HPLC Method C30; 1HRMN (400 MHz, CDCl3): 0.98 (t, 3H), 2,502.63 (m, 2H), 5.82 (br s, 2H), 6.33 (m, 1H), 7.45-7.52 (m, 3H), 7.69 (m, 2H), 8.08 (s, 1H), 8.50 (s, 1H), 9.28 (s, 2H). LCMS m/z = 467.1 [MH]+; RT [HPLC Method C10] = 3.125 min. Example 95: 1-[1-(1-phenyl-1H-1,2,3-triazol-4-yl)propyl]-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine, enantiomer 2; Separated using HPLC Method C30; 1HRMN (400 MHz, MeOD-d4): 0.95 (t, 3H), 2.51-2.67 (m, 2H), 6.27 (m, 1H), 7.48 (m, 2H), 7.52 (m, 3H), 8.39 (s, 1H), 8.66 (s, 1H), 9.31 (s, 2H). LCMS m/z = 467.2 [MH]+; RT [HPLC Method C10] = 2.244 min. Example 96: 4-amino-5-(2-(difluoromethyl)pyrimidin-5-yl)-7-(1-(1-(2-fluorophenyl)-1H-pyrazol-4-yl)ethyl)pyrrolo[1,2-f][1,2,4]triazine-6-carbonitrile, enantiomer 1; Separated using SFC Method F1; 1HRMN (400 MHz, DMSO-d6): 1.82 (d, 3H), 5.02 (q, 1H), 7.07 (t, 1H), 7.31-7.48 (m, 3H), 7.73-7.77 (m, 2H), 8.15-8.16 (m, 2H), 9.05 (s, 2H); LCMS m/z = 476.2 [MH]+; RT [HPLC Method F2] = 6.049 min. Example 97: 4-amino-5-(2-(difluoromethyl)pyrimidin-5-yl)-7-(1-(1-(2-fluorophenyl)- 1H-pyrazol-4-yl)ethyl)pyrrolo[1,2-f][1,2,4]triazine-6-carbonitrile, enantiomer 2; Separated using SFC Method F1; 1HRMN (400 MHz, DMSO-d6): 1.82 (d, 3H), 5.02 (q, 1H), 7.07 (t, 1H), 7.31-7.48 (m, 3H), 7.73-7.77 (m, 2H), 8.15-8.16 (m, 2H), 9.05 (s, 2H); LCMS m/z = 476.2 [MH]+; RT [HPLC Method F2] = 6.599 min. Example 98: 7-(1-(1-(2,5-difluorophenyl)-1H-1,2,3-triazol-4-yl)ethyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)pyrrolo[1,2-f][1,2,4]triazin-4-amine, enantiomer 1; Separated using HPLC Method C24A; 1HRMN (400 MHz, DMSO-d6): 1.55 (d, 3H), 4.76 (q, 1H), 6.68 (s, 1H), 7.04 (br s, 2H), 7.26 (m, 1H), 7.42 (m, 1H), 7.59 (m, 1H), 7.83 (s, 1H), 8.27 (d, 1H), 8.83 (s, 2H); LCMS m/z = 488.0 [MH]+; RT [HPLC Method C1] = 4.359 min. Example 99: 1 -(1 -(1 -(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl)propyl)-3-(2-(trifluoromethyl)pyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, enantiomer 1; Separated using HPLC Method B2; 1HRMN (400 MHz, DMSO-d6): 0.85 (t, 3H), 2.45 (m, 2H), 6.18 (m, 1H), 7.34 (m, 1H), 7.48 (br s, 2H), 7.68 (m, 1H), 7.87 (m, 1H), 8.36 (s, 1H), 8.65 (s, 1H), 9.28 (s, 2H); LCMS m/z = 503.2 [MH]+; RT [C10 HPLC Method] = 3.734 min. Ussing Chamber Electrophysiology Test of CFTR Potentiation in CF Bronchial Epithelial Cells

[0235] Primary cystic fibrosis human bronchial epithelial (CF hBE) cells were expanded and cultured according to published methods (Neuberger et al., Chapter 4 of Cystic Fibrosis, Methods in Molecular Biology vol. 741, pages 39-54 (2011)). Well-differentiated cells (>30 days at air/liquid interface) on Snapwell filters (Corning Costar, cat. no. 3801) were mounted in Ussing chambers (Physiologic Instruments, Inc., San Diego, CA). F508del/F508del cultures were assayed at 27°C and G551D/F508del cells were assayed at 35°C. HEPES-buffered physiological saline (composition (in mM): 137 NaCl, 4 KCl, 1 MgCl2, 1.8 CaCl2, 10 HEPES Na) was used in apical and basolateral chambers. The chambers were bubbled with air to promote mixing, and the voltage was set to zero. Amiloride (30 μM), forskolin (10 μM), test compound (4 increasing concentrations), and CFTRinh-172 (20 μM) were added sequentially with 20 to 25 min between additions. Short-circuit currents were acquired and analyzed using LabScribe2. Responses of test compounds were scaled relative to the responses to DMSO (0%) and the maximal response of a positive control potentiator (100%).

CFTR Potentiation FRT Ion Flux Assay F508del

[0236] Fischer rat thyroid (FRT) cell lines stably expressing recombinant F508del V470 CFTR halide-sensitive yellow fluorescent protein (Pedemonte et al., J. Clin. Invest. 115(9) 2564-71 (2005)) were seeded at 25,000 cells/well in 50 μl/well culture medium in black-walled, clear-bottom tissue culture-treated 384-well plates (Corning, cat. no. 3712). After one day, the cells were preincubated at 27 °C/5% CO2 for 16 to 24 hours. Cells were then washed with dPBS and treated with forskolin (20 μM) and the test compound for 30 min by addition of 20 μL of compound dilution buffer (dPBS containing forskolin and test compound). Plates were loaded into the FLIPR384 fluorescence imaging plate reader (Molecular Devices). After an initial fluorescence reading, iodide buffer (25 μL) (composition (in mM): 137 NaI, 1.5 K2PO4, 8.1 NaH2PO4, 2.7 KCl, 0.5 MgCl2, 1 CaCl2) was added and a second fluorescence reading was taken after approximately 21 seconds. Data treatment involved dividing the second fluorescence reading by the initial fluorescence reading, then scaling the resulting normalized endpoint fluorescence relative to the responses for DMSO (0%) and a positive control enhancer (100%).

Claims (7)

1. Compound CHARACTERIZED by the fact that it presents Formula II: or a pharmaceutically acceptable salt thereof; wherein: W is a five- to six-membered heteroaryl comprising one to three heteroatoms, each independently selected from the group consisting of N, O and S(O)n; and wherein the five- to six-membered heteroaryl is optionally substituted by one to three R3; Y is a five-membered heteroaryl comprising one to four heteroatoms, each independently selected from the group consisting of N, O and S(O)n; wherein the five-membered heteroaryl is optionally substituted by one to three substituents, each independently selected from the group consisting of halo, C1-C6alkyl and C1-C6haloalkyl; Z is C1-C6alkyl or phenyl; wherein the phenyl is optionally substituted by one to three halo; each R1a and R1b is independently selected from the group consisting of -H, -OH, halo, C1-C6alkyl optionally substituted with one to three substituents, each of which is independently selected from the group consisting of halo, -OH, C1-C3alkyloxy, C3-C7cycloalkyl, and a four- to seven-membered heterocycloalkyl comprising one to three heteroatoms, each of which is independently selected from the group consisting of N, O, and S(O)n, C3-C7cycloalkyl optionally substituted with one to three substituents, each of which is independently selected from the group consisting of -OH, halo, and C1-C6alkyl; and four- to seven-membered heterocycloalkyl optionally substituted with one to three substituents, each of which is independently selected from the group consisting of -OH, halo, and C1-C6alkyl; or R1a and R1b together with the carbon to which they are attached form a four- to seven-membered C3-C7cycloalkyl or heterocycloalkyl comprising one to three heteroatoms, each of which is independently selected from the group consisting of N, O, and S(O)n; and wherein the four- to seven-membered C3-C7cycloalkyl or heterocycloalkyl is optionally substituted by one to three substituents, each of which is independently selected from the group consisting of -OH, halo, and C1-C6alkyl; R2 is selected from the group consisting of -H, -CN, halo, and C1-C3alkyl; R3 at each occurrence is independently selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, halo, and C1-C6haloalkyl; and n at each occurrence is independently 0, 1, or 2. 2. The compound of claim 1 wherein (a) W is pyrimidinyl or pyrazinyl, and wherein the pyrimidinyl or pyrazinyl is optionally substituted by one, two or three R3; or (b) the YZ moiety is selected from the group consisting of: or a pharmaceutically acceptable salt thereof. 3. The compound of claim 1 wherein the compound is selected from the group consisting of: 7-{(1R)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine; 7-{(1R)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 4-amino-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 7-{(1R)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 7-{(1R)-1-[1-(2,5-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 7-{(1S)-1-[1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 4-amino-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2,5-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-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]pyrrolo[2,1-f][1,2,4]triazine-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]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 4-amino-7-{(1S)-1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{[3-(2-fluorophenyl)-1,2-oxazol-5-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(propan-2-yl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1S)-1-[1-(propan-2-yl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{(1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 7-{(1S)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; and 7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; or a pharmaceutically acceptable salt thereof; or wherein the compound is selected from the group consisting of: 7-{(1R)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine; 7-{(1R)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 4-amino-7-{(1R)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 7-{(1R)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 4-amino-7-{(1R)-1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 7-{(1R)-1-[1-(2,5-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 7-{(1S)-1-[1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 4-amino-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2,5-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-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]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine; 4-amino-7-{(1S)-1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{[3-(2-fluorophenyl)-1,2-oxazol-5-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1S)-1-[1-(propan-2-yl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-7-{(1S)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; 4-amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{(1S)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; and 4-amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{(1R)-1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile; or a pharmaceutically acceptable salt thereof. 4. Use of the compound as defined in any one of claims 1 to 3, or of a pharmaceutically acceptable salt of said compound, CHARACTERIZED by the fact that it is in the manufacture of a medicament for treating cystic fibrosis, asthma, bronchiectasis, chronic obstructive pulmonary disease (COPD), constipation, diabetes mellitus, dry eye disease, pancreatitis, rhinosinusitis or Sjogren's syndrome in a patient in need of treatment thereof. 5. Pharmaceutical composition CHARACTERIZED by the fact that it comprises a therapeutically effective amount of one or more compounds, as defined in any one of claims 1 to 3, or of a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. 6. The pharmaceutical composition of claim 5 further comprising one or more additional therapeutic agents; wherein the one or more additional therapeutic agents are preferably independently selected from the group consisting of: (a) a CFTR potentiator selected from the group consisting of VX-770 (ivacaftor), GLPF-1837, GLPG-2451, QBW-251, FDL-176, FDL-129, CTP-656, and PTI-P271; (b) a CFTR corrector selected from the group consisting of VX-809 (lumacaftor), VX-661 (tezacaftor), VX-983, VX-152, VX-440, VX-659, GLPF-2737, P247-A, GLPG-2222, GLPG-2665, GLPG-2851, FDL-169, and PTI-C1811; (c) an epithelial sodium channel (ENaC) inhibitor selected from the group consisting of SPX-101, QBW-276, and VX-371; (d) a CFTR enhancer selected from the group consisting of PTI-428 and PTI-130; (e) N-91115 (Cavosonstat); (f) ataluren; (g) QR-010; (h) an autophagy inducer selected from the group consisting of CX-4945 and the combination of cysteamine and epigallocatechin gallate (EGCG); and (i) 4-phenylbutyrate (4-PBA). 7. Pharmaceutical composition, according to claim 5 or 6, CHARACTERIZED by the fact that it is for use in the treatment of cystic fibrosis.