Modulators of cystic fibrosis transmembrane conductance regulator

Abstract

This disclosure provides modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), pharmaceutical compositions containing at least one such modulator, methods of treatment of CFTR mediated diseases, including cystic fibrosis, using such modulators and pharmaceutical compositions, combination pharmaceutical compositions and combination therapies employing those modulators, and processes and intermediates for making such modulators.

Description

MODULATORS OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR

[0001] This application claims the benefit of priority of U.S. Provisional Application No. 63 / 587,955, filed October 4, 2023, the contents of which are incorporated herein by reference in their entirety.

[0002] The disclosure relates to modulators of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), pharmaceutical compositions containing the modulators, methods of treatment of CFTR mediated diseases, including cystic fibrosis, using such modulators, combination therapies and combination pharmaceutical compositions employing such modulators, and processes and intermediates for making such modulators.

[0003] Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 92,000 children and adults worldwide. Despite progress in the treatment of CF, there is no cure.

[0004] In patients with CF, mutations in CFTR endogenously expressed in respiratory epithelia lead to reduced apical anion secretion causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to increased mucus accumulation in the lung and accompanying microbial infections that ultimately cause death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, result in death. In addition, the majority of males with cystic fibrosis are infertile, and fertility is reduced among females with cystic fibrosis.

[0005] Sequence analysis of the CFTR gene has revealed a variety of disease-causing mutations (Cutting, G. R. et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem, B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, greater than 2000 mutations in the CFTR gene have been identified; currently, the CFTR2 database contains information on only 432 of these identified mutations, with sufficient evidence to define 352 mutations as disease-causing. The most prevalent disease-causing mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence and is commonly referred to as the F508del mutation. This mutation occurs in many of the cases of cystic fibrosis and is associated with severe disease.

[0006] The deletion of residue 508 in CFTR prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit the endoplasmic reticulum (ER) and traffic to the plasma membrane. As a result, the number of CFTR channels for anion transport present in the membrane is far less than observed in cells expressing wild-type CFTR,i.e., CFTR having no mutations. In addition to impaired trafficking, the mutation results in defective channel gating. Together, the reduced number of channels in the membrane and the defective gating lead to reduced anion and fluid transport across epithelia. (Quinton, P. M. (1990), FASEB J.4: 2709-2727). The channels that are defective because of the F508del mutation are still functional, albeit less functional than wild-type CFTR channels. (Dalemans et al. (1991), Nature Lond.354: 526-528; Pasyk and Foskett (1995), J. Cell. Biochem.270: 12347- 50). In addition to F508del, other disease-causing mutations in CFTR that result in defective processing, trafficking, synthesis, and / or channel gating could modify anion secretion and therefore modify disease progression and / or severity.

[0007] CFTR is a cAMP / ATP-mediated anion channel that is expressed in a variety of cell types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelial cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. CFTR is composed of 1480 amino acids that encode a protein which is made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking.

[0008] Chloride transport takes place by the coordinated activity of ENaC and CFTR present on the apical membrane and the Na+-K+-ATPase pump and Cl- channels expressed on the basolateral surface of the cell. Secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, which can then passively leave the cell via Cl- channels, resulting in a vectorial transport. Arrangement of Na+ / 2Cl- / K+co-transporter, Na+- K+-ATPase pump and the basolateral membrane K+channels on the basolateral surface and CFTR on the luminal side coordinate the secretion of chloride via CFTR on the luminal side. Because water is probably never actively transported itself, its flow across epithelia depends on tiny transepithelial osmotic gradients generated by the bulk flow of sodium and chloride.

[0009] A number of CFTR modulating compounds have recently been identified. However, compounds that can treat or reduce the severity of cystic fibrosis and other CFTR mediated diseases, and particularly the more severe forms of these diseases, are still needed.

[0010] One aspect of the disclosure provides novel compounds, including compounds of Formula I, tautomers thereof, deuterated derivatives of those compounds and tautomers, andpharmaceutically acceptable salts of any of the foregoing. Formula I encompasses compounds falling within the following structure:tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing (i.e., pharmaceutically acceptable salts of compounds, tautomers, and deuterated derivatives), wherein: Ring A is selected from 7- and 8-membered heterocycles containing 0-2 additional heteroatoms selected from O and N, wherein Ring A is substituted with 0-4 groups selected from: • C3-C6cycloalkyl (substituted with 0-4 groups selected from C1-C4alkyl), • C1-C5 alkyl (substituted with 0-4 groups selected from C3-C6cycloalkyl, halogen, OH, NH2, oxo, and 4- to 6-membered heterocycle); • C1-C4alkoxy (substituted with 0-4 groups selected from C3-C6cycloalkyl, halogen, OH, NH2, and oxo); • 5- and 6-membered heterocycle; • OH; • NH2; and • oxo; wherein two substituents on Ring A taken together with the atoms to which they are bonded may form a ring selected from C3-C6cycloalkyl (further substituted with 0-2 groups selected from C1-C4alkyl and C1-C4alkoxy); Ring B is a 9-12 membered heteroaryl group containing 1-4 heteroatoms selected from N, O, and S, wherein Ring B is substituted with 1-4 groups selected from: • C1-C6alkyl (substituted with 0-3 groups selected from halogen, C1-C3alkoxy, and OH); • C3-C6cycloalkyl, substituted with 0-3 groups selected from: o C1-C6alkyl (substituted with 0-3 groups selected from C1-C3alkoxy and halogen);o OH; and o halogen; • halogen; and • 5- and 6-membered heterocycle; each X is independently selected from CH and N; Z is selected from CH and N; R1is selected from hydrogen, halogen, C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 alkoxy (substituted with 0-5 halogens); each R2is independently selected from C1-C5 alkyl, C1-C3 alkoxy, OH, and halogen; each R3is independently selected from C1-C3 alkyl, C1-C3 alkoxy, OH, and halogen; n is an integer selected from 2 to 5; and p is an integer selected from zero to 3.

[0011] Formula I also includes compounds of Formula I′:tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing (i.e., pharmaceutically acceptable salts of compounds, tautomers, and deuterated derivatives), wherein: Ring A is selected from 7- and 8- membered heterocycles containing 0-2 additional heteroatoms selected from O and N, wherein Ring A is substituted with 0-2 groups selected from: • C3-C6cycloalkyl (substituted with 0-2 groups selected from C1-C4 alkyl), • C1-C5alkyl (substituted with 0-2 groups selected from C3-C6cycloalkyl, halogen, OH, NH2, oxo, and C4-C6 heterocycle); • C1-C4 alkoxy (substituted with 0-2 groups selected from C3-C6cycloalkyl, halogen, OH, NH2, and oxo); • 5- and 6-membered heterocycle; • OH;• NH2; and • oxo; Ring B is a 9-12 membered heteroaryl group containing 1-4 heteroatoms selected from N, O, and S, wherein Ring B is substituted with 1-4 groups selected from: • C1-C6 alkyl (substituted with 0-3 groups selected from halogen, C1-C3 alkoxy, and OH); • C3-C6cycloalkyl, substituted with 0-3 groups selected from: o C1-C6alkyl (substituted with 0-3 groups selected from C1-C3alkoxy and halogen); o OH; and o halogen; • halogen; and • 5- and 6-membered heterocycle; each X is independently selected from CH and N; Z is selected from CH and N; R1is selected from hydrogen, halogen, C1-C5 alkyl, C1-C5 haloalkyl, and C1-C5 alkoxy (substituted with 0-5 halogens); each R2is independently selected from C1-C5 alkyl, C1-C3 alkoxy, OH, and halogen; each R3is independently selected from C1-C3 alkyl, C1-C3 alkoxy, OH, and halogen; n is an integer selected from 2 to 5; and p is an integer selected from zero to 3.

[0012] Formula I also includes compounds of Formula Ia:tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein all variables are as defined for Formula I′.

[0013] Formula I also includes compounds of Formula Ib:tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein all variables are as defined for Formula I′.

[0014] Formula I also includes compounds of Formula Ic:tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein all variables are as defined for Formula I′.

[0015] One aspect of the disclosure provides novel compounds, including compounds of Formula II, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. Formula II encompasses compounds falling within the following structure:tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein R4is selected from: • C3-C6cycloalkyl (substituted with 0-2 groups selected from C1-C4 alkyl),• C1-C5alkyl (substituted with 0-2 groups selected from C3-C6cycloalkyl, halogen, OH, NH2, oxo, and C3-C6heterocycle); • C1-C4 alkoxy (substituted with 0-2 groups selected from C3-C6cycloalkyl, halogen, OH, NH2, and oxo); • 5- to 6-membered heterocycle; and • OH; • NH2; and • oxo; and wherein all other variables are as defined for Formula I′.

[0016] Formula II also includes compounds of Formula IIa:tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein R4is as defined for Formula II, and wherein all other variables are as defined for Formula I′.

[0017] Formula II also includes compounds of Formula IIb:tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein R4is as defined for Formula II, and wherein all other variables are as defined for Formula I′.

[0018] Formula II also includes compounds of Formula IIc:tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein R4is as defined for Formula II, and wherein all other variables are as defined for Formula I′.

[0019] Formula I also includes compounds of Formula IIIa:(IIIa), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein: Y1is selected from O and -CH2-; Y2is selected from NR9and CH; Y3is selected from O and CH; R4is selected from: C1-C4 alkyl (substituted with 0-3 groups selected from halogen and cyclopropyl); C1-C4alkoxy; and C3-C4 cycloalkyl; and R8is selected from C1-C4 alkyl and C3-C4 cycloalkyl, each of which is substituted with 0-1 trifluoromethyl groups and, if R9is present, R9is methyl; or R8and R9are taken together to form a five-membered heterocyclic ring, substituted with 0-2 methyl groups.

[0020] Formula I also includes compounds of Formula IIIb:(IIIb), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein: R4is selected from: C1-C4 alkyl (substituted with 0-3 groups selected from halogen and cyclopropyl); C1-C4 alkoxy; and C3-C4cycloalkyl; and R8is selected from C3 alkyl and C3-C4 cycloalkyl, each of which is substituted with 0-1 trifluoromethyl groups and R9is methyl; or R8and R9are taken together to form a five-membered heterocyclic ring, substituted with 0-2 methyl groups.

[0021] In some embodiments, the compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb are chosen from Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0022] Another aspect of the disclosure provides pharmaceutical compositions comprising at least one compound chosen from the novel compounds disclosed herein, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one pharmaceutically acceptable carrier, which compositions may further include at least one additional active pharmaceutical ingredient. In some embodiments of the pharmaceutical compositions disclosed herein, the at least one additional active pharmaceutical ingredient is at least one other CFTR modulator. In some embodiments, the at least one other CFTR modulator is selected from CFTR potentiators and CFTR modulators.

[0023] Thus, another aspect of the disclosure provides methods of treating the CFTR- mediated disease cystic fibrosis comprising administering at least one compound chosen from the novel compounds disclosed herein, tautomers thereof, deuterated derivatives of thosecompounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one pharmaceutically acceptable carrier, optionally as part of a pharmaceutical composition comprising at least one additional component, to a subject in need thereof. In some embodiments, the at least one additional active pharmaceutical ingredient in the methods of treating disclosed herein is at least one other CFTR modulator. In some embodiments, the at least one other CFTR modulator is selected from CFTR potentiators and CFTR correctors.

[0024] In certain embodiments, the pharmaceutical compositions of the disclosure comprise at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. In certain embodiments, the pharmaceutical compositions of the disclosure comprise at least one compound chosen from Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0025] In some embodiments, compositions comprising at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing may optionally further comprise (a) at least one (i.e., one or more) compound chosen from (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3- dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5- yl)cyclopropanecarboxamide (tezacaftor), 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5- yl)cyclopropane carboxamido)-3-methylpyridin-2-yl)benzoic acid (lumacaftor), deuterated derivatives of tezacaftor and lumacaftor, and pharmaceutically acceptable salts of any of the foregoing; and / or (b) at least one (i.e., one or more) compound chosen from N-[2,4-bis(1,1- dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (ivacaftor), N-(2- (tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide (deutivacaftor), (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16- pentaen-6-ol, and (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol; deuterated derivatives of ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa- 3,4,18-triazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16-pentaen-6-ol, and (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16-pentaen-6-ol; and pharmaceutically acceptable salts of any of the foregoing.

[0026] In some embodiments, compositions comprising at least one compound chosen from Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing may optionally further comprise (a) at least one (i.e., one or more) compound chosen from (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3- dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5- yl)cyclopropanecarboxamide (tezacaftor), 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5- yl)cyclopropane carboxamido)-3-methylpyridin-2-yl)benzoic acid (lumacaftor), deuterated derivatives of tezacaftor and lumacaftor, and pharmaceutically acceptable salts of any of the foregoing, and / or (b) at least one (i.e., one or more) compound chosen from N-[2,4-bis(1,1- dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (ivacaftor), N-(2- (tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide (deutivacaftor), (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16- pentaen-6-ol, and (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol; deuterated derivatives of ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa- 3,4,18-triazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16-pentaen-6-ol, and (6R)-17-amino- 12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo [12.3.1.12,5] nonadeca-1(18),2,4,14,16-pentaen-6-ol; and pharmaceutically acceptable salts of any of the foregoing.

[0027] Another aspect of the disclosure provides methods of treating the CFTR-mediated disease cystic fibrosis comprising administering to a patient in need thereof at least one compound chosen from the novel compounds disclosed herein, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing, and optionally further administering one or more additional CFTR modulating agents selected from tezacaftor, ivacaftor, and lumacaftor.

[0028] In a further aspect, compounds of the disclosure (e.g., compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing), and pharmaceutical compositions comprising those compounds, and optionally further comprising one or more CFTR modulating agents, are used in therapy or in the manufacture of a medicament. In some embodiments, the one or more additional CFTR modulating agents are selected from CFTR potentiators. In some embodiments, the one or more additional CFTR modulating agents are selected from CFTR correctors. In some embodiments, the one or more additional CFTR modulating agents are selected from tezacaftor, lumacaftor, ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18- triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and (6R)-17-amino-12,12- dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5] nonadeca- 1(18),2,4,14,16-pentaen-6-ol; and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.

[0029] A further aspect of the disclosure provides intermediates and methods for making the compounds and compositions disclosed herein. Definitions

[0030] “Tezacaftor” as used herein, refers to (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N- (1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5- yl)cyclopropanecarboxamide, which can be depicted with the following structure:. Tezacaftor may be in the form of a deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative. Tezacaftor and methods of making and using tezacaftor are disclosed in WO 2010 / 053471, WO 2011 / 119984, WO 2011 / 133751, WO 2011 / 133951, WO 2015 / 160787, and US 2009 / 0131492, each of which is incorporated herein by reference.

[0031] “Ivacaftor” as used throughout this disclosure refers to N-[2,4-bis(1,1-dimethylethyl)- 5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide, which is depicted by the structure:. Ivacaftor may also be in the form of a deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative. Ivacaftor and methods of making and using ivacaftor are disclosed in WO 2006 / 002421, WO 2007 / 079139, WO 2010 / 108162, and WO 2010 / 019239, each of which is incorporated herein by reference.

[0032] In some embodiments, a deuterated derivative of ivacaftor (deutivacaftor) is employed in the compositions and methods disclosed herein. A chemical name for deutivacaftor is N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4- dihydroquinoline-3-carboxamide, as depicted by the structure:. Deutivacaftor may be in the form of a further deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative. Deutivacaftor and methods of making and using deutivacaftor are disclosed in WO 2012 / 158885, WO 2014 / 078842, and US Patent No.8,865,902, each of which is incorporated herein by reference.

[0033] “Lumacaftor” as used herein, refers to 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5- yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, which is depicted by the chemical structure:.

[0034] Lumacaftor may be in the form of a deuterated derivative, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a deuterated derivative. Lumacaftor and methods of making and using lumacaftor are disclosed in WO 2007 / 056341, WO 2009 / 073757, and WO 2009 / 076142, each of which is incorporated herein by reference.

[0035] (6R,12R)-17amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18- triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, deuterated derivatives, and pharmaceutically acceptable salts and methods of making and using (6R,12R)-17-amino-12- methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca- 1(18),2,4,14,16-pentaen-6-ol are described in WO 2022 / 032068, WO 2023 / 150236, and WO 2023 / 012230, each of which is incorporated herein by reference.

[0036] (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo [12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, deuterated derivatives, and pharmaceutically acceptable salts and methods of making and using (6R)-17-amino-12,12- dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo [12.3.1.12,5]nonadeca- 1(18),2,4,14,16-pentaen-6-ol are described in WO 2022 / 109573, WO 2023 / 224924, and WO 2023 / 224931, each of which is incorporated herein by reference.

[0037] As used herein, the term “alkyl” refers to a saturated or partially saturated, branched, or unbranched (linear) aliphatic hydrocarbon containing carbon atoms (such as, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms), which may contain a double (alkenyl) or triple (alkynyl) bond between one or more sets of adjacent carbon atoms. Alkyl groups may be substituted or unsubstituted.

[0038] The term “aliphatic” or “aliphatic group,” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted, or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic,” “carbocycle,” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unlessotherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, unless otherwise specified, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments, unless otherwise specified, aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-8 hydrocarbon or bicyclic or tricyclic C8-14 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, and (cycloalkyl)alkenyl. Suitable cycloaliphatic groups include cycloalkyl, bicyclic cycloalkyl (e.g., decalin), bridged bicycloalkyl such as norbornyl or [2.2.2]bicyclo-octyl, and bridged tricyclic such as adamantyl.

[0039] As used herein, the term “unsaturated” means that a moiety has one or more units of unsaturation.

[0040] As used herein, the term “pi bond” means a covalent bond formed by the p orbitals of adjacent atoms. Pi bonds exist where there is a multiple bond, i.e., a double or triple bond, between two atoms. For example, a carbon-carbon double bond consists of one pi bond, and a carbon-carbon triple bond consists of two pi bonds.

[0041] As used herein, the term “haloalkyl group” refers to an alkyl group substituted with one or more halogen atoms, e.g., fluoroalkyl, which refers to an alkyl group substituted with one or more fluorine atoms. In some embodiments, one carbon atom of the alkyl group is substituted with one or more halogen atoms. In some embodiments, each carbon atom of the alkyl group is substituted with one or more halogen atoms. In some embodiments, one or more carbon atoms of the alkyl group is a perhalo carbon atom (i.e., all hydrogen atoms of the alkyl group are substituted by halogen atoms). In some embodiments, each carbon atom of the alkyl group is a perhalo carbon atom. Non-limiting examples of fluoroalkyl include —CHF2, —CH2F, —CF3, —CF2—, and perhaloalkyl, such as —CF2CF3.

[0042] As used herein, the term “halogen” or “halo” means F, Cl, Br, or I.

[0043] As used herein, the terms “oxo” and “=O” refer to a substituent oxygen atom connected to another atom by a double bond.

[0044] The term “alkoxy,” as used herein, refers to an alkyl or cycloalkyl covalently bonded to an oxygen atom. Alkoxy groups may be linear or branched, and substituted or unsubstituted.

[0045] As used herein, “cycloalkyl” refers to a cyclic, bicyclic, tricyclic, or polycyclic non- aromatic hydrocarbon groups having 3 to 12 carbons (such as, for example 3-10 carbons) and may include one or more unsaturated bonds. “Cycloalkyl” groups encompass monocyclic, bicyclic, tricyclic, bridged, fused, and spiro rings, including mono spiro and dispiro rings. Non- limiting examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, dispiro[2.0.2.1]heptane, bicyclo[1.1.1]pentane, and spiro[2,3]hexane. Cycloalkyl groups may be substituted or unsubstituted.

[0046] The term “aryl,” as used herein, is a functional group or substituent derived from an aromatic ring and encompasses monocyclic aromatic rings and bicyclic, tricyclic, and fused ring systems wherein at least one ring in the system is aromatic. An aryl group may be optionally substituted with one or more substituents. Non-limiting examples of aryl groups include phenyl, naphthyl, and 1,2,3,4-tetrahydronaphthalenyl.

[0047] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; and a substitutable nitrogen of a heterocyclic ring, for example, N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)). In some embodiments, “heteroatom” refers to oxygen, sulfur, and nitrogen.

[0048] The term “heteroaliphatic,” as used herein, means aliphatic groups wherein one or more carbon atoms are independently replaced with one or more heteroatoms, for example, oxygen, sulfur, nitrogen, phosphorus, or silicon. In some embodiments, the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaliphatic groups may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include “heterocycle,” “heterocyclyl,” “heterocycloaliphatic,” and “heterocyclic” groups.

[0049] The term “heteroaryl ring,” as used herein, refers to an aromatic ring comprising at least one ring atom that is a heteroatom, such as O, N, S, P, and Si. In some embodiments, the heteroaryl ring contains 1-5 heteroatoms selected from oxygen, sulfur, and nitrogen. In some embodiments, the heteroaryl ring contains 1-3 heteroatoms selected from oxygen, sulfur, and nitrogen. Heteroaryl groups encompass monocyclic rings and bicyclic, tricyclic, bridged, fused, and spiro ring systems (including monospiro and dispiro rings) having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the systemcontains one or more heteroatoms, and wherein each ring in the system contains three to seven ring members. Heteroaryl groups also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloalkyl, or heterocyclyl rings, where the point of attachment is on the heteroaromatic ring. Non-limiting examples of heteroaryl rings include pyridine, quinoline, indole, indoline, azaindole, pyrrolopyrazine, furopyridine, and furopyrazine. A heteroaryl group may be optionally substituted with one or more substituents. In certain embodiments, the term “heteroaryl ring” encompasses heteroaryl rings with various oxidation states, such as heteroaryl rings containing N-oxides and sulfoxides. Non-limiting examples of such heteroaryl rings include pyrimidine N-oxides, quinoline N-oxides, thiophene S-oxides, and pyrimidine N-oxides.

[0050] As used herein, the term “heterocycle” is used interchangeably with “heterocyclyl ring,” and refers to a non-aromatic hydrocarbon containing 3 to 12 atoms in a ring (such as, for example 3-10 atoms) comprising at least one ring atom that is a heteroatom, such as O, N, S, P, or Si and may include one or more unsaturated bonds. In some embodiments, the heterocyclyl ring contains 1-5 heteroatoms selected from oxygen, sulfur, and nitrogen. In some embodiments, the heterocyclyl ring contains 1-3 heteroatoms selected from oxygen, sulfur, and nitrogen. Heterocyclyl rings encompass monocyclic, bicyclic, tricyclic, polycyclic, bridged, fused, and spiro rings, including monospiro and dispiro rings.

[0051] In some embodiments, a C3-C6heterocycle is a heterocycle selected from, for example:

[0052] In some embodiments, a C4-C6heterocycle is a heterocycle selected from, for example:

[0053] The bond designation “” is intended to reflect the presence of an aromatic (i.e.,conjugated) ring system.

[0054] It will be appreciated that certain compounds of this disclosure may exist as separate stereoisomers or enantiomers and / or mixtures of those stereoisomers or enantiomers. As used inthe chemical structures disclosed herein, a “wedge” ( ) or “hash” ( ) bond to a stereogenicatom indicates a chiral center of known absolute stereochemistry (i.e., one stereoisomer). Asused in the chemical structures disclosed herein, a “wavy” bond ( ) to a stereogenic atomindicates a chiral center of unknown absolute stereochemistry (i.e., one stereoisomer). As usedin the chemical structures disclosed herein, a “wavy” bond ( ) to a double-bonded carbonindicates a mixture of E / Z isomers. As used in the chemical structures disclosed herein, a(“straight”) bond to a stereogenic atom indicates where there is a mixture (e.g., racemic or enriched). As used herein, two(“straight”) bonds to a double-bonded carbon indicates that the double bond possesses the E / Z stereochemistry as drawn. As used in the chemical structures A disclosed herein, a (a “wavy” line perpendicular to a “straight” bond to group “A”) indicates that group “A” is a substituent whose point of attachment is at the end of the bond that terminates at the “wavy” line. As used herein, a stereogenic atom that is notated with an (R) or (S) indicates the stereochemical designation of the stereogenic atom under the Cahn-Ingold- Prelog convention.

[0055] Certain compounds can exist as atropisomers. It will be appreciated that certain compounds of this disclosure may exist as separated atropisomers and / or mixtures of those atropisomers, i.e., a subclass of stereoisomers resulting from hindered rotation about single bonds or chirality axis and that can be isolated as separate chemical species. As used herein, a stereogenic unit that is notated with a (P) or (M) indicates the stereochemical designation of the stereogenic unit under the Cahn-Ingold-Prelog convention (basic terminology of stereochemistry, IUPAC Recommendations 1996, Pure & Appl. Chem., Vol 68, No.12, pp. 2193-2222, 1996).

[0056] Certain compounds disclosed herein may exist as tautomers and both tautomeric forms are intended, even though only a single tautomeric structure is depicted. For example, a description of Compound X is understood to include its tautomer Compound Y and vice versa, as well as mixtures thereof:Compound X Compound Y. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.

[0057] “Tert” and “t-” are used interchangeably and mean tertiary.

[0058] Compounds described herein may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the disclosure. It will be appreciated that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” “Substituted,” whether preceded by the term “optionally” or not, indicates that at least one hydrogen of the “substituted” group is replaced by a substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent chosen from a specified group, the substituent may be either the same or different at each position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds.

[0059] The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.

[0060] The term “stable compounds,” as used herein, refers to compounds which possess sufficient stability to allow for their manufacture and which maintain the integrity of the compounds for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into therapeutic products, intermediates for use in production of therapeutic compounds, isolatable or storable intermediates, and / or treating a disease or condition responsive to therapeutic agents).

[0061] In the compounds of this disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated,when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural abundance isotopic composition.

[0062] As used herein, the term “derivative” refers to a collection of molecules having a chemical structure identical to a compound of this disclosure, except that one or more atoms of the molecule may have been substituted with another atom. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C or14C, are within the scope of this disclosure. Such compounds are useful as, for example, analytical tools, probes in biological assays, or compounds with improved therapeutic profiles.

[0063] As used herein, “deuterated derivative(s)” refers to a compound having the same chemical structure as a reference compound, with one or more hydrogen atoms replaced by a deuterium atom. In some embodiments, the one or more hydrogens replaced by deuterium are part of an alkyl group. In some embodiments, the one or more hydrogens replaced by deuterium are part of a methyl group. In chemical structures, deuterium may be represented as “D.” In compounds identified as a deuterated derivative, or containing a “D” substitution, the deuterium atom is present in amounts far exceeding its natural abundance; for example, the compound may have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom).

[0064] As used herein, “CFTR” means cystic fibrosis transmembrane conductance regulator.

[0065] As used herein, the term “modulator” refers to a compound that increases the activity of a biological compound or molecule such as a protein.

[0066] As used herein, the term “CFTR modulator” refers to a compound that increases the activity of CFTR. The increase in activity resulting from a CFTR modulator includes, but is not limited to, compounds that correct, potentiate, stabilize, and / or amplify CFTR.

[0067] As used herein, the terms “corrector” and “CFTR corrector” are used interchangeably and refer to a compound that facilitates the processing and trafficking of CFTR to increase the amount of CFTR at the cell surface. The novel compounds disclosed herein are CFTR correctors. Tezacaftor and lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof as referenced herein, are correctors. Other CFTR correctors include those disclosed in WO 2023 / 034946, WO 2023 / 034992, WO 2021 / 097054, WO 2021 / 097057,WO 2021 / 113806, WO 2021 / 113808, and WO 2021113809, such as SION-109, SION-638, SION-719, and SION-451. Additional CFTR correctors include ABBV-2851, disclosed in WO 2017 / 009804, ABBV-3748; ABBV-3903; and ABBV-119.

[0068] As used herein, the terms “potentiator” and “CFTR potentiator” refer to a compound that increases the channel activity of CFTR protein located at the cell surface, resulting in enhanced ion transport. Ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16- pentaen-6-ol, and (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol; as referenced herein, are CFTR potentiators. It will be appreciated that a description of a combination of compounds that includes a compound of the disclosure (e.g., compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing) will typically but not necessarily include a CFTR potentiator, such as, e.g., ivacaftor, deutivacaftor, (6R,12R)-17-amino-12- methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5] nonadeca- 1(18),2,4,14,16-pentaen-6-ol, and (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19- oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and (6R)-17- amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol; or a deuterated derivative or pharmaceutically acceptable salt of any of the foregoing. In addition, the combination will typically, but not necessarily, include only a single potentiator, but may include more than one corrector. Thus, in some embodiments, a combination of at least one compound of the disclosure (e.g., a compound selected from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing), will include a potentiator selected from ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19- dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and (6R)-17- amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol; or deuterated derivatives or pharmaceutically acceptable salts thereof and may also include another CFTR corrector, such as,e.g., a corrector compound selected from tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof. In some embodiments, such a combination may also include a CFTR potentiator enhancer.

[0069] As used herein, the term “CFTR potentiator enhancer,” “CFTR potentiation enhancer,” and “CFTR co-potentiator” are used interchangeably and refer to a compound that enhances CFTR potentiation.

[0070] The term “compound,” when referring to a compound of this disclosure, refers to a collection of molecules having an identical chemical structure, except that there may be isotopic variation among the constituent atoms of the molecules.

[0071] The phrase “a novel compound of the disclosure” refers to a compound chosen from compounds of any one of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. Specifically excluded from the phrase “a novel compound of the disclosure is any compound disclosed in PCT / US2021 / 053858 (incorporated herein by reference).

[0072] The term “at least one compound selected from,” as used herein, refers to the selection of one or more of the compounds from a specified group. “Selected from” and “chosen from” may be used interchangeably herein.

[0073] A reference to “Compounds 1 to 139” herein is intended to represent a reference to each of Compounds 1 through 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139) encompassed by Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc IIIa, and / or IIIb, and disclosed in Tables 2 and 4 herein, individually or as a group.

[0074] As used herein, the term “active pharmaceutical ingredient” or “therapeutic agent” (“API”) refers to a biologically active compound.

[0075] The terms “patient” and “subject” are used interchangeably and refer to an animal, including a human.

[0076] The terms "effective dose" and "effective amount" are used interchangeably herein and refer to that amount of a compound that produces the desired effect for which it is administered (e.g., improvement in CF or a symptom of CF, or lessening the severity of CF or a symptom of CF). The exact amount of an effective dose will depend on the purpose of thetreatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0077] As used herein, the terms "treatment," "treating," and the like generally mean the improvement in one or more symptoms of CF or lessening the severity of CF or one or more symptoms of CF in a subject. “Treatment,” as used herein, includes, but is not limited to, the following: increased growth of the subject, increased weight gain, reduction of mucus in the lungs, improved pancreatic and / or liver function, reduction of chest infections, and / or reductions in coughing or shortness of breath. Improvements in or lessening the severity of any of these symptoms can be readily assessed according to standard methods and techniques known in the art.

[0078] It should be understood that references herein to methods of treatment (e.g., methods of treating a CFTR mediated disease or a method of treating cystic fibrosis) using one or more compounds of the disclosure optionally in combination with one or more additional CFTR modulating agents (e.g., a compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, optionally in combination with one or more additional CFTR modulating agents) should also be interpreted as references to: - one or more compounds of the disclosure (e.g., a compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, optionally in combination with one or more additional CFTR modulating agents) for use in methods of treating, e.g., cystic fibrosis, optionally in combination with one or more additional CFTR modulating agents; and / or - the use of one or more compounds of the disclosure (e.g., a compound chosen compounds of any of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, optionally in combination with one or more additional CFTR modulating agents) in the manufacture of a medicament for treating, e.g., cystic fibrosis.

[0079] It should be also understood that references herein to methods of treatment (e.g., methods of treating a CFTR mediated disease or a method of treating cystic fibrosis) using a pharmaceutical composition of the disclosure (e.g., a pharmaceutical composition comprising at least one compound chosen from compounds of any of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and optionally further comprising one or more additional CFTR modulating agents) should also be interpreted as references to: - a pharmaceutical composition (e.g., a pharmaceutical composition comprising at least one compound chosen from compounds of any of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and optionally further comprising one or more additional CFTR modulating agents) for use in methods of treating, e.g., cystic fibrosis; and / or - the use of a pharmaceutical composition (e.g., a pharmaceutical composition comprising at least one compound chosen from compounds of any of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and optionally further comprising one or more additional CFTR modulating agents) in the manufacture of a medicament for treating, e.g., cystic fibrosis.

[0080] As used herein, the term “in combination with,” when referring to two or more compounds, agents, or additional active pharmaceutical ingredients, means the administration of two or more compounds, agents, or active pharmaceutical ingredients to the patient prior to, concurrent with, or subsequent to each other.

[0081] As used herein, the terms “about” and “approximately,” when used in connection with amounts, volumes, reaction times, reaction temperatures, etc. mean an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In some embodiments, the terms “about” and “approximately” mean within 1, 2, 3, or 4 standard deviations. In certain embodiments, the terms “about” and “approximately” mean within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%,5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range. In some embodiments, “about” and “approximately” mean within 15% of a given value or range. . In some embodiments, “about” and “approximately” mean within 10% of a given value or range. . In some embodiments, “about” and “approximately” mean within 5% of a given value or range. As used herein, the symbolappearing immediately before a numerical value has the same meaning as the terms “about” and “approximately.”

[0082] The term “at least one” refers to one or more.

[0083] As used herein, the term “solvent” refers to any liquid in which the product is at least partially soluble (solubility of product >1 g / L).

[0084] Non-limiting examples of suitable solvents that may be used in this disclosure include, for example, water (H2O), methanol (MeOH), methylene chloride or dichloromethane (DCM; CH2Cl2), acetonitrile (MeCN; CH3CN; ACN), N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et2O), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0085] As used herein, the term “ambient conditions” means room temperature, open air condition and uncontrolled humidity condition. As used herein, the term “room temperature” or “ambient temperature” means 15 °C to 30 °C.

[0086] As used herein, “mutations” can refer to mutations in the CFTR gene or the CFTR protein. A “CFTR gene mutation” refers to a mutation in the CFTR gene, and a “CFTR protein mutation” refers to a mutation in the CFTR protein. In general, a genetic defect or mutation, or a change in the nucleotides in a gene, results in a mutation in the CFTR protein translated from that gene, or a frame shift(s).

[0087] As used herein, “minimal function (MF) mutations” refer to CFTR gene mutations associated with minimal CFTR function (little-to-no functioning CFTR protein) and include, for example, mutations associated with severe defects in ability of the CFTR channel to open and close, known as defective channel gating or “gating mutations”; mutations associated with severe defects in the cellular processing of CFTR and its delivery to the cell surface; mutations associated with no (or minimal) CFTR synthesis; and mutations associated with severe defects in channel conductance.

[0088] As used herein, the term “F508del” refers to a mutant CFTR protein which is lacking the amino acid phenylalanine at position 508, or to a mutant CFTR gene which encodes for a CFTR protein lacking the amino acid phenylalanine at position 508.

[0089] The disclosure also provides processes for preparing salts of the compounds of the disclosure. A salt of a compound of this disclosure is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. In some embodiments, the salt is a pharmaceutically acceptable salt.

[0090] The term “pharmaceutically acceptable,” as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, and the like, and is commensurate with a reasonable benefit / risk ratio.

[0091] As used herein, the term “pharmaceutically acceptable salt” means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. A “pharmaceutically acceptable counterion” is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient. One of ordinary skill in the art would recognize that, when an amount of “a compound or a pharmaceutically acceptable salt thereof” is disclosed, the amount of the pharmaceutically acceptable salt form of the compound is the amount equivalent to the concentration of the free base of the compound.

[0092] A “free base” form of a compound does not contain an ionically bonded salt. It is noted that the disclosed amounts of the compounds or their pharmaceutically acceptable salts thereof herein are based upon their free base form. For example, “10 mg of at least one compound chosen from Compound I and pharmaceutically acceptable salts thereof” includes 10 mg of Compound I and a concentration of a pharmaceutically acceptable salt of Compound I equivalent to 10 mg of Compound I.

[0093] Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66, 1-19. For example, Table 1 of that article provides the following pharmaceutically acceptable salts:Table 1 of S. M. Berge, et al.:

[0094] Non-limiting examples of pharmaceutically acceptable acid addition salts include: salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid; salts formed with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid; and salts formed by using other methods used in the art, such as ion exchange. Non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-4alkyl)4 salts. This disclosure also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein.Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts. CFTR Modulator Compounds

[0095] One aspect of the disclosure provides novel compounds, including compounds of Formula I, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. Formula I encompasses compounds falling within the following structure:tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing (i.e., salts of compounds, tautomers, and deuterated derivatives), wherein: Ring A is selected from 7- and 8-membered heterocycles containing 0-2 additional heteroatoms selected from O and N, wherein Ring A is substituted with 0-4 groups selected from: • C3-C6cycloalkyl (substituted with 0-4 groups selected from C1-C4 alkyl); • C1-C5alkyl (substituted with 0-4 groups selected from C3-C6cycloalkyl, halogen, OH, NH2, oxo, and 4- to 6-membered heterocycle); • C1-C4alkoxy (substituted with 0-4 groups selected from C3-C6cycloalkyl, halogen, OH, NH2, and oxo); • 5- and 6-membered heterocycle; • OH; • NH2; and • oxo;wherein two substituents on Ring A taken together with the atoms to which they are bonded may form a ring selected from C3-C6cycloalkyl (further substituted with 0-2 groups selected from C1-C4alkyl and C1-C4alkoxy); Ring B is a 9-12 membered heteroaryl group containing 1-4 heteroatoms selected from N, O, and S, wherein Ring B is substituted with 1-4 groups selected from: • C1-C6 alkyl (substituted with 0-3 groups selected from halogen, C1-C3 alkoxy, and OH); • C3-C6cycloalkyl, substituted with 0-3 groups selected from: o C1-C6alkyl (substituted with 0-3 groups selected from C1-C3alkoxy and halogen), o OH, and o halogen; • halogen; and • 5- and 6-membered heterocycle; each X is independently selected from CH and N; Z is selected from CH and N; R1is selected from hydrogen, halogen, C1-C5 alkyl, C1-C5 haloalkyl, and C1-C5 alkoxy (optionally substituted with 0-5 halogens); each R2is independently selected from C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 alkoxy (substituted with 0-5 halogens), OH, and halogens; each R3is independently selected from C1-C3alkyl, C1-C3alkoxy, OH, and halogen; n is an integer selected from 2 to 5; and p is an integer selected from 0 to 3.

[0096] Formula I also includes compounds of Formula I′:tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing (i.e., salts of compounds, tautomers, and deuterated derivatives), wherein: Ring A is selected from 7- and 8- membered heterocycles containing 0-2 additional heteroatoms selected from O and N, wherein Ring A is substituted with 0-2 groups selected from: • C3-C6cycloalkyl (substituted with 0-2 groups selected from C1-C4 alkyl), • C1-C5 alkyl (substituted with 0-2 groups selected from C3-C6cycloalkyl, halogen, OH, NH2, oxo, and C4-C6heterocycle); • C1-C4 alkoxy (substituted with 0-2 groups selected from C3-C6cycloalkyl, halogen, OH, NH2, and oxo); • 5- and 6-membered heterocycle; • OH; • NH2; and • oxo; Ring B is a 9-12 membered heteroaryl group containing 1-4 heteroatoms selected from N, O, and S, wherein Ring B is substituted with 1-4 groups selected from: • C1-C6 alkyl (substituted with 0-3 groups selected from halogen, C1-C3 alkoxy, and OH); • C3-C6cycloalkyl, substituted with 0-3 groups selected from: o C1-C6 alkyl (substituted with 0-3 groups selected from: C1-C3 alkoxy and halogen); o OH; and o halogen; • halogen; and • 5- and 6-membered heterocycle; each X is independently selected from CH and N; Z is selected from CH and N; R1is selected from hydrogen, halogen, C1-C5alkyl, C1-C5haloalkyl, and C1-C5alkoxy (substituted with 0-5 halogens); each R2is independently selected from C1-C5 alkyl, C1-C3 alkoxy, OH, and halogen; each R3is independently selected from C1-C3alkyl, C1-C3alkoxy, OH, and halogen; n is an integer selected from 2 to 5; andp is an integer selected from zero to 3.

[0097] Formula I also includes compounds of Formula Ia:tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein all variables are as defined for Formula I′.

[0098] Formula I also includes compounds of Formula Ib:tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein all variables are as defined for Formula I′.

[0099] Formula I also includes compounds of Formula Ic:tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein all variables are as defined for Formula I′.

[0100] One aspect of the disclosure provides novel compounds, including compounds ofFormula II, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. Formula II encompasses compounds falling within the following structure:tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein R4is selected from: • C3-C6cycloalkyl (substituted with 0-2 groups selected from C1-C4 alkyl), • C1-C5alkyl (substituted with 0-2 groups selected from C3-C6cycloalkyl, halogen, OH, NH2, oxo, and C3-C6heterocycle); • C1-C4alkoxy (substituted with 0-2 groups selected from C3-C6cycloalkyl, halogen, OH, NH2, and oxo); • 5- and 6-membered heterocycle; • OH; • NH2; and • oxo; and wherein all other variables are as defined for Formula I′.

[0101] Formula I also includes compounds of Formula II:tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein R4is selected from:• C3-C6cycloalkyl (substituted with 0-2 groups selected from C1-C4alkyl), • C1-C5alkyl (substituted with 0-2 groups selected from C3-C6cycloalkyl, halogen, OH, NH2, oxo, and C4-C6 heterocycle); • C1-C4alkoxy (substituted with 0-2 groups selected from C3-C6cycloalkyl, halogen, OH, NH2, and oxo); • 5- and 6-membered heterocycle; • OH; • NH2; and • oxo; and wherein all other variables are as defined for Formula I′.

[0102] Formulae I and II also include compounds of Formula IIa:tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein R4is as defined for Formula II, and wherein all other variables are as defined for Formula I′.

[0103] Formulae I and II also include compounds of Formula IIb:(IIb), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein R4is as defined for Formula II, and wherein all other variables are as defined for Formula I′.

[0104] Formulae I and II also include compounds of Formula IIc:tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein R4is as defined for Formula II, and wherein all other variables are as defined for Formula I′.

[0105] Formulae I and II also include compounds of Formula IIIa:(IIIa), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein: Y1is selected from O and -CH2-; Y2is selected from NR9and CH; Y3is selected from O and CH; R4is selected from: C1-C4alkyl (substituted with 0-3 groups selected from halogen and cyclopropyl); C1-C4 alkoxy; and C3-C4 cycloalkyl; and R8is selected from C1-C4alkyl and C3-C4cycloalkyl, each of which is substituted with 0-1 trifluoromethyl groups and, if R9is present, R9is methyl; or R8and R9are taken together to form a five-membered heterocyclic ring, substituted with 0-2 methyl groups.

[0106] Formulae I and II also include compounds of Formula IIIb:tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein: R4is selected from: C1-C4 alkyl (substituted with 0-3 groups selected from halogen and cyclopropyl); C1-C4 alkoxy; and C3-C4cycloalkyl; and R8is selected from C3 alkyl and C3-C4 cycloalkyl, each of which is substituted with 0-1 trifluoromethyl groups and R9is methyl; or R8and R9are taken together to form a five-membered heterocyclic ring, substituted with 0-2 methyl groups.

[0107] In some embodiments of Formula I, Ring A is selected from azepane or azocane, wherein one CH2group is optionally replaced by an O atom, and wherein Ring A is substituted with 0-2 groups selected from: • C3 or C4 cycloalkyl (substituted with 0-1 methyl groups), • C1-C5alkyl (substituted with 0-1 groups selected from C3-C4cycloalkyl); and • C1-C3 alkoxy (substituted with 0-1 groups selected from C3-C4 cycloalkyl); Ring B is a 9-12 membered heteroaryl group containing 2-4 heteroatoms independently selected from N and O, wherein Ring B is substituted with 1-3 groups selected from: • C1-C4 alkyl, substituted with 0-3 groups selected from: o OMe, o halogen, and o OH; • C3-C4cycloalkyl, substituted with 0-1 groups selected from: o C1and C2alkyl (substituted with 0-3 halogen atoms) and o CH2OCH3; • halogen; and• 6-membered heterocycle; X is N; Z is selected from CH and N; R1is selected from H, CH3, OCH3, and F; each R2is CH3; n is 2; and p is zero and R3is absent.

[0108] In some embodiments, Ring A in the compound, tautomer, deuterated derivative, or salt of Formulae I, I′, Ia, Ib, Ic, is selected from:

[0109] In some embodiments, Ring A in the compound, tautomer, deuterated derivative, or salt of Formulae I, I′, Ia, Ib, Ic, is selected from:

[0110] In some embodiments, Ring B in the compound, tautomer, deuterated derivative, or salt of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb is selected from:Q is selected from C and N; each W is independently selected from CH and N, W1is selected from N, CH, and CF; Y is selected from N, NR, O, S, and CR; wherein Ring B contains 1 to 4 nitrogen atoms; R is selected from H and C1-C3alkyl (substituted with 0-1 groups selected from C1-C3alkoxy and OH); R5is selected from H, C1-C4 alkyl, and C3 and C4 cycloalkyl; R6is selected from: • H, • C1-C5alkyl, • C1-C5 haloalkyl, • C3and C4cycloalkyl, substituted with 0-1 groups selected from: o C1-C4alkyl, o CH2OCH3, and o C1-C3 haloalkyl; • 5- and 6-membered heterocycle; R7is selected from C1-C3 alkyl; and R8is selected from C1-C4 alkyl; and wherein R5and R6are not both hydrogen.

[0111] In some embodiments, Ring B in the compound, tautomer, deuterated derivative, or salt of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb is selected from:R is selected from H and C1-C3 (alkyl substituted with 0-1 groups selected from C1-C3 alkoxy and OH); R5is selected from H, C1-C4alkyl, and C3- and C4-cycloalkyl; R6is selected from: • H, • C1-C5alkyl, • C1-C5 haloalkyl, • C3and C4cycloalkyl, substituted with 0-1 groups selected from: o C1-C4 alkyl, o CH2OCH3, and o C1-C3haloalkyl; • 5- and 6-membered heterocycle; R7is selected from C1-C3 alkyl; R8is selected from C1-C4alkyl; and G is selected from halogens; and wherein R, R5and R6are not all simultaneously hydrogen, R5and R6are not simultaneously hydrogen when R is not present, and R6is not hydrogen when R and R5are not present.

[0112] In some embodiments, Ring B in the compound, tautomers, deuterated derivatives, or salts of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb is selected from:

[0113] In some embodiments, Ring B in the compounds, tautomers, deuterated derivatives, or salts of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb is selected from:

[0114] In some embodiments, the compounds of Formulae I or I′ are chosen from Compounds 1 to 107, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

[0115] In some embodiments, the compounds of Formula I or I′ are chosen from Table 3. Table 3.

[0116] In some embodiments, the compounds of Formula I or I′ are chosen from Compounds 108 to 139, tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. Table 4. Structures of Compounds 108 to 139

[0117] Because the general properties of silicon and germanium are similar to those of carbon, replacement of carbon by silicon or germanium can result in compounds with similar biological activity to a carbon-containing original compound.

[0118] In some embodiments, the compounds of the invention include silicon derivatives of the compounds of any of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein at least one carbon atom has been replaced with silicon. In some embodiments, the at least one carbon atom replaced with silicon may be a non-aromatic carbon. In some embodiments, the at least one carbon atom replaced with silicon may be an aromatic carbon. In certain embodiments, the silicon derivatives of the invention may also have one or more hydrogen atoms replaced with deuterium. In certain embodiments, the silicon derivatives of the invention may also have one or more carbon atoms replaced with germanium.

[0119] In some embodiments, the compounds of the invention include germanium derivatives of the compounds of any of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein at least one carbon atom has been replaced with germanium. In some embodiments, the at least one carbon atom replaced with germanium may be a non-aromatic carbon. In some embodiments, the at least one carbon atom replaced with germanium may be an aromatic carbon. In certain embodiments, the germanium derivatives of the invention may also have one or more hydrogen atoms replaced with deuterium. In certain embodiments, the germanium derivatives of the invention may also have one or more carbon atoms replaced with silicon.

[0120] Exemplary embodiments of the invention include, but are not limited to, the following silicon and germanium derivatives:Methods of Treatment

[0121] Any of the novel compounds disclosed herein, such as, for example, a compound chosen from compounds of any of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, can act as a CFTR modulator, i.e., it modulates CFTR activity in the body. Individuals suffering from a mutation in the gene encoding CFTR may benefit from receiving a CFTR modulator. A CFTR mutation may affect the CFTR quantity, i.e., the number of CFTR channels at the cell surface, or it may impact CFTR function, i.e., the functional ability of each channel to open and transport ions. Mutations affecting CFTR quantity include mutations that cause defective synthesis (Class I defect), mutations that cause defective processing and trafficking (Class II defect), mutations that cause reduced synthesis of CFTR (Class V defect), and mutations that reduce the surface stability of CFTR (Class VI defect). Mutations that affect CFTR function include mutations that cause defective gating (Class III defect) and mutations that cause defective conductance (Class IV defect). Some CFTR mutations exhibit characteristics of multiple classes. Certain mutations in the CFTR gene result in cystic fibrosis.

[0122] Thus, in some embodiments, the disclosure provides methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering to the patient an effective amount of any of the novel compounds disclosed herein, such as, for example, a compound chosen from compounds of any of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, alone or in combination with another active ingredient, such as one or more CFTR modulating agents. In some embodiments, the one or more CFTR modulating agents are selected from ivacaftor, deutivacaftor, lumacaftor, and tezacaftor. In some embodiments, the patient has an F508del / minimal function (MF) genotype, F508del / F508del genotype (homozygous for the F508del mutation), F508del / gating genotype, or F508del / residual function (RF) genotype. In some embodiments, the patient is heterozygous and has one F508del mutation. In some embodiments, the patient is homozygous for the N1303K mutation.

[0123] In some embodiments, 1 mg to 500 mg of a compound disclosed herein, a tautomer thereof, deuterated derivatives of the compound and tautomer, or a pharmaceutically acceptable salt of any of the foregoing are administered daily.

[0124] In some embodiments, the patient has at least one F508del mutation in the CFTR gene. In some embodiments, the patient has a CFTR gene mutation that is responsive to a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt of the invention based on in vitro data. In some embodiments, the disclosure also is directed to methods of treatment using isotope-labelled compounds of the afore-mentioned compounds, or pharmaceutically acceptable salts thereof, wherein the formula and variables of such compounds and salts are each and independently as described above or any other embodiments described above, provided that one or more atoms therein have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs naturally (isotope labelled). Examples of isotopes which are commercially available and suitable for the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively.

[0125] The isotope-labelled compounds and salts can be used in a number of beneficial ways. They can be suitable for medicaments and / or various types of assays, such as substrate tissuedistribution assays. For example, tritium (3H)- and / or carbon-14 (14C)-labelled compounds are particularly useful for various types of assays, such as substrate tissue distribution assays, due to relatively simple preparation and excellent detectability. For example, deuterium (2H)-labelled ones are therapeutically useful with potential therapeutic advantages over the non-2H-labelled compounds. In general, deuterium (2H)-labelled compounds and salts can have higher metabolic stability as compared to those that are not isotope-labelled owing to the kinetic isotope effect described below. Higher metabolic stability translates directly into an increased in vivo half-life or lower dosages, which could be desired. The isotope-labelled compounds and salts can usually be prepared by carrying out the procedures disclosed in the synthesis schemes and the related description, in the example part and in the preparation part in the present text, replacing a non-isotope-labelled reactant by a readily available isotope-labelled reactant.

[0126] In some embodiments, the isotope-labelled compounds and salts are deuterium (2H)- labelled ones. In some specific embodiments, the isotope-labelled compounds and salts are deuterium (2H)-labelled, wherein one or more hydrogen atoms therein have been replaced by deuterium. In chemical structures, deuterium may be represented as “D” or “2H.”

[0127] The concentration of the isotope(s) (e.g., deuterium) incorporated into the isotope- labelled compounds and salt of the disclosure may be defined by the isotopic enrichment factor. The term “isotopic enrichment factor” as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. In some embodiments, if a substituent in a compound of the disclosure is denoted as deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Combination Therapies

[0128] One aspect disclosed herein provides methods of treating cystic fibrosis and other CFTR mediated diseases using any of the novel compounds disclosed herein, such as, for example, compounds of any of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomersthereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, in combination with at least one additional active pharmaceutical ingredient.

[0129] In some embodiments, at least one additional active pharmaceutical ingredient is selected from mucolytic agents, bronchodilators, antibiotics, anti-infective agents, and anti- inflammatory agents.

[0130] In some embodiments, the additional therapeutic agent is an antibiotic. Exemplary antibiotics useful herein include tobramycin, including tobramycin inhaled powder (TIP), azithromycin, aztreonam, including the aerosolized form of aztreonam, amikacin, including liposomal formulations thereof, ciprofloxacin, including formulations thereof suitable for administration by inhalation, levofloxacin, including aerosolized formulations thereof, and combinations of two antibiotics, e.g., fosfomycin and tobramycin.

[0131] In some embodiments, the additional agent is a mucolyte. Exemplary mucolytes useful herein include Pulmozyme®.

[0132] In some embodiments, the additional agent is a bronchodilator. Exemplary bronchodilators include albuterol, metaproterenol sulfate, pirbuterol acetate, salmeterol, or terbutaline sulfate.

[0133] In some embodiments, the additional agent is an anti-inflammatory agent, i.e., an agent that can reduce the inflammation in the lungs. Exemplary such agents useful herein include ibuprofen, docosahexaenoic acid (DHA), sildenafil, inhaled glutathione, pioglitazone, hydroxychloroquine, or simvastatin.

[0134] In some embodiments, the additional agent is a nutritional agent. Exemplary nutritional agents include pancrelipase (pancreatic enzyme replacement), including Pancrease®, Pancreacarb®, Ultrase®, or Creon®, Liprotomase® (formerly Trizytek®), Aquadeks®, or glutathione inhalation. In some embodiments, the additional nutritional agent is pancrelipase.

[0135] In some embodiments, at least one additional active pharmaceutical ingredient is selected from CFTR modulating agents. In some embodiments, the at least one additional active pharmaceutical ingredient is selected from CFTR potentiators. In some embodiments, the potentiator is selected from ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16- pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and deuterated derivativesand pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the at least one additional active pharmaceutical ingredient is chosen from CFTR correctors. In some embodiments, the correctors are selected from lumacaftor, tezacaftor, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.

[0136] In some embodiments, the at least one additional active pharmaceutical ingredient is chosen from (a) tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof; and / or (b) ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16- pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.

[0137] In some embodiments, the at least one additional active pharmaceutical ingredient is (a) a compound chosen from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19- dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and (6R)-17- amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, deuterated derivatives of the compound, and pharmaceutically acceptable salts of any of the foregoing, and may optionally include tezacaftor, deuterated derivatives, or pharmaceutically acceptable salts of any of the foregoing.

[0138] Thus, in some embodiments, the combination therapies provided herein comprise (a) a compound selected from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; and (b) at least one compound selected from tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof; or (c) at least one compound selected from ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16- pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing. In other embodiments, the combination therapies provided herein comprise (a) at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139(i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from tezacaftor and pharmaceutically acceptable salts thereof; and (c) at least one compound selected from ivacaftor, deutivacaftor, and pharmaceutically acceptable salts thereof. In still other embodiments, the combination therapies provided herein comprise (a) at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing; (b) at least one compound selected from tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof; and / or (c) at least one compound selected from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18- triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12- dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca- 1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof. In still other embodiments, the combination therapies provided herein comprise (a) a compound chosen from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa- 3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and (6R)-17-amino- 12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16-pentaen-6-ol, deuterated derivatives of the compound, and pharmaceutically acceptable salts of any of the foregoing, and (b) optionally tezacaftor, deuterated derivatives, or pharmaceutically acceptable salts of any of the foregoing.

[0139] In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from tezacaftor and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from lumacaftorand pharmaceutically acceptable salts thereof. In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from ivacaftor and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from deutivacaftor and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16- pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof.

[0140] In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from ivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceuticallyacceptable salts thereof and at least one compound chosen from deutivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16- pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof.

[0141] In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from lumacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from ivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from lumacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from deutivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof. In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at least one compound chosen from lumacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16- pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof.

[0142] In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in combination with at (a) a compound chosen from (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16- pentaen-6-ol and (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, deuterated derivatives of the compound, and pharmaceutically acceptable salts of any of the foregoing, and (b) optionally tezacaftor, deuterated derivatives, or pharmaceutically acceptable salts of any of the foregoing.

[0143] Each of the compounds of the disclosure, (e.g., Compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing), independently can be administered once daily, twice daily, or three times daily. In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered once daily. In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered twice daily.

[0144] In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptablesalts thereof are administered once daily. In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof are administered twice daily.

[0145] In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound chosen from ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16- pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing are administered once daily. In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound chosen from ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16- pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof are administered twice daily.

[0146] In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one compound chosen from ivacaftor, deutivacaftor, (6R,12R)-17- amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12- dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca- 1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof are administered once daily. In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, at least one compound chosen from tezacaftor and pharmaceutically acceptable salts thereof, and at least one compound chosen from ivacaftor, deutivacaftor, (6R,12R)-17- amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18- triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12- dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca- 1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof are administered twice daily.

[0147] In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, at least one compound chosen from ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16- pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof, and at least one compound chosen from lumacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, are administered once daily. In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, at least one compound chosen from ivacaftor, deutivacaftor, (6R,12R)-17-amino-12- methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca- 1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa- 3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuteratedderivatives and pharmaceutically acceptable salts thereof, and at least one compound chosen from lumacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, are administered twice daily.

[0148] In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, are administered once daily and at least one compound chosen from ivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, are administered twice daily. In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound chosen from lumacaftor and pharmaceutically acceptable salts thereof, are administered once daily and at least one compound chosen from ivacaftor and pharmaceutically acceptable salts thereof, are administered twice daily.

[0149] In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, are administered once daily and at least one compound chosen from (6R,12R)-17- amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo [12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15- bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16- pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof, are administered once or twice daily. In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least one compound chosen from lumacaftor and deuterated derivatives andpharmaceutically acceptable salts thereof, are administered once daily and at least one compound chosen from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa- 3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12- dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca- 1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof, are administered once or twice daily.

[0150] Compounds of the disclosure, (e.g., compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing), as well as additional CFTR modulator compounds, such as, e.g., tezacaftor, lumacaftor, ivacaftor, deutivacaftor, (6R,12R)- 17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18- triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12- dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca- 1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof, can be administered in a single pharmaceutical composition or separate pharmaceutical compositions. Such pharmaceutical compositions can be administered once daily or multiple times daily, such as twice daily. As used herein, the phrase that a given amount of API (e.g., tezacaftor, lumacaftor, ivacaftor, deutivacaftor (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16- pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof) is administered once or twice daily or per day means that said given amount is administered per dosing once or twice daily.

[0151] In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in a first pharmaceutical composition; at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition; and at least one compound chosen from ivacaftor and deuteratedderivatives and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.

[0152] In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in a first pharmaceutical composition; at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition; at least one compound chosen from deutivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.

[0153] In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in a first pharmaceutical composition; at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a second pharmaceutical composition; at least one compound chosen from (6R,12R)-17-amino-12- methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca- 1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa- 3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.

[0154] In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in a first pharmaceutical composition; at least one compound chosen from ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18- triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12- dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca- 1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable saltsthereof is administered in a second pharmaceutical composition; at least one compound chosen from lumacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.

[0155] In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, is administered in a first pharmaceutical composition; and at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof and at least one compound chosen from ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)- 13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17- amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts thereof are administered in a second pharmaceutical composition. In some embodiments, the second pharmaceutical composition comprises a half of a daily dose of said at least one compound chosen from ivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, and the other half of the daily dose of said at least one compound chosen from ivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof is administered in a third pharmaceutical composition.

[0156] In some embodiments, at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, at least one compound chosen from tezacaftor and pharmaceutically acceptable salts thereof, and at least one compound chosen from ivacaftor, deutivacaftor, and pharmaceutically acceptable salts thereof are administered in a first pharmaceutical composition. In some embodiments, the first pharmaceutical composition is administered to the patient twice daily. In some embodiments, the first pharmaceutical composition is administered once daily. In some embodiments, the first pharmaceutical composition is administered once daily and, when the first composition comprises ivacaftor, a second composition comprising only ivacaftor is administered once daily.

[0157] Any suitable pharmaceutical compositions can be used for compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, tezacaftor, ivacaftor, deutivacaftor, lumacaftor and tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing. Some exemplary pharmaceutical compositions for tezacaftor and its pharmaceutically acceptable salts can be found in WO 2011 / 119984 and WO 2014 / 014841, all of which is incorporated herein by reference. Some exemplary pharmaceutical compositions for ivacaftor and its pharmaceutically acceptable salts can be found in WO 2007 / 134279, WO 2010 / 019239, WO 2011 / 019413, WO 2012 / 027731, and WO 2013 / 130669, and some exemplary pharmaceutical compositions for deutivacaftor and its pharmaceutically acceptable salts can be found in US 8,865,902, US 9,181,192, US 9,512,079, WO 2017 / 053455, and WO 2018 / 080591, all of which are incorporated herein by reference. Some exemplary pharmaceutical compositions for lumacaftor and its pharmaceutically acceptable salts can be found in WO 2010 / 037066, WO 2011 / 127421, and WO 2014 / 071122, all of which are incorporated herein by reference.

[0158] In some embodiments, this disclosure provides a method of treating cystic fibrosis comprising the step of administering a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt disclosed herein (e.g., compounds of any of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing), or a pharmaceutical composition disclosed herein (e.g., pharmaceutical compositions comprising compounds of any of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing).

[0159] In some embodiments, the method of treating cystic fibrosis further comprises administering at least one additional active therapeutic agent.

[0160] In some embodiments, this disclosure provides use of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt disclosed herein (e.g., compounds of any of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any ofthe foregoing), or a pharmaceutical composition disclosed herein (e.g., pharmaceutical compositions comprising compounds of any of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing), in the manufacture of a medicament for treating cystic fibrosis.

[0161] In some embodiments, the medicament is formulated to be administered with at least one additional active therapeutic agent. In some embodiments, the medicament comprises at least one additional active therapeutic agent.

[0162] In some embodiments, this disclosure provides a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt disclosed herein (e.g., compounds of any of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing), or a pharmaceutical composition disclosed herein (e.g., pharmaceutical compositions comprising compounds of any of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing), for use in the treatment of cystic fibrosis. In some embodiments, this disclosure provides a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt disclosed herein (e.g., compounds of any of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing), or a pharmaceutical composition disclosed herein (e.g., pharmaceutical compositions comprising compounds of any of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing) for use in a method of treating cystic fibrosis.

[0163] In some embodiments, the treatment further comprises administering at least one additional active therapeutic agent.

[0164] In some embodiments, this disclosure provides the use of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt disclosed herein (e.g., compounds of any of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing), or a pharmaceutical composition disclosed herein (e.g., pharmaceutical compositions comprising compounds of any of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing) in the treatment of cystic fibrosis. In some embodiments, this disclosure provides the use of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt disclosed herein (e.g., compounds of any of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing), or a pharmaceutical composition disclosed herein (e.g., pharmaceutical compositions comprising compounds of any of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing) in a method of treating cystic fibrosis.

[0165] In some embodiments, the use further comprises use of at least one additional active therapeutic agent.

[0166] In some embodiments, the at least one additional active therapeutic agent to be administered is selected from mucolytic agents, bronchodilators, antibiotics, anti-infective agents, anti-inflammatory agents, nutritional agents, and CFTR modulators.

[0167] In some embodiments, the at least one additional active therapeutic agent to be administered is selected from CFTR potentiators.

[0168] In some embodiments, the at least one CFTR potentiator to be administered is selected from ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)- 13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17- amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.

[0169] In some embodiments, the at least one additional active therapeutic agent to be administered is selected from CFTR correctors.

[0170] In some embodiments, the at least one CFTR corrector to be administered is selected from lumacaftor, tezacaftor, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.

[0171] In some embodiments, the at least one additional active therapeutic agent to be administered is (a) at least one compound selected from tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof; and (b) at least one compound selected from ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)- 13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17- amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.

[0172] In some embodiments, the at least one additional active therapeutic agent to be administered is (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18- triazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16-pentaen-6-ol, and optionally tezacaftor.

[0173] In some embodiments, the at least one additional active therapeutic agent to be administered is (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and optionally tezacaftor. Pharmaceutical Compositions

[0174] Another aspect of the disclosure provides a pharmaceutical composition comprising at least one novel compound of the disclosure (e.g., a compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing), and at least one pharmaceutically acceptable carrier.

[0175] In some embodiments, the disclosure provides pharmaceutical compositions comprising at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, andpharmaceutically acceptable salts of any of the foregoing, in combination with at least one additional active pharmaceutical ingredient. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR modulator. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR corrector. In some embodiments, the at least one additional active pharmaceutical ingredient is a CFTR potentiator. In some embodiments, the pharmaceutical composition comprises at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, and at least two additional active pharmaceutical ingredients, one of which is a CFTR corrector and one of which is a CFTR potentiator.

[0176] In some embodiments, the disclosure provides a pharmaceutical composition comprising (a) at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, (b) at least one compound chosen from tezacaftor and pharmaceutically acceptable salts thereof, and (c) at least one pharmaceutically acceptable carrier.

[0177] In some embodiments, the disclosure provides a pharmaceutical composition comprising (a) at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, (b) at least one compound chosen from ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19- dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino- 12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing, and (c) at least one pharmaceutically acceptable carrier.

[0178] In some embodiments, the disclosure provides a pharmaceutical composition comprising (a) at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, (b) at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, (c) at least one compound chosen from ivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, and (d) at least one pharmaceutically acceptable carrier.

[0179] In some embodiments, the disclosure provides a pharmaceutical composition comprising (a) at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, (b) at least one compound chosen from tezacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, (c) at least one compound chosen from deutivacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, and (d) at least one pharmaceutically acceptable carrier.

[0180] In some embodiments, the disclosure provides a pharmaceutical composition comprising (a) at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, (a) at least one compound chosen from (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18- triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino-12,12- dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca- 1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing, (b) optionally tezacaftor, deuterated derivatives, or pharmaceutically acceptable salts of any of the foregoing, and (c) at least one pharmaceutically acceptable carrier.

[0181] In some embodiments, the disclosure provides a pharmaceutical composition comprising (a) at least one compound chosen from compounds of Formulae I, I′, Ia, Ib, Ic, II, IIa, IIb, IIc, IIIa, and IIIb, Compounds 1 to 139 (i.e., Compounds 1 to 107 and / or Compounds 108 to 139), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, (b) at least one compound chosen from ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19- dioxa-3,4,18-triazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, (6R)-17-amino- 12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18-tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing, (c) at least one compound chosen from lumacaftor and deuterated derivatives and pharmaceutically acceptable salts thereof, and (d) at least one pharmaceutically acceptable carrier.

[0182] Any pharmaceutical composition disclosed herein may comprise at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is chosen from pharmaceutically acceptable vehicles and pharmaceutically acceptable adjuvants. In some embodiments, the at least one pharmaceutically acceptable is chosen from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants.

[0183] The pharmaceutical compositions described herein are useful for treating cystic fibrosis and other CFTR mediated diseases.

[0184] As described above, pharmaceutical compositions disclosed herein may optionally further comprise at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be chosen from adjuvants and vehicles. The at least one pharmaceutically acceptable carrier, as used herein, includes any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surface active agents, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 21stedition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier is incompatible with the compounds of this disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this disclosure. Non-limiting examples of suitable pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffering agents (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer’s solution, ethyl alcohol, phosphate buffer solutions, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservatives, and antioxidants. Examples I. Abbreviation List ACN: acetonitrile aq: aqueous Boc2O: di-tert-butyl dicarbonate CDMT: 2-chloro-4,6-dimethoxy-1,3,5-triazine Cmpd: compound CV: column volume(s) DCM: dichloromethane de: diastereomeric excess DI: deionized DIBAL: diisobutylaluminum hydride DIEA, DIPEA, DiPEA: N,N-diisopropylethylamine DMA: N,N-dimethylacetamide DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide de: diastereomeric excessee: enantiomeric excess ESI-MS: electrospray ionization-mass spectrometry FA: formic acid FID: free induction decay GC: gas chromatography GCMS: gas chromatography mass spectrometry HMDS: hexamethyldisilazide HPLC: high-performance liquid chromatography IPA: isopropanol LAH: lithium aluminum hydride LC: liquid chromatography LCMS: liquid chromatography mass spectrometry LCMS Rt: LCMS retention time MTBE: methyl tert-butyl ether MeTHF or 2-MeTHF: 2-methyltetrahydrofuran MS: mass spectrometry MSD: mass-selective detector NMP: N-methyl-2-pyrrolidone NMM: N-methylmorpholine NMR: nuclear magnetic resonance Pd(dppf)Cl2: [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) rac: racemic rt, RT: room temperature SFC: supercritical fluid chromatography TBAF: tetra-n-butylammonium fluoride TBDPS: tert-butyldiphenylsilyl TBS: tert-butyldimethylsilyl TEA: triethylamine TEMPO: 2,2,6,6-tetramethylpiperidine 1-oxyl TFA: trifluoroacetic acid THF: tetrahydrofuranTMEDA, TEMED: tetramethylethylenediamine TMS: trimethylsilyl T3P: propanephosphonic acid anhydride TsCl: Tosyl chloride or p-toluenesulfonyl chloride UPLC: Ultra Performance Liquid Chromatography II. General Methods

[0185] Reagents and starting materials were obtained by commercial sources unless otherwise stated and were used without purification.

[0186] Proton and carbon NMR spectra were acquired on either a Bruker Biospin DRX 400 MHz FTNMR spectrometer operating at a1H and13C resonant frequency of 400 and 100 MHz respectively, or on a 300 MHz NMR spectrometer. One dimensional proton and carbon spectra were acquired using a broadband observe (BBFO) probe with 20 Hz sample rotation at 0.1834 and 0.9083 Hz / Pt digital resolution respectively. All proton and carbon spectra were acquired with temperature control at 30 °C using standard, previously published pulse sequences and routine processing parameters.

[0187] NMR (1D & 2D) spectra were also recorded on a Bruker AVNEO 400 MHz spectrometer operating at 400 MHz and 100 MHz respectively equipped with a 5 mm multinuclear Iprobe.

[0188] NMR spectra were also recorded on a Varian Mercury NMR instrument at 300 MHz for1H using a 45 degree pulse angle, a spectral width of 4800 Hz and 28860 points of acquisition. FID were zero-filled to 32k points and a line broadening of 0.3Hz was applied before Fourier transform.19F NMR spectra were recorded at 282 MHz using a 30 degree pulse angle, a spectral width of 100 kHz and 59202 points were acquired. FID were zero-filled to 64k points and a line broadening of 0.5 Hz was applied before Fourier transform.

[0189] NMR spectra were also recorded on a Bruker Avance III HD NMR instrument at 400 MHz for1H using a 30 degree pulse angle, a spectral width of 8000 Hz and 128k points of acquisition. FID were zero-filled to 256k points and a line broadening of 0.3 Hz was applied before Fourier transform.19F NMR spectra were recorded at 377 MHz using a 30 deg pulse angle, a spectral width of 89286 Hz and 128k points were acquired. FID were zero-filled to 256k points and a line broadening of 0.3 Hz was applied before Fourier transform.

[0190] NMR spectra were also recorded on a Bruker AC 250 MHz instrument equipped with a: 5 mm QNP(H1 / C13 / F19 / P31) probe (type: 250-SB, s#23055 / 0020) or on a Varian 500 MHz instrument equipped with an ID PFG, 5 mm, 50-202 / 500 MHz probe (model / part# 99337300). III. General UPLC / HPLC Analytical Methods

[0191] LC method A: Analytical reverse phase UPLC using an Acquity UPLC BEH C18 column (50 × 2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-99% mobile phase B over 2.9 minutes. Mobile phase A = H2O (0.05 % CF3CO2H). Mobile phase B = CH3CN (0.035 % CF3CO2H). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, and column temperature = 60 °C.

[0192] LC method B: Acquity UPLC BEH C18column (30 × 2.1 mm, 1.7 μm particle) made by Waters (pn: 186002349), and a dual gradient run from 1-99% mobile phase B over 1.0 minute. Mobile phase A = H2O (0.05 % CF3CO2H). Mobile phase B = CH3CN (0.035 % CF3CO2H). Flow rate = 1.5 mL / min, injection volume = 1.5 μL, and column temperature = 60 °C.

[0193] LC method C: Reversed phase UPLC using an Acquity UPLC BEH C18 column (50 × 2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 30- 99% mobile phase B over 2.9 minutes. Mobile phase A = H2O (0.05 % CF3CO2H). Mobile phase B = CH3CN (0.035 % CF3CO2H). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, and column temperature = 60 °C.

[0194] LC method D: Merckmillipore Chromolith SpeedROD C18column (50 x 4.6 mm) and a dual gradient run from 5 – 100% mobile phase B over 12 minutes. Mobile phase A = water (0.1 % CF3CO2H). Mobile phase B = acetonitrile (0.1 % CF3CO2H).

[0195] LC method E: Merckmillipore Chromolith SpeedROD C18column (50 x 4.6 mm) and a dual gradient run from 5 – 100% mobile phase B over 6 minutes. Mobile phase A = water (0.1 % CF3CO2H). Mobile phase B = acetonitrile (0.1 % CF3CO2H).

[0196] LC method F: Kinetex Polar C183.0 x 50 mm 2.6 μm, 6 min, 5-95% I in H2O (0.1% Formic Acid) 1.2 mL / min.

[0197] LC method G: Acquity UPLC BEH C18 column (50 × 2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1-30% mobile phase B over 2.9 minutes. Mobile phase A = H2O (0.05 % CF3CO2H). Mobile phase B = CH3CN (0.035 % CF3CO2H). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, and column temperature = 60

[0198] LC method H: water Cortex 2.7 μ C18 (3.0 mm x 50 mm), Temp: 55oC; Flow: 1.2 mL / min; mobile phase: 100% water with 0.1% trifluoroacetic (TFA) acid then 100% acetonitrile with 0.1% TFA, gradient run from 5%-100% mobile phase B over 4 min, with stay at 100% B for 0.5 min, equilibration to 5% B over 1.5 min.

[0199] LC method I: UPLC Luna C18(2) 50 x 3 mm 3 μm. Run: 2.5 min. Mobile phase: Initial 95% H2O 0.1% FA / 5%MeCN 0.1% FA, linear gradient to 95% MeCN 0.1% FA over 1.3 min, hold 1.2 min 95% CH3CN 0.1% FA,T: 45oC, Flow: 1.5 mL / min.

[0200] LC method J: UPLC SunFire C1875 x 4.6 mm 3.5 μm, run: 6 min. Mobile phase conditions: Initial 95% H2O + 0.1% FA / 5% CH3CN + 0.1% FA, linear gradient to 95% CH3CN for 4 min, hold for 2 min at 95% CH3CN. T:45oC, Flow:1.5 mL / min.

[0201] LC method K: Xbridge C184.6 x 75 mm, 5μm, Initial Gradient at 95% NH4HCO3 / 5% MeCN 6 min run with 1 min equilibration gradient 0 to 3 min at 95% MeCN and hold for 3 minutes. Flow 1.5 mL / min.

[0202] LC method L: Luna C183.0 x 50 mm 3.0 μM, Temp: 45oC, Flow: 2.0 mL / min, Run Time: 3 minutes. Mobile Phase: Initial 95% H2O (0.1% Formic Acid) and 5% CH3CN (0.1% FA) linear gradient to 95% CH3CN (0.1% FA) for 2.0 min then hold at 95% CH3CN (0.1% FA) for 1.0 min.

[0203] LC method M: Poroshell 120 EC-C183.0 x 50 mm 2.7 μM, Temp:45oC, Flow: 1,5 mL / min, RunTime: 3 min. Mobile phase conditions: Initial.95% H2O (0.1% Formic Acid) and 5% CH3CN (0.1% FA) linear gradient to 95% CH3CN (0.1% FA) for 1.5 min then hold at 95% CH3CN (0.1% FA) for 1.5 min.

[0204] LC method N: Reversed phase UPLC using an Acquity UPLC BEH C18column (50 × 2.1 mm, 1.7 μm particle) made by Waters (pn: 186002350), and a dual gradient run from 1- 99% mobile phase B over 4.5 minutes. Mobile phase A = H2O (0.05 % TFA). Mobile phase B = acetonitrile (0.035 % TFA). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, and column temperature = 60 °C.

[0205] LC method O: Kinetex Polar C182.6 µm, 50 x 3.0 mm. Temperature: 45oC, Flow: 1.2 mL / min, Run time: 3 min. Mobile phase conditions: Initial 95% water + 0.1% formic acid / 5% acetonitrile + 0.1% formic acid then linear gradient to 95% acetonitrile for 1.5 min then hold for 1.5 min at 95% acetonitrile.

[0206] LC method P: Kinetex Polar C182.6 µm, 50 x 3.0 mm. Temperature: 45oC, Flow: 1.2mL / min, Run time: 6 min. Mobile phase conditions: Initial 95% water + 0.1% formic acid / 5% acetonitrile + 0.1% formic acid then linear gradient to 95% acetonitrile for 3.5 min then hold for 2.5 min at 95% acetonitrile.

[0207] LC method Q: Luna C18(2) 50 x 3 mm, 3 µm. Temperature: 45oC, Flow: 1.5 mL / min, Run time: 3.5 min. Mobile phase conditions: Initial 50% H2O 0.1% FA / 50% MeCN 0.1% FA, linear gradient to 100% MeCN 0.1% FA over 1.5 min then hold for 2 minute at 100% CH3CN 0.1% FA. ESI Positive.

[0208] LC method R: Luna C182.0 x 50mm 3 µm Gradient from 50%H2O + 0.1% FA / 50% MeCN + 0.1% FA to 95% MeCN + 0.1% in 1.5 min and hold for 1.5 minutes. Column temperature: 45oC Runtime: 3 min. ESI Positive.

[0209] LC method S: Luna C18(2) 50 X 3 mm, 3 µm. Temperature: 45oC, Flow: 1.5 mL / min, Run time: 3.5 min. Mobile phase conditions: Initial 95% H2O 0.1% FA / 5% MeCN 0.1% FA, linear gradient to 95% MeCN 0.1% FA over 1.3 min then hold for 2.2 minutes at 95% CH3CN 0.1% FA. ESI Positive.

[0210] LC method T: Luna C18(2) 50 X 3 mm, 3 µm. Temperature: 45oC, Flow: 1.5 mL / min, Run time: 3 min. Mobile phase conditions: Initial 50% water 0.1% FA / 50% MeCN 0.1% FA, linear gradient to 95% MeCN 0.1% FA over 1.5min then hold for 1.5 min at 95% acetonitrile 0.1% FA.

[0211] LC method U: Luna C18(2) 50 X 3 mm, 3 µm. Temperature: 45oC, Flow: 1.5 mL / min, Run time: 3 min. Mobile phase conditions: Initial 95% water 0.1% FA / 5% MeCN 0.1% FA, linear gradient to 95% MeCN 0.1% FA over 1.5 min then hold for 1.5 min at 95% acetonitrile 0.1% FA.

[0212] LC method V: Xbridge C184.6 x 75 mm 5 µm. Temperature: 45oC, Flow: 1.5mL / min, Run time: 6 min. Mobile phase conditions: Initial 50% water 10 mM NH4HCO3 / 50% acetonitrile then linear gradient to 95% acetonitrile for 3 min then hold for 3 min at 95% acetonitrile.

[0213] LC method W: Xbridge C184.6 x 75 mm 5 µm. Temperature: 45oC, Flow: 1.5 mL / min, Run time: 6 min. Mobile phase conditions: Initial 95% water 10 mM NH4HCO3 / 5% acetonitrile then linear gradient to 95% acetonitrile for 3 min then hold for 3 min at 95% acetonitrile.

[0214] LC method X: Xbridge C184.6 x 50 mm 3.5 µm. Temperature: 45oC, Flow: 2 mL / min, Run time: 3 min. Mobile phase conditions: Initial 95% water 10 mM NH4HCO3 / 5%acetonitrile then linear gradient to 95% acetonitrile for 1.5 min then hold for 1.5 min at 95% acetonitrile.

[0215] LC method Y: Xbridge C184.6 x 50 mm 3.5 µm. Temperature: 45oC, Flow: 2 mL / min, Run time: 4 min. Mobile phase conditions: Initial 95% water 10 mM NH4HCO3 / 5% acetonitrile then linear gradient to 95% acetonitrile for 1.5 min then hold for 2.5 min at 95% acetonitrile.

[0216] LC method Z: Luna C18(2) 50 x 3 mm, 3 µm. Temperature: 45oC, Flow: 1.5 mL / min, Run time: 6 min. Mobile phase conditions: Initial 50% water 0.1% FA / 50% MeCN 0.1% FA, linear gradient to 95% MeCN 0.1% FA over 4 min then hold for 2 min at 95% acetonitrile 0.1% FA.

[0217] LC method 1A: Xbridge C184.6 x 75 mm 5 µm. Temperature: 45oC, Flow: 1.5 mL / min, run time: 10 min. Mobile phase conditions: Initial 95% water 10 mM NH4HCO3 / 5% acetonitrile then linear gradient to 95% acetonitrile for 6.5 min then hold for 3.5 min at 95% acetonitrile.

[0218] LC method 1B: Luna C18(2) 50 x 3 mm, 3 µm.Temperature: 45oC, Flow: 1.5 mL / min, Run time: 6 min. Mobile phase conditions: Initial 95% H2O 0.1% FA / 5% MeCN 0.1% FA, linear gradient to 95% MeCN 0.1% FA over 4 min then hold for 2 minute at 95% CH3CN 0.1% FA. ESI Positive.

[0219] LC method 1C: Waters Acquity BEH C181.7 µm 2.1 x 100 mm. Column temp: 40oC, flow rate: 0.5 mL / min. Eluent A: water 0.1 % FA, eluent B: acetonitrile. Conditions: 95% A 5% B, linear gradient to 5% A 95% B for 3 min, hold at 5% A 95% B for 2 min. Total run time: 5 min.

[0220] LC method 1D: Luna C18(2) 50 x 3 mm, 3 µm. Temperature: 45oC, Flow: 1.5 mL / min, Run time: 4 min. Mobile phase conditions: Initial 95% water 0.1% FA / 5% MeCN 0.1% FA, linear gradient to 95% MeCN 0.1% FA over 1.5 min then hold for 2.5 min at 95% acetonitrile 0.1% FA.

[0221] LC method 1E: Waters Acquity BEH C181.7 µm 2.1 x 50 mm. Column temp: 40oC, flow rate: 0.5 mL / min. Eluent A: water 0.1 % FA, eluent B: acetonitrile. Conditions: 50% A 50% B, linear gradient to 5% A 95% B for 3 min, hold at 5% A 95% B for 2 min. Total run time: 5 min.Synthesis of Intermediates IV. Synthesis of substituted chloropyrimidine intermediates Example 1: Preparation of 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]benzoic acidStep 1: tert-Butyl N-tert-butoxycarbonyl-N-(4,6-dichloropyrimidin-2-yl)carbamate

[0222] To a solution of 4,6-dichloropyrimidin-2-amine (300 g, 1.829 mol) in DCM (2.1 L) was added (Boc)2O (838 g, 3.840 mol) followed by DMAP (5.6 g, 45.84 mmol). The mixture was stirred at ambient temperature for 6 h. Additional DMAP (5.6 g, 45.84 mmol) was added and the reaction was continued to stir at ambient temperature for 24 h. The mixture was diluted with water (2.1 L) and the organic phase separated. The organic phase was washed with water (2.1 L), 2.1L of brine, dried over magnesium sulfate, filtered over Celite and concentrated in vacuo affording a light orange oil which had a silt in the slurry. The mixture was diluted with ~500 mL of heptane and filtered using an M filter. The precipitate (starting material) was washed with 250 mL of heptane. The filtrate was concentrated in vacuo affording a thick orange oil which was seeded with solid from a previous experiment and crystallized on standing,affording a light orange hard solid. Tert-butyl N-tert-butoxycarbonyl-N-(4,6-dichloropyrimidin- 2-yl)carbamate (645 g, 97%).1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 1.44 (s, 18H). ESI- MS m / z calc.363.07526, found 364.1 (M+1)+; Retention time: 2.12 minutes (LC method A). Step 2: tert-Butyl N-tert-butoxycarbonyl-N-[4-chloro-6-(2,6-dimethylphenyl)pyrimidin- 2-yl]carbamate.

[0223] All solvents were degassed prior to use. To a slurry of tert-butyl N-tert- butoxycarbonyl-N-(4,6-dichloropyrimidin-2-yl)carbamate (88 g, 241.6 mmol), (2,6- dimethylphenyl)boronic acid (approximately 36.24 g, 241.6 mmol) and Cs2CO3(approximately 196.8 g, 604.0 mmol) in DME (704 mL) and water (176 mL) were added. Pd(dppf)Cl2(approximately 8.839 g, 12.08 mmol) was added and the mixture was vigorously stirred under nitrogen at 80 ºC (reflux) for 1 h (no SM remained). The reaction was cooled to ambient temperature and diluted with water (704 mL). The aqueous phase was separated and extracted with EtOAc (704 mL). The organic phase was washed with 700 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was chromatographed on a 1500 g silica gel column eluting with 0-30% EtOAc / hexanes. The product fractions (eluted at 15% EtOAc) were combined, and concentrated in vacuo affording the product as a clear oil which crystallized on standing. Tert-butyl N-tert-butoxycarbonyl-N-[4-chloro-6-(2,6- dimethylphenyl)pyrimidin-2-yl]carbamate (81.3 g, 78%).1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.30 (dd, J = 8.2, 7.0 Hz, 1H), 7.21 – 7.16 (m, 2H), 2.03 (s, 6H), 1.38 (s, 18H). ESI-MS m / z calc.433.17682, found 434.1 (M+1)+; Retention time: 2.32 minutes (LC method A). Step 3: 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (hydrochloride salt)

[0224] Tert-Butyl N-tert-butoxycarbonyl-N-[4-chloro-6-(2,6-dimethylphenyl) pyrimidin-2- yl]carbamate (514.8 g, 915.9 mmol) was dissolved in dichloromethane (4 L). Hydrogen chloridein p-dioxane (1 L, 4 mol) was added and the mixture was stirred overnight at room temperature. The resulting precipitate was collected by vacuum filtration and dried in vacuo to obtain 4- chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine hydrochloride (213.5 g, 64%) as a white solid (213.5 g, 82%).1H NMR (250 MHz, DMSO-d6) δ 7.45-6.91 (m, 3H), 6.73 (s, 1H), 2.08 (s, 6H). ESI-MS m / z calc.233.072, found 234.1 (M+1)+; Retention time: 2.1 minutes (LC Method C). Step 4: 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine

[0225] 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (hydrochloride salt) (166 g, 614.5 mmol) and 4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (hydrochloride salt) (30 g, 111.0 mmol) were suspended in DCM (2.5 L), treated with NaOH (725 mL of 1 M, 725.0 mmol) and stirred at room temperature for 1 hour.The mixture was transferred into a separatory funnel and left standing over night. The DCM phase was separated and the aqueous phase with insoluble material was extracted twice more with DCM (2 x 500mL). The combined brown DCM phases were stirred over magnesium sulfate and charcoal for 1 hour, filtered and the yellow solution concentrated to a volume of ~ 500 mL. The solution was diluted with heptane (750 mL) and DCM was removed under reduced pressure at 60 °C to give a cream suspension. It was stirred at room temperature for 1 hour, filtered, washed with cold heptane and dried to give 4-chloro-6- (2,6-dimethylphenyl)pyrimidin-2-amine (157 g, 91%) as a cream solid.1H NMR (400 MHz, DMSO-d6) δ 7.28 – 7.14 (m, 3H), 7.10 (d, J = 7.5 Hz, 2H), 6.63 (s, 1H), 2.06 (s, 6H). ESI-MS m / z calc.233.07198, found 234.0 (M+1)+; Retention time: 1.45 minutes (LC method A). Step 5: 3-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid

[0226] 4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (235 g, 985.5 mmol) was dissolved in MeTHF (2.3 L) and cooled in an ice bath under stirring and nitrogen. To the cold solution methyl 3-chlorosulfonylbenzoate (347 g, 1.479 mol) was added in one portion (seemsslightly endothermic) and to the cold pale-yellow solution a solution of 2-methyl-butan-2-ol (Lithium salt) (875 mL of 3.1 M, 2.712 mol) (in heptane) was added dropwise over 1.25 hour (exothermic, internal temperature from 0 to 10 °C). The ice bath was removed, and the greenish solution was stirred for 4 hours at room temperature. To the greenish solution cold HCl (2 L of 1.5 M, 3.000 mol) was added, the phases separated and the organic phase was washed once with water (1L) and once with brine (500 mL). The aqueous phases were back extracted once with MeTHF (350 mL) and the organic phases were combined. This yellow MeTHF solution of methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoate (ESI-MS m / z calc.431.07065, found 432.0 (M+1)+; Retention time: 1.81 minutes) was treated with NaOH (2.3 L of 2 M, 4.600 mol) and stirred at room temperature for 1 hour. The phases were separated and the NaOH phase was washed twice with MeTHF (2 x 500 mL) and the combined organic phases were extracted once with 2 M NaOH (1 x 250 mL). The combined NaOH phases were combined, stirred in an ice bath and slowly acidified by addition of HCl (416 mL of 36 %w / w, 4.929 mol) while keeping the internal temperature between 10 and 20 °C. At the end of the addition (pH ~5-6) the final pH was adjusted to 2-3 by addition of solid citric acid. The formed yellow tacky suspension was stirred at room temperature overnight to give a cream crisp suspension. The solid was collected by filtration, washed with plenty of water and sucked dry for 3 hours. The solid was dried under reduced pressure with a nitrogen leak at 45-50 °C for 120 hours 3-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]benzoic acid (395 g, 96%) was isolated as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 13.44 (s, 1H), 12.46 (s, 1H), 8.48 – 8.39 (m, 1H), 8.25 – 8.15 (m, 1H), 8.15 – 8.08 (m, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.31 (s, 1H), 7.28 – 7.18 (m, 1H), 7.10 (d, J = 7.6 Hz, 2H), 1.84 (s, 6H). ESI-MS m / z calc. 417.055, found 418.0 (M+1)+; Retention time: 1.56 minutes. (LC method A).Example 2: Preparation of 3-[[4-chloro-6-(2,6-dimethylphenyl)-5-methyl-pyrimidin-2- yl]sulfamoyl]benzoic acidStep 1: tert-Butyl N-tert-butoxycarbonyl-N-(4,6-dichloro-5-methyl-pyrimidin-2- yl)carbamate

[0227] To a solution of 4,6-dichloro-5-methyl-pyrimidin-2-amine (57.85 g, 318.47 mmol) in DCM (580 mL) was added tert-butoxycarbonyl tert-butyl carbonate (159.92 g, 168.34 mL, 710.77 mmol) and DMAP (3.96 g, 32.090 mmol) at RT. The reaction was stirred for 3 h. The reaction mixture was quenched with DI H2O (250 mL). DCM (100 mL) was added. The layers were separated, and the aqueous layer was extracted with DCM (2 x 250 mL). The combined organic layers were washed with aqueous saturated NaCl (250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Crude Mass = 125.71 g (Yellow Solid). The yellow solid was triturated with hexanes (300 mL, 3 h), filtered through a Type “M” glass filter by vacuum, and the solids were rinsed with hexanes (2 x 200 mL). Final Product (101.00 g) was obtained as a yellow solid. Tert-butyl N-tert-butoxycarbonyl-N-(4,6-dichloro-5- methyl-pyrimidin-2-yl)carbamate (101.00 g, 80%).1H NMR (500 MHz, Chloroform-d) δ 2.48(s, 3H), 1.47 (s, 18H). ESI-MS m / z calc.377.0909, found 378.0 (M+1)+; Retention time: 3.39 minutes; LC method E. Step 2: tert-Butyl N-tert-butoxycarbonyl-N-[4-chloro-6-(2,6-dimethylphenyl)-5- methyl-pyrimidin-2-yl]carbamate

[0228] To a solution of tert-butyl N-tert-butoxycarbonyl-N-(4,6-dichloro-5-methyl- pyrimidin-2-yl)carbamate (120.85 g, 319.50 mmol) dissolved in DME (850 mL) and water (120 mL) was added (2,6-dimethylphenyl)boronic acid (57.5 g, 383.38 mmol) and cesium carbonate (271 g, 831.75 mmol) at room temperature. The solution was stirred for 10 min while being bubbled with a nitrogen stream. Then Pd(dppf)Cl2 (11.7 g, 15.990 mmol) was added to the solution and heated to 80 °C overnight. The solution was cooled to room temperature before being diluted with water (500 mL) and extracted with ethyl acetate (2 x 1 L). The combined organic layer was washed with brine (1 L) and dried over sodium sulfate before being concentrated in vacuum. The organic residue was filtered through a pad of silica gel and washed with a solution of 1:3 ethyl acetate-hexanes (3 x 1 L) to give tert-butyl N-tert-butoxycarbonyl-N- [4-chloro-6-(2,6-dimethylphenyl)-5-methyl-pyrimidin-2-yl]carbamate (100.71 g, 58%). ESI-MS m / z calc.447.19247, found 448.1 (M+1)+; Retention time: 4.24 minutes; LC method E. Step 3: 4-Chloro-6-(2,6-dimethylphenyl)-5-methyl-pyrimidin-2-amine

[0229] To a solution of tert-butyl N-tert-butoxycarbonyl-N-[4-chloro-6-(2,6- dimethylphenyl)-5-methyl-pyrimidin-2-yl]carbamate (100.71 g, 224.82 mmol) in DCM (500 mL) was added HCl (200 mL of 4 M, 800.00 mmol) in dioxane. The solution was stirred at room temperature overnight before being concentrated in vacuum. The residue was then basified with sodium bicarbonate (500 mL) and extracted with ethyl acetate (1 L). The organic layer waswashed with brine (400 mL) and dried over sodium sulfate. The organic phase was concentrated then the residue was triturated with hexanes (2 x 200 mL) to give 4-chloro-6-(2,6- dimethylphenyl)-5-methyl-pyrimidin-2-amine (54.88 g, 99%) as an off-white solid.ESI-MS m / z calc.247.08763, found 248.2 (M+1)+; Retention time: 2.94 minutes; LC method E. Step 4: Methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)-5-methyl-pyrimidin-2- yl]sulfamoyl]benzoate

[0230] To a solution of 4-chloro-6-(2,6-dimethylphenyl)-5-methyl-pyrimidin-2-amine (35 g, 141.29 mmol) in THF (400 mL) at 0 °C was added methyl 3-chlorosulfonylbenzoate (50 g, 213.08 mmol). Then Lithium tert-amoxide (46.428 g, 159 mL of 40 %w / w, 197.40 mmol) was added to the solution dropwise keeping the temperature below 5 °C. The solution was allowed to warm to room temperature while it stirred for 3 hours. The solution was acidified with 1 M HCl (200 mL) and extracted with ethyl acetate (3 x 200 mL). The organic layer was washed with brine (300 mL) and dried over sodium sulfate. The organic layer was then concentrated under vacuum to give methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)-5-methyl- pyrimidin-2-yl]sulfamoyl]benzoate (63.01 g, 100%) as a yellow solid. ESI-MS m / z calc. 445.0863, found 446.2 (M+1)+; Retention time: 3.63 minutes; LC method E. Step 5: 3-[[4-Chloro-6-(2,6-dimethylphenyl)-5-methyl-pyrimidin-2- yl]sulfamoyl]benzoic acid

[0231] To a solution of methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)-5-methyl-pyrimidin- 2-yl]sulfamoyl]benzoate (59.51 g, 133.45 mmol) in THF (500 mL) was added an aqueous solution of NaOH (300 mL of 2 M, 600.00 mmol) and the mixture was stirred for 2 hours at room temperature. The solution was acidified using 3 M HCl (500 mL) and extracted with ethyl acetate (2 x 500 mL) before being washed with brine (500 mL). The organic layer was driedover sodium sulfate and concentrated under vacuum. The organic residue was then recrystallized with ethanol and filtered to give 3-[[4-chloro-6-(2,6-dimethylphenyl)-5-methyl-pyrimidin-2- yl]sulfamoyl]benzoic acid (34.44 g, 56%) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 8.43 (t, J = 1.8 Hz, 1H), 8.18 (dt, J = 7.8, 1.4 Hz, 1H), 8.10 (ddd, J = 7.9, 2.0, 1.2 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.12 (d, J = 7.6 Hz, 2H), 1.85 (s, 3H), 1.74 (s, 6H). ESI-MS m / z calc.431.07065, found 432.4 (M+1)+; Retention time: 2.43 minutes; LC method E. Example 3: Preparation of 3-[[4-Chloro-6-(2,6-dimethylphenyl)-5-fluoro-pyrimidin-2- yl]sulfamoyl]benzoic acidStep 1: 2-Amino-5-fluoro-pyrimidine-4,6-diol

[0232] To a 2 L flask charged with ethanol (750 mL), solid chunks of sodium metal (21.5 g, 935.20 mmol) were added gradually and carefully, and the mixture was stirred until completely dissolved. Once cooled back to room temperature guanidine (hydrochloride salt) (34.5 g, 361.14 mmol) and diethyl 2-fluoropropanedioate (50 g, 280.65 mmol) were successively added and the reaction was heated at 80 °C for 17 hours. Once cooled to room temperature, the crude mixture was concentrated under reduced pressure to remove most of theethanol. Water was added to complete dissolution, the resulting solution was cooled in an ice bath and acidified to pH of 1-2 using concentrated HCl. The solids were filtered and washed with water (2 x 200 mL) then with acetone (2 x 50 mL) and dried under high vacuum to provide 2-amino-5-fluoro-pyrimidine-4,6-diol hydrate (41.8 g, 91%)) as a pink solid.1H NMR (300 MHz, DMSO-d6) ppm 6.53 (br. S., 1H), 10.97 (br. S., 1H).19F NMR (282 MHz, DMSO-d6) ppm -196.1 (br. S., 1F). ESI-MS m / z calc.145.0288, found 146.1 (M+1)+; Retention time: 0.2 minutes (LC method M). Step 2: 4,6-Dichloro-5-fluoro-pyrimidin-2-amine

[0233] A solution of 2-amino-5-fluoro-pyrimidine-4,6-diol hydrate (21.09 g, 126.46 mmol) in phosphorus oxychloride (101.99 g, 62 mL, 665.16 mmol) was heated to 90 °C and N,N-diethylaniline (25.326 g, 27 mL, 169.71 mmol) was added slowly. The reaction was then heated for 3 hours at 105 °C. The solution was poured in water and neutralized to pH ~5 with 50% aqueous sodium hydroxide solution and refluxed for 1 h. The solution was cooled on ice and the precipitate was filtered and dried. The solid was triturated in dichloromethane (~150 mL), filtered and dried. The solid obtained was then triturated in a mix of acetone / heptanes (1:1, 40 mL), filtered and dried provide the desired 4,6-dichloro-5-fluoro-pyrimidin-2-amine (13.75 g, 59%) as a yellow solid.1H NMR (300 MHz, DMSO-d6) δ 7.44 (br. S., 2H).19F NMR (282 MHz, DMSO-d6) δ -149.01 (s, 1F). ESI-MS m / z calc.180.961, found 182.0 (M+1)+; Retention time: 2.17 minutes. LC method F. Step 3: tert-Butyl N-(4,6-dichloro-5-fluoro-pyrimidin-2-yl)carbamate

[0234] To a stirring solution of 4,6-dichloro-5-fluoro-pyrimidin-2-amine (5.153 g, 27.495 mmol) and Boc anhydride (8.43 g, 38.626 mmol) in anhydrous THF (100 mL) at -78 °C under nitrogen was dropwise added a solution of LiHMDS (50 mL of 1.3 M, 65.000 mmol) in THF. After the addition was complete, the reaction mixture was stirred at this temperature for 2h. The reaction was quenched cold with saturated aqueous ammonium chloride (20 mL) and allowed to warm up to room temperature. The product was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated. The crude was purified by silica gel chromatography using 0 – 15% ethyl acetate in hexane to afford tert-butyl N-(4,6-dichloro-5-fluoro-pyrimidin-2- yl)carbamate (6.632 g, 86%) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 1.45 (s, 9H). Step 4: tert-Butyl N-[4-chloro-6-(2,6-dimethylphenyl)-5-fluoro-pyrimidin-2- yl]carbamate

[0235] A stirring solution of tert-butyl N-(4,6-dichloro-5-fluoro-pyrimidin-2- yl)carbamate (6.815 g, 22.467 mmol) and (2,6-dimethylphenyl)boronic acid (3.06 g, 20.402 mmol) in a mixture of 1,2-dimethoxyethane (55 mL) and water (15 mL) at room temperature was degassed with nitrogen for 30 minutes. Under nitrogen, cesium carbonate (18.3 g, 56.166 mmol) and [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.65 g, 2.2550 mmol) were added. The reaction mixture was heated to 80 °C for 4 h. After cooling to room temperature, water (150 mL) was added, and the product was extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude was purified by silica gel chromatography using 0 – 5% hexanes – ethyl acetate to afford tert-butyl N-[4-chloro-6-(2,6-dimethylphenyl)-5-fluoro- pyrimidin-2-yl]carbamate (2.43 g, 29%) as white solid. ESI-MS m / z calc.351.115, found 352.4 (M+1)+; Retention time: 6.51 minutes, LC method D. Step 5: 4-Chloro-6-(2,6-dimethylphenyl)-5-fluoro-pyrimidin-2-amine

[0236] To a stirring solution of tert-butyl N-[4-chloro-6-(2,6-dimethylphenyl)-5-fluoro- pyrimidin-2-yl]carbamate (2.43 g, 6.4238 mmol) in DCM (23 mL) at room temperature was added a solution of HCl (6.5 mL of 4 M, 26.000 mmol) in 1,4-dioxane. The reaction mixture was stirred at this temperature for 2 h. The reaction mixture was evaporated to dryness. The obtained white solid was resuspended in saturated aqueous sodium bicarbonate (100 mL) and stirred at room temperature for 15 minutes. The product was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The crude was purified by silica gel chromatography using 0 – 15% hexanes – ethyl acetate to afford 4-chloro-6-(2,6-dimethylphenyl)-5-fluoro-pyrimidin-2- amine (1.42 g, 83%) as white solid. ESI-MS m / z calc.251.0626, found 252.3 (M+1)+; Retention time: 5.06 minutes, LC method D. Step 6: Methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)-5-fluoro-pyrimidin-2- yl]sulfamoyl]benzoate

[0237] To a stirring solution of 4-chloro-6-(2,6-dimethylphenyl)-5-fluoro-pyrimidin-2- amine (2.54 g, 10.092 mmol) and methyl 3-chlorosulfonylbenzoate (4.25 g, 18.112 mmol) in anhydrous THF (70 mL) at 0 °C under nitrogen was added dropwise a solution of lithium tert- amoxide (5.8400 g, 20 mL of 40 %w / w, 24.830 mmol) in heptanes. After the addition was complete, the reaction mixture was stirred at this temperature for 1 h. The reaction was quenched cold with 1 M aqueous HCl (180 mL) and then allowed to warm up to room temperature. Volatiles were removed under vacuum and the product was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, and concentrated. The crude was purified by silica gel chromatography using 0 – 20% hexanes – ethyl acetate. The obtained product was triturated with hexanes (100 mL), collected by filtration and dried under vacuum to afford methyl 3-[[4- chloro-6-(2,6-dimethylphenyl)-5-fluoro-pyrimidin-2-yl]sulfamoyl]benzoate (4.381 g, 93%) as white solid. ESI-MS m / z calc.449.0612, found 450.1 (M+1)+; Retention time: 2.72 minutes, LC method E.1H NMR (500 MHz, DMSO-d6) δ 12.49 (s, 1H), 8.43 (t, J = 1.8 Hz, 1H), 8.21 (dt, J= 7.8, 1.4 Hz, 1H), 8.14 (dt, J = 8.0, 1.5 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.14 (d, J = 7.6 Hz, 2H), 3.82 (s, 3H), 1.85 (s, 6H). Step 7: 3-[[4-Chloro-6-(2,6-dimethylphenyl)-5-fluoro-pyrimidin-2- yl]sulfamoyl]benzoic acid

[0238] To a stirring solution of methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)-5-fluoro- pyrimidin-2-yl]sulfamoyl]benzoate (490 mg, 1.0892 mmol) in THF (9 mL) at room temperature was added an aqueous solution of NaOH (4.5 mL of 1 M, 4.5000 mmol). The reaction mixture was stirred at this temperature for 2 h. Water was added (20 mL), and the reaction mixture was acidified with 2 M aqueous HCl to pH ~1. The product was extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated to afford 3-[[4-chloro-6-(2,6-dimethylphenyl)-5-fluoro- pyrimidin-2-yl]sulfamoyl]benzoic acid (463 mg, 93%) as white solid. ESI-MS m / z calc. 435.0456, found 436.4 (M+1)+; Retention time: 5.21 minutes; LC method D. Example 4: Preparation of 3-[[4-chloro-6-(2,6-dimethylphenyl)-5-methoxy-pyrimidin-2- yl]sulfamoyl]benzoic acid Step 1: tert-Butyl N-tert-butoxycarbonyl-N-(4,6-dichloro-5-methoxy-pyrimidin-2- yl)carbamate

[0239] To a solution of 4,6-dichloro-5-methoxy-pyrimidin-2-amine (11.73 g, 60.458 mmol) in DCM (200 mL) was added DMAP (591 mg, 4.8376 mmol) and Boc2O (27.7 g, 29.158 mL, 126.92 mmol). The reaction was stirred for 3 hours at room temperature before being washed with brine (200 mL) and water (200 mL). The organic layer was concentrated in vacuum and dried over sodium sulfate to give tert-butyl N-tert-butoxycarbonyl-N-(4,6-dichloro-5-methoxy-pyrimidin-2-yl)carbamate (21.55 g, 90%). ESI-MS m / z calc.393.08582, found 394.0 (M+1)+; Retention time: 3.44 minutes; LC method E. Step 2: tert-Butyl N-tert-butoxycarbonyl-N-[4-chloro-6-(2,6-dimethylphenyl)-5- methoxy-pyrimidin-2-yl]carbamate

[0240] To a solution of tert-butyl N-tert-butoxycarbonyl-N-(4,6-dichloro-5-methoxy- pyrimidin-2-yl)carbamate (31.58 g, 80.101 mmol) dissolved in DME (225 mL) and water (31 mL) was added (2,6-dimethylphenyl)boronic acid (16.5 g, 110.01 mmol) and cesium carbonate (68 g, 208.71 mmol) at room temperature. The solution was stirred for 10 min while being bubbled with a nitrogen stream. Then Pd(dppf)Cl2(5.86 g, 8.0087 mmol) was added to the solution and heated to 80 °C overnight. The solution was cooled to room temperature before being diluted with water (250 mL) and extracted with ethyl acetate (2 x 300mL). The combined organic layers were washed with brine (400 mL) and dried over sodium sulfate before being concentrated under vacuum. The organic residue was purified by silica gel chromatography eluting 0-60% ethyl acetate-hexanes to give tert-butyl N-tert-butoxycarbonyl-N-[4-chloro-6- (2,6-dimethylphenyl)-5-methoxy-pyrimidin-2-yl]carbamate (50.35 g, 135%). ESI-MS m / z calc. 463.1874, found 464.2 (M+1)+; Retention time: 3.68 minutes; LC method E. Step 3: 4-Chloro-6-(2,6-dimethylphenyl)-5-methoxy-pyrimidin-2-amine

[0241] To a solution of tert-butyl N-tert-butoxycarbonyl-N-[4-chloro-6-(2,6- dimethylphenyl)-5-methoxy-pyrimidin-2-yl]carbamate (50.35 g, 108.52 mmol) in DCM (500 mL) was added HCl (100 mL of 4 M, 400.00 mmol) in dioxane. The solution was stirred at room temperature overnight before being concentrated under vacuum. The residue was thenbasified with sodium bicarbonate (400 mL) and extracted with ethyl acetate (500 mL). The organic layer was washed with brine (500 mL) and dried over sodium sulfate. The organic phase was concentrated then triturated with hexanes (2 x 50 mL) to give 4-chloro-6-(2,6- dimethylphenyl)-5-methoxy-pyrimidin-2-amine (10.16 g, 36%). ESI-MS m / z calc.263.08255, found 264.1 (M+1)+; Retention time: 2.73 minutes; LC method E. Step 4: Methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)-5-methoxy-pyrimidin-2- yl]sulfamoyl]benzoate

[0242] To a solution of 4-chloro-6-(2,6-dimethylphenyl)-5-methoxy-pyrimidin-2-amine (223 mg, 0.8456 mmol) in THF (6 mL) at 0°C was added methyl 3-chlorosulfonylbenzoate (496 mg, 2.1137 mmol). Then Lithium tert-amoxide (584.00 mg, 2 mL of 40 %w / w, 2.4830 mmol) was added to the solution dropwise keeping the temperature below 5 °C. The solution was allowed to warm to room temperature while it stirred for 3 hours. The solution was acidified with 1 M HCl (5 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with brine (20 mL) and dried over sodium sulfate. The organic layer was then concentrated under vacuum to give methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)-5-methoxy-pyrimidin-2-yl]sulfamoyl]benzoate (386 mg, 99%) as a yellow solid. ESI-MS m / z calc.461.0812, found 462.1 (M+1)+; Retention time: 3.18 minutes; LC method E. Step 5: 3-[[4-Chloro-6-(2,6-dimethylphenyl)-5-methoxy-pyrimidin-2- yl]sulfamoyl]benzoic acid

[0243] To a solution of methyl 3-[[4-chloro-6-(2,6-dimethylphenyl)-5-methoxy-pyrimidin-2- yl]sulfamoyl]benzoate (386 mg, 0.8356 mmol) in THF (10 mL) was added an aqueous solution of NaOH (5 mL of 1 M, 5.0000 mmol) and stirred for 1 hour at room temperature. The solution was acidified using 1 M HCl (5 mL) and extracted with ethyl acetate (2 x 20 mL) before beingwashed with brine (20 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum to give 3-[[4-chloro-6-(2,6-dimethylphenyl)-5-methoxy-pyrimidin-2- yl]sulfamoyl]benzoic acid (314 mg, 84%) as a white solid. ESI-MS m / z calc.447.06558, found 448.1 (M+1)+; Retention time: 2.9 minutes; LC method E. Example 5: Preparation of 6-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]pyridine-2-carboxylic acid Step 1: Methyl 6-benzylsulfanylpyridine-2-carboxylate

[0244] To a solution of phenylmethanethiol (28.408 g, 26.800 mL, 228.72 mmol) in THF (600 mL) was added NaH (11.200 g, 60 %w / w, 280.03 mmol) in a few portions at 0°C. The slurry was warmed to room temperature and stirred for 30 min, then methyl 6-bromopyridine-2- carboxylate (50 g, 231.45 mmol) was added as a single portion. After 3 h, the reaction was diluted with ether (800 mL) and quenched with water (400 mL) and saturated sodium bicarbonate (50 mL). The layers were separated, and the organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to yield methyl 6- benzylsulfanylpyridine-2-carboxylate (56.35 g, 89%) as a yellow oil.1H NMR (500 MHz, DMSO-d6) δ 7.84 – 7.77 (m, 1H), 7.77 – 7.73 (m, 1H), 7.52 (m, 1H), 7.48 (d, J = 7.8 Hz, 2H), 7.28(t, J = 7.2, 7.2 Hz, 2H), 7.24 – 7.18 (m, 1H), 4.44 (s, 2H), 3.90 (d, J = 1.2 Hz, 3H). ESI-MS m / z calc.259.0667, found 260.1 (M+1)+; Retention time: 3.2 minutes; LC method E. Step 2: Methyl 6-chlorosulfonylpyridine-2-carboxylate

[0245] A solution of methyl 6-benzylsulfanylpyridine-2-carboxylate (121.62 g, 431.47 mmol) in DCM (950 mL) and DI water (300 mL) was cooled in a -1 – 0 °C ice bath and, with vigorous stirring, sulfuryl chloride (228.14 g, 140 mL, 1.6396 mol) was added dropwise while the temperature was maintained below 5 °C. After the addition, the organic phase was separated, washed with DI water (2 x 500 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was dissolved in DCM (500 mL). Hexanes (1000 mL) was added, and the DCM was slowly evaporated off. The white precipitate was filtered by vacuum and the solids were washed with Hexanes (2 x 500 mL). The filtered solids were collected. The residue solids in the filtrate were filtered and dissolved in DCM (500 mL). The DCM solution was transferred to a 1 L round-bottom flask and concentrated under vacuum. The residue was dissolved in DCM (200 mL). Hexanes (600 mL) was added and the DCM was slowly evaporated off. The white precipitation was filtered by vacuum and the solids were washed with hexanes (2 x 500 mL) After drying, methyl 6-chlorosulfonylpyridine-2-carboxylate (56.898 g, 55%) was isolated.1H NMR (500 MHz, Chloroform-d) δ 8.48 (dd, J = 7.8, 1.1 Hz, 1H), 8.31 (dd, J = 7.9, 1.1 Hz, 1H), 8.25 (t, J = 7.8 Hz, 1H), 4.08 (s, 3H). ESI-MS m / z calc. 234.97061, found 236.1 (M+1)+; Retention time: 1.74 minutes; LC method E. Step 3: Methyl 6-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]pyridine-2-carboxylate

[0246] A solution of 4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-amine (16.63 g, 71.161 mmol) and methyl 6-chlorosulfonylpyridine-2-carboxylate (16.8 g, 71.294 mmol) dissolved in anhydrous THF (680 mL) was cooled to – 78 °C. Then Lithium bis(trimethylsilyl)amide (143 mL of 1 M, 143.00 mmol) in solution in THF was added dropwise. The mixture was allowed to warm up to 0 °C slowly and then 1M aqueous HCl (146 mL) was added, followed by DI water (680 mL). The THF was evaporated, and the aqueous phase was extracted with chloroform (3 x 250 mL). The combined organic layers were washed with saturated aqueous NaCl (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude was recrystallized in 10 % Acetone in Hexanes (500 mL). The white precipitate was filtered and rinsed with acetone (2 x 100 mL) to give methyl 6-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin- 2-yl]sulfamoyl]pyridine-2-carboxylate (15.79 g, 50%). ESI-MS m / z calc.432.06592, found 433.3 (M+1)+; Retention time: 5.5 minutes; LC method D. Step 4: 6-[[4-Chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]pyridine- 2-carboxylic acid

[0247] To a solution of methyl 6-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2- yl]sulfamoyl]pyridine-2-carboxylate (15.79 g, 36.477 mmol) in THF (180 mL) was added aqueous sodium hydroxide (182 mL of 1 M, 182.00 mmol). The reaction was stirred at RT for 1h. The THF was evaporated, and the aqueous layer was washed with diethyl ether (2 x 200 mL). The aqueous layer was acidified to pH 2 with 1 M Aqueous HCl (250 mL). The precipitate was filtered and the white solid was rinsed with DI water (2 x 250 mL). The solids were dried under vacuum to give 6-[[4-chloro-6-(2,6-dimethylphenyl)pyrimidin-2-yl]sulfamoyl]pyridine-2- carboxylic acid (14.3444 g, 93%).1H NMR (250 MHz, DMSO-d6) δ 8.14 – 7.99 (m, 3H), 7.21 – 7.11 (m, 1H), 7.03 (d, J = 7.7 Hz, 2H), 6.92 (s, 1H), 1.78 (s, 6H). ESI-MS m / z calc.418.05026, found 419.1 (M+1)+; Retention time: 2.61 minutes; LC method E. V. Synthesis of substituted bicyclic bromopyrazine and bromoindole intermediates Example 6: Preparation of 3-bromo-6-tert-butyl-5-methyl-pyrrolo[2,3-b]pyrazine Step 1: 6-Bromo-3-(3,3-dimethylbut-1-ynyl)pyrazin-2-amine

[0248] A solution of 3,6-dibromopyrazin-2-amine (10.085 g, 39.878 mmol) in anhydrous THF (100 mL) was bubbled with nitrogen for 5 minutes, then triethylamine (5.8080 g, 8 mL, 57.397 mmol), CuI (764 mg, 4.0116 mmol) and PdCl2(PPh3)2 (1.388 g, 1.9775 mmol) were added. The reaction was stirred at room temperature for 30 minutes. To the reaction mixture was slowly added dropwise 3,3-dimethylbut-1-yne (3.3350 g, 5 mL, 40.600 mmol) at room temperature. The reaction was stirred at room temperature for 1 h then was diluted with EtOAc (100 mL). The suspension was filtered through Celite, and the pad was rinsed with EtOAc (3 x 75 mL). The combined organic filtrates evaporated under reduced pressure (to remove THF). The crude product was solubilized in EtOAc (150 mL) and the solution was washed with a 50% brine solution (100 mL) and brine (100 mL), then was dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The material was purified by trituration in MTBE / Heptane (2 / 1) (50 mL). The suspension was filtered, washed with MTBE / heptane (25 mL) and dried under high vacuum to give a yellow solid. The product was then purified by normal phase chromatography eluting from 0-70% EtOAc in heptanes (no separation). The product was then purified by reverse phase chromatography eluting from 5-60% I in water (0,1% FA) (the product came out in the I flush). The product was then repurified by reverse phase chromatography eluting from 55-85% I in water (0.1% FA) to give 2 fractions. Fraction 1 contained the pure desired compound while fraction 2 contained the desired product with a dimeric impurity. Fraction 2 was repurified by reverse phase chromatography eluting from 40- 80% I in water (0.1 % FA) to give the pure desired compound. Both lots of pure compound were mixed together to give 6-bromo-3-(3,3-dimethylbut-1-ynyl)pyrazin-2-amine (5.8 g, 57%) as a light yellow solid. ESI-MS m / z calc.253.0215, found 254.0 (M+1)+; Retention time: 1.97 minutes.1H NMR (400 MHz, DMSO-d6) δ 7.79 (s, 1H), 6.87 (br. S., 2H), 1.31 (s, 9H). LC method O. Step 2: 3-Bromo-6-tert-butyl-5H-pyrrolo[2,3-b]pyrazine

[0249] To a stirred solution of 6-bromo-3-(3,3-dimethylbut-1-ynyl)pyrazin-2-amine (7.50 g, 29.51 mmol) in t-BuOH (80 mL) was added sodium tert-butoxide (14.25 g, 148.3 mmol). The reaction mixture was stirred at 80 °C for 4 h, then allowed to cool down to ambient temperature. The volatiles were removed under reduced pressure and the residue was diluted with ice-cold water (250 mL). The suspension was stirred at 0-4 °C (ice-water bath) for 15 min. The solid was filtered and washed with water (3 x 30 ml) and air-dried. The filter-cake was taken up in acetonitrile and concentrated under reduced pressure and the azeotropic water removal process repeated three times. Then the solid was dried under reduced pressure to furnish 3-bromo-6-tert- butyl-5H-pyrrolo[2,3-b]pyrazine as a tan solid (7.23 g, 96%),1H NMR (400 MHz, DMSO) δ 12.25 (s, 1H), 8.37 (s, 1H), 6.37 (s, 1H), 1.37 (s, 9H)., ESI-MS m / z calc.253.02145, found 255.9 (M+3)+; Retention time: 1.47 minutes. LC method A. Step 3: 3-Bromo-6-tert-butyl-5-methyl-pyrrolo[2,3-b]pyrazine

[0250] Sodium hydride (60% w / w in oil) (2.18 g, 54.505 mmol) was added portion-wise to a solution of 3-bromo-6-tert-butyl-5H-pyrrolo[2,3-b]pyrazine (6.71 g, 25.084 mmol) in anhydrous DMF (128 mL) at 0°C. The suspension was stirred at this temperature for 30 min. Dimethyl sulfate (4.7988 g, 3.6 mL, 38.046 mmol) was added and left stirring at 0 °C for 15 min. The reaction was then stirred at room temperature for 1 h. The reaction mixture was cooled down to 0°C and quenched with saturated aqueous ammonium chloride solution (250 mL). The resulting precipitate was filtered and washed with water (2 x 50 mL). The precipitate was dissolved in EtOAc (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting precipitate was purified by reversed phase chromatography (Gradient: 5% MeOH in water, then 60-85% MeOH in water). The desired fractions were combined and concentrated under reduced pressure to afford 3-bromo-6-tert-butyl-5-methyl-pyrrolo[2,3- b]pyrazine (5.96 g, 84%) as a light yellow solid.1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 6.52 (s, 1H), 4.01 (s, 3H), 1.51 (s, 9H). ESI-MS m / z calc.267.0371, found 268.2 (M+1)+; Retention time: 1.95 minutes. LC method I. Example 7: Preparation of 3-bromo-6-tert-butyl-5-(trideuteriomethyl)pyrrolo[2,3- b]pyrazine Step 1: 3-Bromo-6-tert-butyl-5-(trideuteriomethyl)pyrrolo[2,3-b]pyrazine

[0251] To a solution of 3-bromo-6-tert-butyl-5H-pyrrolo[2,3-b]pyrazine (2.50 g, 9.837 mmol) in DMF (25 mL) at 0 °C was added NaH (in mineral oil) (650 mg of 60 %w / w, 16.25 mmol). The reaction mixture was stirred for 20 minutes then trideuterio(iodo)methane (1.75 g, 12.07 mmol) was added. The reaction mixture was stirred for 1 h and ice was added carefully (caution! Rapid effervescence). The suspension was diluted with water and was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate (3 x 25 mL) and the combined organics were washed with water (20 mL), brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to furnish 3-bromo-6-tert-butyl-5-(trideuteriomethyl)pyrrolo[2,3-b]pyrazine as an orange-brown oil (1.88 g, 70%),1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 6.48 (s, 1H), 1.50 (s, 9H)., ESI-MS m / z calc.270.05594, found 271.08 (M+1)+; Retention time: 1.71 minutes. LC method A. Example 8: Preparation of 2-bromo-6-tert-butyl-5-methyl-pyrrolo[2,3-b]pyrazine Step 1: 5-Bromo-3-(3,3-dimethylbut-1-ynyl)pyrazin-2-amine

[0252] A stirred solution of 3,5-dibromopyrazin-2-amine (5.00 g, 19.77 mmol) in anhydrous THF (80 mL) was sparged with nitrogen for 10 min. Then triethylamine (3.5 mL, 25.11 mmol), CuI (305 mg, 1.601 mmol) and PdCl2(PPh3)2(556 mg, 0.7921 mmol) were added, in that order, at ambient temperature. The heterogeneous yellow mixture was cooled to 0 °C and 3,3- dimethylbut-1-yne (1.62 g, 19.72 mmol) was added dropwise over 5 min. After stirring the reaction for 3 h at that temperature, it was diluted with ethyl acetate (100 mL). The suspension was filtered over a pad of Celite, and the filter cake was rinsed with ethyl acetate (3 x 50 mL). The filtrate was washed with water (2 x 50 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The combined organics were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to furnish 5-bromo-3-(3,3- dimethylbut-1-ynyl)pyrazin-2-amine (5.02 g, 100%) as an orange-yellow solid. ESI-MS m / z calc.253.02145, found 254.0 (M+1)+; Retention time: 1.57 minutes. LC method A. Step 2: 2-Bromo-6-tert-butyl-5H-pyrrolo[2,3-b]pyrazine

[0253] To a stirred solution of 5-bromo-3-(3,3-dimethylbut-1-ynyl)pyrazin-2-amine (5.02 g, 19.75 mmol) in t-BuOH (50 mL) was added sodium tert-butoxide (9.49 g, 98.75 mmol). The reaction mixture was stirred at 80 °C for 4 h then was allowed to cool down to ambient temperature. The volatiles were removed under reduced pressure and the residue was taken up in water (50 mL). The resulting dark suspension was stirred at 0-4 °C for 15 min, then filtered off. The solid was washed with water (3 x 20 mL) and dried under reduced pressure to furnish 2-bromo-6-tert-butyl-5H-pyrrolo[2,3-b]pyrazine (4.65 g, 93%) as a tan solid.1H NMR (400 MHz, DMSO) δ 12.20 (s, 1H), 8.25 (s, 1H), 6.36 (d, J = 2.0 Hz, 1H), 1.38 (s, 9H). ESI-MS m / z calc. 253.02145, found 254.0 (M+1)+; Retention time: 1.39 minutes. LC method A. Step 3: 2-Bromo-6-tert-butyl-5-methyl-pyrrolo[2,3-b]pyrazine

[0254] To a stirred solution of 2-bromo-6-tert-butyl-5H-pyrrolo[2,3-b]pyrazine (500 mg, 1.967 mmol) in anhydrous DMF (8 mL) was added NaH (in mineral oil) (115 mg of 60 %w / w, 2.875 mmol) at 0 °C under nitrogen. After stirring the reaction mixture for 20 min, iodomethane (340 mg, 2.395 mmol) was added. After another 1 h, at that temperature, ice was added very carefully (caution! Rapid effervescence). The suspension was diluted with cold water (100 mL) and stirring was continued at that temperature for 10 min. The solid was filtered and washed with water (3 x 25 mL) and dried in vacuo to furnish 2-bromo-6-tert-butyl-5-methyl- pyrrolo[2,3-b]pyrazine as a dark brown solid (492 mg, 93%).1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 6.49 (s, 1H), 3.96 (s, 3H), 1.46 (s, 9H). ESI-MS m / z calc.267.0371, found 267.9 (M+1)+; Retention time: 1.58 minutes. LC method A. Example 9: Preparation of 2-bromo-7-isopropyl-quinoxaline Step 1: 1-Fluoro-4-isopropenyl-2-nitro-benzene

[0255] To a solution of 4-bromo-1-fluoro-2-nitro-benzene (10.01 g, 45.501 mmol) and sodium carbonate (5.31 g, 50.100 mmol) in 1,4-dioxane (200 mL) and water (50 mL) was sparged with nitrogen. Bis(triphenylphosphine)palladium(II)chloride (659.3 mg, 0.9393 mmol) was added and the mixture was sparged with nitrogen. Isopropenylboronic acid pinacol ester (8.3927 g, 9.43 mL, 49.944 mmol) was added and the mixture was stirred at 80 °C for 3 hours. The mixture was cooled to rt, filtered over Celite, washed with MTBE (3x 20 mL) and the volatiles of the filtrate were removed under reduced pressure. The mixture was diluted with water (200 mL) and extracted with MTBE (3x150 mL). The organic phases were combined,washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford the crude 1-fluoro-4-isopropenyl-2-nitro-benzene (10.5 g, 125%) without further purification as a brown semi-solid. ESI-MS m / z calc.181.16, no ionization; Retention time: 2.12 minutes.1H NMR (400 MHz, Chloroform-d) δ 8.12 (dd, J = 7.1, 2.4 Hz, 1H), 7.75 – 7.69 (m, 1H), 7.29 – 7.21 (overlapped with chloroform, m, 1H), 5.43 (s, 1H), 5.24 (s, 1H), 2.17 (s, 3H).19F NMR (377 MHz, Chloroform-d) δ -119.85 (s, 1F). LC method O. Step 2: Methyl 2-(4-isopropenyl-2-nitro-anilino)acetate

[0256] A solution of 1-fluoro-4-isopropenyl-2-nitro-benzene (8.2 g, 44.584 mmol) in anhydrous DMA (150 mL) was sparged with nitrogen. Methyl 2-aminoacetate (hydrochloride salt) (7.59 g, 60.452 mmol) and DIPEA (21.518 g, 29 mL, 166.49 mmol) were added and the mixture was stirred at 80 °C for 1 hour. The mixture was cooled to rt and poured into water (500 mL). The mixture was stirred at rt for 48 hours. The resulting precipitate was filtered and washed with water (2 x 20 mL). Purification by silica gel chromatography (Gradient 0 – 80% EtOAc in heptane) afforded after evaporation of the volatiles methyl 2-(4-isopropenyl-2-nitro- anilino)acetate (7.20 g, 64%) as a first crop as an orange solid. ESI-MS m / z calc.250.0954, found 251.1 (M+1)+; Retention time: 2.22 minutes1H NMR (400 MHz, Chloroform-d) δ 8.47 – 8.37 (m, 1H), 8.29 (d, J = 2.4 Hz, 1H), 7.67 (dd, J = 8.8, 2.2 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 5.35 (s, 1H), 5.10 – 5.05 (m, 1H), 4.14 (d, J = 5.4 Hz, 2H), 3.84 (s, 3H), 2.15 (br s, 3H). The fractions containing a second crop were combined and evaporated under reduced pressure to afford methyl 2-(4-isopropenyl-2-nitro-anilino)acetate (1.3 g, 12%) as an orange solid. ESI-MS m / z calc.250.0954, found 251.1 (M+1)+; Retention time: 2.28 minutes1H NMR (400 MHz, Chloroform-d) δ 8.47 – 8.36 (m, 1H), 8.29 (d, J = 2.2 Hz, 1H), 7.67 (dd, J = 8.8, 2.2 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 5.38 – 5.34 (m, 1H), 5.10 – 5.05 (m, 1H), 4.14 (d, J = 5.4 Hz, 2H), 3.84 (s, 3H), 2.15 (s, 3H). LC method O. Step 3: 7-Isopropyl-3,4-dihydro-1H-quinoxalin-2-one

[0257] A solution of methyl 2-(4-isopropenyl-2-nitro-anilino)acetate (7.2 g, 28.742 mmol) in MeOH (200 mL) was sparged with nitrogen. Palladium on carbon (10% wt, 50% wet) (696.3 mg, 5 %w / w, 0.3271 mmol) was added and the mixture was sparged with nitrogen and then with hydrogen. The mixture was stirred under hydrogen atmosphere (balloon) at rt for 48 hours. Palladium on carbon (10% wt, 50% wet) (621.8 mg, 5 %w / w, 0.2921 mmol) was added and the mixture was flushed with nitrogen and then with hydrogen. The mixture was stirred under hydrogen atmosphere (balloon) at rt for 16 hours. The mixture was filtered over Celite, and the volatiles of the filtrate were removed under reduced pressure to afford 7-isopropyl-3,4-dihydro- 1H-quinoxalin-2-one (5.24 g, 88%) as a yellow oil. ESI-MS m / z calc.190.1106, found 191.2 (M+1)+; Retention time: 1.85 minutes1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 6.66 – 6.55 (m, 3H), 5.75 (s, 1H), 3.65 (d, J = 1.7 Hz, 2H), 2.70 (dt, J = 13.6, 6.8 Hz, 1H), 1.12 (d, J = 6.8 Hz, 6H). LC method O. Step 4: 7-Isopropyl-1H-quinoxalin-2-one

[0258] To a solution of 7-isopropyl-3,4-dihydro-1H-quinoxalin-2-one (5.32 g, 27.545 mmol) in MeOH (200 mL) was added KotBu in THF (42 mL of 1 M, 42.000 mmol). Oxygen was flushed into the mixture for 5 min and the reaction was stirred under O2atmosphere for 16 hours at rt. The volatiles were removed under reduced pressure. The crude was diluted with water (100 mL) and TFA was added (5 mL) to neutralize the reaction. The aqueous layer was extracted with EtOAC (3 x 100 mL). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to afford 7-isopropyl- 1H-quinoxalin-2-one (4.23 g, 81%) as a yellow solid. ESI-MS m / z calc.188.095, found 189.2 (M+1)+; Retention time: 1.84 minutes1H NMR (400 MHz, DMSO-d6) δ 12.33 (br s, 1H), 8.09 (s, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.22 (dd, J = 8.3, 2.0 Hz, 1H), 7.14 (d, J = 2.0 Hz, 1H), 2.98 (spt, J = 6.8 Hz, 1H), 1.23 (d, J = 6.8 Hz, 6H). LC method O.Step 5: 2-Bromo-7-isopropyl-quinoxaline

[0259] To a solution of 7-isopropyl-1H-quinoxalin-2-one (4.23 g, 22.428 mmol) in acetonitrile (150 mL) were added POBr3(9.05 g, 31.568 mmol) and potassium carbonate (4.52 g, 32.705 mmol) at room temperature. The mixture was stirred for 3 hours at 80 °C. The mixture was allowed to cool down and was placed into an ice bath at 0 °C. Water (150 mL) was added and the mixture was allowed to warm up to rt. Acetonitrile was removed under reduced pressure and the remaining aqueous layer was extracted with EtOAc (3 x 100 mL). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. Purification by silica gel chromatography (Gradient 0 – 20% EtOAc in heptane) afforded after evaporation of the volatiles 2-bromo-7-isopropyl-quinoxaline (4.73 g, 83%) as an orange oil. ESI-MS m / z calc.250.0106, found 251.1 (M+1)+; Retention time: 3.34 minutes1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.09 – 8.01 (m, 1H), 7.89 – 7.82 (m, 2H), 3.16 (spt, J = 6.9 Hz, 1H), 1.30 (d, J = 6.8 Hz, 6H). LC method P. Example 10: Preparation of 5-bromo-2-tert-butyl-3-methyl-imidazo[4,5-b]pyrazine Step 1: 5-Bromo-N3-methyl-pyrazine-2,3-diamine

[0260] Methyl amine in methanol (10 mL of 40 %w / v, 128.8 mmol) was added to 3,5- dibromopyrazin-2-amine (2.00 g, 7.908 mmol) and stirred for 10 min. Then water (2.0 mL) was added to the tan solution and the capped microwave tube was stirred in a microwave reactor at 130 °C (setting: very high absorption) for 1 h. The reaction was allowed to cool to ambient temperature and extracted with dichloromethane (3 x 20 mL), washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to furnish 5-bromo-N3- methyl-pyrazine-2,3-diamine as a tan solid (1.580 g, 98%)1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 4.28 (s, 1H), 4.09 (s, 2H), 3.02 (d, J = 5.0 Hz, 3H). ESI-MS m / z calc.201.98541, found 203.0 (M+1)+; Retention time: 0.61 minutes. LC method A.Step 2: 5-Bromo-2-tert-butyl-3-methyl-imidazo[4,5-b]pyrazine

[0261] In flask was added pivalic acid (34 g, 332.90 mmol), 2,2-dimethylpropanoyl 2,2- dimethylpropanoate (14.672 g, 16 mL, 78.777 mmol) and 5-bromo-N3-methyl-pyrazine-2,3- diamine (7.8 g, 38.186 mmol). The flask was equipped with a Vigreux column and the reaction was stirred at 130 °C for 18 hours. The reaction was allowed to cool down to room temperature and was diluted with ethyl acetate (100 mL), washed with a 1M aqueous solution of NaOH (2 x 100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude 5-bromo-2-tert-butyl-3-methyl-imidazo[4,5-b]pyrazine (21.6 g, 95%) as a dark red oil.1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 4.02 (s, 3H), 1.59 (s, 9H). ESI-MS m / z calc.268.0324, found 269.2 (M+1)+; Retention time: 1.69 minutes. LC method I. Example 11: Preparation of 3-bromo-5-methyl-6-[1- (trifluoromethyl)cyclopropyl]pyrrolo[2,3-b]pyrazine Step 1: 6-Bromo-3-[2-[1-(trifluoromethyl)cyclopropyl]ethynyl]pyrazin-2-amine

[0262] In a flask under nitrogen was added THF (200 mL). nitrogen was flushed into the mixture for 10 min.1-Ethynyl-1-(trifluoromethyl)cyclopropane (10 g, 70.843 mmol), 3,6- dibromopyrazin-2-amine (35.83 g, 141.68 mmol), triethylamine (21.780 g, 30 mL, 215.24 mmol), bis(triphenylphosphine)palladium(II) dichloride (987.7 mg, 1.4072 mmol) and copper iodide (272.2 mg, 1.4292 mmol) were added. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 4 hours. The reaction mixture was filtered on Celite and the cake was washed with acetonitrile (5 x 30 mL). Water with 0.1% formic acid (200 mL) was added in the filtrate and the precipitate was collected by filtration. The solid was dissolved in I (50 mL) and water + 0.1% formic acid was added until a precipitate formed. The solid was collected by filtration. This step was done 4 times until the starting material was removed fromthe crude. The desired product 6-bromo-3-[2-[1-(trifluoromethyl)cyclopropyl]ethynyl]pyrazin-2- amine (19.66 g, 76%) was obtained as a yellow solid. ESI-MS m / z calc.304.9775, found 306.0 (M+1)+; Retention time: 2.05 minutes.1H NMR (400 MHz, Chloroform-d) δ 7.97 (s, 1H), 5.15 (br s, 2H), 1.50 – 1.44 (m, 2H), 1.41 – 1.34 (m, 2H).19F NMR (377 MHz, Chloroform-d) δ - 70.07 (s, 3F). LC method O. Step 2: 3-Bromo-5-methyl-6-[1-(trifluoromethyl)cyclopropyl]pyrrolo[2,3- b]pyrazine

[0263] To a solution of 6-bromo-3-[2-[1-(trifluoromethyl)cyclopropyl]ethynyl]pyrazin-2- amine (19.66 g, 53.761 mmol) in anhydrous DMF (150 mL) at 0°C under nitrogen, was added NaH (4.5 g, 60 %w / w, 112.51 mmol). The mixture was stirred at 70 °C for 1 hour. The mixture was allowed to cool down to 0 °C. A solution of dimethyl sulfate (13.566 g, 10.2 mL, 107.55 mmol) in anhydrous DMF (50 mL) was added dropwise to the mixture at 0 °C over 15 minutes. The mixture was stirred at 0 °C for 1 hour. Then, a saturated aqueous solution of ammonium chloride (250 mL) and water (250 mL) were added. The aqueous phase was extracted with EtOAc (3 x 250 mL). The organic phases were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. Purification by silica gel chromatography (Gradient 0 – 10% EtOAc in heptane) afforded after evaporation of the volatiles 3-bromo-5-methyl-6-[1-(trifluoromethyl)cyclopropyl]pyrrolo[2,3-b]pyrazine (14.03 g, 81%) as a light yellow solid. ESI-MS m / z calc.318.9932, found 320.0 (M+1)+; Retention time: 2.17 minutes1H NMR (400 MHz, Chloroform-d) δ 8.51 (s, 1H), 6.77 (s, 1H), 3.92 (s, 3H), 1.64 – 1.57 (overlapped with water, m, 2H), 1.28 – 1.22 (m, 2H).19F NMR (377 MHz, Chloroform-d) δ -68.75 (s, 3F). LC method O. Example 12: An alternative preparation of 3-bromo-5-methyl-6-[1- (trifluoromethyl)cyclopropyl]pyrrolo[2,3-b]pyrazine Step 1: Triisopropyl-[3-(trifluoromethyl)but-3-en-1-ynyl]silane

[0264] To a pressure tube were added CuI (41 mg, 0.2153 mmol) and bis(triphenylphosphine)palladium(II) dichloride (77 mg, 0.1094 mmol). The mixture was dried under vacuum for 15 min. Then, THF (2 mL) and TEA (2.5410 g, 3.5 mL, 25.111 mmol) were added, followed by ethynyl(triisopropyl)silane (2 g, 10.966 mmol) and cold 2-bromo-3,3,3- trifluoro-prop-1-ene (2.5 g, 14.290 mmol). The tube was closed and heated for 20 min at 50 °C in an oil bath. The reaction mixture was cooled to room temperature, partitioned between pentane (100 mL) and saturated aqueous ammonium chloride (50 mL) containing HCl (30 mL of 1 M, 30.000 mmol) and water (50 mL). The aqueous phase was separated and extracted with pentane (2 x 50 mL). The combined organics were dried on magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified on silica gel by elution in 100% pentane to provide triisopropyl-[3-(trifluoromethyl)but-3-en-1-ynyl]silane (2.76 g, 87%) as a clear oil1H NMR (400 MHz, CDCl3) δ 6.05 (q, J = 1.3 Hz, 1H), 5.89 (q, J = 1.2 Hz, 1H), 1.12 - 1.08 (m, 21H).19F NMR (377 MHz, CDCl3) δ -68.20 (s, 3F). Step 2: Triisopropyl-[2-[1-(trifluoromethyl)cyclopropyl]ethynyl]silane

[0265] LiHMDS (10.3 mL of 1 M, 10.300 mmol) was added to triisopropyl-[3- (trifluoromethyl)but-3-en-1-ynyl]silane (1 g, 3.4369 mmol) and diphenyl(methyl)sulfonium tetrafluoroborate (1.38 g, 4.7898 mmol) in solution in THF (2 mL) maintained at -78 °C. The reaction mixture was left to slowly warm up to room temperature over 18 h. The reaction mixture was diluted with pentane (15 mL) and filtered on a silica gel column and the desired product was eluted with pentane. The filtrates were concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography on a C18 column using a 5 to 100% gradient of acetonitrile in pure water. The fractions containing the desired fraction werecombined and extracted with pentane (3 x 50 mL). The pentane phases were combined, washed with water (20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide triisopropyl-[2-[1-(trifluoromethyl)cyclopropyl]ethynyl]silane (550 mg, 52%) as a clear oil.1H NMR (400 MHz, CDCl3) δ 1.30 - 1.26 (m, 2H), 1.17 - 1.12 (m, 2H), 1.08 - 1.04 (m, 21H).19F NMR (377 MHz, CDCl3) δ -70.80 (s, 3F). Step 3: 6-Bromo-3-[2-[1-(trifluoromethyl)cyclopropyl]ethynyl]pyrazin-2-amine

[0266] Under a nitrogen atmosphere in a microwave vial were added 3,6-dibromopyrazin-2- amine (8.5 g, 33.611 mmol), triisopropyl-[2-[1-(trifluoromethyl)cyclopropyl]ethynyl]silane (5 g, 16.354 mmol), CuI (625 mg, 3.2817 mmol), Pd(PPh3)2Cl2 (574 mg, 0.8178 mmol), PPh3 (430 mg, 1.6394 mmol), TEA (1.8150 g, 2.5 mL, 17.937 mmol), and THF (35 mL). The vial was capped and the mixture was warmed-up to 60 °C, and TBAF (in THF) (17 mL of 1 M, 17.000 mmol) was introduced dropwise in the vial via a syringe. The reaction mixture was left stirring at this temperature for 3 h and then left to cool to room temperature. The mixture was filtered on a pad of silica gel, and the pad was eluted with ethyl acetate. The combined filtrates were concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel using a gradient of 0 to 100% ethyl acetate in heptanes. The collected fractions were combined and concentrated under reduced pressure. The resulting residue was purified using multiple reverse phase chromatography passes (3 x) on a C18column using a 5 to 100% gradient of acetonitrile in pure water to provide 6-bromo-3-[2-[1- (trifluoromethyl)cyclopropyl]ethynyl]pyrazin-2-amine (3.31 g, 63%) as a yellow solid ESI-MS m / z calc.304.9775, found 305.9 (M+1)+; Retention time: 2.27 minutes Step 4: 3-Bromo-5-methyl-6-[1-(trifluoromethyl)cyclopropyl]pyrrolo[2,3- b]pyrazine

[0267] To a solution of 6-bromo-3-[2-[1-(trifluoromethyl)cyclopropyl]ethynyl]pyrazin-2- amine (19.66 g, 53.761 mmol) in anhydrous DMF (150 mL) at 0°C under nitrogen, was added NaH (4.5 g, 60 %w / w, 112.51 mmol). The mixture was stirred at 70 °C for 1 hour. The mixture was allowed to cool down to 0 °C. A solution of dimethyl sulfate (13.566 g, 10.2 mL, 107.55 mmol) in anhydrous DMF (50 mL) was added drop-wise to the mixture at 0 °C over 15 minutes. The mixture was stirred at 0 °C for 1 h. Then, a saturated aqueous solution of ammonium chloride (250 mL) and water (250 mL) were added. The aqueous phase was extracted with EtOAc (3 x 250 mL). The organic phases were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. Purification by silica gel chromatography (Gradient 0 - 10% EtOAc in heptane) afforded after evaporation of the volatiles 3-bromo-5-methyl-6-[1-(trifluoromethyl)cyclopropyl]pyrrolo[2,3-b]pyrazine (14.03 g, 81%) as a light yellow solid. ESI-MS m / z calc.318.9932, found 320.0 (M+1)+; Retention time: 2.17 minutes1H NMR (400 MHz, Chloroform-d) δ 8.51 (s, 1H), 6.77 (s, 1H), 3.92 (s, 3H), 1.64 - 1.57 (overlapped with water, m, 2H), 1.28 - 1.22 (m, 2H).19F NMR (377 MHz, Chloroform-d) δ -68.75 (s, 3F). Example 13: Preparation of 3-bromo-8,8-dimethyl-6H,7H,8H-pyrazino[2,3-b]pyrrolizine Step 1: tert-Butyl 2-(hydroxymethyl)-3,3-dimethyl-pyrrolidine-1-carboxylate

[0268] To a solution of 1-tert-butoxycarbonyl-3,3-dimethyl-pyrrolidine-2-carboxylic acid (4.5 g, 18.496 mmol) in THF (80 mL) was added borane dimethyl sulfide (4.2400 g, 5.3 mL, 55.812 mmol) dropwise. The mixture was stirred at 50 °C for 10 min and cooled down to room temperature. MeOH (10 mL) was added, and the mixture was stirred at room temperature for 1 h. Concentration of the reaction mixture under reduced pressure afforded tert-butyl 2- (hydroxymethyl)-3,3-dimethyl-pyrrolidine-1-carboxylate (4.2 g, 99%) as a colorless oil.1H NMR (400 MHz, Chloroform-d) δ 3.80 – 3.70 (m, 1H), 3.60 – 3.30 (m, 5H), 1.74 – 1.55 (m,2H), 1.48 (s, 9H), 1.08 (s, 3H), 0.95 (s, 3H). ESI-MS m / z calc.229.1678, found 174.2 (M-55)+; Retention time: 1.97 minutes. LC method O. Step 2: tert-Butyl 2-formyl-3,3-dimethyl-pyrrolidine-1-carboxylate

[0269] To a solution of tert-butyl 2-(hydroxymethyl)-3,3-dimethyl-pyrrolidine-1-carboxylate (4.2 g, 18.297 mmol) in water-saturated DCM (150 mL) was added DMP (15 g, 35.366 mmol). The mixture was stirred at room temperature for 16 h. Silica (20 g) was added, and the volatiles were removed under reduced pressure. Purification by silica gel chromatography (Gradient: 0-10 % EtOAc in heptanes) yielded after evaporation of the volatiles tert-butyl 2-formyl-3,3- dimethyl-pyrrolidine-1-carboxylate (4.2 g, 96%) as a colorless oil ESI-MS m / z calc.227.1521, found 172.2 (M-55)+; Retention time: 2.03 minutes.1H NMR (400 MHz, Chloroform-d) δ 9.54 – 9.41 (m, 1H), 3.74 – 3.46 (m, 3H), 1.77 – 1.65 (m, 2H), 1.48 – 1.40 (m, 9H), 1.17 (s, 3H), 1.09 – 1.02 (m, 3H). LC method O. Step 3: tert-Butyl 2-[(3,5-dibromopyrazin-2-yl)-hydroxy-methyl]-3,3-dimethyl- pyrrolidine-1-carboxylate

[0270] A dried 100-mL flask under nitrogen was charged with 2,2,6,6-tetramethylpiperidine (510 mg, 3.6105 mmol) and THF (20 mL). The mixture was cooled to -40 °C and a n-BuLi solution in hexanes (1.5 mL of 2.5 M, 3.7500 mmol) was added dropwise. The mixture was stirred at 0 °C for 20 minutes and cooled to -100 °C. A solution of 2,6-dibromopyrazine (710 mg, 2.9847 mmol) in THF (7 mL) was added dropwise over 40 minutes. After addition, the mixture was slowly warmed to -90 °C over 23 minutes and kept at -90 °C - -86 °C (bath temperature) for 8 minutes. The mixture was re-cooled to -100 °C and a solution of tert-butyl 2- formyl-3,3-dimethyl-pyrrolidine-1-carboxylate (617 mg, 2.5788 mmol) in THF (5 mL) was added dropwise over 15 minutes. After addition, the mixture was stirred at -100 °C for 10 minutes. A solution of HOAc (180 mg, 3 mmol) in THF (3 mL) was added dropwise to quenchthe reaction. The cooling bath was removed and heptanes (75 mL) was added, followed by saturated aqueous sodium bicarbonate (10 mL). The two layers were separated, and the aqueous phase was extracted with heptanes-EtOAc (3:1, 28 mL) and EtOAc (30 mL). The combined organic layers were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (Gradient: 5-80% MeCN in water with 0.1% formic acid). The desired fractions were collected, neutralized with saturated aqueous sodium bicarbonate (2 mL) and concentrated under reduced pressure to remove most of MeCN. The residue was extracted with DCM (3 x 20 mL). The combined organic layers were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 2-[(3,5-dibromopyrazin-2-yl)-hydroxy-methyl]-3,3-dimethyl- pyrrolidine-1-carboxylate (1.087 g, 91%) as a light-brown oil. ESI-MS m / z calc.463.0106, found 364.0 (M-99)+; Retention time: 2.21 minutes. LC method O. Step 4: (3,5-Dibromopyrazin-2-yl)-(3,3-dimethylpyrrolidin-2-yl)methanol

[0271] Concentrated HBr (in water) (6.4368 g, 9 mL, 38.186 mmol) was added to a solution of tert-butyl 2-[(3,5-dibromopyrazin-2-yl)-hydroxy-methyl]-3,3-dimethyl-pyrrolidine-1- carboxylate (1.4 g, 2.8772 mmol) in diethyl ether (18 mL) and water (9 mL). The reaction mixture was stirred for 16 h at room temperature and then concentrated under reduced pressure. The resulting residue was quenched with aqueous sodium bicarbonate (25 mL) until pH = 4-5. The resulting aqueous solution was purified by reversed-phase chromatography (C18column. Gradient: 0-20 % MeCN in water with 0.1 % formic acid). The volatiles were removed under reduced pressure from the fractions containing the product to afford (3,5-dibromopyrazin-2-yl)- (3,3-dimethylpyrrolidin-2-yl)methanol (Hydrobromic Acid (1)) (1.1 g, 83%) as a white solid. ESI-MS m / z calc.362.9582, found 363.9 (M+1)+; Retention time: 1.54 minutes.1H NMR (400 MHz, DMSO-d6) δ 9.25 (br s, 1H), 9.01 (s, 1H), 8.86 (br s, 1H), 6.63 (d, J = 4.2 Hz, 1H), 5.21 (dd, J = 7.1, 4.2 Hz, 1H), 3.72 – 3.57 (m, 1H), 3.20 (br s, 2H), 1.90 – 1.72 (m, 2H), 1.01 (s, 3H), 0.74 (s, 3H). LC method O.Step 5: 3-bromo-8,8-dimethyl-6H,7H,8H-pyrazino[2,3-b]pyrrolizine

[0272] To a solution of (3,5-dibromopyrazin-2-yl)-(3,3-dimethylpyrrolidin-2-yl)methanol (trifluoroacetate salt) (4.7 g, 9.8005 mmol) in MeCN (85 mL) was added TEA (10.164 g, 14 mL, 100.44 mmol). The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was cooled down to 0 °C and Ms2O (5 g, 28.703 mmol) was added portion wise. The reaction mixture was stirred at 0 °C for 1.5 h. Water (30 mL) and brine (40 mL) were added and the mixture was extracted with EtOAc (3 x 75 mL). The combined organic layers were washed with saturated aqueous solution of sodium bicarbonate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (Gradient: 0-20 % EtOAc in heptanes) yielded after evaporation of the volatiles and dried under high vacuum 3-bromo-8,8-dimethyl-6H,7H,8H-pyrazino[2,3- b]pyrrolizine (2.4 g, 91%) as a tan solid.1H NMR (400 MHz, Chloroform-d) δ 8.40 (s, 1H), 6.30 (s, 1H), 4.26 (br. T, J = 6.7 Hz, 2H), 2.42 (br. T, J = 6.8 Hz, 2H), 1.46 (s, 6H). ESI-MS m / z calc.265.0215, found 266.0 (M+1)+; Retention time: 2.87 minutes. LC method P. Example 14: Preparation of 3-bromo-5-methyl-6-[1- (trifluoromethyl)cyclobutyl]pyrrolo[2,3-b]pyrazine Step 1: 6-Bromo-3-[2-[1-(trifluoromethyl)cyclobutyl]ethynyl]pyrazin-2-amine

[0273] A solution of 3,6-dibromopyrazin-2-amine (1.56 g, 6.169 mmol) in anhydrous THF (31 mL) was bubbled with nitrogen for 5 minutes, then triethylamine (1.05 mL, 7.533 mmol), CuI (94 mg, 0.4936 mmol) and PdCl2(PPh3)2 (175 mg, 0.2493 mmol) were added. The reaction mixture was cooled to 0 °C and 1-ethynyl-1-(trifluoromethyl)-cyclobutane (910.5 mg, 6.147 mmol) was slowly added dropwise. The reaction was stirred at 0 °C for 5 hours, then was diluted with EtOAc. The suspension was filtered through Celite, and the pad was rinsed with EtOAc. The product was purified by silica gel chromatography (120 g column, Gradient: 0-50 % EtOAcin Hexane, 30 min) and reverse phase chromatography (C18, water / I (0-100% over 25 min) to afford 6-bromo-3-[2-[1-(trifluoromethyl)cyclobutyl]ethynyl]pyrazin-2-amine as a yellow solid (1.1408 g, 57%),1H NMR (400 MHz, DMSO) δ 7.86 (s, 1H), 7.12 (s, 2H), 2.70 – 2.53 (m, 4H), 2.21 – 2.12 (m, 1H), 2.07 – 1.95 (m, 1H). ESI-MS m / z calc.318.9932, found 320.022 (M+1)+; Retention time: 0.672 minutes. LC method B. Step 2: 3-Bromo-6-[1-(trifluoromethyl)cyclobutyl]-5H-pyrrolo[2,3-b]pyrazine

[0274] To a suspension of 6-bromo-3-[2-[1-(trifluoromethyl)cyclobutyl]ethynyl]pyrazin-2- amine (1.24 g, 3.874 mmol) in t-BuOH (13 mL) was added sodium tert-butoxide (2.18 g, 19.43 mmol). The reaction mixture was stirred at 90 °C for 4 hours then was allowed to cool down to room temperature. The volatiles were removed under reduced pressure and the residue was suspended in water (10 ml). The suspension was stirred for 10 minutes in an ice-cold bath and extracted with EtOAc. The organic layers were concentrated under reduced pressure. The orange solid was dried under reduced pressure to afford 3-bromo-6-[1-(trifluoromethyl)cyclobutyl]-5H- pyrrolo[2,3-b]pyrazine (1.24 g, 99%).1H NMR (400 MHz, DMSO) δ 8.43 (s, 1H), 6.74 (s, 1H), 2.74 – 2.59 (m, 4H), 2.12 – 1.91 (m, 2H). ESI-MS m / z calc.318.9932, found 319.9 (M+1)+; Retention time: 0.62 minutes. LC method B. Step 3: 3-Bromo-5-methyl-6-[1-(trifluoromethyl)cyclobutyl]pyrrolo[2,3- b]pyrazine

[0275] To a solution of 3-bromo-6-[1-(trifluoromethyl)cyclobutyl]-5H-pyrrolo[2,3- b]pyrazine (909.4 mg, 2.812 mmol) in DMF (20 mL) at 0 °C was added NaH (in mineral oil) (136 mg of 60 %w / w, 3.400 mmol). The reaction mixture was stirred for 25 minutes then methyl iodide (196 µL, 3.148 mmol) was added. The reaction mixture was stirred for 1 hour in an ice bath and then ice was added to the reaction. The suspension was diluted with water and was stirred at room temperature for 10 minutes. The solid was filtered and washed with water anddried in vacuo to afford 3-bromo-5-methyl-6-[1-(trifluoromethyl)cyclobutyl]pyrrolo[2,3- b]pyrazine (889.6 mg, 94%) as a beige solid.1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 6.54 (s, 1H), 3.71 (s, 3H), 2.87 – 2.78 (m, 2H), 2.74 – 2.62 (m, 2H), 2.37 – 2.22 (m, 1H), 2.07 – 1.94 (m, 1H). ESI-MS m / z calc.333.00885, found 333.97 (M+1)+; Retention time: 0.71 minutes. LC method B. Example 15: Preparation of 3-bromo-5-methyl-6-(2,2,2-trifluoro-1,1-dimethyl- ethyl)pyrrolo[2,3-b]pyrazine Step 1: 6-Bromo-3-(4,4,4-trifluoro-3,3-dimethyl-but-1-ynyl)pyrazin-2-amine

[0276] In a flask under nitrogen atmosphere containing a solution of 4,4,4-trifluoro-3,3- dimethyl-but-1-yne (11.31 g, 83.092 mmol) in THF (250 mL) were added 3,6-dibromopyrazin- 2-amine (9.15 g, 36.181 mmol), triethylamine (12.342 g, 17 mL, 121.97 mmol), bis(triphenylphosphine)palladium(II) dichloride (3.52 g, 5.0150 mmol) and copper iodide (800 mg, 4.2006 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. Bis(triphenylphosphine)palladium(II) dichloride (1.57 g, 2.2368 mmol) and copper iodide (450 mg, 2.3628 mmol) were added to the mixture and the mixture was flushed with nitrogen for 5 min. The mixture was stirred for 2 hours at rt under nitrogen atmosphere. Additional Bis(triphenylphosphine)palladium(II) dichloride (1.583 g, 2.2553 mmol) and copper iodide (472 mg, 2.4783 mmol) were added to the mixture and the mixture was flushed with nitrogen for 5 min. The mixture was stirred for 16 hours at rt under nitrogen atmosphere. The reaction mixture was filtered on Celite, and the cake was washed with acetonitrile (5 x 30 mL). Purification by reversed-phase chromatography (C18column. Gradient 5 - 80% acetonitrile in water with 0.1% formic acid) was performed. The fractions containing the product were combined and the volatiles were removed under reduced pressure. The aqueous phase was extracted with EtOAc (3 x 100 mL). The organic phases were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford 6-bromo-3-(4,4,4-trifluoro-3,3-dimethyl-but-1-ynyl)pyrazin-2-amine (6.82 g, 60%) as a yellow solid. ESI-MS m / z calc.306.9932, found 308.1 (M+1)+; Retention time: 2.13minutes1H NMR (400 MHz, Chloroform-d) δ 7.98 (s, 1H), 5.11 (br s, 2H), 1.56 (overlapped with water, s, 6H).19F NMR (377 MHz, Chloroform-d) δ -77.85 (s, 3F). LC method O. Step 2: 3-Bromo-5-methyl-6-(2,2,2-trifluoro-1,1-dimethyl-ethyl)pyrrolo[2,3- b]pyrazine

[0277] To a solution of 6-bromo-3-(4,4,4-trifluoro-3,3-dimethyl-but-1-ynyl)pyrazin-2-amine (10.8 g, 35.019 mmol) in anhydrous DMF (280 mL), in a flame dried flask, at 0°C under nitrogen, was added NaH (3.15 g, 60 % w / w, 78.758 mmol). The mixture was stirred at 70 °C for 60 min. The mixture was allowed to cool down to 0 °C. A solution of dimethyl sulfate (8.7780 g, 6.6 mL, 69.594 mmol) in anhydrous DMF (100 mL) was added dropwise to the mixture at 0 °C over 45 min using a syringe driver. The mixture was stirred at 0 °C for an additional 10 min. Then, a saturated aqueous solution of NH4Cl (2 L) and water (2 L) were added. The mixture was stirred at rt for 10 min. The precipitate was collected by filtration, washed with cold water (3 x 50 mL) and dried under high vacuum to afford 3-bromo-5-methyl- 6-(2,2,2-trifluoro-1,1-dimethyl-ethyl)pyrrolo[2,3-b]pyrazine (10 g, 87%) as a brown solid. ESI- MS m / z calc.321.0088, found 322.0 (M+1)+; Retention time: 2.18 minutes. LC method O. Example 16: Preparation of 3-bromo-5-methyl-6-spiro[2.3]hexan-5-yl-pyrrolo[2,3- b]pyrazine Step 1: Methyl spiro[2.3]hexane-5-carboxylate

[0278] To a solution of diethylzinc in hexanes (119 mL of 1 M, 119.00 mmol) in DCM (27.5 mL) was added a solution of TFA (13.480 g, 9.2 mL, 117.04 mmol) in DCM (27.5 mL) dropwise at 0 °C over 30 min. A solution of diiodomethane (30.239 g, 9.2 mL, 111.77 mmol) in DCM (27.5 mL) was added dropwise at 0 °C over 45 min. The reaction mixture was stirred at 0°C for 1 h. A solution of methyl 3-methylenecyclobutanecarboxylate (5 g, 38.445 mmol) in DCM (27.5 mL) was added to the reaction mixture. The reaction mixture was allowed to warm to room temperature for 48 h. A saturated ammonium chloride solution (100 mL) was added, and the mixture was extracted with DCM (3 x 50 mL). The organic phases were combined, washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and carefully evaporated under reduced pressure to afford the crude methyl spiro[2.3]hexane-5-carboxylate (12.5 g, 100%) as a yellow liquid.1H NMR (400 MHz, Chloroform-d) δ 3.71 (s, 3H), 3.34 - 3.24 (m, 1H), 2.55 - 2.46 (m, 2H), 2.29 - 2.19 (m, 2H), 0.53 - 0.38 (m, 4H). ESI-MS m / z calc. 140.0837, found 141.1 (M+1)+; Retention time: 1.91 minutes. LC method O. Step 2: spiro[2.3]Hexane-5-carboxylic acid

[0279] To a stirred solution of methyl spiro[2.3]hexane-5-carboxylate (37.5 g, 9.0954 mmol) in DCE (22 mL) was added NaOH (1.1 g, 27.502 mmol) in MeOH (10 mL). The mixture was stirred at room temperature for 16 h. Ether (50 mL) and water (80 mL) were added, and the phases were separated. The aqueous phase was washed with ether (2 x 80 mL) and then acidified with a 6 N HCl solution (5 mL). The aqueous phase was extracted with DCM (3 x 100 mL) and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford spiro[2.3]hexane-5-carboxylic acid (890 mg, 76%) as a clear oil.1H NMR (400 MHz, DMSO-d6) δ 12.06 (br s, 1H), 3.17 (tt, J = 9.4, 7.3 Hz, 1H), 2.38 - 2.29 (m, 2H), 2.23 - 2.13 (m, 2H), 0.50 - 0.32 (m, 4H). ESI-MS m / z calc.126.0681, found 127.2 (M+1)+; Retention time: 1.59 minutes. LC method O. Step 3: spiro[2.3]Hexan-5-ylmethanol

[0280] To a solution of spiro[2.3]hexane-5-carboxylic acid (7.28 g, 46.974 mmol) in anhydrous THF (216 mL) at 0°C was added dropwise a borane-THF complex (60 mL of 1 M, 60.000 mmol) solution under nitrogen. The reaction mixture was stirred at room temperature for16 h, then was quenched with water (50 mL), a saturated aqueous solution of sodium bicarbonate (50 mL) and diethyl ether (400 mL) and water (350 mL) were added. The aqueous phase was extracted with diethyl ether (2 x 100 mL) and the combined organics were washed with brine (600 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford spiro[2.3]hexan-5-ylmethanol (7.9 g, 100%) as a yellow liquid.1H NMR (400 MHz, Chloroform-d) δ 3.73 - 3.69 (m, 2H), 2.67 - 2.54 (m, 1H), 2.21 - 2.12 (m, 2H), 1.90 - 1.82 (m, 2H), 0.46 - 0.34 (m, 4H), (1H missing, labile proton). Step 4: spiro[2.3]Hexane-5-carbaldehyde

[0281] To a stirring mixture of spiro[2.3]hexan-5-ylmethanol (7.467 g, 51.191 mmol) and TEMPO (925 mg, 5.9202 mmol) in DCM (80 mL) at 0 °C was added a solution of sodium bromide (3.1 g, 30.128 mmol) in water (40 mL). This suspension was stirred at that temperature for 15 min then a solution of sodium hypochlorite (in water) (53 mL of 10 % w / v, 71.196 mmol) with sodium bicarbonate (8.9 g, 105.94 mmol) was added dropwise over 1 h, while avoiding using the excess of sodium bicarbonate at the bottom of the flask. The mixture was stirred at 0 °C for 30 minutes then it was diluted with distilled water (40 mL). The aqueous phase was separated then extracted with DCM (3 x 70 mL). The combined organics were washed with brine (250 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford spiro[2.3]hexane-5-carbaldehyde (5.6389 g, 100%) as a light yellow liquid.1H NMR (400 MHz, Chloroform-d) δ 9.80 (d, J = 2.3 Hz, 1H), 3.32 - 3.19 (m, 1H), 2.45 - 2.21 (m, 4H), 0.54 - 0.35 (m, 4H). Step 5: 5-(2,2-Dibromovinyl)spiro[2.3]hexane

[0282] To a solution of spiro[2.3]hexane-5-carbaldehyde (6.52 g, 59.190 mmol) in DCM (290 mL) was added triphenylphosphine (47 g, 177.40 mmol). The mixture was placed in a water bath and a solution of CBr4 (30 g, 89.558 mmol) in DCM (40 mL) was added dropwise over 1 hour. The mixture was stirred at room temperature for 16 hours. The reaction mixturewas concentrated under reduced pressure and the resulting precipitate was triturated in pentane (100 mL). The solvent was filtered on a silica pad and the silica cake was washed with pentane (3 x 100 mL). The solvent was removed under reduced pressure. Purification by silica gel chromatography (isocratic: 100% heptanes) yielded after evaporation of the volatiles 5-(2,2- dibromovinyl)spiro[2.3]hexane (16.7 g, 66%) as a colorless liquid.1H NMR (400 MHz, Chloroform-d) δ 6.67 (d, J = 8.6 Hz, 1H), 3.38 - 3.23 (m, 1H), 2.37 - 2.27 (m, 2H), 2.16 - 2.07 (m, 2H), 0.52 - 0.36 (m, 4H). ESI-MS m / z calc.305.8867, found no ionization; Retention time: 2.39 minutes. LC method O. Step 6: 5-Ethynylspiro[2.3]hexane

[0283] To a solution of 5-(2,2-dibromovinyl)spiro[2.3]hexane (13.6 g, 31.651 mmol) in anhydrous THF (113 mL) was added n-BuLi (solution in hexanes) (28 mL of 2.5 M, 70.000 mmol) dropwise over 30 minutes at -78 °C. After addition, the reaction mixture was stirred at - 78 °C for 1 hour and 30 minutes. Then it was quenched with an aqueous saturated ammonium chloride (2.2 mL) solution, dried over anhydrous sodium sulfate, and filtered over cotton to give 5-ethynylspiro[2.3]hexane (3.3602 g, 100%) as a solution in THF (113 mL). The product was used as a solution for the next step. Step 7: 6-Bromo-3-(2-spiro[2.3]hexan-5-ylethynyl)pyrazin-2-amine

[0284] In a flask under nitrogen atmosphere containing a solution of 5- ethynylspiro[2.3]hexane (3.36 g, 31.649 mmol) in THF (26 mL) were added 3,6- dibromopyrazin-2-amine (4.6 g, 17.826 mmol), TEA (7.3326 g, 10.1 mL, 72.464 mmol), PdCl2(PPh3)2(1.3 g, 1.8151 mmol) and CuI (345 mg, 1.7934 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 hours. The reaction mixture was filtered on celite, and the cake was washed with acetonitrile (5 x 50 mL). The organics were concentrated under reduced pressure and the resulting residue was purified by reversed-phasechromatography (C18 column. Gradient: 5-100 % MeCN in water with 0.1 % formic acid) to afford after evaporation of the MeCN and extraction with DCM (3 x 150 mL) 6-bromo-3-(2- spiro[2.3]hexan-5-ylethynyl)pyrazin-2-amine (3.52 g, 71%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.79 (s, 1H), 6.99 (br s, 2H), 3.50 (tt, J = 8.9, 7.7 Hz, 1H), 2.49 - 2.34 (m, 4H), 0.52 - 0.40 (m, 4H). ESI-MS m / z calc.277.0215, found 278.1 (M+1)+; Retention time: 2.17 minutes. LC method O. Step 8: 3-Bromo-5-methyl-6-spiro[2.3]hexan-5-yl-pyrrolo[2,3-b]pyrazine

[0285] To a solution of 6-bromo-3-(2-spiro[2.3]hexan-5-ylethynyl)pyrazin-2-amine (3.52 g, 12.642 mmol) in anhydrous DMF (22 mL), in a flame-dried flask at 0°C under nitrogen, was added NaH (1.1 g, 60 %w / w, 27.503 mmol) portion-wise. The mixture was allowed to warm up to room temperature and was stirred for 16 hours. Dimethyl sulfate (3.5838 g, 2.7 mL, 28.356 mmol) in DMF (7 mL) was added dropwise at 0°C over 15 minutes, and the reaction was stirred for 30 minutes. Water (150 mL), a saturated aqueous solution of ammonium chloride (50 mL) and EtOAc (200 mL) were added, and the phases were separated. The organic phase was washed with water (2 x 200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. Purification by silica gel chromatography (Gradient 0 - 10% EtOAc in heptanes) afforded after evaporation of the volatiles and freeze-drying 3-bromo-5- methyl-6-spiro[2.3]hexan-5-yl-pyrrolo[2,3-b]pyrazine (1.65 g, 44%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 8.42 (s, 1H), 6.56 (d, J = 0.9 Hz, 1H), 3.94 - 3.83 (m, 1H), 3.72 (s, 3H), 2.60 - 2.47 (m, 4H), 0.64 - 0.56 (m, 2H), 0.54 - 0.46 (m, 2H). ESI-MS m / z calc.291.0371, found 292.1 (M+1)+; Retention time: 3.31 minutes. LC method P.Example 17: Preparation of 3-bromo-5-methyl-6-(2,2,2-trifluoro-1,1-dimethyl- ethyl)pyrrolo[2,3-b]pyrazine Step 1: 6-Bromo-3-(4,4,4-trifluoro-3,3-dimethyl-but-1-ynyl)pyrazin-2-amine

[0286] In a flask under nitrogen atmosphere containing a solution of 4,4,4-trifluoro-3,3- dimethyl-but-1-yne (11.31 g, 83.092 mmol) in THF (250 mL) were added 3,6-dibromopyrazin- 2-amine (9.15 g, 36.181 mmol), triethylamine (12.342 g, 17 mL, 121.97 mmol), bis(triphenylphosphine)palladium(II) dichloride (3.52 g, 5.0150 mmol) and copper(I) iodide (800 mg, 4.2006 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. Bis(triphenylphosphine)palladium(II) dichloride (1.57 g, 2.2368 mmol) and copper(I) iodide (450 mg, 2.3628 mmol) were added to the mixture and the mixture was flushed with nitrogen for 5 min. The mixture was stirred for 2 hours at rt under nitrogen atmosphere. Additional Bis(triphenylphosphine)palladium(II) dichloride (1.583 g, 2.2553 mmol) and copper iodide (472 mg, 2.4783 mmol) were added to the mixture and the mixture was flushed with nitrogen for 5 min. The mixture was stirred for 16 hours at rt under nitrogen atmosphere. The reaction mixture was filtered on Celite, and the cake was washed with acetonitrile (5 x 30 mL). Purification by reversed-phase chromatography (C18 column. Gradient 5 - 80% acetonitrile in water with 0.1% formic acid) was performed. The fractions containing the product were combined and the volatiles were removed under reduced pressure. The aqueous phase was extracted with EtOAc (3 x 100 mL). The organic phases were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford 6-bromo-3-(4,4,4-trifluoro-3,3-dimethyl-but-1-ynyl)pyrazin-2-amine (6.82 g, 60%) as a yellow solid. ESI-MS m / z calc.306.9932, found 308.1 (M+1)+; Retention time: 2.13 minutes1H NMR (400 MHz, Chloroform-d) δ 7.98 (s, 1H), 5.11 (br s, 2H), 1.56 (overlapped with water, s, 6H).19F NMR (377 MHz, Chloroform-d) δ -77.85 (s, 3F). LC method O.Step 2: 3-Bromo-5-methyl-6-(2,2,2-trifluoro-1,1-dimethyl-ethyl)pyrrolo[2,3- b]pyrazine

[0287] To a solution of 6-bromo-3-(4,4,4-trifluoro-3,3-dimethyl-but-1-ynyl)pyrazin-2-amine (10.8 g, 35.019 mmol) in anhydrous DMF (280 mL), in a flame dried flask, at 0°C under nitrogen, was added NaH (3.15 g, 60 %w / w, 78.758 mmol). The mixture was stirred at 70 °C for 60 minutes. The mixture was allowed to cool down to 0 °C. A solution of dimethyl sulfate (8.7780 g, 6.6 mL, 69.594 mmol) in anhydrous DMF (100 mL) was added dropwise to the mixture at 0 °C over 45 min using a syringe driver. The mixture was stirred at 0 °C for an additional 10 minutes. Then, a saturated aqueous solution of NH4Cl (2 L) and water (2 L) were added. The mixture was stirred at rt for 10 minutes. The precipitate was collected by filtration, washed with cold water (3 x 50 mL) and dried under high vacuum to afford 3-bromo-5-methyl- 6-(2,2,2-trifluoro-1,1-dimethyl-ethyl)pyrrolo[2,3-b]pyrazine (10 g, 87%) as a brown solid. ESI- MS m / z calc.321.0088, found 322.0 (M+1)+; Retention time: 2.18 minutes. LC method O. VI. Synthesis of substituted bicyclic esters and alkyl-phosphonate intermediates Example 18: Preparation of 1-(6-tert-butyl-5-methyl-pyrrolo[2,3-b]pyrazin-3-yl)-2- dimethoxyphosphoryl-ethanone Step 1: 6-Chloro-3-(3,3-dimethylbut-1-ynyl)pyrazin-2-amine

[0288] In a stirred solution of 3-bromo-6-chloro-pyrazin-2-amine (10 g, 47.975 mmol) in triethylamine (100 mL) nitrogen was bubbled for 10 minutes.3,3-Dimethylbut-1-yne (3.9200 g, 5.6 mL, 47.721 mmol) was added, followed by bis(triphenylphosphine)palladium(II) dichloride (1.67 g, 2.3793 mmol) and copper iodide (450 mg, 2.3628 mmol). Nitrogen was bubbled into the mixture for 5 minutes. The mixture was stirred at room temperature for 3 hours. The mixturewas diluted by EtOAc (200 mL), was filtered on a pad of Celite and the pad was rinsed with EtOAc (250 mL). Water (250 mL) was then added and the filtrate was washed with water (3 x 250 mL) and brine (1 x 200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford crude of 6-chloro-3-(3,3-dimethylbut-1-ynyl)pyrazin-2-amine (10 g, 94%) as an brownish solid;1H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 6.85 (br. S., 2H), 1.31 (s, 9H). ESI-MS m / z calc.209.072, found 210.2 (M+1)+; Retention time: 1.76 minutes. The crude was used for the next step without further purification. ESI-MS m / z calc.209.07198, found 210.2 (M+1)+; Retention time: 1.76 minutes; LC method I. Step 2: 6-tert-Butyl-3-chloro-5-methyl-pyrrolo[2,3-b]pyrazine

[0289] To a solution of 6-chloro-3-(3,3-dimethylbut-1-ynyl)pyrazin-2-amine (8.8 g, 41.466 mmol) in DMF (120 mL) was added potassium tert-butoxide (24 g, 213.88 mmol). The reaction mixture was heated at 80 °C for 30 minutes and was allowed to cool down to room temperature. To the reaction mixture at room temperature was added methyl iodide (11.400 g, 5 mL, 80.316 mmol) dropwise over 20 minutes and the reaction was stirred for 45 minutes. To the reaction mixture at room temperature was again added methyl iodide (11.400 g, 5 mL, 80.316 mmol) dropwise over 20 minutes and the reaction was stirred for 15 minutes. A saturated aqueous solution of sodium thiosulfate (50 mL) was added, and the mixture was stirred for 1 hour. The reaction mixture was diluted with water (100 mL), brine (100 mL) and ethyl acetate (100 mL) and the phases were separated. The aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (3 x 150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude 6-tert-butyl-3- chloro-5-methyl-pyrrolo[2,3-b]pyrazine (9.6 g, 76%) as dark red oil.1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 6.49 (s, 1H), 3.99 (s, 3H), 1.51 (s, 9H). ESI-MS m / z calc.223.0876, found 224.2 (M+1)+; Retention time: 1.93 minutes. LC method I. Step 3: Methyl 6-tert-butyl-5-methyl-pyrrolo[2,3-b]pyrazine-3-carboxylate

[0290] To a suspension of 6-tert-butyl-3-chloro-5-methyl-pyrrolo[2,3-b]pyrazine (8.65 g, 36.850 mmol) in MeOH (50 mL) was added triethylamine (6.5340 g, 9 mL, 64.572 mmol). Nitrogen was bubbled into the mixture for 15 minutes and then Pd(dppf)Cl2.DCM (906 mg, 1.1094 mmol) was added. Nitrogen bubbling was then continued for 5 minutes. The mixture was then stirred at 80 °C under 60 psi carbon monoxide pressure for 18 hours. The mixture was then allowed to cool down to room temperature, was filtered on a Celite pad followed by a silica gel pad and concentrated in vacuo. Water (100 mL) and EtOAc (100 mL) were then added, and the mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford crude methyl 6-tert-butyl-5-methyl-pyrrolo[2,3-b]pyrazine-3-carboxylate (9.53 g, 90%) as an orange oil. It was engaged in the following step without any further purification.1H NMR (400 MHz, CDCl3) δ 9.17 (s, 1H), 6.60 (s, 1H), 4.10 (s, 3H), 4.04 (s, 3H), 1.55 (s, 9H). ESI-MS m / z calc.247.1321, found 248.2 (M+1)+; Retention time: 1.7 minutes. LC method I. Step 4: 1-(6-tert-Butyl-5-methyl-pyrrolo[2,3-b]pyrazin-3-yl)-2- dimethoxyphosphoryl-ethanone

[0291] LiHMDS (in THF) (41 mL of 1 M, 41.000 mmol) was added to a solution of dimethyl methylphosphonate (2.5212 g, 2.2 mL, 20.320 mmol) in THF (130 mL) maintained at 0°C. This solution was left stirring for 30 min at this temperature. A solution of methyl 6-tert-butyl-5- methyl-pyrrolo[2,3-b]pyrazine-3-carboxylate (4.53 g, 18.300 mmol) in THF (50 mL) was added at 0°C. The reaction was stirred at 0°C for 90 minutes. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride (50 mL).1 N aqueous HCl (100 mL) was added dropwise to the suspension until the solid mostly dissolved. The layers were then separated, and the aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (Gradient: 0-5 % MeOH in DCM) to afford 2.53 g of pure product as a yellow solid. The mixed fractions were combined, evaporated under reduced pressure, and purified by reversed-phase chromatography (5%-100% MeCN in water) to afford 3.04 g of pure product as a yellow solid. The two products werecombined to afford 1-(6-tert-butyl-5-methyl-pyrrolo[2,3-b]pyrazin-3-yl)-2- dimethoxyphosphoryl-ethanone (5.45 g, 88%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 6.66 (s, 1H), 4.11 (s, 3H), 4.07 (d, J = 22.3 Hz, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 1.56 (s, 9H). ESI-MS m / z calc.339.1348, found 340.2 (M+1)+; Retention time: 3.62 minutes. LC method J. Example 19: Preparation of methyl 5-methyl-6-(1-methylcyclopropyl)pyrrolo[2,3- b]pyrazine-3-carboxylate Step 1: Trimethyl-[2-(1-methylcyclopropyl)ethynyl]silane

[0292] To a solution of 2-cyclopropylethynyl(trimethyl)silane (8.54 g, 10.047 mL, 61.758 mmol) in Et2O (70 mL) at room temperature was slowly added n-BuLi in hexanes (30 mL of 2.5 M, 75.000 mmol) over 20 minutes. The reaction mixture was stirred at room temperature for 18 hours, then the reaction was cooled down to -15 °C in a dry-ice / acetone bath. To the reaction mixture was slowly added dropwise methyl iodide (9.5760 g, 4.2 mL, 67.466 mmol) over 10 minutes. The resulting solution was stirred at -10 °C for 10 minutes, and then at 0 °C for 1 hour. The reaction mixture was allowed to warm to room temperature for 1 hour. The reaction mixture was diluted with diethyl ether (50 mL) and water (50 mL) and brine (50 mL) were added. The phases were separated, and the aqueous phase was extracted with diethyl ether (3 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (Eluent: 100% Heptane) afforded trimethyl-[2-(1-methylcyclopropyl)ethynyl]silane (2.63 g, 19%) as a light yellow liquid. GC-MS m / z calc.152.1021, found 152.00 (M), retention time 5.041 minutes. GC-MS method: Column HP 5 ms Ultra Inert 30 m x 250 μm x 0.25 μm, control mode: flow: 3.3 mL / min, split ratio mode: 33:1, split flow: 165 mL / min., carrier gas: He. Injector temperature 250oC, FID temperature 300oC, MSD transfer line 250oC, solvent delay: 3 min. Oven temperature: isotherm at 40oC for 1 min, then linear heating at 10oC / min until 100oC, then 20oC / min until 220oC then isotherm 220oC for 4 min. Run time 17 min. Step 2: 6-Chloro-3-[2-(1-methylcyclopropyl)ethynyl]pyrazin-2-amine

[0293] To a sealed tube equipped with a stir bar were added copper(I) iodide (221 mg, 1.1604 mmol), bis(triphenylphosphine)palladium(II) chloride (330 mg, 0.4702 mmol), triphenylphosphine (234 mg, 0.8922 mmol), cesium fluoride (4.6 g, 30.282 mmol), 3-bromo-6- chloro-pyrazin-2-amine (3.15 g, 15.112 mmol), poly(ethylene glycol) 200 MW (3.0 mL), triethylamine (25 mL) and water (1.5 mL). The vial was capped and the mixture sparged with nitrogen for 15 minutes while being stirred at room temperature. Trimethyl-[2-(1- methylcyclopropyl)ethynyl]silane (2.63 g, 11.621 mmol) was then added and the tube was sealed. The reaction mixture was allowed to stir at 80 °C for 17 hours. The mixture was allowed to cool to room temperature then was diluted with ethyl acetate (50 mL), water (50 mL) and brine (50 mL). The phases were separated, and the organic layer was washed with a 50% aqueous saturated sodium chloride solution (2 x 50 mL). The combined aqueous layers were extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (Gradient: 0-30% EtOAc in heptane) afforded 6-chloro-3-[2-(1-methylcyclopropyl)ethynyl]pyrazin-2-amine (2.23 g, 82%) as a yellow solid. ESI-MS m / z calc.207.05632, found 208.2 (M+1)+; Retention time: 1.76 minutes; LC method I. Step 3: 3-Chloro-5-methyl-6-(1-methylcyclopropyl)pyrrolo[2,3-b]pyrazine

[0294] To a solution of 6-chloro-3-[2-(1-methylcyclopropyl)ethynyl]pyrazin-2-amine (2.23 g, 9.5682 mmol) in DMF (30 mL) was added potassium tert-butoxide (3.3 g, 29.409 mmol). The reaction mixture was heated at 80 °C for 50 min then the reaction was allowed to cool down to room temperature before methyl iodide (2.7360 g, 1.2 mL, 19.276 mmol) was added dropwise. The reaction was stirred at room temperature for 1 hour then potassium tert-butoxide (1.02 g, 1.1308 mL, 9.0899 mmol) and methyl iodide (2.2800 g, 1 mL, 16.063 mmol) were again added. The reaction mixture was stirred at room temperature for 18 hours then was diluted with H2O(100 mL), ethyl acetate (50 mL) and brine (100 mL). The phases were separated, and the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with a 50% solution of brine (4 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was diluted with EtOAc (30 mL) and activated carbon (1.5 g was added). The suspension was stirred for 10 minutes then the solution was filtered on a silica pad and washed with EtOAc (200 mL). The filtrate was concentrated under reduced pressure to afford 3-chloro-5-methyl-6-(1- methylcyclopropyl)pyrrolo[2,3-b]pyrazine (1.88 g, 82%) as a brown solid. ESI-MS m / z calc. 221.07198, found 222.2 (M+1)+; Retention time: 1.88 minutes; LC method I. Step 4: Methyl 5-methyl-6-(1-methylcyclopropyl)pyrrolo[2,3-b]pyrazine-3- carboxylate

[0295] To a solution of 3-chloro-5-methyl-6-(1-methylcyclopropyl)pyrrolo[2,3-b]pyrazine (4.56 g, 19.788 mmol) in methanol (40 mL) was added triethylamine (5.8080 g, 8 mL, 57.397 mmol). The solution was sparged with nitrogen for 15 minutes then Pd(dppf)Cl2.DCM (872 mg, 1.0678 mmol) was added. The suspension was sparged with nitrogen for 5 minutes then was stirred at 100 °C under 50 psi of carbon monoxide for 18 hours. The mixture was allowed to cool down to room temperature and was filtered through Celite, washed with EtOAc (2 x 25 mL) and the filtrate was concentrated in vacuo. Purification by silica gel chromatography (Gradient: 0-50% EtOAc in heptane) afforded methyl 5-methyl-6-(1- methylcyclopropyl)pyrrolo[2,3-b]pyrazine-3-carboxylate (4.24 g, 85%) as a light yellow solid.1H NMR (400 MHz, CDCl3) δ 9.17 (s, 1H), 6.52 (s, 1H), 4.04 (s, 3H), 4.02 (s, 3H), 1.49 (s, 3H), 1.07 – 1.00 (m, 2H), 0.95 – 0.89 (m, 2H). ESI-MS m / z calc.245.11642, found 246.2 (M+1)+; Retention time: 1.66 minutes; LC method I. Example 20: Preparation of 1-(6-tert-butyl-7-methyl-pyrrolo[2,3-d]pyrimidin-2-yl)-2- dimethoxyphosphoryl-ethanone Step 1: 5-Bromo-2-chloro-N-methyl-pyrimidin-4-amine

[0296] To a solution of 5-bromo-2,4-dichloro-pyrimidine (16 g, 70.214 mmol) in methanol (130 mL) was added dropwise methylamine in ethanol (461.54 mg, 1.85 mL of 33 %w / w, 4.9041 mmol) at 0 °C. The mixture was stirred for 20 minutes at 0 °C and for 3 hours at room temperature. The solvent was evaporated, and the residue was solubilized with ethyl acetate (100 mL). The organic layer was washed with a saturated aqueous solution of sodium bicarbonate (2 X 100 mL) and a saturated aqueous solution of NaCl (100 mL). The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure and recrystallized in heptane and ethyl acetate. The solid was filtered on Buchner funnel, rinsed with heptane and dried under high vacuum to give 5-bromo-2-chloro-N-methyl-pyrimidin-4-amine (13.7 g, 86%) as a white crystalline solid1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 5.62 (br. S, 1H), 3.09 (d, J = 4.9 Hz, 3H) ESI-MS m / z calc.220.9355, found 222.0 (M+1)+; Retention time: 1.51 minutes. LC method I. Step 2: 2-Chloro-5-(3,3-dimethylbut-1-ynyl)-N-methyl-pyrimidin-4-amine

[0297] 5-Bromo-2-chloro-N-methyl-pyrimidin-4-amine (8.459 g, 36.122 mmol) was solubilized in THF (80 mL) and triethylamine (80 mL) was added dropwise to the solution. CuI (340 mg, 1.7852 mmol) and bis(triphenylphosphine)palladium(II)chloride (1.27 g, 1.8094 mmol) were added. The mixture was purged with nitrogen for 5 minutes and 3,3-dimethyl-1- butyne (3.6018 g, 5.4 mL, 43.848 mmol) was added. The mixture was stirred for 1.5 hours at 50 °C. The reaction was diluted in ethyl acetate (200 mL) and filtered over a pad of celite. Then, the celite was rinsed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure and purified by reverse flash chromatography (gradient : acetonitrile in aqueous formic acid solution 0.1 %, 5 to 80 %, 12 CV) to afford 2-chloro-5-(3,3-dimethylbut-1-ynyl)-N-methyl- pyrimidin-4-amine (5.725 g, 57%)1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 5.54 (br. S, 1H), 3.08 (d, J = 4.9 Hz, 3H), 1.33 (s, 9H) as a yellow solid ESI-MS m / z calc.223.0876, found 224.2 (M+1)+; Retention time: 1.88 minutes. LC method I.Step 3: 6-tert-Butyl-2-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine

[0298] To a solution of 2-chloro-5-(3,3-dimethylbut-1-ynyl)-N-methyl-pyrimidin-4-amine (5.725 g, 20.422 mmol) in THF (140 mL) was added TBAF in THF (61 mL of 1 M, 61.000 mmol) and the mixture was stirred overnight at 65 °C. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc (400 mL) and the mixture was washed with water (2 x 200 mL) and brine (2 x 300 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Then, the crude product was purified by reverse flash chromatography on silica gel (gradient: 0 to 80 % acetonitrile in aqueous formic acid solution, 12 CV). The pure fractions were concentrated under reduce pressure. The aqueous phase was extracted with EtOAc (50 mL). Organic layer was washed with sodium bicarbonate (3 x 100 mL) and brine (100 mL). Then, the organic layer was dried under sodium sulfate and evaporated under reduced pressure to afford 6-tert-butyl-2-chloro-7-methyl-pyrrolo[2,3- d]pyrimidine (4.166 g, 91%) as a white solid1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 6.32 (s, 1H), 3.97 (s, 3H), 1.48 (s, 9H) ESI-MS m / z calc.223.0876, found 220.2 (M+1)+; Retention time: 1.25 minutes. LC method I. Step 4: Methyl 6-tert-butyl-7-methyl-pyrrolo[2,3-d]pyrimidine-2-carboxylate

[0299] To a stirred solution of 6-tert-butyl-2-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine (4.166 g, 18.604 mmol) and triethylamine (5.8080 g, 8 mL, 57.397 mmol) in methanol (45 mL) under nitrogen atmosphere was added Pd(dppf)Cl2.DCM (3.34 g, 4.0899 mmol). Nitrogen was bubbled for 15 minutes to the mixture and the reaction was stirred overnight at 100 °C under 60 psi of carbon monoxide. The reaction was then cooled down to room temperature and concentrated under reduced pressure. The crude was purified by flash chromatography on silica- gel (gradient : 5 to 60 % ethyl acetate in heptanes; 15 CV) and the volatiles were concentrated under reduced pressure to afford methyl 6-tert-butyl-7-methyl-pyrrolo[2,3-d]pyrimidine-2-carboxylate (3.05 g, 66%) as a white solid1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 6.45 (s, 1H), 4.10 (s, 3H), 4.07 (s, 3H),1.51 (s, 9H) ESI-MS m / z calc.247.1321, found 248.2 (M+1)+; Retention time: 1.6 minutes. LC method I. Step 5: 1-(6-tert-Butyl-7-methyl-pyrrolo[2,3-d]pyrimidin-2-yl)-2- dimethoxyphosphoryl-ethanone

[0300] To a stirred solution of dimethyl methylphosphonate (400 µL, 3.740 mmol) in THF (17.6 mL) at -78 °C was added dropwise LiHMDS (in THF solution) (4.85 mL of 1 M, 4.850 mmol). The reaction mixture was stirred at -78 °C for 15 minutes and then a solution of methyl 6-tert-butyl-7-methyl-pyrrolo[2,3-d]pyrimidine-2-carboxylate (602 mg, 2.434 mmol) in anhydrous THF (5.6 mL) was added dropwise over 5 minutes. The reaction was stirred at -78 °C for 10 minutes. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride (5 mL) and the biphasic mixture was vigorously stirred at room temperature for 5 minutes. The layers were then separated, and the aqueous layer was extracted with EtOAc (2 x 5 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by normal phase chromatography (40 g of silica gel, 0-100% of EtOAc-Hex, 15 minute run) to give a light yellow oil of 1-(6-tert-butyl-7-methyl-pyrrolo[2,3-d]pyrimidin-2-yl)-2-dimethoxyphosphoryl-ethanone (583 mg, 71%) ESI-MS m / z calc.339.1348, found 340.606 (M+1)+; Retention time: 1.001 minutes. LC method A. Example 21: Preparation of 2-dimethoxyphosphoryl-1-[5-methyl-6-[1- (trifluoromethyl)cyclopropyl]pyrrolo[2,3-b]pyrazin-3-yl]131xtracte Step 1: 1-(2,2-Dibromovinyl)-1-(trifluoromethyl)cyclopropane

[0301] To a solution of 1-(trifluoromethyl)cyclopropanecarbaldehyde (13.886 g, 100.56 mmol) in DCM was added CBr4 (50 g, 150.77 mmol). The mixture was placed in a water bathand triphenylphosphine (80 g, 305.01 mmol) was added portion-wise over 1 hour. The mixture was stirred at room temperature for 16 hours. The precipitate was filtered on a Celite pad and the Celite cake was washed with DCM (2 x 20 mL). The filtrate was carefully evaporated under reduced pressure and the product was triturated in pentanes (300 mL) for 4 hours. The precipitate was filtered on a silica pad and the silica cake was washed with pentane (3 x 50 mL). The solvent was carefully removed under reduced pressure to afford 1-(2,2-dibromovinyl)-1- (trifluoromethyl)cyclopropane (27.5 g, 70%) as a colorless liquid. Step 2: 1-Ethynyl-1-(trifluoromethyl)cyclopropane

[0302] To a solution of 1-(2,2-dibromovinyl)-1-(trifluoromethyl)cyclopropane (27.5 g, 70.175 mmol) in anhydrous THF (200 mL) was added n-BuLi (solution in hexanes) (62 mL of 2.5 M, 155.00 mmol) dropwise over 30 minutes at -78°C. After addition, the reaction mixture was stirred at -78°C for 1.5 h. Then it was quenched with ammonium chloride (7 mL), dried over magnesium sulfate and filtered on a pad of celite to give 1-ethynyl-1- (trifluoromethyl)cyclopropane as a solution in THF. The product was used as a solution for the next step. Step 3: 6-Chloro-3-[2-[1-(trifluoromethyl)cyclopropyl]ethynyl]pyrazin-2-amine

[0303] In a flask under nitrogen atmosphere containing a solution of 1-ethynyl-1- (trifluoromethyl)cyclopropane (9.4104 g, 70.175 mmol) in THF were added 3-bromo-6-chloro- pyrazin-2-amine (7.29 g, 34.973 mmol), triethylamine (11.616 g, 16 mL, 114.79 mmol), bis(triphenylphosphine)palladium(II) dichloride (2.53 g, 3.6045 mmol) and copper iodide (725 mg, 3.8068 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere (sealed tube) for 16 hours. The reaction mixture was filtered on Celite and the cake was washed with acetonitrile (5 x 30 mL). The organics were concentrated under reducedpressure and the resulting residue was purified by silica gel chromatography (0-100% EtOAc in Heptanes) to afford 6-chloro-3-[2-[1-(trifluoromethyl)cyclopropyl]ethynyl]pyrazin-2-amine (8.80 g, 96%) as an orange solid. ESI-MS m / z calc.261.0281, found 262.2 (M+1)+; Retention time: 1.8 minutes. LC method I. Step 4: 3-Chloro-6-[1-(trifluoromethyl)cyclopropyl]-5H-pyrrolo[2,3-b]pyrazine

[0304] Potassium tert-butoxide (12 g, 106.94 mmol) was added to a solution of 6-chloro-3- [2-[1-(trifluoromethyl)cyclopropyl]ethynyl]pyrazin-2-amine (8.80 g, 33.602 mmol) in tert- butanol (170 mL) and heated at 70 °C for 16 h. The mixture was allowed to cool down to room temperature, then quenched with water (20 mL). The volatiles were removed under reduced pressure and saturated aqueous ammonium chloride solution (300 mL) was added. The mixture was cooled at 0 °C and stirred for 20 minutes. The resulting precipitate was filtered and washed with distilled water (2 x 50 mL). The precipitate was dissolved in EtOAc (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide 3-chloro- 6-[1-(trifluoromethyl)cyclopropyl]-5H-pyrrolo[2,3-b]pyrazine (8.74 g, 99%) as a brown solid. ESI-MS m / z calc.261.0281, found 262.2 (M+1)+; Retention time: 1.74 minutes. This product was used in the next step without further purification. LC method I. Step 5: 3-Chloro-5-methyl-6-[1-(trifluoromethyl)cyclopropyl]pyrrolo[2,3- b]pyrazine

[0305] Sodium hydride (60% w / w in oil) (1.18 g, 29.503 mmol) was added portion-wise to a solution of 3-chloro-6-[1-(trifluoromethyl)cyclopropyl]-5H-pyrrolo[2,3-b]pyrazine (3.81 g, 14.242 mmol) in DMF (76 mL) at 0°C. The suspension was stirred at this temperature for 15 min. Dimethyl sulfate (2.7993 g, 2.1 mL, 22.193 mmol) was added and left stirring at 0°C for 15 min. The reaction was then stirred at room temperature for 1 h. The reaction mixture was cooled back to 0°C and quenched with saturated aqueous ammonium chloride solution (100 mL). Theresulting precipitate was filtered, washed with pure water (2 x 25mL) and a small volume of heptanes (5 mL) then dried under high vacuum to provide 3.65 g of the desired product as a brown solid. The filtrate was extracted with EtOAc (3 x 50 mL) and the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting precipitate was purified by reversed phase chromatography (Gradient : 5-100 % MeCN in water) to provide 318 mg of the desired product as a dark yellow solid. The two product obtained were combined to afford 3-chloro-5-methyl-6- [1-(trifluoromethyl)cyclopropyl]pyrrolo[2,3-b]pyrazine (3.96 g, 101%) as a brown solid. ESI- MS m / z calc.275.0437, found 276.2 (M+1)+; Retention time: 1.89 minutes. LC method I. Step 6: Methyl 5-methyl-6-[1-(trifluoromethyl)cyclopropyl]pyrrolo[2,3- b]pyrazine-3-carboxylate

[0306] To a suspension of 3-chloro-5-methyl-6-[1-(trifluoromethyl)cyclopropyl]pyrrolo[2,3- b]pyrazine (3.96 g, 14.351 mmol) in anhydrous methanol (72 mL) was added triethylamine (4.5012 g, 6.2 mL, 44.483 mmol). Nitrogen was bubbled into the mixture for 15 minutes and then Pd(dppf)Cl2.DCM (592 mg, 0.7249 mmol) was added. Nitrogen bubbling was then continued for 5 minutes. The mixture was then stirred at 100°C under 50 psi of carbon monoxide pressure for 18 hours. The mixture was then allowed to cool down to room temperature and was filtered on a Celite pad. The Celite cake was washed with EtOAc (2 x 30 mL) and concentrated under reduced pressure. Water (100 mL) and EtOAc (100 mL) were then added, and the mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude was purified by silica gel chromatography (Gradient: 0-60% EtOAc in heptane) to afford methyl 5-methyl-6-[1- (trifluoromethyl)cyclopropyl]pyrrolo[2,3-b]pyrazine-3-carboxylate (3.72 g, 85%) as a light yellow solid.1H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 6.86 (s, 1H), 4.06 (s, 3H), 4.03 (s, 3H), 1.69 – 1.64 (m, 2H), 1.32 – 1.27 (m, 2H).19F NMR (377 MHz, CDCl3) δ -68.55 (s, 3F). ESI-MS m / z calc.299.0882, found 300.0 (M+1)+; Retention time: 3.96 minutes. LC method J.Step 7: 2-Dimethoxyphosphoryl-1-[5-methyl-6-[1- (trifluoromethyl)cyclopropyl]pyrrolo[2,3-b]pyrazin-3-yl]135xtracte

[0307] In an oven-dried round bottom flask, [methoxy(methyl)phosphoryl]oxymethane (190 µL, 1.753 mmol) was dissolved in THF (12.5 mL). It was cooled to 0 °C before the dropwise addition of a solution of [bis(trimethylsilyl)amino]lithium (3.4 mL of 1 M, 3.400 mmol) in THF. After stirring for 30 minutes at 0 °C, a solution of methyl 5-methyl-6-[1- (trifluoromethyl)cyclopropyl]pyrrolo[2,3-b]pyrazine-3-carboxylate (500 mg, 1.671 mmol) in THF (5 mL) was then added. The reaction mixture was stirred at 0 °C for 3 hours and at room temperature overnight. The reaction was quenched with the addition of saturated aqueous ammonium chloride solution (50 mL). After stirring for 1 hour, it was extracted with EtOAc (2× 50 mL). Organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (0-100% EtOAc / hexanes over 15 minutes) provided 2-dimethoxyphosphoryl-1-[5-methyl-6-[1- (trifluoromethyl)cyclopropyl]pyrrolo[2,3-b]pyrazin-3-yl]135xtracte (340 mg, 52%) as a yellow oil that crystallized upon standing. ESI-MS m / z calc.391.09088, found 392.1 (M+1)+; Retention time: 0.57 minutes. LC method B. Example 22: Preparation of 2-dimethoxyphosphoryl-1-[5-methyl-6-[1- (trifluoromethyl)cyclopropyl]pyrrolo[2,3-b]pyrazin-3-yl]135xtracte Step 1: 6-Chloro-3-(4,4,4-trifluoro-3,3-dimethyl-but-1-ynyl)pyrazin-2-amine

[0308] In a flask under nitrogen atmosphere were dissolved 3-bromo-6-chloro-pyrazin-2- amine (963 mg, 4.6199 mmol) and CuI (93 mg, 0.4883 mmol) in THF (20 mL).4,4,4-Trifluoro- 3,3-dimethyl-but-1-yne (691 mg, 5.0766 mmol) and triethylamine (958.32 mg, 1.32 mL, 9.4705 mmol) were then added and the mixture was degassed with nitrogen for 10 min. PdCl2(PPh3)2(326 mg, 0.4645 mmol) was added and the mixture was re-degassed for another 5 min. The flask was sealed, and the reaction was stirred at room temperature for 2 hours. The mixture was filtered through Celite, washed with EtOAc (30 mL) and the filtrate concentrated in vacuo. Purification was done by reverse-phase chromatography (Gradient: 5-100 % MeOH in water with 0.1 % formic acid) to give 6-chloro-3-(4,4,4-trifluoro-3,3-dimethyl-but-1-ynyl)pyrazin-2- amine (654 mg, 54%) as an orange solid.1H NMR (400 MHz, Chloroform-d) δ 7.89 (s, 1H), 5.10 (br. S., 2H), 1.57 (s, 6H).19F NMR (377 MHz, Chloroform-d) δ -77.87 (s, 3F). ESI-MS m / z calc.263.0437, found 264.2 (M+1)+; Retention time: 1.84 minutes. LC method I. Step 2: 3-Chloro-6-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-5H-pyrrolo[2,3- b]pyrazine

[0309] In a dried-flask under nitrogen atmosphere was dissolved 6-chloro-3-(4,4,4-trifluoro- 3,3-dimethyl-but-1-ynyl)pyrazin-2-amine (3.87 g, 14.459 mmol) in dry THF (60 mL). The solution was cooled to 0°C and potassium tert-butoxide (1M solution in THF) (28 mL of 1 M, 28.000 mmol) was slowly added. The reaction mixture was heated to reflux for 2 hours. The crude was cooled down to room temperature, diluted with EtOAc (20 mL) and quenched with water (15 mL). The aqueous layer was extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with brine (2 x 15 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude was purified by reverse-phase chromatography (Gradient: 5- 100 % MeOH in water with 0.1 % formic acid) to afford 3-chloro-6-(2,2,2-trifluoro-1,1- dimethyl-ethyl)-5H-pyrrolo[2,3-b]pyrazine (2.4 g, 32%)1H NMR (400 MHz, Chloroform-d) δ 8.78 (br. S., 1H), 8.46 (s, 1H), 6.71 (d, J = 2.0 Hz, 1H), 1.66 (s, 6H).19F NMR (377 MHz, Chloroform-d) δ -75.83 (s, 3F). ESI-MS m / z calc.263.0437, found 264.2 (M+1)+; Retention time: 1.77 minutes. LC method I. Step 3: 3-Chloro-5-methyl-6-(2,2,2-trifluoro-1,1-dimethyl-ethyl)pyrrolo[2,3- b]pyrazine

[0310] To a solution of 3-chloro-6-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-5H-pyrrolo[2,3- b]pyrazine (3.55 g, 13.465 mmol) in dry DMF (80 mL) at 0 °C was added NaH (60% dispersion in mineral oil) (1.7 g, 42.504 mmol) portion-wise. The mixture was stirred at 0 °C for 10 minutes then dimethyl sulfate (3.4580 g, 2.6 mL, 27.416 mmol) was added dropwise over 20 min. The reaction was stirred at room temperature for 2 hours and cooled to 0 °C, water (20 mL) was slowly added followed by MeTHF (20 mL). The aqueous phase was extracted with MeTHF (4 x 15 mL). The combined organic layers were then washed with brine (2 x 15 mL), dried over anhydrous sodium sulfate, and filtered. The crude mixture was concentrated in vacuo and was then purified by reverse-phase chromatography (Gradient: 5-100 % MeCN in water with 0.1 % formic acid) to give 3-chloro-5-methyl-6-(2,2,2-trifluoro-1,1-dimethyl-ethyl)pyrrolo[2,3- b]pyrazine (3 g, 80%) as a tan solid.1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 6.99 (s, 1H), 3.95 (s, 3H), 1.76 (s, 6H).19F NMR (377 MHz, DMSO-d6) δ -73.79 (s, 3F). ESI-MS m / z calc.277.0594, found 278.1 (M+1)+; Retention time: 4.54 minutes. LC method I. Step 4: Methyl 5-methyl-6-(2,2,2-trifluoro-1,1-dimethyl-ethyl)pyrrolo[2,3- b]pyrazine-3-carboxylate

[0311] To a suspension of 3-chloro-5-methyl-6-(2,2,2-trifluoro-1,1-dimethyl- ethyl)pyrrolo[2,3-b]pyrazine (1.6 g, 5.0707 mmol) in anhydrous methanol (15 mL) was added triethylamine (1.0080 g, 1.4 mL, 9.9615 mmol). Nitrogen was bubbled into the mixture for 15 minutes and then Pd(dppf)Cl2.DCM (410 mg, 0.5021 mmol) was added. Nitrogen was bubbled for 5 minutes. The mixture was then stirred at 90 °C under 50 psi of carbon monoxide pressure for 3 hours. The crude was filtered on a Celite pad, washed with EtOAc (15 mL) and concentrated under reduced pressure. Water (15 mL) was added, and the mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude was purified by silica gel chromatography (Gradient: 0-70% EtOAc in heptane)to afford methyl 5-methyl-6-(2,2,2-trifluoro-1,1-dimethyl-ethyl)pyrrolo[2,3-b]pyrazine-3- carboxylate (960 mg, 62%) as a light-yellow solid. ESI-MS m / z calc.301.1038, found 302.2 (M+1)+; Retention time: 4.05 minutes.1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 7.05 (s, 1H), 4.04 (s, 3H), 3.94 (s, 3H), 1.79 (s, 6H).19F NMR (377 MHz, DMSO-d6) δ -73.62 (s, 3F). ESI-MS m / z calc.301.10382, found 302.2 (M+1)+; Retention time: 4.05 minutes; LC method J. Step 5: 2-Dimethoxyphosphoryl-1-[5-methyl-6-[1- (trifluoromethyl)cyclopropyl]pyrrolo[2,3-b]pyrazin-3-yl]138xtracte

[0312] In an oven-dried round bottom flask, [methoxy(methyl)phosphoryl]oxymethane (190 µL, 1.753 mmol) was dissolved in THF (12.5 mL). It was cooled to 0 °C before the dropwise addition of a solution of [bis(trimethylsilyl)amino]lithium (3.4 mL of 1 M, 3.400 mmol) in THF. After stirring for 30 minutes at 0 °C, a solution of methyl 5-methyl-6-[1- (trifluoromethyl)cyclopropyl]pyrrolo[2,3-b]pyrazine-3-carboxylate (500 mg, 1.671 mmol) in THF (5 mL) was then added. The reaction mixture was stirred at 0 °C for 3 hours and at room temperature overnight. The reaction was quenched with the addition of saturated aqueous ammonium chloride solution (50 mL). After stirring for 1 hour, it was extracted with EtOAc (2× 50 mL). Organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (0- 100% EtOAc / hexanes over 15 minutes) provided 2-dimethoxyphosphoryl-1-[5-methyl-6-[1- (trifluoromethyl)cyclopropyl]pyrrolo[2,3-b]pyrazin-3-yl]138xtracte (340 mg, 52%) as a yellow oil that crystallized upon standing. ESI-MS m / z calc.391.09088, found 392.1 (M+1)+; Retention time: 0.57 minutes. LC method B. Example 23: Preparation of 2-dimethoxyphosphoryl-1-(2-isopropyl-3-methyl-imidazo[4,5- b]pyrazin-5-yl)138xtracte Step 1: 5-Bromo-N3-methyl-pyrazine-2,3-diamine

[0313] A suspension of 3,5-dibromopyrazin-2-amine (1 g, 3.9542 mmol) in MeNH2 in water (10 mL of 40 %w / v, 128.80 mmol) was heated in a microwave reactor at 130 °C for 1 h. The reaction was cooled to room temperature and extracted with DCM (3 x 15 mL), dried over MgSO4, filtered and concentrated in vacuo to provide 5-bromo-N3-methyl-pyrazine-2,3-diamine (802 mg, 100%) as a tan solid.1H NMR (400 MHz, Chloroform-d) δ 7.43 (s, 1H), 4.48 (s, 1H), 4.24 (s, 2H), 2.99 (d, J = 5.0 Hz, 3H). ESI-MS m / z calc.201.98541, found 203.1 (M+1)+; Retention time: 2.4 minutes; LC method D. Step 2: 5-Bromo-2-isopropyl-3-methyl-imidazo[4,5-b]pyrazine

[0314] To a solution of 2-methylpropanoyl 2-methylpropanoate (248.04 mg, 0.260 mL, 1.5679 mmol) in isobutyric acid (2 mL) was added 5-bromo-N3-methyl-pyrazine-2,3-diamine (300 mg, 1.4775 mmol) and the reaction was stirred at room temperature for 10 minutes then heated in a microwave reactor at 130 °C for 5 h and 20 min. To the reaction was added 2- methylpropanoyl 2-methylpropanoate (477.00 mg, 0.500 mL, 3.0153 mmol) and it was heated at 130° C for 2 h. The reaction was cooled to room temperature and diluted with DCM (30 mL) and the organic phase was washed with 1 M NaOH (30 mL). The aqueous phase was back extracted with DCM (3 x 25 mL) and filtered through filter paper to remove emulsions. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (loaded onto a 12 g silica cartridge with benzene, and eluted with 0-40% EtOAc in hexanes over a 30 min gradient) to provide 5-bromo- 2-isopropyl-3-methyl-imidazo[4,5-b]pyrazine (270 mg, 72%) as an off white solid.1H NMR (500 MHz, Chloroform-d) δ 8.50 (s, 1H), 3.83 (s, 3H), 3.25 (hept, J = 6.8 Hz, 1H), 1.47 (d, J = 6.8 Hz, 6H).13C NMR (126 MHz, CDCl3) δ 165.38, 147.56, 141.09, 132.60, 28.70, 27.58, 20.77. ESI-MS m / z calc.254.01671, found 255.4 (M+1)+; Retention time: 2.87 minutes; LC method D. Step 3: Methyl 2-isopropyl-3-methyl-imidazo[4,5-b]pyrazine-5-carboxylate

[0315] To a solution of 5-bromo-2-isopropyl-1-methyl-imidazo[4,5-b]pyrazine (4.03 g, 15.797 mmol) in MeOH (80 mL) was added Pd(dppf)Cl2 – DCM complex (1.25 g, 1.5307 mmol) then TEA (32.670 g, 45 mL, 322.86 mmol) was added. The vessel was sealed and pressurized with CO gas (100 psi) and vented 3 times, then re-pressurized at 100 psi and heated at 80° C for 30 minutes. The reaction was cooled to room temperature and stirred at 100 psi for 12 h. Then the pressure was released, and the mixture was concentrated in vacuo. The reaction was diluted with toluene and the TEA salts were filtered off through a pad of celite. The supernatant was concentrated in vacuo and the residue was purified by flash chromatography (loaded with toluene onto a 120 g silica cartridge pre-equilibrated with 1% TEA in hexanes, and eluted with 0-50% EtOAc in hexanes over a 60 min gradient and held at 47% EtOAc for 15 min) to provide methyl 2-isopropyl-1-methyl-imidazo[4,5-b]pyrazine-5-carboxylate (2.8 g, 76%) as a colorless solid. ESI-MS m / z calc.234.11168, found 235.3 (M+1)+; Retention time: 2.18 minutes; LC method D. Step 4: 2-Dimethoxyphosphoryl-1-(2-isopropyl-3-methyl-imidazo[4,5-b]pyrazin- 5-yl)140xtracte

[0316] In an oven-dried round bottom flask, [methoxy(methyl)phosphoryl]oxymethane (501 mg, 4.038 mmol) was dissolved in THF (20 mL). The solution was cooled to 0 °C. A solution of [bis(trimethylsilyl)amino]lithium (8.1 mL of 1 M, 8.100 mmol) was added dropwise. After stirring at 0 °C for 30 minutes, a solution of methyl 2-isopropyl-3-methyl-imidazo[4,5- b]pyrazine-5-carboxylate (946 mg, 4.038 mmol) in THF (5 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 30 minutes and at room temperature for 1 hour. The reaction was quenched with the addition of saturated aqueous ammonium chloride solution (50 mL). After stirring for 1 hour, it was extracted with EtOAc (2× 50 mL). Organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (0-100% EtOAc / hexanes over 30 minutes) provided dimethyl (2-(2-isopropyl-1-methyl-1H-imidazo[4,5-b]pyrazin-6-yl)-2-oxoethyl)phosphonate (382 mg, 29%) as a yellow oil. ESI-MS m / z calc.326.11438, found 327.2 (M+1)+; Retention time: 0.79 minutes. LC method A. Example 24: Preparation of 2-dimethoxyphosphoryl-1-[6-(1-methylcyclopropyl)furo[2,3- b]pyrazin-2-yl]141xtracte Step 1: 5-Chloro-1-[(4-methoxyphenyl)methyl]-3-[2-(1- methylcyclopropyl)ethynyl]pyrazin-2-one

[0317] To a 20 mL microwave vial was charged 3,5-dichloro-1-[(4- methoxyphenyl)methyl]pyrazin-2-one (350 mg, 1.228 mmol), bis(triphenylphosphine)palladium(II) dichloride (16 mg, 0.02280 mmol), CuI (10 mg, 0.05251 mmol) in DMF (2.5 mL) and TEA (1.0 mL, 7.175 mmol). Then, 1-ethynyl-1-methyl- cyclopropane (100 mg, 1.248 mmol) was added, and the vessel was sealed. The mixture was irradiated at 80°C µW for 10 min. The reaction mixture was allowed to cool, diluted with DCM (20 mL) and washed with water (2x10 mL). The organic layer was washed with brine (10 mL), dried with sodium sulfate, filtered, and concentrated under vacuo. The resulting material was purified by silica gel chromatography (40 g of silica) using a gradient eluent of 100% hexanes to 80% ethyl acetate in hexanes to afford as a yellow oil 5-chloro-1-[(4-methoxyphenyl)methyl]-3- [2-(1-methylcyclopropyl)ethynyl]pyrazin-2-one (287 mg, 71%),1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.38 – 7.30 (m, 2H), 6.95 – 6.87 (m, 2H), 4.96 (s, 2H), 3.73 (s, 3H), 1.31 (s, 3H), 1.04 – 0.96 (m, 2H), 0.88 – 0.80 (m, 2H). ESI-MS m / z calc.328.09787, found 329.2 (M+1)+; Retention time: 1.83 minutes; LC method A. Step 2: 2-Chloro-6-(1-methylcyclopropyl)furo[2,3-b]pyrazine

[0318] To a solution of 5-chloro-1-[(4-methoxyphenyl)methyl]-3-[2-(1- methylcyclopropyl)ethynyl]pyrazin-2-one (283 mg, 0.8607 mmol) in DCM (5.0 mL), trifluoromethanesulfonate (6 mg, 0.02335 mmol) (silver salt) and TFA (600 µL, 7.788 mmol) were added and stirred at room temperature for 90 minutes. The residue was concentrated in vacuo and purified by silica gel chromatography (40 g of silica) using a gradient eluent of 100% hexanes to 30% ethyl acetate in hexanes to give as a pale yellow solid 2-chloro-6-(1- methylcyclopropyl)furo[2,3-b]pyrazine (148.0 mg, 82%),1H NMR (400 MHz, MeOH-d4) δ 8.14 (s, 1H), 6.73 (s, 1H), 1.55 (s, 3H), 1.41 – 1.34 (m, 2H), 1.07 – 0.99 (m, 2H). ESI-MS m / z calc. 208.04034, found 209.2 (M+1)+; Retention time: 1.76 minutes; LC method A. Step 3: Methyl 6-(1-methylcyclopropyl)furo[2,3-b]pyrazine-2-carboxylate

[0319] A mixture of 2-chloro-6-(1-methylcyclopropyl)furo[2,3-b]pyrazine (144 mg, 0.6902 mmol) and Pd(dppf)Cl2.DCM (58 mg, 0.07102 mmol) and TEA (450 µL, 3.229 mmol) in MeOH (6 mL) in a steel bomb equipped with a stir bar was purged with carbon monoxide (2 g, 68.92 mmol) three times. The reaction mixture was heated to 100°C with 150 psi of carbon monoxide and stirred for 14h. The reaction mixture was allowed to cool to rt. The reaction mixture was filtered through a pad of celite, washed with ethyl acetate, filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (12 g of silica) using a gradient eluent of 100% hexanes to 50% ethyl acetate in hexanes to give as a white solid methyl 6-(1- methylcyclopropyl)furo[2,3-b]pyrazine-2-carboxylate (77 mg, 48%),1H NMR (400 MHz, Chloroform-d) δ 8.94 (s, 1H), 6.71 (s, 1H), 4.05 (s, 3H), 1.56 (s, 3H), 1.47 – 1.42 (m, 2H), 1.03 – 0.99 (m, 2H). ESI-MS m / z calc.232.0848, found 233.3 (M+1)+; Retention time: 1.44 minutes; LC method A. Step 4: 2-dimethoxyphosphoryl-1-[6-(1-methylcyclopropyl)furo[2,3-b]pyrazin-2- yl]142xtracte

[0320] A flask was flame-dried then cooled down to room temperature using a nitrogen stream and charged with dimethyl methylphosphonate (823.60 mg, 710 μL, 6.6379 mmol) and anhydrous THF (35 mL). The solution was cooled down to 0 °C and a solution of LiHMDS in THF (13.0 mL of 1 M, 13.000 mmol) was added dropwise. The reaction was stirred at 0 °C for 30 minutes after which time a solution of methyl 6-(1-methylcyclopropyl)furo[2,3-b]pyrazine-2- carboxylate (1.5 g, 6.4525 mmol) in anhydrous THF (15 mL) was added dropwise. The reaction was stirred at 0 °C for 1 hour then quenched by the addition of a saturated aqueous solution of ammonium chloride (100 ml). The mixture was allowed to reach room temperature and vigorously stirred for 30 minutes. The layers were then separated, and the aqueous layers was extracted with ethyl acetate (3 x 40 mL) and the combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude was purified by flash chromatography on silica-gel (gradient: 0 to 100% ethyl acetate in heptanes; 10 CV, then 100% ethyl acetate; 4 CV). The desired fractions were concentrated under reduced pressure, dried under high vacuum to afford 2-dimethoxyphosphoryl-1-[6-(1- methylcyclopropyl)furo[2,3-b]pyrazin-2-yl]-acetaldehyde (1.58 g, 75%) as a light yellow powder. ESI-MS m / z calc.324.0875, found 325.2 (M+1)+; Retention time: 1.64 minutes. LC method I. Example 25: Preparation of 1-(6-tert-butylfuro[2,3-b]pyrazin-2-yl)-2- dimethoxyphosphoryl-ethanone Step 1: 5-Chloro-3-(3,3-dimethylbut-1-ynyl)-1-[(4- methoxyphenyl)methyl]pyrazin-2-one

[0321] To a 20 mL microwave vial was charged 3,5-dichloro-1-[(4- methoxyphenyl)methyl]pyrazin-2-one (457 mg, 1.603 mmol), bis(triphenylphosphine) palladium(II) dichloride (21 mg, 0.02992 mmol), CuI (14 mg, 0.07351 mmol) in DMF (3.5 mL) and TEA (1.3 mL, 9.327 mmol). Then, 3,3-dimethylbut-1-yne (290 µL, 2.429 mmol) was added and the vessel was sealed. The mixture was irradiated at 80°C µW for 10 min. The reaction mixture was allowed to cool, diluted with DCM (20 mL) and washed with water (2x10 mL). Theorganic layer was washed with brine (10 mL), dried with sodium sulfate, filtered and concentrated under vacuo. The resulting material was purified by silica gel chromatography (24 g of silica) using a gradient eluent of 100% hexanes to 80% ethyl acetate in hexanes to afford as a yellow oil 5-chloro-3-(3,3-dimethylbut-1-ynyl)-1-[(4-methoxyphenyl)methyl]pyrazin-2-one (457 mg, 86%),1H NMR (400 MHz, MeOH-d4) δ 7.77 (s, 1H), 7.38 – 7.29 (m, 2H), 6.96 – 6.88 (m, 2H), 5.05 (s, 2H), 3.78 (s, 3H), 1.34 (s, 9H). ESI-MS m / z calc.330.1135, found 331.2 (M+1)+; Retention time: 1.92 minutes; LC method A. Step 2: 6-tert-Butyl-2-chloro-furo[2,3-b]pyrazine

[0322] To a solution of 5-chloro-3-(3,3-dimethylbut-1-ynyl)-1-[(4- methoxyphenyl)methyl]pyrazin-2-one (453 mg, 1.369 mmol) in DCM (9.0 mL), trifluoromethanesulfonate (18 mg, 0.07006 mmol) (silver salt) and TFA (950 µL, 12.33 mmol) were added and stirred at room temperature for 90 minutes. The residue was concentrated in vacuo and purified by silica gel chromatography (40 g of silica) using a gradient eluent of 100% hexanes to 30% ethyl acetate in hexanes to give as an off-white solid 6-tert-butyl-2-chloro- furo[2,3-b]pyrazine (258.0 mg, 89%),1H NMR (400 MHz, MeOH-d4) δ 8.21 (s, 1H), 6.73 (s, 1H), 1.43 (s, 9H). ESI-MS m / z calc.210.05598, found 211.2 (M+1)+; Retention time: 1.9 minutes. LC method A. Step 3: Methyl 6-tert-butylfuro[2,3-b]pyrazine-2-carboxylate

[0323] A mixture of 6-tert-butyl-2-chloro-furo[2,3-b]pyrazine (295 mg, 1.400 mmol) and Pd(dppf)Cl2.DCM (115 mg, 0.1408 mmol) and TEA (900 µL, 6.457 mmol) in MeOH (10 mL) in a steel pressure vessel equipped with a stir bar was purged with carbon monoxide (4 g, 137.8 mmol) three times. The reaction mixture was heated to 100°C with 120 psi of carbon monoxide and stirred for 14 h. The reaction mixture was allowed to cool to rt. The reaction mixture was filtered through a pad of celite, washed with ethyl acetate, filtrate was concentrated in vacuo.The residue was purified by silica gel chromatography (40 g of silica) using a gradient eluent of 100% hexanes to 50% ethyl acetate in hexanes to give as a white solid methyl 6-tert- butylfuro[2,3-b]pyrazine-2-carboxylate (238 mg, 73%)1H NMR (400 MHz, Chloroform-d) δ 9.01 (s, 1H), 6.69 (s, 1H), 4.06 (s, 3H), 1.45 (s, 9H). ESI-MS m / z calc.234.10045, found 235.3 (M+1)+; Retention time: 1.53 minutes. LC method A. Step 4: 1-(6-tert-Butylfuro[2,3-b]pyrazin-2-yl)-2-dimethoxyphosphoryl-ethanone

[0324] To a stirred solution of dimethyl methylphosphonate (3.48 g, 3.0000 mL, 28.047 mmol) in dry THF (155 mL) at 0 °C was added dropwise LiHMDS (in THF solution) (53 mL of 1 M, 53.000 mmol). The reaction mixture was then stirred at 0 °C for 30 minutes and then a solution of methyl 6-tert-butylfuro[2,3-b]pyrazine-2-carboxylate (6.22 g, 26.553 mmol) in dry THF (62 mL) was added. The reaction was stirred at 0 °C for 90 minutes. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride (20 mL) and the biphasic mixture was vigorously stirred at room temperature for 30 minutes. The layers were then separated, and the aqueous layer was extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude mixture was purified by silica gel chromatography, eluting with a gradient of 0 to 40% of acetone in heptane. The fractions containing the desired product were combined and the organic solvent was evaporated in vacuo to afford 1-(6-tert- butylfuro[2,3-b]pyrazin-2-yl)-2-dimethoxyphosphoryl-ethanone (8.29 g, 96%) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 6.68 (s, 1H), 4.02 (d, J = 22.7 Hz, 2H), 3.80 (s, 3H), 3.78 (s, 3H), 1.45 (s, 9H). ESI-MS m / z calc.326.1032, found 327.2 (M+1)+; Retention time: 3.92 minutes. LC method J. Example 26: Preparation of –(7-cyclopropyl-6-isopropyl-furo[2,3-b]pyrazin-2-yl)-2- dimethoxyphosphoryl-ethanone Step 1: 2-Chloro-7-iodo-6-isopropyl-furo[2,3-b]pyrazine

[0325] To a solution of 5-chloro-1-[(4-methoxyphenyl)methyl]-3-(3-methylbut-1- ynyl)pyrazin-2-one (1.39 g, 4.3879 mmol) in dry DCM (28 mL), Iodine (1.4 g, 5.5160 mmol) in DCM (28 mL) was added slowly for 30 minutes and the resulting mixture was stirred at room temperature for 30 min. The solvent was evaporated, and the residue was subjected to silica gel column chromatography in 0% to 10% ethyl acetate in hexanes. Collected fractions were combined and concentrated. The residue was triturated with hexane (10 mL) for 30 minutes. The precipitate was filtered and washed with hexane to afford 2-chloro-7-iodo-6-isopropyl-furo[2,3- b]pyrazine (1.1 g, 74%) as a pale yellow solid.1H NMR (500 MHz, CDCl3) δ 8.15 (s, 1H), 3.43 (hept, J = 6.9 Hz, 1H), 1.40 (d, J = 6.9 Hz, 6H). ESI-MS m / z calc.321.93698, found 323.1 (M+1)+; Retention time: 3.14 minutes; LC method E. Step 2: 2-Chloro-7-cyclopropyl-6-isopropyl-furo[2,3-b]pyrazine

[0326] To a 250 mL screw top vessel was added 2-chloro-7-iodo-6-isopropyl-furo[2,3- b]pyrazine (0.953 g, 2.955 mmol), potassium cyclopropyltrifluoroborate (434 mg, 2.933 mmol), cesium carbonate (3.104 g, 9.527 mmol), Xantphos (122 mg, 0.2108 mmol), and PdOAc2 (36 mg, 0.1603 mmol) in THF (20 mL). The reaction mixture was degassed for 10 minutes, then sealed and heated in an oil bath at 150°C for 90 minutes. The reaction was cooled to RT, diluted with ethyl acetate, and washed with water, and brine. Then the organic layer was dried over sodium sulfate, filtered, and concentrated. The crude material was then purified by silica chromatography (80 g of silica, collect by ELSD) using a gradient eluent of 100% hexane to 40% ethyl acetate in hexanes over 25 min (compound elutes at 25% ethyl acetate) followed by a second purification using reverse phase HPLC chromatography (1-99% acetonitrile / 5 mM aqueous HCl over 20 min) which afforded the desired white solid as 2-chloro-7-cyclopropyl-6- isopropyl-furo[2,3-b]pyrazine (135 mg, 19%),1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 3.50– 3.35 (m, 1H), 1.82 – 1.71 (m, 1H), 1.40 (s, 3H), 1.38 (s, 3H), 1.19 – 1.11 (m, 2H), 1.03 – 0.91 (m, 2H). ESI-MS m / z calc.236.07164, found 237.1 (M+1)+; Retention time: 2.09 minutes. LC method A. Step 3: Methyl 7-cyclopropyl-6-isopropyl-furo[2,3-b]pyrazine-2-carboxylate

[0327] A mixture of 2-chloro-7-cyclopropyl-6-isopropyl-furo[2,3-b]pyrazine (135 mg, 0.5703 mmol) and Pd(dppf)Cl2.DCM (47 mg, 0.05755 mmol) and TEA (400 µL, 2.870 mmol) in MeOH (2.0 mL) in a steel pressure vessel equipped with a stir bar was purged with excess carbon monoxide (1.6 g, 55.14 mmol). The reaction mixture was heated to 100°C with 100 psi of carbon monoxide and stirred for 16 h. The reaction mixture was allowed to cool to rt. The reaction mixture was filtered through a pad of celite, washed with ethyl acetate, filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (40 g of silica) using a gradient eluent of 100% hexanes to 55% ethyl acetate in hexanes (compound elutes at 25% ethyl acetate) to afford a white solid methyl 7-cyclopropyl-6-isopropyl-furo[2,3- b]pyrazine-2-carboxylate (118 mg, 80%). ESI-MS m / z calc.260.1161, found 261.1 (M+1)+; Retention time: 1.75 minutes. LC method A. Step 4: 1-(7-Cyclopropyl-6-isopropyl-furo[2,3-b]pyrazin-2-yl)-2- dimethoxyphosphoryl-ethanone

[0328] A flask was heat gun-dried then cooled down to room temperature using a nitrogen stream and charged with dimethyl methylphosphonate (92 µL, 0.8601 mmol) and anhydrous THF (5.0 mL). The solution was cooled down to 0°C and a solution of LiHMDS in THF (1.9 mL of 1 M, 1.900 mmol) was added dropwise. The reaction was stirred at 0°C for 30 minutes after which time a solution of methyl 7-cyclopropyl-6-isopropyl-furo[2,3-b]pyrazine-2- carboxylate (118 mg, 0.4533 mmol) and methyl 7-cyclopropyl-6-isopropyl-furo[2,3-b]pyrazine- 2-carboxylate (100 mg, 0.3842 mmol) in anhydrous THF (2.2 mL) was added dropwise. Thereaction was stirred at 0°C for 90 minutes then allowed to warm to rt and stirred an additional 30 minutes. The mixture was then quenched by the addition of a saturated aqueous solution of ammonium chloride (10 mL). The mixture was allowed to stir at room temperature vigorously stirred for 30 minutes. The layers were then separated, and the aqueous layers was extracted with ethyl acetate (2 x 10 mL) and the combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude was then purified by silica chromatography (40 g of silica) using a gradient eluent of 100% hexanes to 100% ethyl acetate over 20 minutes followed by a gradient of 100% dichloromethane to 20% methanol in dichloromethane over 25 minutes. The desired fractions were concentrated under reduced pressure, and dried under high vacuum to afford 1-(7-cyclopropyl-6-isopropyl-furo[2,3- b]pyrazin-2-yl)-2-dimethoxyphosphoryl-ethanone (170 mg, 56%), ESI-MS m / z calc.352.1188, found 353.3 (M+1)+; Retention time: 1.6 minutes. LC method A. Example 27: Preparation of 1-(5-cyclobutyl-6-methyl-pyrrolo[2,3-b]pyrazin-3-yl)-2- dimethoxyphosphoryl-ethanone Step 1: 6-Bromo-3-prop-1-ynyl-pyrazin-2-amine

[0329] A solution of (E)-1-bromoprop-1-ene (2.3 g, 19.01 mmol) in dry THF (131 mL) was cooled -78 °C followed by the addition of butyllithium (14.8 mL of 2.5 M, 37.00 mmol) and the mixture was stirred for 20 min at -78 °C. Then the mixture was warmed to 0°C and water (992 µL, 55.07 mmol) was added and the mixture was stirred for 5 min at this temperature. Then, 3,6- dibromopyrazin-2-amine (4,350 mg, 17.20 mmol), trans-dichloro-bis(triphenylphosphine) palladium(II) (1.8 g, 2.564 mmol), copper iodide (491 mg, 2.578 mmol) and triethylamine (7.6 mL, 54.53 mmol) were added and the mixture was slowly warmed to room temperature and stirred for 22 hours. The dark mixture was diluted with 50 ml of ethyl acetate and filtered through thin layer of celite and dried under reduced pressure. This was then purified by silica chromatography (40 g, 0% to 20% EtOAc in Hexane (over 7 min), 10% MeOH in DCM (over 23 Min). This gave 2 aliquots of the desired product 6-bromo-3-prop-1-ynyl-pyrazin-2-amine (1.11 g, 30%) ESI-MS m / z calc.210.9745, found 213.944 (M+1)+; Retention time: 0.903minutes and 6-bromo-3-prop-1-ynyl-pyrazin-2-amine (2.34 g, 49%) ESI-MS m / z calc.210.9745, found 213.944 (M+1)+; Retention time: 0.895 minutes. LC method A. Step 2: 3-Bromo-6-methyl-5H-pyrrolo[2,3-b]pyrazine

[0330] To a solution of 6-bromo-3-prop-1-ynyl-pyrazin-2-amine (1.21 g, 4.964 mmol) in t- BuOH (10.4 mL) was added potassium tert-butoxide (2.79 g, 24.86 mmol). The reaction mixture was stirred at 100 °C for 17 hours then was allowed to cool down to room temperature. The volatiles were removed under reduced pressure and the residue was diluted with water (250 mL) and stirred at 0°C for 5 minutes and was filtered. The solid was washed with water (3 x 100 mL) and was diluted in acetonitrile (500 mL). The solution was concentrated under reduced pressure and the solid was triturated in acetonitrile (3 x 100 mL) and filtered. The solid was dried under reduced pressure to afford 3-bromo-6-methyl-5H-pyrrolo[2,3-b]pyrazine (1.07 g, 91%).1H NMR (400 MHz, DMSO) δ 12.14 (s, 1H), 8.38 (s, 1H), 6.39 (d, J = 1.1 Hz, 1H), 2.48 – 2.45 (m, 3H). ESI-MS m / z calc.210.9745, found 213.999 (M+1)+; Retention time: 1.088 minutes. LC method N. Step 3: 3-Bromo-5-cyclobutyl-6-methyl-pyrrolo[2,3-b]pyrazine

[0331] 3-Bromo-6-methyl-5H-pyrrolo[2,3-b]pyrazine (3.65 g, 14.29 mmol) was dissolved in anhydrous DMF (60.6 mL) then cooled to 0 °C. Cyclobutane iodide (6.76 g, 37.14 mmol) was added then sodium hydride (1.6 g of 60 %w / w, 40.00 mmol) was added in 4 portions over 10 minutes. Once addition was complete the reaction was stirred at 0 °C for 30 minutes then heated to 75 °C and stirred for 2.5 hours. The reaction was quenched by cautious, dropwise addition of ammonium chloride, then evaporated to dryness under reduced pressure. The residue was partitioned between EtOAc and water, and the layers were separated. The aqueous layer was further extracted with EtOAc (2 times). The combined extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. This was then purifiedby silica chromatography (80 g, 0% to 25% EtOAc in hexanes over 25 Min) to give 3-bromo-5- cyclobutyl-6-methyl-pyrrolo[2,3-b]pyrazine (1.20 g, 29%)1H NMR (400 MHz, DMSO) δ 8.43 (s, 1H), 6.49 – 6.45 (m, 1H), 5.03 – 4.90 (m, 1H), 3.12 – 2.96 (m, 2H), 2.52 (d, J = 1.0 Hz, 3H), 2.47 – 2.36 (m, 2H), 1.98 – 1.74 (m, 2H). ESI-MS m / z calc.265.02145, found 267.977 (M+1)+; Retention time: 2.288 minutes. LC method N. Step 4: Methyl 5-cyclobutyl-6-methyl-pyrrolo[2,3-b]pyrazine-3-carboxylate

[0332] To a suspension of 3-bromo-5-cyclobutyl-6-methyl-pyrrolo[2,3-b]pyrazine (1.20 g, 4.329 mmol) in MeOH (27.6 mL) was added Triethylamine (1.37 g, 13.54 mmol). Nitrogen was bubbled into the mixture for 15 minutes and then Pd(dppf)Cl2.DCM (3.7 g, 4.531 mmol) was added. Nitrogen bubbling was then continued for 5 minutes. The mixture was then stirred at 100°C under 125 psi of carbon monoxide pressure for 1 hour. The reaction mixture was dried under reduced pressure and taken up in EtOAc and passed through celite and the liquid was dried under reduced pressure. This was then purified by silica chromatography (40 g, 0% to 25% EtOAc in Hexane (over 25 Min)). This material was then triturated in EtOAc and hexanes and filtered which gave the desired product methyl 5-cyclobutyl-6-methyl-pyrrolo[2,3-b]pyrazine-3- carboxylate (469 mg, 44%)1H NMR (400 MHz, DMSO) δ 8.98 (s, 1H), 6.57 (s, 1H), 5.07 (ttd, J = 9.4, 8.0, 1.0 Hz, 1H), 3.93 (s, 3H), 3.22 – 3.06 (m, 2H), 2.61 (s, 3H), 2.51 – 2.38 (m, 2H), 2.02 – 1.76 (m, 2H). ESI-MS m / z calc.245.11642, found 246.078 (M+1)+; Retention time: 1.63 minutes. LC method N. Step 5: 1-(5-Cyclobutyl-6-methyl-pyrrolo[2,3-b]pyrazin-3-yl)-2- dimethoxyphosphoryl-ethanone

[0333] A flask was flame-dried then cooled down to room temperature using a nitrogen stream and charged with [methoxy(methyl)phosphoryl]oxymethane (587 µL, 5.417 mmol) and anhydrous THF (25.5 mL). The solution was cooled down to -78 °C and a solution of (diisopropylamino)lithium (2.6 mL of 2 M, 5.200 mmol) was added dropwise. The reaction was stirred for 1 hour at -78 °C and a solution of methyl 5-cyclobutyl-6-methyl-pyrrolo[2,3- b]pyrazine-3-carboxylate (664 mg, 2.707 mmol) in anhydrous THF (6.8 mL) was added dropwise. The reaction was then stirred at -78 °C for 30 minutes then slowly taken to 0 °C for 30 minutes. The reaction was then quenched by the addition of a saturated aqueous solution of ammonium chloride (50 mL). The biphasic mixture was vigorously stirred for 30 minutes, then the layers were separated, and the aqueous layer was extracted with ethyl acetate (3 x 75 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. This was then purified by silica chromatography (24 g, 0% to 25% EtOAc in Hexane (over 25 Min), 25% to 100% EtOAc in hexanes (over 5 Min), 0% to 15% MeOH in DCM (over 10 Min)) This gave the desired product 1-(5-cyclobutyl-6-methyl- pyrrolo[2,3-b]pyrazin-3-yl)-2-dimethoxyphosphoryl-ethanone (416 mg, 45%) ESI-MS m / z calc. 337.11914, found 338.24 (M+1)+; Retention time: 1.417 minutes. LC method N. Example 28: Preparation of 1-(6-tert-butyl-7-methyl-furo[2,3-b]pyrazin-2-yl)-2- dimethoxyphosphoryl-ethanone Step 1: Methyl 7-bromo-6-tert-butyl-furo[2,3-b]pyrazine-2-carboxylate

[0334] To a solution of methyl 6-tert-butylfuro[2,3-b]pyrazine-2-carboxylate (3.1 g, 13.23 mmol) in DMF (62 mL) at 0 °C was added N-bromo-succinimide (8.25 g, 46.35 mmol). The reaction mixture was stirred then heated at 60°C for 4 h. The reaction mixture was quenched with sodium bicarbonate (40 mL), diluted with EtOAc (200 mL), washed with sodium bisulfate solution (40 mL), water (3 x 40 mL), dried over sodium sulfate, filtered, concentrated in vacuo. The residue was purified by normal phase flash chromatography (120 g of silica gel, 0-40% EtOAc to Hex, 15 minute run) to give a clear oil of methyl 7-bromo-6-tert-butyl-furo[2,3- b]pyrazine-2-carboxylate (3.0 g, 72%) ESI-MS m / z calc.312.01096, found 312.985 (M+1)+; Retention time: 1.583 minutes. LC method A.Step 2: Methyl 6-tert-butyl-7-methyl-furo[2,3-b]pyrazine-2-carboxylate

[0335] Under an argon atmosphere, a vial with stir bar containing methyl 7-bromo-6-tert- butyl-furo[2,3-b]pyrazine-2-carboxylate (1.6 g, 5.109 mmol) was added tripotassium phosphate (3.25 g, 15.31 mmol), Pd(PPh3)4(590 mg, 0.5106 mmol) and trimethylboroxine (1.5 mL, 10.25 mmol). Degassed DMF (48 mL) and degassed water (9.6 mL) were added to the mixture. The mixture was sealed under argon and heated at 170°C in a microwave reactor for 30 min, then cooled to room temperature. To the reaction mixture was added 1 M NaOH (until pH=10) and washed with diethyl ether (50 mL) and EtOAc (50 mL). The aqueous was acidified with 1 M HCl (until pH = 3), then extracted with EtOAc (3 x 25 mL). washed with 1 M HCl (until pH = 3), dried over sodium sulfate, filtered, and concentrated in vacuo. The mixture was purified via normal phase flash chromatography (80g of silica gel, 0-50% EtOAc-hexanes, 15 minute run) to give a crude clear oil of 6-tert-butyl-7-methyl-furo[2,3-b]pyrazine-2-carboxylic acid (958 mg, 70%) ESI-MS m / z calc.234.10045, found 235.018 (M+1)+; Retention time: 1.261 minutes. To a solution of the crude intermediate 6-tert-butyl-7-methyl-furo[2,3-b]pyrazine-2-carboxylic acid (958 mg, 70%) in anhydrous DMF (21 mL) was added potassium carbonate (2.09 g, 15.12 mmol) and methyl iodide (965 µL, 15.50 mmol) and stirred 90 minutes at room temperature. The reaction was quenched with saturated aqueous and extracted with EtOAc (3 x 25 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by normal phase flash chromatography (80g of silica gel, 0- 20 EtOAc-hexanes, 15 minute run) to give a clear oil of methyl 6-tert-butyl-7-methyl-furo[2,3- b]pyrazine-2-carboxylate (761 mg, 59%) ESI-MS m / z calc.248.11609, found 249.489 (M+1)+; Retention time: 1.488 minutes. LC method A.Step 3: 1-(6-tert-Butyl-7-methyl-furo[2,3-b]pyrazin-2-yl)-2- dimethoxyphosphoryl-ethanone

[0336] To a stirred solution of dimethyl methylphosphonate (500 µL, 4.675 mmol) in THF (22 mL) at -78 °C was added dropwise LiHMDS (in THF solution) (6.0 mL of 1 M, 6.000 mmol). The reaction mixture was stirred at -78 °C for 15 minutes and then a solution of methyl 6-tert-butyl-7-methyl-furo[2,3-b]pyrazine-2-carboxylate (753.3 mg, 3.034 mmol) in anhydrous THF (7.0 mL) was added dropwise over 5 minutes. The reaction was stirred at -78 °C for 10 minutes. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride (5 mL) and the biphasic mixture was vigorously stirred at room temperature for 5 minutes. The layers were then separated, and the aqueous layer was extracted with EtOAc (2 x 5 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by normal phase chromatography (80 g of silica gel, 20-99% of EtOAc-Hex, 15 minutes run) to give a light- yellow oil of 1-(6-tert-butyl-7-methyl-furo[2,3-b]pyrazin-2-yl)-2-dimethoxyphosphoryl- ethanone (766 mg, 74%) ESI-MS m / z calc.340.1188, found 341.432 (M+1)+; Retention time: 1.417 minutes. LC method A. Example 29: Preparation of 2-dimethoxyphosphoryl-1-[5-isopropyl-7-(2- methoxyethyl)pyrrolo[2,3-b]pyrazin-3-yl]153xtracte Step 1: 3-Chloro-5-isopropyl-pyrrolo[2,3-b]pyrazine

[0337] 3-Chloro-5H-pyrrolo[2,3-b]pyrazine (4.0 g, 26.05 mmol) was dissolved in anhydrous DMF (104.9 mL) then cooled to 0 °C.2-iodopropane (3.2 mL, 32.06 mmol) was added then sodium hydride (1.53 g of 60 %w / w, 38.25 mmol) was added in portions over 10 minutes. Once addition was complete the reaction was stirred at 0 °C for 30 minutes then warmed up to room temperature and stirred for 90 minutes. The reaction was quenched by cautious, dropwiseaddition of ammonium chloride, then evaporated to dryness under reduced pressure. The residue was partitioned between EtOAc and water, and the layers were separated. The aqueous layer was further extracted with EtOAc (2 x) The combined extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel using 0-100% EtOAc / hexanes to give 3- chloro-5-isopropyl-pyrrolo[2,3-b]pyrazine (3.690 g, 72%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.58 (d, J = 3.7 Hz, 1H), 6.70 (d, J = 3.7 Hz, 1H), 5.08 (hept, J = 6.8 Hz, 1H), 1.55 (s, 3H), 1.53 (s, 3H). ESI-MS m / z calc.195.05632, found 196.9 (M+1)+; Retention time: 1.39 minutes. LC method A. Step 2: 3-Chloro-5-isopropyl-pyrrolo[2,3-b]pyrazine-7-carbaldehyde

[0338] POCl3 (1.8 mL, 19.31 mmol) was added dropwise to a solution of 3-chloro-5- isopropyl-pyrrolo[2,3-b]pyrazine (3.69 g, 18.86 mmol) in DMF (18.63 mL) at 0 °C under argon. The reaction mixture was stirred for 20 minutes at room temperature then the reaction mixture was heated at 60 °C for 1 hour. After 1 hour, the mixture was carefully added to an ice / water bath while stirring. Afterwards, NaOAc was added to the ice / water solution. The aqueous solution was extracted with DCM (3X). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using 0-100% EtOAc / hexanes to give 3-chloro-5- isopropyl-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (1.800 g, 43%) as a white solid.1H NMR (400 MHz, CDCl3) δ 10.26 (s, 1H), 8.62 (s, 1H), 8.24 (s, 1H), 5.12 (hept, J = 6.8 Hz, 1H), 1.61 (d, J = 6.8 Hz, 6H). ESI-MS m / z calc.223.05124, found 224.1 (M+1)+; Retention time: 1.23 minutes. LC method A. Step 3: 3-Chloro-5-isopropyl-7-[(Z)-2-methoxyvinyl]pyrrolo[2,3-b]pyrazine

[0339] To a suspension of methoxymethyl(triphenyl)phosphonium chloride (4.553 g, 12.88 mmol) in THF (39 mL) at 0°C was added NaHMDS in THF (16.1 mL of 1 M, 16.10 mmol) dropwise. The mixture was stirred at 0°C for 45 min. A solution of 3-chloro-5-isopropyl- pyrrolo[2,3-b]pyrazine-7-carbaldehyde (1.8 g, 8.048 mmol) in THF (21.13 mL) was added dropwise. The mixture was stirred at 0°C for 1 hour. The mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using 0-100% EtOAc / hexanes over 25 minutes to give 3-chloro-5-isopropyl-7-[(Z)-2-methoxyvinyl]pyrrolo[2,3-b]pyrazine (1.400 g, 69%) as a yellow oil (mixture of Z and E isomer, ~1:1 ratio). ESI-MS m / z calc.251.08253, found 252.1 (M+1)+; Retention time: 1.82 minutes and 1.76 minutes. LC method A. Step 4: 3-Chloro-5-isopropyl-7-(2-methoxyethyl)pyrrolo[2,3-b]pyrazine

[0340] To a solution of 3-chloro-5-isopropyl-7-[(Z)-2-methoxyvinyl]pyrrolo[2,3-b]pyrazine (~1:1 mixture of isomers, 30 mg, 0.1192 mmol) in EtOAc (12.0 mL) under nitrogen was added palladium on carbon (63.9 mg of 10 %w / w, 0.06005 mmol). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 1 h. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel using 0-100% EtOAc / hexanes over 20 minutes to give 3-chloro-5-isopropyl-7-(2-methoxyethyl)pyrrolo[2,3-b]pyrazine (19.8 mg, 65%) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.44 (s, 1H), 5.03 (hept, J = 6.8 Hz, 1H), 3.74 (t, J = 6.7 Hz, 2H), 3.39 (s, 3H), 3.09 (td, J = 6.6, 1.0 Hz, 2H), 1.52 (d, J = 6.8 Hz, 6H). ESI-MS m / z calc.253.09819, found 254.1 (M+1)+; Retention time: 1.57 minutes. LC method A.Step 5: Methyl 5-isopropyl-7-(2-methoxyethyl)pyrrolo[2,3-b]pyrazine-3- carboxylate

[0341] To a suspension of 3-chloro-5-isopropyl-7-(2-methoxyethyl)pyrrolo[2,3-b]pyrazine (422.3 mg, 1.664 mmol) in MeOH (9.7 mL) was added triethylamine (0.7 mL, 5.022 mmol). Nitrogen was bubbled into the mixture for 15 minutes and then Pd(dppf)Cl2.DCM (137.4 mg, 0.1683 mmol) was added. Nitrogen bubbling was then continued for 5 minutes. The mixture was then stirred at 100°C under 80-100 psi of carbon monoxide pressure for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using 0-100% EtOAc / hexanes over 20 minutes to give methyl 5-isopropyl-7-(2-methoxyethyl)pyrrolo[2,3-b]pyrazine-3-carboxylate (401.7 mg, 87%) as a yellow-orange oil.1H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 7.72 – 7.71 (m, 1H), 5.27 (hept, J = 6.8 Hz, 1H), 4.04 (s, 3H), 3.76 (t, J = 6.6 Hz, 2H), 3.39 (s, 3H), 3.14 (t, J = 0.9 Hz, 2H), 1.53 (d, J = 6.8 Hz, 6H). ESI-MS m / z calc.277.14264, found 278.4 (M+1)+; Retention time: 1.2 minutes. LC method A. Step 6: 2-Dimethoxyphosphoryl-1-[5-isopropyl-7-(2-methoxyethyl)pyrrolo[2,3- b]pyrazin-3-yl]156xtracte

[0342] A flask was flame-dried then cooled down to room temperature using a nitrogen stream, and charged with dimethyl methylphosphonate (0.22 mL, 2.057 mmol) and anhydrous THF (15.4 mL). The solution was cooled down to -78 °C and a solution of LiHMDS in THF (4.5 mL of 1 M, 4.500 mmol) was added dropwise. The reaction was stirred for 1 hour at -78 °C and a solution of methyl 5-isopropyl-7-(2-methoxyethyl)pyrrolo[2,3-b]pyrazine-3-carboxylate (401.7 mg, 1.448 mmol) in anhydrous THF (4.1 mL) was added dropwise. The reaction wasthen stirred at -78 °C for 1.5 h then slowly allowed to reach room temperature and stirred at room temperature for 30 minutes. The reaction was then quenched by the addition of a saturated aqueous solution of ammonium chloride (50 mL). The biphasic mixture was vigorously stirred for 30 minutes, then the layers were separated and the aqueous layer was extracted with ethyl acetate (5 x 15 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using 0-20% MeOH / DCM over 20 minutes to give 2-dimethoxyphosphoryl-1-[5-isopropyl-7-(2-methoxyethyl)pyrrolo[2,3-b]pyrazin-3- yl]acetaldehyde (485.9 mg, 91%) as an orange oil.1H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 7.75 (s, 1H), 5.11 (p, J = 6.8 Hz, 1H), 4.09 (s, 1H), 4.03 (s, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 3.76 – 3.72 (m, 2H), 3.39 (s, 3H), 3.14 (t, J = 0.9 Hz, 2H), 1.60 (d, J = 6.8 Hz, 6H). ESI-MS m / z calc.369.14536, found 370.4 (M+1)+; Retention time: 1.11 minutes. LC method A. Example 30: Preparation of 1-[6-tert-Butyl-7-(2-methoxyethyl)-5-methyl-pyrrolo[2,3- b]pyrazin-3-yl]-2-dimethoxyphosphoryl-ethanone Step 1: 3-Bromo-6-tert-butyl-5-methyl-pyrrolo[2,3-b]pyrazine-7-carbaldehyde

[0343] To a solution of 3-bromo-6-tert-butyl-5-methyl-pyrrolo[2,3-b]pyrazine (1.0 g, 3.729 mmol) in DMF (12.0 mL) was added dropwise phosphorus oxychloride (1.05 mL, 11.27 mmol) at room temperature. The mixture was heated to 70°C and stirred overnight. The mixture was cooled to room temperature and then it was quenched with water (10 mL) dropwise (exothermic). The solution was extracted with EtOAc (3 x 50 mL) then the combined organic phases were washed with aqueous saturated solution of sodium bicarbonate (50 mL), brine (50 mL) then concentrated under vacuum. The crude product was purified by flash chromatography on silica gel using 0-10% DCM / MeOH to provide 3-bromo-6-tert-butyl-5-methyl-pyrrolo[2,3- b]pyrazine-7-carbaldehyde (652.2 mg, 59%) as an orange solid.1H NMR (400 MHz, CDCl3) δ 10.70 (s, 1H), 8.65 (s, 1H), 4.11 (s, 3H), 1.72 (s, 9H). ESI-MS m / z calc.295.032, found 296.0 (M+1)+; Retention time: 1.41 minutes. LC method A.Step 2: 3-Bromo-6-tert-butyl-7-[(Z)-2-methoxyvinyl]-5-methyl-pyrrolo[2,3- b]pyrazine

[0344] To a suspension of methoxymethyl(triphenyl)phosphonium chloride (1.27 g, 3.594 mmol) in THF (14.13 mL) at 0°C was added NaHMDS in THF (4.41 mL of 1 M, 4.410 mmol) dropwise. The mixture was stirred at 0°C for 45 min. A solution of 3-bromo-6-tert-butyl-5- methyl-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (652.2 mg, 2.202 mmol) in THF (8 mL) was added dropwise. The mixture was stirred at 0°C for 1 hour. The mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using 0-100% EtOAc / hexanes over 25 minutes to give 3-bromo-6-tert-butyl-7-[(Z)-2-methoxyvinyl]-5-methyl-pyrrolo[2,3- b]pyrazine (625.1 mg, 88%) as a yellow oil (mixture of Z and E isomers). ESI-MS m / z calc. 323.06332, found 324.1 (M+1)+; Retention time: 2.01 minutes. LC method A. Step 3: methyl 6-tert-butyl-7-[(Z)-2-methoxyvinyl]-5-methyl-pyrrolo[2,3- b]pyrazine-3-carboxylate

[0345] To a suspension of 3-bromo-6-tert-butyl-7-[(Z)-2-methoxyvinyl]-5-methyl- pyrrolo[2,3-b]pyrazine (625.1 mg, 1.928 mmol) in methanol (2.0 mL) was added triethylamine (0.81 mL, 5.811 mmol). Nitrogen was bubbled into the mixture for 15 minutes and then Pd(dppf)Cl2.DCM (80.6 mg, 0.09870 mmol) was added. Nitrogen bubbling was then continued for 5 minutes. The mixture was then stirred at 100°C under 50 psi carbon monoxide pressure for 18 hours. The mixture was then allowed to cool down to room temperature, was filtered on a Celite pad and concentrated. The resulting crude product was purified by silica gelchromatography (Gradient: 0-100% EtOAc in hexane over 25 minutes) to afford methyl 6-tert- butyl-7-[(Z)-2-methoxyvinyl]-5-methyl-pyrrolo[2,3-b]pyrazine-3-carboxylate (496.7 mg, 85%). ESI-MS m / z calc.303.1583, found 304.3 (M+1)+; Retention time: 1.37 minutes. LC method A. Step 4: Methyl 6-tert-butyl-7-(2-methoxyethyl)-5-methyl-pyrrolo[2,3-b]pyrazine- 3-carboxylate

[0346] A solution of methyl 6-tert-butyl-7-[(Z)-2-methoxyvinyl]-5-methyl-pyrrolo[2,3- b]pyrazine-3-carboxylate (496.7 mg, 1.637 mmol) in THF (31.1 mL) was bubbled with nitrogen over 5 minutes and then palladium on carbon (90.3 mg, 0.08485 mmol) was added. The resulting mixture was bubbled with hydrogen for 10 minutes and then was stirred at room temperature under balloon of hydrogen for 3 days. The crude was filtered through celite, washed with ethyl acetate, and concentrated under reduced pressure to provide crude methyl 6-tert- butyl-7-(2-methoxyethyl)-5-methyl-pyrrolo[2,3-b]pyrazine-3-carboxylate (534.5 mg, 59%) as a yellow oil. ESI-MS m / z calc.305.17395, found 306.5 (M+1)+; Retention time: 1.46 minutes. LC method A. Step 5: 1-[6-tert-Butyl-7-(2-methoxyethyl)-5-methyl-pyrrolo[2,3-b]pyrazin-3-yl]- 2-dimethoxyphosphoryl-ethanone

[0347] A flask was flame-dried then cooled down to room temperature using a nitrogen stream and charged with dimethyl methylphosphonate (0.27 mL, 2.524 mmol) and anhydrous THF (21 mL). The solution was cooled down to -78 °C and a solution of LiHMDS in THF (5.3 mL of 1 M, 5.300 mmol) was added dropwise. The reaction was stirred for 1 hour at -78 °C and a solution of methyl 6-tert-butyl-7-(2-methoxyethyl)-5-methyl-pyrrolo[2,3-b]pyrazine-3-carboxylate (534.5 mg, 1.750 mmol) in anhydrous THF (5.5 mL) was added dropwise. The reaction was then stirred at -78 °C for 1.5 h then slowly allowed to reach room temperature and stirred for 30 minutes. The reaction was then quenched by the addition of a saturated aqueous solution of ammonium chloride (50 mL). The biphasic mixture was vigorously stirred for 30 minutes, then the layers were separated, and the aqueous layer was extracted with ethyl acetate (5 x 15 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using 0-20% MeOH / DCM over 20 minutes to give 1-[6-tert- butyl-7-(2-methoxyethyl)-5-methyl-pyrrolo[2,3-b]pyrazin-3-yl]-2-dimethoxyphosphoryl- ethanone (550.7 mg, 79%) as a orange oil. ESI-MS m / z calc.397.17667, found 398.2 (M+1)+; Retention time: 1.36 minutes. LC method A. VII. Synthesis of substituted alkyl aldehyde intermediates Example 31: Preparation of tert-Butyl (4S)-2,2-dimethyl-4-[(1S)-3-methyl-1-(3- oxopropoxy)butyl]oxazolidine-3-carboxylate Step 1: tert-Butyl (4S)-4-(1-hydroxy-3-methyl-butyl)-2,2-dimethyl-oxazolidine-3- carboxylate

[0348] To a solution of tert-butyl (4S)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylate (18.9 g, 82.434 mmol) in anhydrous THF (300 mL) at -78 °C was added dropwise a THF solution of isobutylmagnesium chloride (80 mL of 2 M, 160.00 mmol). The reaction was let stirred in the dry-ice bath for 20 hours allowing the temperature to slowly warm to room temperature. To the reaction mixture at 0 °C was added a saturated aqueous solution of ammonium chloride (200 mL) and EtOAc (200 mL). To the bi-phasic solution was added brine (200 mL) and the phases were separated. The aqueous layer was extracted with EtOAc (2 x 100 mL) and the combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography (Gradient: 0-20% EtOAc in heptane) afforded tert-butyl (4S)-4-(1-hydroxy-3-methyl-butyl)-2,2-dimethyl-oxazolidine-3-carboxylate (19.7 g, 79%) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 4.20 – 3.53 (overlapped with EtOAc, m, 4H), 2.00 – 1.77 (m, 1H), 1.61 (br. S., 4H), 1.50 (s, 12H), 1.42 – 1.32 (m, 1H), 1.22 – 1.08 (m, 1H), 0.99 – 0.94 (m, 3H), 0.92 (d, J = 6.6 Hz, 3H). ESI-MS m / z calc.287.2097, found 310.2 (M+23)+; Retention time: 1.89 minutes. LC method I. Step 2: tert-Butyl (4S)-4-[1-(3-te...

Claims

CLAIMS 1. A compound selected from compounds of Formula I:tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein: Ring A is selected from 7- and 8-membered heterocycles containing 0-2 additional heteroatoms selected from O and N, wherein Ring A is substituted with 0-4 groups selected from: C3-C6cycloalkyl (further substituted with 0-4 groups selected from C1-C4alkyl); C1-C5 alkyl (substituted with 0-4 groups selected from C3-C6cycloalkyl, halogen, OH, NH2, oxo, and 4- to 6-membered heterocycle); C1-C4alkoxy (substituted with 0-4 groups selected from C3-C6cycloalkyl, halogen, OH, NH2, and oxo); 5- and 6-membered heterocycle; OH; NH2; and oxo; wherein two substituents on Ring A taken together with the atoms to which they are bonded may form a ring selected from C3-C6cycloalkyl (further substituted with 0-2 groups selected from C1-C4 alkyl and C1-C4 alkoxy); Ring B is a 9-12 membered heteroaryl group containing 1-4 heteroatoms selected from N, O, and S, wherein Ring B is substituted with 1-4 groups selected from: C1-C6 alkyl (substituted with 0-3 groups selected from halogen, C1-C3 alkoxy, and OH);C3-C6cycloalkyl, substituted with 0-3 groups selected from: C1-C6alkyl (substituted with 0-3 groups selected from C1-C3alkoxy and halogen), OH, and halogen; halogen; and 5- and 6-membered heterocycle; each X is independently selected from CH and N; Z is selected from CH and N; R1is selected from H, C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 alkoxy (substituted with 0-5 halogens), and halogen; each R2is independently selected from C1-C5alkyl, C1-C5haloalkyl, C1-C5alkoxy (substituted with 0-5 halogens), OH, and halogen; each R3is independently selected from C1-C3 alkyl, C1-C3 alkoxy, OH, and halogen; n is an integer selected from 2 to 5; and p is an integer selected from zero to 3.

2. A compound selected from compounds of Formula I′:tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein: Ring A is selected from 7- and 8-membered heterocycles containing 0-2 additional heteroatoms selected from O and N, wherein Ring A is substituted with 0-2 groups selected from:C3-C6cycloalkyl (substituted with 0-2 groups selected from C1-C4 alkyl); C1-C5alkyl (substituted with 0-2 groups selected from C3-C6cycloalkyl, halogen, OH, NH2, oxo, and C4-C6heterocycle); C1-C4 alkoxy (substituted with 0-2 groups selected from C3-C6cycloalkyl, halogen, OH, NH2, and oxo); 5- and 6-membered heterocycle; OH; NH2; and oxo; Ring B is a 9-12 membered heteroaryl group containing 1-4 heteroatoms selected from N, O, and S, wherein Ring B is substituted with 1-4 groups selected from: C1-C6alkyl (substituted with 0-3 groups selected from halogen, C1-C3alkoxy, and OH); C3-C6cycloalkyl, substituted with 0-3 groups selected from: C1-C6 alkyl (substituted with 0-3 groups selected from: C1-C3 alkoxy and halogen), OH, and halogen; halogen; and 5- and 6-membered heterocycle; each X is independently selected from CH and N; Z is selected from CH and N; R1is selected from H, C1-C5alkyl, C1-C5haloalkyl, C1-C5alkoxy (substituted with 0-5 halogens), and halogen; each R2is independently selected from C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 alkoxy (further substituted with 0-5 halogens), OH, and halogen; each R3is independently selected from C1-C3alkyl, C1-C3alkoxy, OH, and halogen;n is an integer selected from 2 to 5; and p is zero to 3.

3. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein the compound is selected from compounds of Formula Ia:tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

4. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein the compound is selected from compounds of Formula Ib:tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

5. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein the compound is selected from compounds of Formula Ic:tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

6. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 or claim 2, wherein the compound is selected from compounds of Formula II:tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein each R4is independently selected from: C3-C6cycloalkyl (substituted with 0-3 groups selected from halogen and C1-C4alkyl); C1-C5 alkyl (substituted with 0-3 groups selected from C3-C6cycloalkyl, halogen, OH, NH2, oxo, and 4- to 6-membered heterocycle); C1-C4alkoxy (substituted with 0-3 groups selected from C3-C6cycloalkyl, halogen, OH, NH2, and oxo); 5- and 6-membered heterocycle; OH;NH2; and oxo.

7. A compound selected from compounds of Formula II:tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein each R4is independently selected from: C3-C6cycloalkyl (substituted with 0-2 groups selected from halogen and C1-C4alkyl); C1-C5 alkyl (substituted with 0-2 groups selected from C3-C6cycloalkyl, halogen, OH, NH2, oxo, and C3-C6heterocycle); C1-C4alkoxy (substituted with 0-2 groups selected from C3-C6cycloalkyl, halogen, OH, NH2, and oxo); 5- and 6-membered heterocycle; OH; NH2; and oxo. Ring B is a 9-12 membered heteroaryl group containing 1-4 heteroatoms selected from N, O, and S, wherein Ring B is substituted with 1-4 groups selected from: C1-C6 alkyl (substituted with 0-3 groups selected from halogen, C1-C3 alkoxy, and OH); C3-C6cycloalkyl, substituted with 0-3 groups selected from:C1-C6 alkyl (substituted with 0-3 groups selected from C1-C3 alkoxy and halogen), OH, and halogen; halogen; and 5- and 6-membered heterocycle; each X is independently selected from CH and N; Z is selected from CH and N; R1is selected from H, C1-C5alkyl, C1-C5haloalkyl, C1-C5alkoxy (substituted with 0-5 halogens), and halogen; each R2is independently selected from C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 alkoxy (further substituted with 0-5 halogens), OH, and halogen; each R3is independently selected from C1-C3alkyl, C1-C3alkoxy, OH, and halogen; n is an integer selected from 2 to 5; and p is zero to 3.

8. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 6 or claim 7, wherein the compound is selected from compounds of Formula IIa:tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

9. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 6 or claim 7, wherein the compound is selected from compounds of Formula IIb:(IIb), tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

10. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 6 or claim 7, wherein the compound is selected from compounds of Formula IIc:tautomers of those compounds, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

11. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein the compound is selected from compounds of Formula IIIa:(IIIa),tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein: Y1is selected from O and -CH2-; Y2is selected from NR9and CH; Y3is selected from O and CH; R4is selected from: C1-C4 alkyl (substituted with 0-3 groups selected from halogen and cyclopropyl); C1-C4 alkoxy; and C3-C4cycloalkyl; and R8is selected from C1-C4 alkyl and C3-C4 cycloalkyl, each of which is substituted with 0-1 trifluoromethyl groups and, if R9is present, R9is methyl; or R8and R9are taken together to form a five-membered heterocyclic ring, substituted with 0-2 methyl groups.

12. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein the compound is selected from compounds of Formula IIIb:(IIIb), tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein: R4is selected from: C1-C4 alkyl (substituted with 0-3 groups selected from halogen and cyclopropyl); C1-C4alkoxy; and C3-C4 cycloalkyl; and R8is selected from C3 alkyl and C3-C4 cycloalkyl, each of which is substituted with 0-1 trifluoromethyl groups and R9is methyl; or R8and R9are taken together to form a five-membered heterocyclic ring, substituted with 0-2 methyl groups.

13. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 5, wherein: Ring A is selected from azepane and azocane, wherein one CH2 group is optionally replaced by an O atom, and wherein Ring A is substituted with 0-2 groups selected from: C3and C4cycloalkyl (substituted with 0-1 methyl groups), C1-C5 alkyl (substituted with 0-1 groups selected from C3 and C4 cycloalkyl); and C1-C3 alkoxy (substituted with 0-1 groups selected from C3 and C4 cycloalkyl); Ring B is a 9-12 membered heteroaryl group containing 2-4 heteroatoms independently selected from N and O, wherein Ring B is substituted with 1-3 groups selected from: C1-C4 alkyl (substituted with 0-3 groups selected from OMe, halogen, and OH); C3and C4cycloalkyl, substituted with 0-1 groups selected from: C1and C2alkyl (substituted with 0-3 halogen atoms) and CH2OCH3; halogen; and 6-membered heterocycle; X is N; Z is selected from CH and N; R1is selected from H, CH3, OCH3, and F; each R2is CH3; R3is absent; n is 2; and p is zero.

14. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 5, wherein Ring A is selected from:

15. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 10, wherein Ring B is selected from:Q is selected from C and N; each W is independently selected from CH and N; W1is selected from N, CH, and CF; Y is selected from N, O, S, and CR; Ring B contains 1 to 4 nitrogen atoms; R is selected from H and C1-C3alkyl (substituted with 0-1 groups selected from C1-C3alkoxy); R5is selected from H, C1-C4 alkyl, and C3 and C4 cycloalkyl; R6is selected from: H; C1-C5 alkyl; C1-C5 haloalkyl;C3 and C4 cycloalkyl (substituted with 0-1 groups selected from C1-C4 alkyl, CH2OCH3, and C1-C3haloalkyl); and 5- and 6-membered heterocycle; R7is selected from C1-C3 alkyl; and R8is selected from C1-C4alkyl; and wherein R5and R6are not both hydrogen.

16. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 10, wherein Ring B is selected from:R is selected from H and C1-C3 alkyl (substituted with 0-1 groups selected from C1-C3 alkoxy); R5is selected from H, C1-C4alkyl, and C3and C4cycloalkyl; R6is selected from: H; C1-C5alkyl; C1-C5haloalkyl;C3 and C4 cycloalkyl (substituted with 0-1 groups selected from C1-C4 alkyl, CH2OCH3, and C1-C3haloalkyl); and 5- and 6-membered heterocycle; R7is selected from C1-C3 alkyl; R8is selected from C1-C4alkyl; and G is selected from halogens; and wherein R, R5and R6are not all simultaneously hydrogen, R5and R6are not simultaneously hydrogen when R is not present, and R6is not hydrogen when R and R5are not present.

17. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 10, wherein Ring B is selected from: ,,, , ,18. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, selected from:tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

19. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, selected fromtautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.

20. A compound selected from compounds of Formula I:tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing, wherein: Ring A is selected from 7- and 8-membered heterocycles containing 0-2 additional heteroatoms selected from O and N, wherein Ring A is substituted with 0-4 groups selected from: C3-C6cycloalkyl (further substituted with 0-4 groups selected from C1-C4 alkyl); C1-C5alkyl (substituted with 0-4 groups selected from C3-C6cycloalkyl, halogen, OH, NH2, oxo, and 4- to 6-membered heterocycle); C1-C4 alkoxy (substituted with 0-4 groups selected from C3-C6cycloalkyl, halogen, OH, NH2, and oxo); 5- and 6-membered heterocycle; OH; NH2; andoxo; wherein two substituents on Ring A taken together with the atoms to which they are bonded may form a ring selected from C3-C6cycloalkyl (further substituted with 0-2 groups selected from C1-C4 alkyl and C1-C4 alkoxy); Ring B is a 9-12 membered heteroaryl group containing 1-4 heteroatoms selected from N, O, and S, wherein Ring B is substituted with 1-4 groups selected from: C1-C6 alkyl (substituted with 0-3 groups selected from halogen, C1-C3 alkoxy, and OH); C3-C6cycloalkyl, substituted with 0-3 groups selected from: C1-C6alkyl (substituted with 0-3 groups selected from C1-C3alkoxy and halogen), OH, and halogen; halogen; and 5- and 6-membered heterocycle; each X is independently selected from CH and N; Z is selected from CH and N; R1is selected from H, C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 alkoxy (substituted with 0-5 halogens), and halogen; each R2is independently selected from C1-C5alkyl, C1-C5haloalkyl, C1-C5alkoxy (substituted with 0-5 halogens), OH, and halogen; each R3is independently selected from C1-C3 alkyl, C1-C3 alkoxy, OH, and halogen; n is an integer selected from 2 to 5; p is an integer selected from zero to 3; and wherein one or more carbon atoms are replaced by silicon and / or germanium.

21. A pharmaceutical composition comprising a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 20 and at least one pharmaceutically acceptable carrier.

22. The pharmaceutical composition according to claim 21, further comprising at least one additional active therapeutic agent.

23. The pharmaceutical composition according to claim 22, wherein at least one additional active therapeutic agents are (a) at least one compound selected from tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof; and (b) at least one compound selected from ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16- pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.

24. The pharmaceutical composition according to claim 22, wherein the at least one additional active therapeutic agents are (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)- 13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16-pentaen-6-ol, and optionally tezacaftor.

25. A method of treating cystic fibrosis comprising the step of administering the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 20 or the pharmaceutical composition according to any one of claims 21 to 24.

26. The method according to claim 25, wherein the method further comprises administering at least one additional active therapeutic agent.

27. The method according to claim 26, wherein the at least one additional active therapeutic agent to be administered is (a) at least one compound selected from tezacaftor, lumacaftor, and deuterated derivatives and pharmaceutically acceptable salts thereof; and (b) at least one compound selected from ivacaftor, deutivacaftor, (6R,12R)-17-amino-12-methyl-6,15- bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16- pentaen-6-ol, (6R)-17-amino-12,12-dimethyl-6,15-bis(trifluoromethyl)-19-oxa-3,4,13,18- tetrazatricyclo[12.3.1.12,5]nonadeca-1(18),2,4,14,16-pentaen-6-ol, and deuterated derivatives and pharmaceutically acceptable salts of any of the foregoing.

28. The method according to claim 26, wherein the method further comprises the step of administering (6R,12R)-17-amino-12-methyl-6,15-bis(trifluoromethyl)-13,19-dioxa-3,4,18-triazatricyclo[12.3.1.12,5] nonadeca-1(18),2,4,14,16-pentaen-6-ol, and optionally administering tezacaftor.

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