Compounds, compositions, and methods of using thereof

Abstract

The present disclosure relates to heterocyclic compounds, pharmaceutically acceptable salts thereof, and pharmaceutical preparations thereof. Also described herein are compositions and the use of such compounds in methods of treating diseases and conditions mediated by deficient CFTR activity, in particular cystic fibrosis.

Description

Compounds, Compositions, and Methods of Using Thereof BACKGROUND[1] Cystic fibrosis (CF), an autosomal recessive disorder, is caused by functional deficiency of the cAMP-activated plasma membrane chloride channel, cystic fibrosis transmembrane conductance regulator (CFTR), which can result in damage to the lung, pancreas and other organs. The gene encoding CFTR has been identified and sequenced (See Gregory, R. J. et al. (1990) Nature 347:382-386; Rich, D. P. et al. (1990) Nature 347:358-362; Riordan, J. R. et al. (1989) Science 245:1066-1073). CFTR, a member of the ATP binding cassette (ABC) superfamily is composed of two six membrane-spanning domains (MSD1 and MSD2), two nucleotide binding domains (NBD1 and NBD2), a regulatory region (R) and four cytosolic loops (CL1-4). Normally, CFTR protein is located primarily in the apical membrane of epithelial cells where it functions to conduct anions, including chloride, bicarbonate and thiocyanate into and out of the cell. CFTR may have a regulatory role over other electrolyte channels, including the epithelial sodium channel ENaC.[2] In cystic fibrosis patients, the absence or dysfunction of CFTR leads to exocrine gland dysfunction and a multisystem disease, characterized by pancreatic insufficiency and malabsorption, as well as abnormal mucociliary clearance in the lung, mucostasis, chronic lung infection and inflammation, decreased lung function and ultimately respiratory failure.[3] While more than 1,900 mutations have been identified in the CFTR gene, a detailed understanding of how each CFTR mutation may impact channel function is known for only a subset. (Derichs, European Respiratory Review, 22:127, 58-65 (2013)). The most frequent CFTR mutation is the in-frame deletion of phenylalanine at residue 508 (ΔF508) in the first nucleotide binding domain (NBD1). Over 80% of cystic fibrosis patients have the deletion at residue 508 in at least one allele. The loss of this key phenylalanine renders the CFTR NBD1 domain conformationally unstable at physiological temperature and compromises the integrity of the interdomain interface between NBD1 and CFTR’s second transmembrane domain (ICL4). The ΔF508 mutation causes production of misfolded CFTR protein which, rather than traffic to the plasma membrane, is instead retained in the endoplasmic reticulum and targeted for degradation by the ubiquitin-proteasome system.[4] The loss of a functional CFTR channel at the plasma membrane disrupts ionic homeostasis and airway surface hydration leading to reduced lung function. Reduced periciliary liquid volume and increased mucus viscosity impede mucociliary clearance resulting in chronic infection and inflammation. In the lung, the loss of CFTR-function leads to numerous physiological effects downstream of altered anion conductance that result in the dysfunction of additional organs such as the pancreas, intestine and gall bladder.[5] Guided, in part, by studies of the mechanistic aspects of CFTR misfolding and dysfunction, small molecule CFTR modulators have been identified, that can increase CFTR channel function.[6] Despite the identification of compounds that modulate CFTR, there is no cure for this fatal disease and identification of new compounds and new methods of therapy are needed as well as new methods for treating or lessening the severity of cystic fibrosis and other CFTR mediated conditions and diseases in a patient.SUMMARY[7] In one aspect, the present application is directed to a compound of Formula I:(I),or a pharmaceutically acceptable salt thereof, wherein A, R3, R4, L1, L2, M, W, X1, X2, n and p are defined herein.[8] Disclosed herein are combination therapies of compounds of Formula (I), and methods of using, methods of making, and pharmaceutical compositions thereof. DETAILED DESCRIPTIONCompounds [9] In certain aspects, the present application is directed to a compound of Formula I:(I),or a pharmaceutically acceptable salt thereof,whereinRing A is selected from the group consisting of , , , and ;wherein Ring B is selected from the group consisting of , , , , , and ;X1 is -C(H)=, -C(R4)=, or -N=;X2 is -C(H)=, -C(R4)=, or -N=;L1 is a bond or -C(=O)-;L2 is an optionally substituted C4-8 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen;M is =O or =N(H);W is selected from the group consisting of -N(H)-, -N(R2)-, and ;each R1 is independently selected from the group consisting of H, halogen, optionally substituted C1-5alkyl, and optionally substituted -O-C1-8alkyl, wherein -O-C1-8alkyl is optionally substituted with 1-3 instances of halogen;R2 is selected from the group consisting of optionally substituted C1-5alkyl, optionally substituted 4-7 membered cycloalkyl, optionally substituted 4-7 membered heterocyclyl, wherein C1-5alkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of optionally substituted halogen, C1-3alkyl, optionally substituted 4-7 membered cycloalkyl, optionally substituted 4-7 membered heterocyclyl, and -C(=O)OH;each R3 is H, halogen, or optionally substituted C1-3alkyl;each R4 is H, halogen, or optionally substituted C1-3alkyl;m is selected from the group consisting of 1, 2, 3, 4, and 5;n is selected from the group consisting of 1, 2, 3, and 4; and p is 1 or 2.

[10] In some embodiments, the compound is a compound of Formula (II):(II),or a pharmaceutically acceptable salt thereof.

[11] In some embodiments, the compound is a compound of Formula (III):(III),or a pharmaceutically acceptable salt thereof.

[12] In some embodiments, the compound is a compound of Formula (IV):(IV),or a pharmaceutically acceptable salt thereof.

[13] In some embodiments, the compound is a compound of Formula (V):(V),or a pharmaceutically acceptable salt thereof. 

[14] In some embodiments, the compound is a compound of Formula (VI):(VI),or a pharmaceutically acceptable salt thereof.

[15] In some embodiments, the compound is a compound of Formula (VII):(VII),or a pharmaceutically acceptable salt thereof.

[16] In some embodiments, the compound is a compound of Formula (VIII):(VIII),or a pharmaceutically acceptable salt thereof.

[17] In some embodiments, the compound is a compound of Formula (VIII):(IX),or a pharmaceutically acceptable salt thereof. 

[18] In some embodiments, the compound is a compound of Formula (VII):(X),or a pharmaceutically acceptable salt thereof. A

[19] In some embodiments, Ring A is selected from the group consisting of , , , and . In some embodiments, A is selected from the group consisting of , , and . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . In some embodiments, A is . B

[20] In some embodiments, Ring B is selected from the group consisting of , , , , , and . In some embodiments, B is selected from the group consisting of , , and . In some embodiments, B is . In some embodiments, B is . In some embodiments, B is . In some embodiments, B is . In some embodiments, B is . In some embodiments, B is . In some embodiments, B is . In some embodiments, B is . X1 and X2

[21] In some embodiments, X1 is -C(H)=, -C(R4)=, or -N=. In some embodiments, X1 is -C(R4)=. In some embodiments, X1 is -CH=. In some embodiments, X1 is -CF=. In some embodiments, X1 is -N=. In some embodiments, X2 is -C(H)=, -C(R4)=, or -N=. In some embodiments, X2 is -C(R4)=. In some embodiments, X2 is -CH=. In some embodiments, X1 is -CF=. In some embodiments, X2 is -N=.

[22]  W

[23] In some embodiments, W is selected from the group consisting of -NH, -NR2, and . In some embodiments, W is -NH. In some embodiments, W is -NR2. In some embodiments, W is . In some embodiments, W is -NR2, wherein R2 is optionally substituted C1-5alkyl, wherein R2 is optionally substituted with 1-3 instances of a substituent independently selected from the group consisting of C1-3alkyl, 4-7 membered cycloalkyl, 4-7 membered heterocyclyl, and -C(=O)OH. In some embodiments, W is -NR2, and wherein R2 is independently selected from the group consisting of H, -CH3, , , , , , and .

[24] In some embodiments, W is -NR2, and wherein R2 is selected from the group consisting of -CH3, ,, , ,,,,,,, ,,,,,,,,,,,,, , , ,,, ,,,,, ,,,,,, ,,, , ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,, ,, and . L1

[25] In some embodiments, L1 is a bond or -C(=O)-. In some embodiments, L1 is a bond. In some embodiments, L1 is -C(=O)-. L2

[26] In some embodiments, L2 is an optionally substituted C4-8 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen. In some embodiments, L2 is an optionally substituted C5-8 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen. In some embodiments, L2 is an optionally substituted C6-8 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen. In some embodiments, L2 is an optionally substituted C7-8 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen. In some embodiments, L2 is an optionally substituted C5-6 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen. In some embodiments, L2 is an optionally substituted C5-7 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen.In some embodiments, L2 is an optionally substituted C4-8 alkylene chain, wherein 1 methylene unit is optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen. In some embodiments, L2 is an optionally substituted C5-8 alkylene chain, wherein 1 methylene unit is optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen. In some embodiments, L2 is an optionally substituted C6-8 alkylene chain, wherein 1 methylene unit is optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen. In some embodiments, L2 is an optionally substituted C7-8 alkylene chain, wherein 1 methylene unit is optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen. In some embodiments, L2 is an optionally substituted C5-6 alkylene chain, wherein 1 methylene unit is optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen. In some embodiments, L2 is an optionally substituted C5-7 alkylene chain, wherein 1 methylene unit is optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen.

[27] In some embodiments, L2 is an optionally substituted C4-8 alkylene chain, wherein 2 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen. In some embodiments, L2 is an optionally substituted C5-8 alkylene chain, wherein 2 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen. In some embodiments, L2 is an optionally substituted C6-8 alkylene chain, wherein 2 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen. In some embodiments, L2 is an optionally substituted C7-8 alkylene chain, wherein 2 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen. In some embodiments, L2 is an optionally substituted C5-6 alkylene chain, wherein 2 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen. In some embodiments, L2 is an optionally substituted C5-7 alkylene chain, wherein 2 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen.

[28] In some embodiments, L2 is an optionally substituted C4-8 alkylene chain, wherein 3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen. In some embodiments, L2 is an optionally substituted C5-8 alkylene chain, wherein 3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen. In some embodiments, L2 is an optionally substituted C6-8 alkylene chain, wherein 3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen. In some embodiments, L2 is an optionally substituted C7-8 alkylene chain, wherein 3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen. In some embodiments, L2 is an optionally substituted C5-6 alkylene chain, wherein 3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen. In some embodiments, L2 is an optionally substituted C5-7 alkylene chain, wherein 3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen.

[29] In some embodiments, L2 is an optionally substituted C4-8 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1 instance of halogen. In some embodiments, L2 is an optionally substituted C5-8 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1 instance of halogen. In some embodiments, L2 is an optionally substituted C6-8 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1 instance of halogen. In some embodiments, L2 is an optionally substituted C7-8 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1 instance of halogen. In some embodiments, L2 is an optionally substituted C5-6 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1 instance of halogen. In some embodiments, L2 is an optionally substituted C5-7 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1 instance of halogen.

[30] In some embodiments, L2 is an optionally substituted C4-8 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 2 instances of halogen. In some embodiments, L2 is an optionally substituted C5-8 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 2 instances of halogen. In some embodiments, L2 is an optionally substituted C6-8 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 2 instances of halogen. In some embodiments, L2 is an optionally substituted C7-8 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 2 instances of halogen. In some embodiments, L2 is an optionally substituted C5-6 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 2 instances of halogen. In some embodiments, L2 is an optionally substituted C5-7 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 2 instances of halogen.

[31] In some embodiments, L2 is an optionally substituted C4-8 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 3 instances of halogen. In some embodiments, L2 is an optionally substituted C5-8 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 3 instances of halogen. In some embodiments, L2 is an optionally substituted C6-8 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 3 instances of halogen. In some embodiments, L2 is an optionally substituted C7-8 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 3 instances of halogen. In some embodiments, L2 is an optionally substituted C5-6 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 3 instances of halogen. In some embodiments, L2 is an optionally substituted C5-7 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 3 instances of halogen.

[32] In some embodiments, L2 is an optionally substituted C4-8 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 4 instances of halogen. In some embodiments, L2 is an optionally substituted C5-8 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 4 instances of halogen. In some embodiments, L2 is an optionally substituted C6-8 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 4 instances of halogen. In some embodiments, L2 is an optionally substituted C7-8 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 4 instances of halogen. In some embodiments, L2 is an optionally substituted C5-6 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 4 instances of halogen. In some embodiments, L2 is an optionally substituted C5-7 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 4 instances of halogen.

[33] In some embodiments, L2 is an optionally substituted C5-6alkylene chain, wherein 1 methylene unit is optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 2 instances of halogen. R1

[34] In some embodiments, each R1 is independently selected from the group consisting of H, halogen, optionally substituted C1-5alkyl, and optionally substituted -O-C1-8alkyl, wherein -O-C1-8alkyl is optionally substituted with 1-3 instances of halogen. In some embodiments, each R1 is independently selected from the group consisting of H, halogen, and optionally substituted -O-C1-8alkyl, wherein -O-C1-8alkyl is optionally substituted with 1-3 instances of halogen. In some embodiments, R1 is H. In some embodiments, R1 is halogen.

[35] In some embodiments, each R1 is independently -O-C1-8alkyl, wherein -O-C1-8alkyl is optionally substituted with 1-3 instances of halogen. In some embodiments, each R1 is independently -O-C1-8alkyl, wherein -O-C1-8alkyl is optionally substituted with 1-3 instances of fluoro. In some embodiments, each R1 is independently -O-C1-8alkyl, wherein -O-C1-8alkyl is optionally substituted with 1-3 instances of chloro. In some embodiments, each R1 is independently -O-C1-8alkyl, wherein -O-C1-8alkyl is optionally substituted with 1-3 instances of bromo. In some embodiments, each R1 is independently -O-C1-8alkyl, wherein -O-C1-8alkyl is optionally substituted with 1-3 instances of iodo.

[36] In some embodiments, each R1 is independently selected from the group consisting of -CH3, , , , , ..and . In some embodiments, each R1 is independently selected from the group consisting of , , , and . In some embodiments R1 is . In some embodiments, R1 is . In some embodiments, R1 is . In some embodiments, R1 is . R2

[37] In some embodiments, R2 is hydrogen or optionally substituted C1-5alkyl, wherein C1-5alkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of optionally substituted C1-3alkyl, optionally substituted 4-7 membered cycloalkyl, optionally substituted 4-7 membered heterocyclyl, and -C(=O)OH. In some embodiments, R2 is hydrogen. In some embodiments, R2 is optionally substituted C1-5alkyl. In some embodiments, R2 is optionally substituted C2-5alkyl. In some embodiments, R2 is optionally substituted C3-5alkyl. In some embodiments, R2 is optionally substituted C4-5alkyl. In some embodiments, R2 is optionally substituted C1-4alkyl. In some embodiments, R2 is optionally substituted C2-4alkyl. In some embodiments, R2 is optionally substituted C3-4alkyl. In some embodiments, R2 is -CH3.

[38] In some embodiments, R2 is selected from the group consisting of -CH3, ,, , ,,,,,,, ,,,,,,,,,,,,, , , ,,, ,,,,, ,,,,,, ,,, , ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,, ,, and . R3

[39] In some embodiments, each R3 is H, halogen, or optionally substituted C1-3alkyl. In some embodiments, R3 is H. In some embodiments, R3 is halogen. In some embodiments, R3 is fluoro. In some embodiments, R3 is chloro. In some embodiments, R3 is bromo. In some embodiments, R3 is iodo. In some embodiments, R3 is optionally substituted C1-3alkyl. In some embodiments, R3 is optionally substituted C1-2alkyl. In some embodiments, R3 is optionally substituted C2-3alkyl. In some embodiments, R3 is -CH3. R4

[40] In some embodiments, each R4 is H, halogen, or optionally substituted C1-3alkyl. In some embodiments, R4 is H. In some embodiments, R4 is halogen. In some embodiments, R4 is fluoro. In some embodiments, R4 is chloro. In some embodiments, R4 is bromo. In some embodiments, R4 is iodo. In some embodiments, R4 is optionally substituted C1-3alkyl. In some embodiments, R4 is optionally substituted C1-2alkyl. In some embodiments, R4 is optionally substituted C2-3alkyl. m

[41] In some embodiments, m is 0. In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. n

[42] In some embodiments, n is 0. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2.  p

[43] In some embodiments, p is 0. In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2. 

[44] In another aspect, the compound of Formula (I) is selected from a compound of Table 1, or pharmaceutically acceptable thereof:Table 1Compound No.StructureIUPAC name16-[3-(3,3-dimethylbutoxy) phenyl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide26-[3-(3,3-dimethylbutoxy)phenyl]-14-oxa-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide36-[3-(3,3-dimethylbutoxy)-5-fluoro-phenyl]-9,20-dimethyl-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(24),4(26),6,8(13),9,11,21(25),22-octaene 2,2-dioxide43-[6-[3-(3,3-dimethylbutoxy)phenyl]-2,2-dioxo-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]-2,2-dimethyl-propanoic acid53-[2,2-dioxo-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]-2,2-dimethyl-propanoic acid62-[[6-[3-(3,3-dimethylbutoxy)phenyl]-2,2-dioxo-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]-2-methyl-pentanoic acid7(P1)(2R)-2-[[6-[3-(3,3-dimethylbutoxy)phenyl]-2,2-dioxo-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]-2-methyl-pentanoic acid7(P2)(2S)-2-[[6-[3-(3,3-dimethylbutoxy)phenyl]-2,2-dioxo-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]-2-methyl-pentanoic acid82-cyclohexyl-3-[6-[3-(3,3-dimethylbutoxy)phenyl]-2,2-dioxo-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]-2-methyl-propanoic acid91-[[6-[3-(3,3-dimethylbutoxy)phenyl]-2,2-dioxo-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]cyclohexanecarboxylic acid106-[3-(3,3-dimethylbutoxy)phenyl]-2λ6,5-dithia-3,20,26-triazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide116-[3-(3,3-dimethylbutoxy)phenyl]-2λ6,5,19λ6-trithia-3,20,26-triazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2,19,19-tetraoxide126-[3-(3,3-dimethylbutoxy)phenyl]-2λ6,5,19λ6-trithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2,19,19-tetraoxide133-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15(27),16,18,22(26),23-nonaen-14-yl]-2,2-dimethyl-propanoic acid143-[2-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15(27),16,18,22(26),23-nonaen-14-yl]-1,1-dimethyl-ethyl]-2H-1,2,4-oxadiazol-5-one153-[(1R)-1-[[6-[3-(3,3-dimethylbutoxy)phenyl]-2,2-dioxo-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]-1-methyl-butyl]-2H-1,2,4-oxadiazol-5-one162-[[14,14-difluoro-2,2-dioxo-6-[3-(trifluoromethoxy)phenyl]-16-oxa-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]-2-methyl-pentanoic acid176-[3-(3,3-dimethylbutoxy)phenyl]-14,14-difluoro-2λ6,5-dithia-3,17,20,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide18(2'R,5R)-2'-(6-ethoxy-2-pyridyl)-8-methyl-2,2-dioxo-spiro[12-oxa-2λ6-thia-3,16,21-triazatricyclo[15.3.1.06,11]henicosa-1(21),6,8,10,17,19-hexaene-5,1'-cyclopropane]-4-one19(2'S,5S)-2'-(6-ethoxy-2-pyridyl)-8-methyl-2,2-dioxo-spiro[12-oxa-2λ6-thia-3,16,21-triazatricyclo[15.3.1.06,11]henicosa-1(21),6,8,10,17,19-hexaene-5,1'-cyclopropane]-4-one20-P1(2R)-2-[[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]methyl]-2-methyl-pentanoic acid20-P2(2S)-2-[[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]methyl]-2-methyl-pentanoic acid21-P1(2R)-3-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]propane-1,2-diol21-P2(2S)-3-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]propane-1,2-diol2214-(2-methylsulfonylethyl)-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide233-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propanoic acid 243-[20-imino-20-oxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propanoic acid 253-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propan-1-ol 261-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaen-14-yl]-2-methyl-propane-2-sulfonamide 271-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaen-14-yl]-2-methyl-propan-2-ol28-P114-[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaene 20,20-dioxide28-P214-[(3S)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaene 20,20-dioxide29-P114-[[(5R)-2-methyl-1,1-dioxo-1,2-thiazolidin-5-yl]methyl]-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaene 20,20-dioxide29-P214-[[(5S)-2-methyl-1,1-dioxo-1,2-thiazolidin-5-yl]methyl]-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaene 20,20-dioxide3014-(2-methyl-2-methylsulfanyl-propyl)-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaene 20,20-dioxide3114-(2-methyl-2-methylsulfonyl-propyl)-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaene 20,20-dioxide32-P114-[[(3R)-tetrahydropyran-3-yl]methyl]-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaene 20,20-dioxide32-P214-[[(3S)-tetrahydropyran-3-yl]methyl]-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaene 20,20-dioxide33N-cyclopropylsulfonyl-3-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaen-14-yl]-2,2-dimethyl-propanamide343-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,16,21,24,26-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15,17,19(27),22,24-nonaen-14-yl]-2,2-dimethyl-propanoic acid3525-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,23,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaene 20,20-dioxide366-[3-(3,3-dimethylbutoxy)phenyl]-14,14-difluoro-2λ6,5-dithia-3,20,26-triazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide373-[19,19-dioxo-24-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-5,19λ6-dithia-13,20,23,25,26-pentazatetracyclo[19.3.1.114,18.02,6]hexacosa-1(25),2(6),3,14(26),15,17,21,23-octaen-13-yl]-2,2-dimethyl-propanoic acid382-[[6-[3-(3,3-dimethylbutoxy)phenyl]-2,2,16,16-tetraoxo-2λ6,5,16λ6-trithia-3,17,20,25,26-pentazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]-2-methyl-pentanoic acid393-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-6,8,14,21,24,26,27-heptazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2(7),3,5,15(27),16,18,22,24-nonaen-14-yl]-2,2-dimethyl-propanoic acid403-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,23,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaen-14-yl]-2,2-dimethyl-propanoic acid41 6-[3-(3,3-dimethylbutoxy)phenyl]-14,17-dioxa-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa- 1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide42 6-[3-(3,3-dimethylbutoxy)phenyl]-17-oxa-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide43 6-[3-(3,3-dimethylbutoxy)-5-fluoro-phenyl]-9-methyl-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide44-P1 (2R)-2-[[2,2-dioxo-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]-2-methyl-pentanoic acid44-P2 (2S)-2-[[2,2-dioxo-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]-2-methyl-pentanoic acid45 (2R)-2-[[2,2-dioxo-6-[3-(trifluoromethoxy)phenyl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]-2-methyl-pentanoic acid46-P1 (2S)-2-[[6-[3-(3,3-dimethylbutoxy)phenyl]-2,2-dioxo-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]-2-methyl-pentanenitrile46-P2 (2R)-2-[[6-[3-(3,3-dimethylbutoxy)phenyl]-2,2-dioxo-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]-2-methyl-pentanenitrile47 (2R)-2-[[6-[3-(3,3-dimethylbutoxy)phenyl]-2,2-dioxo-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]-2-methyl-pentanamide48 (2R)-2-[[2,2-dioxo-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]-2-methyl-pentanenitrile49 (2R)-2-[[2,2-dioxo-6-[3-(2,2,2-trifluoroethoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]-2-methyl-pentanoic acid50 3-[(1R)-1-[[2,2-dioxo-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]-1-methyl-butyl]-2H-1,2,4-oxadiazol-5-one51 3-[6-[3-(3,3-dimethylbutoxy)phenyl]-2,2-dioxo-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]cyclohexanecarboxylic acid52-P1 (2R)-2-[[14,14-difluoro-2,2-dioxo-6-[3-(trifluoromethoxy)phenyl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]-2-methyl-pentanoic acid52-P2 (2S)-2-[[14,14-difluoro-2,2-dioxo-6-[3-(trifluoromethoxy)phenyl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]-2-methyl-pentanoic acid53 6-[3-(3,3-dimethylbutoxy)phenyl]-14,14-difluoro-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide54 14,14-difluoro-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide55 8,8-difluoro-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide56 6-[3-(2,2-difluoro-3,3-dimethyl-butoxy)phenyl]-25-fluoro-14-methyl-2λ6,5-dithia-3,20,26-triazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide57 6-[3-(3,3-dimethylbutoxy)phenyl]-14-methyl-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide58-P1 (4S)-4-methyl-4-[[25-(5-methyl-2-thienyl)-20,20-dioxo-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]methyl]heptanoic acid58-P2 (4R)-4-methyl-4-[[25-(5-methyl-2-thienyl)-20,20-dioxo-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]methyl]heptanoic acid59-P1 (2R)-2-[[20,20-dioxo-25-(2-thienyl)-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]methyl]-2-methyl-pentanoic acid59-P2 (2S)-2-[[20,20-dioxo-25-(2-thienyl)-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]methyl]-2-methyl-pentanoic acid60 8,8-difluoro-25-(5-methyl-2-thienyl)-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide61 (2R)-2-[[2,2-dioxo-6-[6-(2,2,2-trifluoroethoxy)-2-pyridyl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]-2-methyl-pentanoic acid62 2-[[6-[3-(3,3-dimethylbutoxy)phenyl]-2,2,16,16-tetraoxo-2λ6,5,16λ6-trithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]-2-methyl-pentanoic acid63 25-[3-(3,3-dimethylbutoxy)phenyl]-8,8-difluoro-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide64 8,8-difluoro-25-[3-(trifluoromethoxy)phenyl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide65-P1 (2R)-2-[[20,20-dioxo-25-[6-(2,2,2-trifluoroethoxy)-2-pyridyl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]methyl]-2-methyl-pentanoic acid65-P2 (2S)-2-[[20,20-dioxo-25-[6-(2,2,2-trifluoroethoxy)-2-pyridyl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]methyl]-2-methyl-pentanoic acid66 3-[20,20-dioxo-25-[3-(trifluoromethoxy)phenyl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propanoic acid67 3-[20,20-dioxo-25-[3-(2,2,2-trifluoroethoxy)pyrazol-1-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propanoic acid68 3-[14,14-difluoro-2,2-dioxo-6-[3-(2,2,2-trifluoroethoxy)phenyl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]-2,2-dimethyl-propanoic acid69 6-[3-(3,3-dimethylbutoxy)phenyl]-14,14-difluoro-2λ6,5-dithia-3,20,22,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide70-P1 (3S)-3-[[6-[3-(2,2-difluoro-3,3-dimethyl-butoxy)-4-fluoro-phenyl]-2,2-dioxo-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]-3-methyl-hexanenitrile70-P2 (3R)-3-[[6-[3-(2,2-difluoro-3,3-dimethyl-butoxy)-4-fluoro-phenyl]-2,2-dioxo-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]-3-methyl-hexanenitrile71 3-[8,8-difluoro-20,20-dioxo-25-[3-(2,2,2-trifluoroethoxy)phenyl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propanoic acid72 14,14-difluoro-6-[3-(trifluoromethoxy)phenyl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide73 25-[3-(3,3-dimethylbutoxy)phenyl]-8-methyl-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide74 14,14-difluoro-6-[3-(trifluoromethoxy)phenyl]-2λ6,5-dithia-3,20,26-triazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide75 3-[25-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-8,8-difluoro-20,20-dioxo-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propanoic acid76 14,14-difluoro-6-[6-(trifluoromethoxy)-2-pyridyl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide77 8-methyl-25-[6-(trifluoromethoxy)-2-pyridyl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide78 14,14-difluoro-6-[6-(trifluoromethoxy)-2-pyridyl]-2λ6,5-dithia-3,20,26-triazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide79 3-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propanamide80 3-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propanenitrile81 1-[6-[3-(3,3-dimethylbutoxy)phenyl]-14,14-difluoro-2,2-dioxo-2λ6,5-dithia-3,20,26-triazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]-2-morpholino-ethanone82 4-[8,8-difluoro-20,20-dioxo-25-[3-(trifluoromethoxy)phenyl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-4-oxo-butanoic acid83 25-[3-(2,2-dimethylpropoxy)phenyl]-8,8-difluoro-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide84 6-[3-(3,3-dimethylbutoxy)phenyl]-14,14-difluoro-2λ6,5,19λ6-trithia-3,20,26-triazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2,19,19-tetraoxide85 6-[3-(3,3-dimethylbutoxy)phenyl]-14,14-difluoro-2λ6,5,19λ6-trithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2,19,19-tetraoxide86 6-[3-(2,2-dimethylpropoxy)phenyl]-14,14-difluoro-2λ6,5-dithia-3,20,26-triazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide87 14,14-difluoro-6-[3-(2,2,2-trifluoroethoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,26-triazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide88 14,14-difluoro-6-[3-(4,4,4-trifluoro-3,3-dimethyl-butoxy)phenyl]-2λ6,5-dithia-3,20,26-triazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide89 14,14-difluoro-6-[3-(4,4,4-trifluoro-3,3-dimethyl-butoxy)phenyl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide90 8,8-difluoro-25-[3-(2,2,2-trifluoroethoxy)pyrazol-1-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide91 3-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-N-tetrahydropyran-4-yl-propanamide92 3-[25-[3-(2,2-dimethylpropoxy)phenyl]-8,8-difluoro-20,20-dioxo-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]propane-1,2-diol93 N-(azetidin-3-yl)-3-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propanamide94 2-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-N,N-dimethyl-ethanamine95 2-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]acetic acid96 2-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-N-tetrahydropyran-4-yl-acetamide97 14-[(1-methylpyrrolidin-2-yl)methyl]-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide98 25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide99 8,8-difluoro-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,16,21,26-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide100 25-[2-(3,3,3-trifluoro-2,2-dimethyl-propoxy)thiazol-4-yl]-20λ6-thia-14,16,21,26-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide101 25-[3-(3,3-dimethylbutoxy)phenyl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide102 6-[6-(trifluoromethoxy)-2-pyridyl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide103 6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide104 25-[3-(2,2-dimethylpropoxy)pyrazol-1-yl]-8,8-difluoro-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide105 1-[14,14-difluoro-2,2-dioxo-6-[3-(4,4,4-trifluoro-3,3-dimethyl-butoxy)phenyl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]-2-morpholino-ethanone106 25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-11-oxa-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide107 6-[3-(trifluoromethoxy)phenyl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide108 6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,22,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide109 14,14-difluoro-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,22,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide110 3-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propan-1-ol111 25-[3-(4,4,4-trifluoro-3,3-dimethyl-butoxy)phenyl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide112 8,8-difluoro-25-[3-(4,4,4-trifluoro-3,3-dimethyl-butoxy)phenyl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide113 3-[25-[3-(3,3-dimethylbutoxy)phenyl]-20,20-dioxo-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propanoic acid114 6-[3-(4,4,4-trifluoro-3,3-dimethyl-butoxy)phenyl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide115 3-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propan-1-amine116 3-[8,8-difluoro-20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propanoic acid117 3-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)-1,2,4-thiadiazol-5-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propanoic acid118 2-[2,2-dioxo-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]-N-tetrahydropyran-4-yl-acetamide119 2,2-dimethyl-3-[8-methyl-20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-9-oxa-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]propanoic acid120 3-[8,8-difluoro-20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-10-oxa-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propanoic acid121 20-(2-methylsulfanylethyl)-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide122 25-[3-(2,2-difluoro-3,3-dimethyl-butoxy)-4-fluoro-phenyl]-14-(2-methylsulfanylethyl)-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide123 25-[3-(2,2-difluoro-3,3-dimethyl-butoxy)-4-fluoro-phenyl]-14-(2-methylsulfonylethyl)-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide124 20-(pyrrolidin-2-ylmethyl)-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide125 3-[14,14-difluoro-2,2-dioxo-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,22,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]-2,2-dimethyl-propanoic acid126-P1 3-[2,2-dioxo-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]-1-methyl-cyclobutanol126-P2 3-[2,2-dioxo-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]-1-methyl-cyclobutanol127 3-[14,14-difluoro-2,2-dioxo-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]-2,2-dimethyl-propanoic acid128 20-(2-methylsulfonylethyl)-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide129 3-[2,2-dioxo-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]propane-1,2-diol130 25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,26-triazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide131 2-[[2,2-dioxo-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]cyclopropanecarboxylic acid132 4-[2,2-dioxo-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]-1,1,1-trifluoro-butan-2-ol133 20-[2-methyl-2-(2H-tetrazol-5-yl)propyl]-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide134 2-[2,2-dioxo-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]ethanol135 20-(azetidin-3-ylmethyl)-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide136 1-[2,2-dioxo-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]-2-methyl-propan-2-ol137 20-[(1,1-dioxothiolan-2-yl)methyl]-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide138-P1 (2S)-2-[[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]methyl]-2-methyl-pentanoic acid138-P2 (2R)-2-[[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]methyl]-2-methyl-pentanoic acid139 3-[8,8-difluoro-20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-10-oxa-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propan-1-ol140 8,8-difluoro-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-10-oxa-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide141 3-[8,8-difluoro-20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-10-oxa-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propanoic acid142-P1 (2R)-3-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]propane-1,2-diol142-P2 (2S)-3-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]propane-1,2-diol143 3-[8,8-difluoro-20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-10-oxa-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propan-1-ol144 25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)-1,2,4-thiadiazol-5-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide145 2-[[2,2-dioxo-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]-3,3-dimethyl-butanoic acid146 3-[25-[3-(3,3-dimethylbutoxy)phenyl]-20,20-dioxo-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propanoic acid147 4-[8,8-difluoro-20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-10-oxa-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-1,1,1-trifluoro-butan-2-ol148 3-[25-[3-(3,3-dimethylbutoxy)phenyl]-20,20-dioxo-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propan-1-ol149 1-[8,8-difluoro-20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-10-oxa-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2-methyl-propan-2-amine150 14-(cyclopropylmethyl)-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide151 14-propyl-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide152 1-[8,8-difluoro-20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-10-oxa-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2-methyl-propan-2-amine153 4-[25-[3-(3,3-dimethylbutoxy)phenyl]-20,20-dioxo-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-1,1,1-trifluoro-butan-2-ol154 3-[25-[3-(3,3-dimethylbutoxy)phenyl]-8,8-difluoro-20,20-dioxo-10-oxa-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propanoic acid155 1-[25-[3-(3,3-dimethylbutoxy)phenyl]-8,8-difluoro-20,20-dioxo-10-oxa-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2-methyl-propan-2-ol156 25-[3-(3,3-dimethylbutoxy)phenyl]-14-(2-methylsulfanylethyl)-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide157 25-[3-(3,3-dimethylbutoxy)phenyl]-14-(2-methylsulfonylethyl)-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide158 25-[3-(3,3-dimethylbutoxy)phenyl]-14-(2-methylsulfinylethyl)-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide159 3-[25-[3-(3,3-dimethylbutoxy)phenyl]-8,8-difluoro-20,20-dioxo-10-oxa-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propan-1-ol160 4-[25-[3-(3,3-dimethylbutoxy)phenyl]-8,8-difluoro-20,20-dioxo-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-1,1,1-trifluoro-butan-2-ol161 14-(morpholin-2-ylmethyl)-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide162 25-[3-(3,3-dimethylbutoxy)phenyl]-14-(2-methylsulfonylethyl)-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide163 4-[8,8-difluoro-20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-1,1,1-trifluoro-butan-2-ol164 1-[[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]methyl]cyclopropanecarboxylic acid165 3-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-N-methylsulfonyl-propanamide166 [3-[[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,18,21,24,26-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]methyl]oxetan-3-yl]methanol167 3-[[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]methyl]tetrahydrofuran-3-carboxamide168 3-[[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]methyl]tetrahydrofuran-3-carboxylic acid169 3-[20,20-dioxo-25-(2-thienyl)-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propanoic acid170 3-[[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]methyl]pyrrolidine-3-carbonitrile171 3-[[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]methyl]tetrahydrofuran-3-carbonitrile172 3-[[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]methyl]oxetane-3-carboxylic acid173 3-[21,21-dioxo-26-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-21λ6-thia-10,11,15,22,25,27,28-heptazapentacyclo[21.3.1.18,11.116,20.02,7]nonacosa-1(26),2,4,6,8(29),9,16,18,20(28),23(27),24-undecaen-15-yl]-2,2-dimethyl-propanoic acid174 3-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-10,14,21,24,26,27-hexazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-10-yl]-2,2-dimethyl-propanoic acid175 1-[[8,8-difluoro-20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-10-oxa-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]methyl]cyclopropanecarboxylic acid176 [1-[[8,8-difluoro-20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-10-oxa-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]methyl]cyclopropyl]methanol177 14-(morpholin-3-ylmethyl)-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide178 1-[8,8-difluoro-20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-10-oxa-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2-methyl-propan-2-ol179 3-[8,8-difluoro-20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-10,14,21,24,26,27-hexazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propanoic acid180 8,8-difluoro-14-(2-methylsulfanylethyl)-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-10-oxa-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide181 8,8-difluoro-14-(2-methylsulfonylethyl)-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-10-oxa-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide182 3-[10-hydroxy-10-methyl-20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propanoic acid183 3-[8,8-difluoro-20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-10-oxa-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propan-1-amine184 3-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaen-14-yl]butanoic acid185 14-(tetrahydropyran-4-ylmethyl)-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaene 20,20-dioxide186 14-(tetrahydrofuran-3-ylmethyl)-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaene 20,20-dioxide187 8,8-difluoro-14-(tetrahydrofuran-3-ylmethyl)-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-10-oxa-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaene 20,20-dioxide188 3-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaen-14-yl]-2-methyl-propane-1,2-diol189 8,8-difluoro-14-(tetrahydrofuran-3-ylmethyl)-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-10,14,21,24,26,27-hexazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaene 20,20-dioxide190 3-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaen-14-yl]-2-methyl-propanoic acid191 4-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaen-14-yl]-2-methyl-butan-2-ol192 4-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaen-14-yl]-2,2-dimethyl-butanoic acid193 4-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaen-14-yl]-2-methyl-butan-2-amine194 4-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15(27),16,18,22(26),23-nonaen-14-yl]-2-methyl-butan-2-ol195 3-[25-[3-(3,3-dimethylbutoxy)phenyl]-20,20-dioxo-20λ6-thia-14,16,21,24,26-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15,17,19(27),22,24-nonaen-14-yl]-2,2-dimethyl-propanoic acid196 2-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaen-14-yl]acetic acid197 3-[20,20-dioxo-25-(2-thienyl)-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15(27),16,18,22(26),23-nonaen-14-yl]-2,2-dimethyl-propanoic acid198 3-[20,20-dioxo-25-(2-thienyl)-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15(27),16,18,22(26),23-nonaen-14-yl]-2,2-dimethyl-propan-1-ol199 2-[[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaen-14-yl]methyl]pentanoic acid200 3-[8,8-difluoro-10-methyl-20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-10,14,21,24,26,27-hexazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaen-14-yl]-2,2-dimethyl-propanoic acid201 3-[8,8-difluoro-10-isopropyl-20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-10,14,21,24,26,27-hexazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaen-14-yl]-2,2-dimethyl-propanoic acid202 3-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,16,21,24,26-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15,17,19(27),22,24-nonaen-14-yl]-2,2-dimethyl-propan-1-ol203 4-[8,8-difluoro-20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-10-oxa-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaen-14-yl]-3,3-dimethyl-butan-2-one204 3-[25-(5-methoxy-2-thienyl)-20,20-dioxo-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaen-14-yl]-2,2-dimethyl-propanoic acid205 3-[20,20-dioxo-25-(2-thienyl)-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaen-14-yl]-2,2-dimethyl-propan-1-ol206 3-[25-(5-methoxy-2-thienyl)-20,20-dioxo-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaen-14-yl]-2,2-dimethyl-propan-1-ol207 2-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaen-14-yl]ethanol208 3-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaen-14-yl]-2-hydroxy-2-methyl-propanoic acid209 8,8-difluoro-14-[2-methyl-2-(1H-pyrazol-3-yl)propyl]-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-10-oxa-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaene 20,20-dioxide210 3-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,16,21,26-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propanoic acid211 3-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,16,21,26-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15,17,19(27),22(26),23-nonaen-14-yl]-2,2-dimethyl-propan-1-ol212 N-cyclopropylsulfonyl-3-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15(27),16,18,22(26),23-nonaen-14-yl]-2,2-dimethyl-propanamide213 1-[[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaen-14-yl]methyl]-2-methyl-cyclopentane-1,2-diol214 2-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaen-14-yl]-1-methyl-cyclopentanol215 14-[2-(2-methylpyrrolidin-2-yl)ethyl]-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,24,26,27-pentazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(26),2,4,6,15(27),16,18,22,24-nonaene 20,20-dioxide216 1-[20,20-dioxo-25-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-20λ6-thia-14,21,26,27-tetrazatetracyclo[20.3.1.115,19.02,7]heptacosa-1(25),2,4,6,15(27),16,18,22(26),23-nonaen-14-yl]-2-methyl-propan-2-ol   Definitions

[45] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art of the present disclosure. The following references provide one of skill with a general definition of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below, unless specified otherwise.In this disclosure, "comprises," "comprising," "containing" and "having" and the like can have the meaning ascribed to them in U.S. Patent law and can mean " includes," "including," and the like; "consisting essentially of" or "consists essentially" likewise has the meaning ascribed in U.S. Patent law and the term is open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments.

[46] Unless specifically stated or obvious from context, as used herein, the term "or" is understood to be inclusive. Unless specifically stated or obvious from context, as used herein, the terms "a", "an", and "the" are understood to be singular or plural.

[47] The term “acyl” is art-recognized and refers to a group represented by the general formula hydrocarbyl-C(O)-, preferably alkyl-C(O)-.

[48] The term “acylamino” is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbyl-C(O)NH-.

[49] The term “acyloxy” is art-recognized and refers to a group represented by the general formula hydrocarbyl-C(O)O-, preferably alkyl-C(O)O-.

[50] The term “alkoxy” refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.

[51] The term “alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[52] The term “alkenyl”, as used herein, refers to a straight chained or branched aliphatic group containing at least one double bond. Typically, an alkenyl group has from 2 to about 20 carbon atoms, preferably from 2 to about 10, more preferably from 2-6 or 2-4. unless otherwise defined. The term “alkenyl” is intended to include both "unsubstituted alkenyls" and "substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[53] An “alkyl” group or “alkane” is a straight chained or branched non-aromatic hydrocarbon which is completely saturated. Typically, a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10, more preferably from 1-6 or 1-4. unless otherwise defined. Examples of straight chained and branched alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A C1-C6 straight chained or branched alkyl group is also referred to as a "lower alkyl" group.

[54] Moreover, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, if not otherwise specified, can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, and the like.

[55] 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 "carbocycle" "cycloaliphatic" or "cycloalkyl"), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 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. 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 or (cycloalkyl)alkenyl.

[56] The term “Cx-y” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. For example, the term “Cx-yalkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-tirfluoroethyl, etc. C0 alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. The terms “C2-yalkenyl” and “C2-yalkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

[57] The term “alkylamino”, as used herein, refers to an amino group substituted with at least one alkyl group.

[58] The term “alkylthio”, as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkyl-S-.

[59] The term “haloalkyl”, as used herein, refers to an alkyl group in which at least one hydrogen has been replaced with a halogen, such as fluoro, chloro, bromo, or iodo. Exemplary haloalkyl groups include trifluoromethyl, difluoromethyl, fluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.

[60] The term “alkynyl”, as used herein, refers to a straight chained or branched aliphatic group containing at least one triple bond. Typically, an alkenyl group has from 2 to about 20 carbon atoms, preferably from 2 to about 10, more preferably from 2-6 or 2-4. unless otherwise defined. The term “alkynyl” is intended to include both "unsubstituted alkynyls" and "substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[61] The term “aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group.

[62] The term “aryl” as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably, the ring is a 6- to 10-membered ring, such as a 5- to 7-membered ring, more preferably a 6-membered ring. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[63] The terms “carbocycle”, and “carbocyclic”, as used herein, refers to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocycle includes both aromatic carbocycles and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond.

[64] The term “carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene and bicyclo[4.1.0]hept-3-ene. “Carbocycles” may be substituted at any one or more positions capable of bearing a hydrogen atom.

[65] A “cycloalkyl” group is a cyclic hydrocarbon which is completely saturated. “Cycloalkyl” includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 9 carbon atoms unless otherwise defined. The second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused cycloalkyl” refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings.

[66] A “cycloalkenyl” group is a cyclic hydrocarbon containing one or more double bonds. The cycloalkenyl ring may have 3 to 10 carbon atoms, such as 4 to 9 carbon atoms. As such, cycloalkenyl groups can be monocyclic or multicyclic. Individual rings of such multicyclic cycloalkenyl groups can have different connectivities, e.g., fused, bridged, spiro, etc. in addition to covalent bond substitution. Exemplary cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentyl, cyclohexenyl, cycloheptenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl and 1,5-cyclooctadienyl.

[67] Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornanyl, bicyclo[3.2.1 ]octanyl, octahydro-pentalenyl, spiro[4.5]decanyl, cyclopropyl, and adamantyl.

[68] The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group.

[69] The term “carbonate” is art-recognized and refers to a group -OCO2-R10, wherein R10 represents a hydrocarbyl group.

[70] The term “carboxy”, as used herein, refers to a group represented by the formula CO2H.

[71] The term “ester”, as used herein, refers to a group -C(O)OR10 wherein R10 represents a hydrocarbyl group.

[72] The term “ether”, as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.

[73] The terms “halo” and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.

[74] The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.

[75] The term "heteroalkyl", as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent.

[76] The terms “heteroaryl” and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 3- to 10-membered rings, more preferably 5- to 9-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heteroaryl” and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.

[77] Individual rings of such multicyclic heteroaryl groups can have different connectivities, e.g., fused, etc. in addition to covalent bond substitution. Exemplary heteroaryl groups include furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1 ,3,5-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,3-oxadiazolyl, 1 ,3,5-thiadiazolyl, 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1 ,2,4-triazinyl, 1 ,2,3-triazinyl, 1 ,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1 ]pyrindinyl, benzo[b]thiophenyl, 5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl and benzoxazinyl, etc. In general, the heteroaryl group typically is attached to the main structure via a carbon atom.

[78] The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[79] The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heterocyclyl” and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

[80] Individual rings of such multicyclic heterocycloalkyl groups can have different connectivities, e.g., fused, bridged, spiro, etc. in addition to covalent bond substitution. Exemplary heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, azindinyl, azetidinyl, oxiranyl, methylenedioxyl, chromenyl, barbituryl, isoxazolidinyl, 1 ,3-oxazolidin-3-yl, isothiazolidinyl, 1 ,3-thiazolidin-3-yl, 1 ,2-pyrazolidin-2-yl, 1 ,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1 ,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, piperizin-2-onyl, piperizin-3-onyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl, imidazolidinyl, 2-imidazolidinyl, 1 ,4-dioxanyl, 8-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, octahydro-2H-pyrido[1 ,2-a]pyrazinyl, 3-azabicyclo[4.1.0]heptanyl, 3-azabicyclo[3.1 .0]hexanyl 2-azaspiro[4.4]nonanyl, 7-oxa-1 -aza-spiro[4.4]nonanyl, 7-azabicyclo[2.2.2]heptanyl, octahydro-1H-indolyl, etc. In general, the heterocycloalkyl group typically is attached to the main structure via a carbon atom or a nitrogen atom.

[81] The term “heterocyclylalkyl”, as used herein, refers to an alkyl group substituted with a heterocycle group.

[82] The term “hydrocarbyl”, as used herein, refers to a group that is bonded through a carbon atom that does not have a =O or =S substituent, and typically has at least one carbon-hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =O substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.The term “hydroxyalkyl”, as used herein, refers to an alkyl group substituted with a hydroxy group.

[83] The term “lower” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer non-hydrogen atoms in the substituent, preferably six or fewer. A “lower alkyl”, for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).

[84] As described herein, compounds of the disclosure may contain “optionally substituted” moieties. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable 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 selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. 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, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[85] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; —(CH2)0-4R∘; —(CH2)0-4OR∘; —O(CH2)0-4R∘, —O—(CH2)0-4C(O)OR∘; —(CH2)0-4CH(OR∘)2; —(CH2)0-4SR∘; —(CH2)0-4Ph, which may be substituted with R∘; —(CH2)0-4O(CH2)0-1Ph which may be substituted with R∘; —CH═CHPh, which may be substituted with R∘; —(CH2)0-4O(CH2)0-1-pyridyl which may be substituted with R∘; —NO2; —CN; —N3; —(CH2)0-4N(R∘)2; —(CH2)0-4N(R∘)C(O)R∘; —N(R∘)C(S)R∘; —(CH2)0-4N(R∘)C(O)NR∘ 2; —N(R∘)C(S)NR∘ 2; —(CH2)0-4N(R∘)C(O)OR∘; —N(R∘)N(R∘)C(O)R∘; —N(R∘)N(R∘)C(O)NR∘ 2; —N(R∘)N(R∘)C(O)OR∘; —(CH2)0-4C(O)R∘; —C(S)R∘; —(CH2)0-4C(O)OR∘; —(CH2)0-4C(O)SR∘; —(CH2)0-4C(O)OSiR∘ 3; —(CH2)0-4OC(O)R∘; —OC(O)(CH2)0-4SR∘, SC(S)SR∘; —(CH2)0-4SC(O)R∘; —(CH2)0-4C(O)NR∘ 2; —C(S)NR∘ 2; —C(S)SR∘; —SC(S)SR∘, —(CH2)0-4OC(O)NR∘ 2; —C(O)N(OR∘)R∘; —C(O)C(O)R∘; —C(O)CH2C(O)R∘; —C(NOR∘)R∘; —(CH2)0-4SSR∘; —(CH2)0-4S(O)2R∘; —(CH2)0-4S(O)2OR∘; —(CH2)0-4OS(O)2R∘; —S(O)2NR∘ 2; —(CH2)0-4S(O)R∘; —N(R∘)S(O)2NR∘ 2; —N(R∘)S(O)2R∘; —N(OR∘)R∘; —C(NH)NR∘ 2; —P(O)2R∘; —P(O)R∘ 2; —OP(O)R∘ 2; —OP(O)(OR∘)2; SiR∘ 3; —(C1-4 straight or branched alkylene)O—N(R∘)2; or —(C1-4 straight or branched alkylene)C(O)O—N(R∘)2, wherein each R∘ may be substituted as defined below and is independently hydrogen, C1-6 aliphatic, —CH2Ph, —O(CH2)0-1Ph, —CH2-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R∘, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[86] Suitable monovalent substituents on R∘ (or the ring formed by taking two independent occurrences of R∘ together with their intervening atoms), are independently halogen, —(CH2)0-2R●, -(haloR●), —(CH2)0-2OH, —(CH2)0-2OR●, —(CH2)0-2CH(OR●)2; —O(haloR●), —CN, —N3, —(CH2)0-2C(O)R●, —(CH2)0-2C(O)OH, —(CH2)0-2C(O)OR●, —(CH2)0-2SR●, —(CH2)0-2SH, —(CH2)0-2NH2, —(CH2)0-2NHR●, —(CH2)0-2NR● 2, —NO2, —SiR● 3, —OSiR● 3, —C(O)SR●, —(C1-4 straight or branched alkylene)C(O)OR●, or —SSR● wherein each R● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4 aliphatic, —CH2Ph, —O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R∘ include ═O and ═S.

[87] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: ═O, ═S, ═NNR*2, ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)2R*, ═NR*, ═NOR*, —O(C(R*2))2-3O—, or —S(C(R*2))2-3S—, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: —O(CR*2)2-3O—, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[88] Suitable substituents on the aliphatic group of R* include halogen, —R●, -(haloR●), —OH, —OR●, —O(haloR●), —CN, —C(O)OH, —C(O)OR●, —NH2, —NHR●, —NR● 2, or —NO2, wherein each R● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, —CH2Ph, —O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[89] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include —R†, —NR† 2, —C(O)R†, —C(O)OR†, —C(O)C(O)R†, —C(O)CH2C(O)R†, —S(O)2R†, —S(O)2NR† 2, —C(S)NR† 2, —C(NH)NR† 2, or —N(R†)S(O)2R†; wherein each R† is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted —OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[90] Suitable substituents on the aliphatic group of R† are independently halogen, —R●, -(haloR●), —OH, —OR●, —O(haloR●), —CN, —C(O)OH, —C(O)OR●, —NH2, —NHR●, —NR● 2, or —NO2, wherein each R● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, —CH2Ph, —O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[91] The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”. Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.

[92] The term “silyl” refers to a silicon moiety with three hydrocarbyl moieties attached thereto. 

[93] The term “protecting group” refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl (“NVOC”) and the like. Representative hydroxyl protecting groups include, but are not limited to, those where the hydroxyl group is either acylated (esterified) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives and allyl ethers.

[94] The present disclosure also includes various isomers and mixtures thereof. Certain of the compounds of the present disclosure may exist in various stereoisomeric forms. Stereoisomers are compounds which differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. “Enantiomer” means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms. “R” and “S” represent the configuration of substituents around one or more chiral carbon atoms. When a chiral center is not defined as R or S, either a pure enantiomer or a mixture of both configurations is present.

[95] “Racemate” or “racemic mixture” means a compound of equimolar quantities of two enantiomers, wherein such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light. In certain embodiments, compounds of the present disclosure may be racemic.

[96] In certain embodiments, compounds of the present disclosure may be enriched in one enantiomer. For example, a compound of the present disclosure may have greater than about 30% ee, about 40% ee, about 50% ee, about 60% ee, about 70% ee, about 80% ee, about 90% ee, or even about 95% or greater ee. In certain embodiments, compounds of the present disclosure may have more than one stereocenter. In certain such embodiments, compounds of the present disclosure may be enriched in one or more diastereomer. For example, a compound of the present disclosure may have greater than about 30% de, about 40% de, about 50% de, about 60% de, about 70% de, about 80% de, about 90% de, or even about 95% or greater de.

[97] In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one enantiomer of a compound (e.g., of Formula I). An enantiomerically enriched mixture may comprise, for example, at least about 60 mol percent of one enantiomer, or more preferably at least about 75, about 90, about 95, or even about 99 mol percent. In certain embodiments, the compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than about 10%, or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or less than about 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture. For example, if a composition or compound mixture contains about 98 grams of a first enantiomer and about 2 grams of a second enantiomer, it would be said to contain about 98 mol percent of the first enantiomer and only about 2% of the second enantiomer.

[98] In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one diastereomer of a compound (e.g., of Formula I). A diastereomerically enriched mixture may comprise, for example, at least about 60 mol percent of one diastereomer, or more preferably at least about 75, about 90, about 95, or even about 99 mol percent.

[99] The compounds of the present disclosure may be prepared as individual isomers by either isomer specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.

[100] When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by weight pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by weight optically pure. Percent optical purity by weight is the ratio of the weight of the enantiomer that is present divided by the combined weight of the enantiomer that is present and the weight of its optical isomer.

[101] In the pictorial representation of the compounds given through this application, a thickened tapered line () indicates a substituent which is above the plane of the ring to which the asymmetric carbon belongs and a dotted line () indicates a substituent which is below the plane of the ring to which the asymmetric carbon belongs.

[102] As used herein a compound of the present disclosure can be in the form of one of the possible rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.  

[103] The term "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and / or dogs; and / or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and / or turkeys. Preferred subjects are humans.

[104] As used herein, a therapeutic that “prevents” a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[105] The term “treating” means to decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease. Treatment includes treating a symptom of a disease, disorder or condition. Without being bound by any theory, in some embodiments, treating includes augmenting deficient CFTR activity.

[106] A “therapeutically effective amount”, as used herein refers to an amount that is sufficient to achieve a desired therapeutic effect. For example, a therapeutically effective amount can refer to an amount that is sufficient to improve at least one sign or symptom of cystic fibrosis.

[107] A “response” to a method of treatment can include a decrease in or amelioration of negative symptoms, a decrease in the progression of a disease or symptoms thereof, an increase in beneficial symptoms or clinical outcomes, a lessening of side effects, stabilization of disease, partial or complete remedy of disease, among others.

[108] As used herein, “CFTR” means cystic fibrosis transmembrane conductance regulator. Loss of function mutations of CFTR are a cause of cystic fibrosis and lead to exocrine gland dysfunction and abnormal mucociliary clearance. Mutations in the CFTR gene or protein may result in reduced activity of CFTR. The most common mutation is a specific mutation of the deletion of three nucleotides of the codon for phenylalanine at position 508 (about 70% of cystic fibrosis patients) referred to as “ΔF508”. The ΔF508 mutation decreases the stability of the CFTR NBD1 domain and limits CFTR interdomain assembly. A patient can be ΔF508 homozygous or ΔF508 heterozygous (ΔF508 / ΔF508). In particular mutations, the result is a gating mutation leading to a low probability of the ion channel in the open position. Such mutations include but are not limited to G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, and G1349D.

[109] As used herein, the term “CFTR modulator” refers to a compound that increases the activity of CFTR. In certain aspects, a CFTR modulator is a CFTR corrector or a CFTR potentiator or a dual-acting compound having activities of a corrector and a potentiator. These dual acting agents are useful when the mutations result in absence or reduced amount of synthesized CFTR protein.

[110] As used herein, the term “CFTR corrector” refers to a compound that increases the amount of functional CFTR protein to the cell surface and thus enhances ion transport. The CFTR correctors partially “rescue” misfolding of CFTR, thereby permitting its maturation and functional expression on the cell surface and may modify the folding environment and compounds that interact directly to modify folding and conformational maturation during synthesis. Examples of correctors include, but are not limited to, VX-809, VX-661, VX-152, VX-440, VX-983, and GLPG2222.

[111] As used herein, the term “CFTR potentiator” refers to a compound that increases the ion channel activity of CFTR protein located at the cell surface, resulting in enhanced ion transport. CFTR potentiators repair the defective channel functions caused by mutations. Examples of potentiators include, but are not limited to, ivacaftor (VX770), deuterated ivacaftor (CPT 656), genistein and GLPG1837.

[112] As used herein, the term “CTFR pharmacological chaperone” (PC) refers to compounds that stabilize the CTFR protein in its native state by binding directly to the protein.

[113] As used herein, the term “CTFR proteostasis regulator” (PR) refers to compounds that enhance the protein folding efficiency within the cell. PRs can alter the activity of transcriptional, folding and / or membrane trafficking machinery, as well as impeding the degradation of partially folded, but functional, conformers at the endoplasmic reticulum (ER) or plasma membrane.

[114] As used herein, “CFTR disease or condition” refers to a disease or condition associated with deficient CFTR activity, for example, cystic fibrosis, congenital bilateral absence of vas deferens (CBAVD), acute, recurrent, or chronic pancreatitis, disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis, smoking-related lung diseases, such as chronic obstructive pulmonary disease (COPD), chronic sinusitis, dry eye disease, protein C deficiency, A.beta.-lipoproteinemia, lysosomal storage disease, type 1 chylomicronemia, mild pulmonary disease, lipid processing deficiencies, type 1 hereditary angioedema, coagulation-fibrinolyis, hereditary hemochromatosis, CFTR-related metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, and Sjogren's syndrome. Alternative Embodiments

[115] In an alternative embodiment, compounds described herein may also comprise one or more isotopic substitutions. For example, hydrogen may be 2H (D or deuterium) or 3H (T or tritium); carbon may be, for example, 13C or 14C; oxygen may be, for example, 18O; nitrogen may be, for example, 15N,and the like. In other embodiments, a particular isotope (e.g., 3H, 13C, 14C, 18O, or 15N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound.Methods of Use

[116] Disclosed herein are methods of treating deficient CFTR activity in a cell, comprising contacting the cell with a compound of formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, contacting the cell occurs in a subject in need thereof, thereby treating a disease or disorder mediated by deficient CFTR activity.

[117] Also, disclosed herein are methods of treating a disease or a disorder mediated by deficient CFTR activity comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is a mammal, preferably a human. In some embodiments, the disease is associated with the regulation of fluid volumes across epithelial membranes, particularly an obstructive airway disease such as CF or COPD.

[118] Such diseases and conditions include, but are not limited to, cystic fibrosis, asthma, smoke induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), congenital pneumonia, intestinal malabsorption, celiac disease, nasal polyposis, non-tuberculous mycobacterial infection, pancreatic steatorrhea, intestinal atresia, liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, I-cell disease / pseudo-Hurler, mucopolysaccharidoses, Sandhof / Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy / hyperinsulemia, Diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders, Huntington's, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, myotonic dystrophy, spongiform encephalopathies, hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, Sjogren's disease, Osteoporosis, Osteopenia, bone healing and bone growth, bone repair, bone regeneration, reducing bone resorption, increasing bone deposition, Gorham's Syndrome, chloride channelopathies, myotonia congenita, Bartter's syndrome type III, Dent's disease, hyperekplexia, epilepsy, hyperekplexia, lysosomal storage disease, Angelman syndrome, Primary Ciliary Dyskinesia (PCD), PCD with situs inversus, PCD without situs inversus and ciliary aplasia.

[119] Such diseases and conditions include, but are not limited to, cystic fibrosis, congenital bilateral absence of vas deferens (CBAVD), acute, recurrent, or chronic pancreatitis, disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis, chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis, congenital pneumonia, intestinal malabsorption, celiac disease, nasal polyposis, non-tuberculous mycobacterial infection, pancreatic steatorrhea, intestinal atresia, dry eye disease, protein C deficiency, Abetalipoproteinemia, lysosomal storage disease, type 1 chylomicronemia, mild pulmonary disease, lipid processing deficiencies, type 1 hereditary angioedema, coagulation-fibrinolyis, hereditary hemochromatosis, CFTR-related metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, and Sjogren's syndrome. In some embodiments, the disease is cystic fibrosis.

[120] Provided herein are methods of treating cystic fibrosis, comprising administering to a subject in need thereof, a compound as disclosed herein or a pharmaceutically acceptable salt thereof. Also provided herein are methods of lessening the severity of cystic fibrosis, comprising administering to a subject in need thereof, a compound as disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is a human. In some embodiments, the subject is at risk of developing cystic fibrosis, and administration is carried out prior to the onset of symptoms of cystic fibrosis in the subject.

[121] Provided herein are compounds as disclosed herein for use in treating a disease or condition mediated by deficient CFTR activity. Also provided herein are uses of a compound as disclosed herein for the manufacture of a medicament for treating a disease or condition mediated by deficient CFTR activity.

[122] The compounds and methods described herein can be used to treat subjects who have deficient CFTR activity and harbor CFTR mutations like ΔF508. The ΔF508 mutation impedes normal CFTR folding, stability, trafficking, and function by decreasing the stability of CFTR’s NBD1 domain, the competency of CFTR domain-domain assembly, or both. Due their impact on the ICL4 interface, a CFTR corrector with an ICL4-directed mechanism can be effective in subjects harboring the following mutations: ΔF508-CFTR (>70% of all CF patients harbor at least one copy) and mutations that cause ICL4 interface instability for example: G85E, H139R, H1054D, L1065P, L1077P, R1066C and other CFTR mutations where ICL4 interface stability is compromised.

[123] Provided herein are kits for use in measuring the activity of CFTR or a fragment thereof in a biological sample in vitro or in vivo. The kit can contain: (i) a compound as disclosed herein, or a pharmaceutical composition comprising the disclosed compound, and (ii) instructions for: a) contacting the compound or composition with the biological sample; and b) measuring activity of said CFTR or a fragment thereof. In some embodiments, the biological sample is biopsied material obtained from a mammal or extracts thereof; blood, saliva, urine, feces, semen, tears, other body fluids, or extracts thereof. In some embodiments, the mammal is a human.Combination Treatments

[124] As used herein, the term "combination therapy" means administering to a subject (e.g., human) two or more CFTR modulators, or a CFTR modulator and an agent such as antibiotics, ENaC inhibitors, GSNO (S-nitrosothiol s-nitrosoglutathione) reductase inhibitors, and a CRISPR Cas correction therapy or system (as described in US 2007 / 0022507 and the like).

[125] In certain embodiments, the method of treating or preventing a disease or condition mediated by deficient CFTR activity comprises administering a compound as disclosed herein conjointly with one or more other therapeutic agent(s). In some embodiments, one other therapeutic agent is administered. In other embodiments, at least two other therapeutic agents are administered.

[126] Additional therapeutic agents include, for example, ENaC inhibitors, mucolytic agents, bronchodilators, antibiotics, anti-infective agents, anti-inflammatory agents, ion channel modulating agents, therapeutic agents used in gene therapy, agents that reduce airway surface liquid and / or reduce airway surface PH, CFTR correctors, and CFTR potentiators, or other agents that modulate CFTR activity.

[127] In some embodiments, at least one additional therapeutic agent is selected from one or more CFTR modulators, one or more CFTR correctors and one or more CFTR potentiators.

[128] Non-limiting examples of CFTR modulators, correctors and potentiators include VX-770 (Ivacaftor), VX-809 (Lumacaftor, 3-(6-(I-(2,2-5 difluorobenzo[d][1, 3]dioxo1-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid, VX-661 (Tezacaftor, I-(2,2-difluoro-1, 3-benzodioxo1-5-yl)-N-[ I-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-l, I-dimethylethyl)- IH-indol-5-yl]- cyclopropanecarboxamide), VX-983, VX-152, VX-440, VX-445, VX-659, VX-371, VX-121, Orkambi, compounds described in US20190248809A1, Ataluren (PTC 124) (3-[5-(2-fluorophenyl)-1, 2,4-oxadiazo1-3-yl]benzoic acid), PTI-130 (Proteostasis), PTI-801, PTI-808, PTI-428, N91115.74 (cavosonstat), QBW251 (Novartis) compounds described in WO2011113894, compounds N30 Pharmaceuticals (e.g., WO 2014 / 186704), deuterated ivacaftor (e.g., CTP-656 or VX-561), GLPG2222, GLPG3221, GLPG2451, GLPG3067, GLPG2851, GLPG2737, GLPG1837 (N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide), GLPG2665 (Galapagos), ABBV-191 (Abbvie), ABBV-974, FDL 169 (Flatley Discovery lab), FDL 176, FDL438, FDL304, FD2052160, FD1881042, FD2027304, FD2035659, FD2033129, FD1860293, CFFT-Pot01, CFFT-Pot-02, P-1037, glycerol, phenylbutyrate, and the like. Non-limiting examples of anti-inflammatory agents are N6022 (3-(5-(4-(IH-imidazol-I-yl)10 phenyl)-I-(4-carbamoyl-2-methylphenyl)-'H-pyrrol-2-yl) propanoic acid), Ibuprofen, Lenabasum (anabasum), Acebilustat (CTX-4430), LAU-7b, POL6014, docosahexaenoic acid, alpha-1 anti-trypsin, sildenafil. Additional therapeutic agents also include, but are not limited to a mucolytic agent, a modifier of mucus rheology (such as hypertonic saline, mannitol, and oligosaccharide based therapy), a bronchodilator, an anti-infective (such as tazobactam, piperacillin, rifampin, meropenem, ceftazidime, aztreonam, tobramycin, fosfomycin, azithromycin, vancomycin, gallium and colistin), an anti-infective agent, an anti-inflammatory agent, a CFTR modulator other than a compound of the present disclosure, and a nutritional agent. Additional therapeutic agents can include treatments for comorbid conditions of cystic fibrosis, such as exocrine pancreatic insufficiency which can be treated with Pancrelipase or Liprotamase.

[129] Examples of CFTR potentiators include, but are not limited to, Ivacaftor (VX-770), CTP-656, NVS-QBW251, PTI-808, ABBV-3067, ABBV-974, ABBV-191, FDL176, FD1860293, GLPG2451, GLPG1837, and N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide. Examples of potentiators are also disclosed in publications: WO2005120497, WO2008147952, WO2009076593, WO2010048573, WO2006002421, WO2008147952, WO2011072241, WO2011113894, WO2013038373, WO2013038378, WO2013038381, WO2013038386, WO2013038390, WO2014180562, WO2015018823, and U.S. patent application Ser. Nos. 14 / 271,080, 14 / 451,619 and 15 / 164,317.

[130] Non-limiting examples of correctors include Lumacaftor (VX-809), 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl}cyclopropane carboxamide (VX-661), VX-983, GLPG2222, GLPG2665, GLPG2737, GLPG3221, GLPG2851, VX-152, VX-440, VX-121, VX-445, VX-659, PTI-801, FDL169, FDL304, FD2052160, and FD2035659. Examples of correctors are also disclosed in US20160095858A1, US20190248809A1, and U.S. application Ser. Nos. 14 / 925,649 and 14 / 926,727.

[131] In certain embodiments, the additional therapeutic agent is a CFTR amplifier. CFTR amplifiers enhance the effect of known CFTR modulators, such as potentiators and correctors. Examples of CFTR amplifier include PTI130 and PTI-428. Examples of amplifiers are also disclosed in publications: WO2015138909 and WO2015138934.

[132] In certain embodiments, the additional therapeutic agent is an agent that reduces the activity of the epithelial sodium channel blocker (ENaC) either directly by blocking the channel or indirectly by modulation of proteases that lead to an increase in ENaC activity (e.g., serine proteases, channel-activating proteases). Exemplary of such agents include camostat (a trypsin-like protease inhibitor), QAU145, 552-02, ETD001, GS-9411, INO-4995, Aerolytic, amiloride, AZD5634, and VX-371. Additional agents that reduce the activity of the epithelial sodium channel blocker (ENaC) can be found, for example, in PCT Publication No. WO2009074575 and WO2013043720; and U.S. Pat. No. 8,999,976.

[133] In one embodiment, the ENaC inhibitor is VX-371. In one embodiment, the ENaC inhibitor is SPX-101 (S18).

[134] In certain embodiments, the additional therapeutic agent is an agent that modulates the activity of the non-CFTR Cl- channel TMEM16A. Non-limiting examples of such agents include TMEM16A activators, denufosol, Melittin, Cinnamaldehyde, 3,4,5-Trimethoxy-N-(2-methoxyethyl)-N-(4-phenyl-2-thiazolyl)benzamide, INO-4995, CLCA1, ETX001, ETD002 and phosphatidylinositol diC8-PIP2, and TMEM16A inhibitors, 10bm, Arctigenin, dehydroandrographolide, Ani9, Niclosamide, and benzbromarone.

[135] In certain embodiments, the combination of a compound of Formula (I), with a second therapeutic agent may have a synergistic effect in the treatment of cancer and other diseases or disorders mediated by adenosine. In other embodiments, the combination may have an additive effect.

[136] In some embodiments, an additional therapeutic agent is a compound disclosed in WO2023 / 034946 or WO 2023 / 034992, both of which are incorporated by reference in their entirety. Pharmaceutical Compositions

[137] The compositions and methods of the present disclosure may be utilized to treat a subject in need thereof. In certain embodiments, the subject is a mammal such as a human, or a non-human mammal. When administered to subject, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the present disclosure and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop.

[138] A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the present disclosure. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the present disclosure. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

[139] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[140] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[141] A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anally, rectally or vaginally (for example, as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin, or as an eye drop). The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.

[142] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[143] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the present disclosure, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[144] Formulations of the present disclosure suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound of the present disclosure as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste.

[145] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[146] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[147] The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[148] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[149] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[150] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metal hydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[151] Formulations of the pharmaceutical compositions for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more active compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

[152] Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral ointment.

[153] Alternatively or additionally, compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

[154] Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[155] Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[156] The ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[157] Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[158] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present disclosure to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[159] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this disclosure. Exemplary ophthalmic formulations are described in U.S. Publication Nos. 2005 / 0080056, 2005 / 0059744, 2005 / 0031697 and 2005 / 004074 and U.S. Patent No. 6,583,124, the contents of which are incorporated herein by reference. If desired, liquid ophthalmic formulations have properties similar to that of lacrimal fluids, aqueous humor or vitreous humor or are compatible with such fluids. A preferred route of administration is local administration (e.g., topical administration, such as eye drops, or administration via an implant).

[160] The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[161] Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[162] Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[163] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[164] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[165] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.

[166] For use in the methods of this disclosure, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[167] Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow-release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinacious biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.

[168] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[169] The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and like factors well known in the medical arts.

[170] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By “therapeutically effective amount” is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the subject's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the present disclosure. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).

[171] In general, a suitable daily dose of an active compound used in the compositions and methods of the present disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[172] If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain embodiments of the present disclosure, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.

[173] In certain embodiments, the dosing follows a 3+3 design. The traditional 3+3 design requires no modeling of the dose–toxicity curve beyond the classical assumption for cytotoxic drugs that toxicity increases with dose. This rule-based design proceeds with cohorts of three patients; the first cohort is treated at a starting dose that is considered to be safe based on extrapolation from animal toxicological data, and the subsequent cohorts are treated at increasing dose levels that have been fixed in advance. In some embodiments, the three doses of a compound of formula (I) range from about 100 mg to about 1000 mg orally, such as about 200 mg to about 800 mg, such as about 400 mg to about 700 mg, such as about 100 mg to about 400 mg, such as about 500 mg to about 1000 mg, and further such as about 500 mg to about 600 mg. Dosing can be three times a day when taken with without food, or twice a day when taken with food. In certain embodiments, the three doses of a compound of formula (I) range from about 400 mg to about 800 mg, such as about 400 mg to about 700 mg, such as about 500 mg to about 800 mg, and further such as about 500 mg to about 600 mg twice a day. In certain preferred embodiments, a dose of greater than about 600 mg is dosed twice a day.

[174] If none of the three patients in a cohort experiences a dose-limiting toxicity, another three patients will be treated at the next higher dose level. However, if one of the first three patients experiences a dose-limiting toxicity, three more patients will be treated at the same dose level. The dose escalation continues until at least two patients among a cohort of three to six patients experience dose-limiting toxicities (i.e., ≥ about 33% of patients with a dose-limiting toxicity at that dose level). The recommended dose for phase II trials is conventionally defined as the dose level just below this toxic dose level.

[175] In certain embodiments, the dosing schedule can be about 40 mg / m2 to about 100 mg / m2, such as about 50 mg / m2 to about 80 mg / m2, and further such as about 70 mg / m2 to about 90 mg / m2 by IV for 3 weeks of a 4-week cycle.

[176] In certain embodiments, compounds of the present disclosure may be used alone or conjointly administered with another type of therapeutic agent. As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the subject, which may include synergistic effects of the two compounds). For example, the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either concomitantly or sequentially. In certain embodiments, the different therapeutic compounds can be administered within one h, 12 h, 24 h, 36 h, 48 h, 72 h, or a week of one another. Thus, a subject who receives such treatment can benefit from a combined effect of different therapeutic compounds.

[177] In certain embodiments, conjoint administration of compounds of the present disclosure with one or more additional therapeutic agent(s) (e.g., one or more additional chemotherapeutic agent(s)) provides improved efficacy relative to each individual administration of the compound of the present disclosure (e.g., compound of formula I or Ia) or the one or more additional therapeutic agent(s). In certain such embodiments, the conjoint administration provides an additive effect, wherein an additive effect refers to the sum of each of the effects of individual administration of the compound of the present disclosure and the one or more additional therapeutic agent(s).

[178] This present disclosure includes the use of pharmaceutically acceptable salts of compounds of the present disclosure in the compositions and methods of the present disclosure. A salt of a compound of this present 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. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.

[179] A “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 present disclosure. 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.

[180] Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesu1fonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2- sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.

[181] In certain embodiments, contemplated salts of the present disclosure include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, contemplated salts of the present disclosure include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the present disclosure include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.

[182]  The pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[183] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[184] Although specific embodiments of the present disclosure will now be described with reference to the preparations and schemes, it should be understood that such embodiments are by way of example only and merely illustrative of but a small number of the many possible specific embodiments which can represent applications of the principles of the present disclosure. Various changes and modifications will be obvious to those of skill in the art given the benefit of the present disclosure and are deemed to be within the spirit and scope of the present disclosure as further defined in the appended claims.

[185] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one having ordinary skill in the art to which this disclosure belongs. Although other compounds or methods can be used in practice or testing, certain preferred methods are now described in the context of the following preparations and schemes.

[186] A number of synthetic protocols were used to produce the compounds described herein. These synthetic protocols (see schemes below) have common intersections and can be used alternatively for synthesis of the compounds described herein. Enumerated Embodiments

[187] The present disclosure includes the following enumerated embodiments:1. A compound of Formula (I):(I),or a pharmaceutically acceptable salt thereof,whereinRing A is selected from the group consisting of , , and ;wherein Ring B is selected from the group consisting of , , and ;X is -C(R1)= or -N=;L1 is a bond or -C(=O)-;L2 is an optionally substituted C4-8 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen;W is selected from the group consisting of -NH, -NR2, and ;each R1 is independently selected from the group consisting of H, halogen, and optionally substituted -O-C1-8alkyl, wherein -O-C1-8alkyl is optionally substituted with 1-3 instances of halogen;R2 is hydrogen or optionally substituted C1-5alkyl, wherein C1-5alkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of optionally substituted C1-3alkyl, optionally substituted 4-7 membered cycloalkyl, optionally substituted 4-7 membered heterocyclyl, and -C(=O)OH;each R3 is H, halogen, or optionally substituted C1-3alkyl;each R4 is H, halogen, or optionally substituted C1-3alkyl;m is selected from the group consisting of 0, 1, 2, 3, 4, and 5;n is selected from the group consisting of 0, 1, 2, 3, and 4; and p is selected from the group consisting of 0, 1, 2, and 3. 2. The compound of embodiment 1, wherein the compound is a compound of Formula (II):(II),or a pharmaceutically acceptable salt thereof. 3. The compound of embodiment 1, wherein the compound is a compound of Formula (III):(III),or a pharmaceutically acceptable salt thereof. 4. The compound of embodiment 1, wherein the compound is a compound of Formula (IV):(IV),or a pharmaceutically acceptable salt thereof. 5. The compound of embodiment 1, wherein the compound is a compound of Formula (V):(V),or a pharmaceutically acceptable salt thereof. 6. The compound of embodiment 1, wherein the compound is a compound of Formula (VI):(VI),or a pharmaceutically acceptable salt thereof. 7. The compound of embodiment 1, wherein the compound is a compound of Formula (VII):(VII),or a pharmaceutically acceptable salt thereof. 8. The compound of any one of embodiments 1-7, wherein X is -N=. 9. The compound of any one of embodiments 1-7, wherein X is -C(R1)=. 10. The compound of embodiment 9, wherein X is -CH=. 11. The compound of embodiment 9, wherein X is -CF=. 12. The compound of any one of embodiments 1-11, wherein L1 is a bond. 13. The compound of any one of embodiments 1-11, wherein L1 is -C(=O)-. 14. The compound of any one of embodiments 1-13, wherein L2 is an optionally substituted C5-6alkylene chain, wherein 1 methylene unit is optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 2 instances of halogen. 15. The compound of any one of embodiments 1-13, wherein each R1 is independently -O-C1-8alkyl, wherein -O-C1-8alkyl is optionally substituted with 1-3 instances of halogen. 16. The compound of embodiment 15, wherein the halogen is fluoro. 17. The compound of any one of embodiments 1-13, wherein each R1 is independently selected from the group consisting of , , , and . 18. The compound of any one of embodiments 1-17, wherein W is -NR2, wherein R2 is optionally substituted C1-5alkyl, wherein R2 is optionally substituted with 1-3 instances of a substituent independently selected from the group consisting of C1-3alkyl, 4-7 membered cycloalkyl, 4-7 membered heterocyclyl, and -C(=O)OH. 19. The compound of any one of embodiments 1-17, wherein W is -NR2, and wherein R2 is selected from the group consisting of -CH3, , , , , , and . 20. The compound of embodiment 19, wherein R2 is -CH3. 21. The compound of any one of embodiments 1-20, wherein at least one R3 is -CH3. 22. The compound of any one of embodiments 1-20, wherein at least one R3 is halogen. 23. The compound of any one of embodiments 1-20, wherein at least one R4 is halogen. 24. The compound of any one of embodiments 1-20, wherein m is 1 or 2. 25. The compound of any one of embodiments 1-20, wherein n is 1 or 2. 26. The compound of any one of embodiments 1-20, wherein p is 1 or 2. 27. A compound selected from:or a pharmaceutically acceptable salt thereof. 28. The compound of embodiment 27, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof. 29. The compound of any one of embodiments 1-28, wherein the compound is a CFTR corrector. 30. A pharmaceutical composition comprising a compound of any one of the preceding embodiments, and one or more pharmaceutically acceptable carriers or excipients. 31. The pharmaceutical composition of embodiment 30, further comprising one or more CFTR therapeutic agents. 32. A method of treating deficient CFTR activity in a cell, comprising contacting the cell with a compound of any one of embodiments 1–29, or the pharmaceutical composition of embodiment 30 or 31. 33. The method of embodiment 32, wherein contacting the cell occurs in a subject in need thereof, thereby treating a CFTR-mediated condition and / or disease. 34. The method of embodiment 33, wherein the disease or condition is selected from cystic fibrosis, asthma, smoke induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, I-cell disease / pseudo-Hurler, mucopolysaccharidoses, Sandhof / Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy / hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders, Huntington's, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, myotonic dystrophy, spongiform encephalopathies, hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, Sjogren's disease, Osteoporosis, Osteopenia, bone healing and bone growth, bone repair, bone regeneration, reducing bone resorption, increasing bone deposition, Gorham's Syndrome, chloride channelopathies, myotonia congenita, Bartter's syndrome type III, Dent's disease, hyperekplexia, epilepsy, hyperekplexia, lysosomal storage disease, Angelman syndrome, Primary Ciliary Dyskinesia (PCD), PCD with situs inversus, PCD without situs inversus and ciliary aplasia. 35. The method of embodiment 33 or 34, wherein the disease or condition is selected from cystic fibrosis, congenital bilateral absence of vas deferens (CBAVD), acute, recurrent, or chronic pancreatitis, disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis, chronic obstructive pulmonary disease (COPD), chronic sinusitis, dry eye disease, protein C deficiency, Abetalipoproteinemia, lysosomal storage disease, type 1 chylomicronemia, mild pulmonary disease, lipid processing deficiencies, type 1 hereditary angioedema, coagulation-fibrinolyis, hereditary hemochromatosis, CFTR-related metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, and Sjogren's syndrome. 36. The method of any one of embodiments 33-35, wherein the disease or condition is cystic fibrosis. 37. A method of treating cystic fibrosis in a subject, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-29, or the pharmaceutical composition of embodiment 30 or 31. 38. The method of embodiment 37, wherein the subject is human. 39. The method according to embodiment 37 or 38, wherein said subject is at risk of developing cystic fibrosis, and wherein said administering step is carried out prior to the onset of symptoms of cystic fibrosis in said subject. AnalyticalMethods

[188] The 1H NMR spectra were recorded at Bruker AC 400 MHz or Varian Mercury 400 spectrometer with an ASW 5 mm probe, and usually recorded at ambient temperature in a deuterated solvent, such as D2O, CH3OH-d4, DMSO-d6 or CDCl3 unless otherwise noted.  Chemical shifts values (δ) are indicated in parts per million (ppm) with reference to tetramethylsilane (TMS) as the internal standard and coupling constants (J) in hertz (Hz).

[189] High Pressure Liquid Chromatography-Mass Spectrometry (LCMS) experiments to determine the retention time and associated MS. The LCMS was performed using one of the following methods: LCMS (Method 1): Column: Sunfire C18, 3.5 µm 4.6 × 50 mm. Mobile Phase: A: water (0.01%TFA). B: ACN (0.01%TFA). Gradient: 5%-95% B in 1.5 min. Flow Rate: 2.0 ml / min. Oven Temperature: 50 °C. Mass Range: 110-1000 UV: 214 nm; 254 nm.  LCMS (Method 2): Column: Poroshell 120 EC-C18 (3.0 × 30 mm, 2.7 µm). Mobile phase: A: H2O (0.01%TFA). B: ACN (0.01%TFA). Elution program: Gradient from 5% B increase to 95% B within 1.0 min, 95% B for 0.8 min. Temperature: 50 ℃. Detection: UV (214 nm, 254 nm) and MS (ESI, Pos mode, 110 to 1500 amu).  LCMS (Method 3): Column: HALO C18 (4.6 × 30 mm, 3.7 µm). Mobile phase: A: H2O (0.01%TFA). B: ACN (0.01%TFA).Elution program: Gradient from 5 to 95% of B in 1.5 min at 1.8 ml / min. Temperature: 50 ºC. Detection: UV (214 nm; 254 nm) and MS (ESI, Pos mode, 103 to 1000 amu). LCMS (Method 4): Column: Xbridge C18(2) (4.6 x 50 mm, 3.5 µm). Mobile phase: A: H2O (10 mmol NH4HCO3). B: ACN.Elution program: Gradient from 5 to 90% of B in 1.4 min at 1.8 ml / min.Temperature: 50 ºC. Detection: UV (214 nm, 254 nm) and MS (ESI, Pos mode, 105 to 900 amu). LCMS (Method 5): Column: Xbridge C18 (4.6 x 50 mm, 3.5 µm). Mobile phase: A: H2O (10 mmol NH4HCO3). B: ACN.Elution program: Gradient from 10 to 95% of B in 1.5 min at 1.8 ml / min.Temperature: 50 ºC. Detection: UV (214 nm, 254 nm) and MS (ESI, NEG mode, 70 to 900 amu). LCMS (Method 6): Column Agilent Infinity Lab Poroshell 120EC-C18 4.6 x 50mm 4 micron Mobile Phase: A: Water (0.01% TFA) B:ACN(0.01% TFA)Gradient: 10% increase to 95%B within 1.5 min,95%B for 1.5 min; Flow Rate: 1.8 ml / minColumn Temperature:50 °C Detection: UV (214, 254 nm) and MS (ESI, Pos mode,110 to 1500 amu) LCMS (Method 7): Column: Kinetex EVO C18 100A, 4.6 * 50 mm, 2.6 µm.Mobile Phase: A: water (0.01% TFA) B: ACN(0.01% TFA).Gradient: 5%B increase to 95%B within 1.3 min, 95%B for 1.7 min. Flow Rate: 1.8 ml / min.Column Temperature: 50 °C Detection: UV (214, 254 nm) and MS (ESI, Pos mode, 110 to 1500 amu). LCMS (Method 8): Mobile Phase: A: Water (10 mM NH4HCO3) B: ACN.Gradient: 5%B increase to 95% B within 1.3 min,95%B for 1.7 min. Flow Rate: 1.8 ml / min.Column: Xtimate C18, 3.5um, 4.6*50mmColumn Temperature: 40 °C. Detection: UV (214, 254 nm) and MS (ESI, Pos mode,110 to 1000 amu).EXAMPLESAbbreviations ACN acetonitrileAUC area under the curveBoc tert-butyloxycarbonylCF cystic fibrosisCFTR cystic fibrosis transmembrane conductance regulatorDAST diethylaminosulfur trifluorideDEA diethyl amineDBU 1,8-Diazabicyclo[5.4.0]undec-7-eneDCE 1,2-dichloroethaneDCM dichloromethane / methylene chlorideDIAD diisopropyl azodicarboxylateDIEA N,N-DiisopropylethylamineDMAP 4-dimethylaminopyridineDMF dimethylformamideDMSO dimethyl sulfoxideDppf 1,1'-Bis(diphenylphosphino)ferroceneDTT dithiothreitolEA ethyl acetateESI electron spray ionizationHATU hexafluorophosphate azabenzotriazole tetramethyl uroniumHPLC high performance liquid chromatographyLC liquid chromatographyLCMS liquid chromatography-mass spectrometryLDA lithium diisopropylamideMOM-Br bromo(methoxy)methaneMS mass spectrometryMSD membrane-spanning domainNBD nucleotide binding domainNIS N-iodosuccinimidePCC pyridinium chlorochromatePd / C Palladium on carbonPE petroleum etherRT LC retention time (min).rt room temperatureSFC supercritical fluid chromatographyS-BINAP (S)-(−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthaleneTBS tert-ButyldimethylsilylTFA trifluoroacetic acidTEA triethylamineTIPS triisopropylsilylTHF tetrahydrofuranTHP tetrahydropyranTLC thin-layer chromatographyTMEDA tetramethylethylenediamineTMS-CF3 Trimethyl(trifluoromethyl)silaneTs tosylVT transepithelial voltageSynthesis of the IntermediatesIntermediate 1:tert-Butyl (6-(2-bromophenyl)hexyl)carbamateStep 1. Synthesis of tert-butyl N-[(6E)-6-(p-tolylsulfonylhydrazono)hexyl]carbamate

[190] To a solution of tert-butyl N-(6-oxohexyl)carbamate (5.10 g, 23.7 mmol) in methanol (60 mL) was added p-toluenesulfonohydrazide (4.41 g, 23.7 mmol). The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated and purified by flash column chromatography on silica gel (eluting with PE : EA = 1:1) to give tert-butyl N-[(6E)-6-(p-tolylsulfonylhydrazono)hexyl]carbamate (6.00 g, 15.6 mmol, 66.0 % yield) as a white solid.LCMS (Method 4): LC retention time = 1.94 min. MS (ESI) m / z 284.1 [M+H-tBuOCO]+.Step 2. Synthesis of tert-butyl N-[6-(2-bromophenyl)hexyl]carbamate

[191] To a solution of tert-butyl N-[(6E)-6-(p-tolylsulfonylhydrazono)hexyl]carbamate (6.00 g, 15.6 mmol) and (2-bromophenyl)boronic acid (4.71 g, 23.5 mmol) in 1,4-dioxane (30 mL) was added potassium carbonate (4.32 g, 31.3 mmol). The reaction mixture was stirred at 120 °C for 16 h, then cooled to rt. The mixture was diluted with water (20 mL) and extracted with EA (50 mL × 3). The organic extracts were combined and washed with brine, dried over Na2SO4,and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluting with PE : EA = 10:1) to give tert-butyl N-[6-(2-bromophenyl)hexyl]carbamate (1.70 g, 4.77 mmol, 30.5 % yield) as a yellow oil.LCMS (Method 4): LC retention time = 2.43 min. MS (ESI) m / z 300, 302 [M+H-tBu]+.Intermediate1A:tert-Butyl N-[6-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]hexyl]carbamateStep 1. Synthesis of tert-butyl N-[6-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]hexyl]carbamate

[192] To a solution of tert-butyl N-[6-(2-bromophenyl)hexyl]carbamate (6000 mg, 16.8 mmol) in 1,4-dioxane (100 mL) were added bis(pinacolato)diboron (6414 mg, 25.3 mmol), potassium acetate (4958 mg, 50.5 mmol) and 1,1'-bis(diphenylphosphino)ferrocenedichloro palladium (II) dichloromethane complex (370 mg, 0.505 mmol) under N2. The mixture was stirred at 100 °C for 4 h under N2. The mixture was concentrated to afford a residue which was purified by column chromatography on silica gel (eluting with petroleum ether : ethyl acetate = 10:1) to give tert-butyl N-[6-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]hexyl]carbamate (6000 mg, 14.7 mmol, 87.5 % yield) as a colorless oil. LCMS (Method 2): LC retention time = 2.22 min. MS (ESI) m / z 304.3 [M+H- tBuOCO]+.Intermediate 2:2-[6-(2-Bromophenyl)-6,6-difluoro-hexyl]isoindoline-1,3-dione Step 1. Synthesis of 2-[6-(2-bromophenyl)hex-5-ynyl]isoindoline-1,3-dione

[193] To a solution of 2-hex-5-ynylisoindoline-1,3-dione (15000 mg, 66.0 mmol) in THF (300 mL) were added 1-bromo-2-iodobenzene (10 mL, 79.2 mmol), bis(triphenylphosphine) palladium (II) chloride (1500 mg, 2.14 mmol), copper (I) iodide (1500 mg, 7.88 mmol), and triethylamine (45 mL, 323 mmol).  The mixture was stirred at rt for 4 h. The solids were filtered off. The filtrate was concentrated to give a residue which was purified by column chromatography on silica gel (eluting with petroleum ether : ethyl acetate = 3:1) to obtain 2-[6-(2-bromophenyl)hex-5-ynyl]isoindoline-1,3-dione (20000 mg, 51.8 mmol, 78.5 % yield)  as an off-white solid.LCMS (Method 1): LC retention time = 2.68 min. MS (ESI) m / z 382.0, 384 [M+H]+.Step 2. Synthesis of 2-[6-(2-bromophenyl)-6-oxo-hexyl]isoindoline-1,3-dione 

[194] A solution of 2-[6-(2-bromophenyl)hex-5-ynyl]isoindoline-1,3-dione (30000 mg, 78.5 mmol) in sulfuric acid (116 mL, 2169 mmol) was stirred at room temperature for 15 min to give a suspension.  The mixture was poured into ice water (1.5 L) and the pH adjusted to 8 with solid Na2CO3. The aqueous mixture was extracted with EA (500 mL × 3). The combined organic extracts were concentrated to give a residue which was purified by flash column chromatography on silica gel (eluting with PE : EA = 3:1) to give 2-[6-(2-bromophenyl)-6-oxo-hexyl]isoindoline-1,3-dione (15000 mg, 35.6 mmol, 45.4 % yield) as a light yellow solid.LCMS (Method 1): LC retention time = 2.53 min. MS (ESI) m / z 400.1, 402 [M+H]+.Step 3. Synthesis of 2-[6-(2-bromophenyl)-6,6-difluoro-hexyl]isoindoline-1,3-dione

[195] To a solution of 2-[6-(2-bromophenyl)-6-oxo-hexyl]isoindoline-1,3-dione (20.00 g, 50.0 mmol) in chloroform (60 mL) was added diethylamino-sulfur trifluoride (60 mL, 454 mmol). The mixture was stirred at 70 °C for 16 h. The mixture was poured into ice water (500 mL) and the pH adjusted to 8 with solid Na2CO3. The aqueous mixture was extracted with EA (300 mL × 2). The organic extracts were combined, washed with brine (100 mL), dried over Na2SO4, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with PE : EA = 5:1) to give 2-[6-(2-bromophenyl)-6,6-difluoro-hexyl]isoindoline-1,3-dione (10.00 g, 23.7 mmol, 47.4 % yield) as a brown solid.LCMS (Method 4): LC retention time = 1.86 min. MS (ESI) m / z 439.1, 441 [M+NH4]+.Intermediate 2A:2-[6,6-Difluoro-6-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]hexyl]isoindoline-1,3-dioneStep 1. Synthesis of 2-[6,6-difluoro-6-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]hexyl]isoindoline-1,3-dione

[196] To a solution of 2-[6-(2-bromophenyl)-6,6-difluoro-hexyl]isoindoline-1,3-dione (Intermediate2, 500 mg, 1.18 mmol) in 1,4-dioxane (10 mL) was added 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (II) dichloromethane complex (CAS#: 72287-26-4, 87 mg, 0.118 mmol), bis(pinacolato)diboron (301 mg, 1.18 mmol) and potassium acetate (232 mg, 2.37 mmol). The mixture was stirred at 90 °C for 12 h under N2. The reaction mixture was poured into water (50 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with 10% EtOAc in petroleum ether, to give 2-[6,6-difluoro-6-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]hexyl]isoindoline-1,3-dione (250 mg, 0.533 mmol, 45.0 % yield) as a colorless oil.LCMS (Method 4): LC retention time = 2.13 min. MS (ESI) m / z 487.0 [M+H2O]+.Intermediate 3:tert-Butyl (6-(2-bromophenyl)heptyl)carbamateStep 1. Synthesis of methyl (6E)-6-(p-tolylsulfonylhydrazono)heptanoate

[197] To a solution of methyl 6-oxoheptanoate (5.00 g, 31.6 mmol) in 1,4-dioxane (60 mL) was added p-toluenesulfonohydrazide (5.89 g, 31.6 mmol). The reaction mixture was stirred at 80 oC for 1 h.  The reaction mixture was concentrated and purified by flash column chromatography on silica gel (eluting with PE : EA = 1:1) to give methyl (6E)-6-(p-tolylsulfonylhydrazono)heptanoate (9.30 g, 28.5 mmol, 90.2 % yield)  as a white solid.LCMS (Method 4): LC retention time = 1.84 min. MS (ESI) m / z 327.1 [M+H]+.Step 2. Synthesis of methyl 6-(2-bromophenyl)heptanoate

[198] To a solution of methyl (6E)-6-(p-tolylsulfonylhydrazono)heptanoate (5.00 g, 15.3 mmol)  and (2-bromophenyl)boronic acid (6.15 g, 30.6 mmol)  in 1,4-dioxane (30 mL)  was added potassium carbonate (8.47 g, 61.3 mmol). The mixture was stirred at 120 °C for 16 h. Then the reaction was diluted with water (20 mL) and extracted with EA (50 mL × 3). The separated organic phases were combined and washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluting with PE : EA = 10:1) to afford methyl 6-(2-bromophenyl)heptanoate (1.60 g, 5.35 mmol, 34.9 % yield)  as a yellow oil.LCMS (Method 4): LC retention time = 2.37 min. MS (ESI) m / z 316.1, 318.1 [M+H2O]+.Step 3. Synthesis of 6-(2-bromophenyl)heptan-1-ol

[199] To a suspension of lithium aluminum hydride (0.11 g, 3.01 mmol) in THF (10 mL)  was added methyl 6-(2-bromophenyl)heptanoate (600 mg, 2.01 mmol)  at 0 °C. The mixture was stirred at 0 °C for 30 min. The reaction was quenched by slowly adding 15% aqueous NaOH (0.11 mL). Anhydrous Na2SO4 was added to the mixture and stirring was continued for several minutes. The solid was removed by filtration through a Celite pad. The filtrate was concentrated under vacuum to give 6-(2-bromophenyl)heptan-1-ol (520 mg, 1.92 mmol, 95.6 % yield)  as a colorless oil. This sample was used directly in the next step without further purification.LCMS (Method 4): LC retention time = 2.13 min. MS (ESI) m / z 288.1, 290.1 [M+H2O]+.Step 4. Synthesis of 6-(2-bromophenyl)heptyl methanesulfonate

[200] To a solution of 6-(2-bromophenyl)heptan-1-ol (520 mg, 1.92 mmol)  and triethylamine (0.80 mL, 5.75 mmol) in DCM (5 mL) was added methane sulfonyl chloride (0.18 mL, 2.30 mmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 30 min, diluted with water (20 mL), and extracted with DCM (20 mL× 3). The organic phases were combined, washed with brine, and dried over Na2SO4. The organics were concentrated under vacuum to give 6-(2-bromophenyl)heptyl methanesulfonate (680 mg,1.95 mmol, 101.5 % yield) as a colorless oil which was used directly in the next step without purification.LCMS (Method 4): LC retention time = 2.23 min. MS (ESI) m / z 364.1, 366.1 [M+H2O]+.Step 5. Synthesis of 6-(2-bromophenyl)heptan-1-amine

[201] To a solution of 6-(2-bromophenyl)heptyl methane sulfonate (680 mg, 1.95 mmol)  in 1,4-dioxane (2 mL) was added ammonium hydroxide (68 mg, 1.95 mmol). The reaction mixture was stirred at 80 °C for 3 h. Then the mixture was concentrated under vacuum to give 6-(2-bromophenyl)heptan-1-amine (500 mg, 1.85 mmol, 95.1 % yield) as a yellow oil which was used directly in the next step without purification.LCMS (Method 4): LC retention time = 1.97 min. MS (ESI) m / z 270.1, 272.1 [M+H]+.Step 6. Synthesis of tert-butyl N-[6-(2-bromophenyl)heptyl]carbamate

[202] To a solution of 6-(2-bromophenyl)heptan-1-amine (500 mg, 1.85 mmol) and triethylamine (0.77 mL, 5.55 mmol)  in DCM (10 mL) was added dropwise di-tert-butyl dicarbonate (0.86 mL, 3.70 mmol). The reaction mixture was stirred at rt for 30 min, concentrated under reduced pressure, and purified by reversed-phase chromatography (C18, eluting with 0.1% NH4HCO3 in water,10-100% ACN) to give tert-butyl N-[6-(2-bromophenyl)heptyl]carbamate (400 mg, 1.08 mmol, 58.4 % yield)  as a colorless oil.LCMS (Method 4): LC retention time = 2.50 min. MS (ESI) m / z 314.1, 316.1 [M+H-tBu]+.Intermediate 3A:tert-Butyl (6-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)heptyl)carbamateStep 1. Synthesis of tert-butyl (6-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)heptyl)carbamate

[203] Intermediate 3A was synthesized by following the procedures used for the synthesis ofIntermediate 2A, except starting from Intermediate 3.LCMS (Method 4): LC retention time = 2.66 min. MS (ESI) m / z 288.1 [M+H-100]+.Intermediate 4:tert-Butyl (3-(2-bromophenethoxy)propyl)carbamateStep 1. Synthesis of 2-[3-[2-(2-bromophenyl)ethoxy]propyl]isoindoline-1,3-dione

[204] To a solution of 2-(2-bromophenyl)ethanol (5000 mg, 24.9 mmol) in DMF (20 mL) was added 2-(3-bromopropyl)isoindoline-1,3-dione (8001 mg, 29.8 mmol) and potassium tert-butoxide (8371 mg, 74.6 mmol). The reaction was stirred at rt for 16 h under nitrogen. The reaction mixture was cooled to room temperature, quenched with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrate sodium sulfate, filtered, and concentrated. The residue was purified by HPLC to yield 2-[3-[2-(2-bromophenyl)ethoxy]propyl]isoindoline-1,3-dione (1930 mg, 4.97 mmol, 20.0 % yield) as a yellow solid.LCMS (Method 1): LC retention time = 2.20 min. MS (ESI) m / z 388.0, 390.0 [M+H]+.Step 2. Synthesis of 2-[3-[2-(2-bromophenyl)ethoxy]propyl]isoindoline-1,3-dione

[205] To a solution of 2-[3-[2-(2-bromophenyl)ethoxy]propyl]isoindoline-1,3-dione (1930 mg, 4.97 mmol) in methanol (10 mL) was added hydrazine hydrate (1 mL).The reaction was stirred at 60 ℃ for 3 h . The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic extracts were washed with brine (50 mL × 3), dried over anhydrate sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (40 g silica gel column eluting with 30% ethyl acetate in petroleum ether) to yield 3-[2-(2-bromophenyl)ethoxy]propan-1-amine (1200 mg, 4.65 mmol, 93.5 % yield) as a yellow oilLCMS (Method 1): LC retention time = 1.47 min. MS (ESI) m / z 258.1, 260.1 [M+H]+.Step 3. Synthesis oftert-butyl N-[3-[2-(2-bromophenyl)ethoxy]propyl]carbamate

[206] To a solution of 3-[2-(2-bromophenyl)ethoxy]propan-1-amine (1200 mg, 4.65 mmol) in DCM (10 mL) was added di-tert-butyl dicarbonate (1.3 mL, 5.58 mmol) and N,N-diisopropylethylamine (2.4 mL, 13.9 mmol). The reaction was stirred at 25 ℃ for 3 h quenched with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrate sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (40 g silica gel column, eluting with 30% ethyl acetate in petroleum ether) to yield tert-butyl N-[3-[2-(2-bromophenyl)ethoxy]propyl]carbamate (1310 mg, 3.66 mmol, 78.7 % yield) as a yellow solid.LCMS (Method 1): LC retention time = 2.04 min. MS (ESI) m / z 257.1, 259.1 [M+H-BOC]+.Intermediate 4A:tert-Butyl N-[3-[2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethoxy]propyl]carbamateIntermediate 4A was synthesized by following procedures similar to those used in the synthesis of Intermediate 2A, except starting from Intermediate 4 .LCMS (Method 1): LC retention time = 2.10 min. MS (ESI) m / z 306.3 [M+H-BOC]+.Intermediate 5:tert-Butyl N-[3-[2-(2-bromophenyl)-2,2-difluoro-ethoxy]propyl]carbamateStep 1. Synthesis of ethyl 2-(2-bromophenyl)-2,2-difluoro-acetate

[207] To a solution of 1-bromo-2-iodobenzene (30 mL, 230 mmol) in DMSO (300 mL) was added copper (37.96 g, 597 mmol) and ethyl bromodifluoroacetate (33 mL, 253 mmol). The reaction was stirred at 50 °C for 16 h under N2. The reaction mixture was poured into water (3000 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic extracts were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 4% EtOAc in petroleum ether to give ethyl 2-(2-bromophenyl)-2,2-difluoro-acetate (31.00 g, 111 mmol, 48.4 % yield) as a colorless oil.LCMS (Method 4): LC retention time = 2.44 min. MS (ESI) m / z 279, 281 [M+H]+.Step 2. Synthesis of 2-(2-bromophenyl)-2,2-difluoro-ethanol

[208] To a solution of ethyl 2-(2-bromophenyl)-2,2-difluoro-acetate (31.00 g, 111 mmol) in methanol (100 mL) was added sodium borohydride (5.04 g, 133 mmol) in five portions at 0 °C. The mixture was stirred at 0 °C for 30 min followed by the addition of 2N aqueous HCl (100 mL) at 0 °C. and the resulting mixture was extracted with EA (100 mL × 3), the organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with PE : EA = 5:1 ) to give 2-(2-bromophenyl)-2,2-difluoro-ethanol (23.00 g, 97.0 mmol, 87.4 % yield) as a colorless oil.LCMS (Method 3): LC retention time = 2.01 min. MS (ESI) m / z not observed. Step 3. Synthesis of 3-[2-(2-bromophenyl)-2,2-difluoro-ethoxy]propan-1-ol

[209] To a solution of 2-(2-bromophenyl)-2,2-difluoro-ethanol (5000 mg, 21.1 mmol), tetrabutylammonium bromide (680 mg, 2.11 mmol) and 3-bromo-1-propanol (2.2 mL, 25.3 mmol) in 1,4-dioxane (17 mL) was added sodium hydroxide (11.2M, 4.3 mL, 48.2 mmol). The reaction mixture was stirred at rt for 16 h. The reaction was quenched with water (30 mL),. the aqueous mixture was extracted with EA (30 mL × 3). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 0-50% EA in PE) to give 3-[2-(2-bromophenyl)-2,2-difluoro-ethoxy]propan-1-ol (3000 mg, 10.1 mmol, 47.7 % yield) as a yellow oil.LCMS (Method 1): LC retention time = 1.83 min. MS (ESI) m / z 317.0, 319 [M+Na]+. Step 4. Synthesis of3-[2-(2-bromophenyl)-2,2-difluoro-ethoxy]propyl methanesulfonate

[210] To a solution of 3-[2-(2-bromophenyl)-2,2-difluoro-ethoxy]propan-1-ol (3000 mg, 10.2 mmol) and triethylamine (3.5 mL, 25.4 mmol) in DCM (30 mL) was added methanesulfonyl chloride (1.0 mL, 13.2 mmol) dropwise. The mixture was stirred at rt for 1 h, followed by the addition of water (30 mL). The resulting mixture was extracted with DCM (30 mL × 3). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to give 3-[2-(2-bromophenyl)-2,2-difluoro-ethoxy]propyl methanesulfonate (3000 mg, 7.23 mmol, 71.2 % yield) as a yellow oil which was used in next step without purification.LCMS (Method 1): LC retention time = 1.87 min. MS (ESI) m / z 373.0, 375.0 [M+H]+. Step 5. Synthesis of3-[2-(2-bromophenyl)-2,2-difluoro-ethoxy]propan-1-amine

[211] To a solution of 3-[2-(2-bromophenyl)-2,2-difluoro-ethoxy]propyl methanesulfonate (3000 mg, 8.04 mmol) in 1,4-dioxane (15 mL) was added ammonium hydroxide (15 mL, 385 mmol). The mixture was stirred at 80 °C for 16 h, cooled to rt, followed by the addition of water (30 mL). The resulting mixture was extracted with EA (30 mL × 3). The combined organic extracts were washed with brine (30 mL) dried over Na2SO4, and concentrated to afford 3-[2-(2-bromophenyl)-2,2-difluoro-ethoxy]propan-1-amine (2800 mg, 3.81 mmol, 47.4 % yield) as a yellow oil.LCMS (Method 1): LC retention time = 1.36 min. MS (ESI) m / z 294.0, 296.0 [M+H]+.Step 6. Synthesis of tert-butyl N-[3-[2-(2-bromophenyl)-2,2-difluoro-ethoxy]propyl]carbamate 

[212] To a solution of 3-[2-(2-bromophenyl)-2,2-difluoro-ethoxy]propan-1-amine (13.00 g, 44.2 mmol) and triethylamine (18 mL, 133 mmol) in DCM (50 mL) was added di-tert-butyl dicarbonate (15 mL, 66.3 mmol) dropwise. The reaction mixture was stirred at rt for 30 min. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography on silica gel (eluting with PE : EA = 5 : 1) to give tert-butyl N-[3-[2-(2-bromophenyl)-2,2-difluoro-ethoxy]propyl]carbamate (17.00 g, 43.1 mmol, 97.6 % yield) as a colorless oil.LCMS (Method 4): LC retention time = 2.14 min. MS (ESI) m / z 294.0, 296.0 [M+H-Boc]+.Intermediate 5A:tert-Butyl (3-(2,2-difluoro-2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethoxy)propyl)carbamate

[213] Intermediate 5A was synthesized by following procedures similar to those used to prepare Intermediate 2A, except using Intermediate 5 as a starting material.LCMS (Method 4): LC retention time = 2.66 min. MS (ESI) m / z no MS signal was observed.Intermediate 6:tert-Butyl (3-(4-(2-bromophenyl)-1H-pyrazol-1-yl)propyl)carbamate Step 1. Synthesis of tert-butyl N-[3-(4-iodopyrazol-1-yl)propyl]carbamate

[214] To a solution of 4-iodo-1H-pyrazole (5000 mg, 25.8 mmol) in DMF (50 mL) was added sodium hydride (1237 mg, 51.6 mmol) at 0 °C under N2. The mixture was stirred at rt for 1 h, cooled to 0 °C under N2, and tert-butyl N-(3-bromopropyl)carbamate (12275 mg, 51.6 mmol)  was added dropwise at 0 °C over 10 min. The mixture was stirred at rt for 3 h. The reaction was quenched with saturated aqueous NH4Cl solution (50 mL) at 0 °C, and the resulting mixture was extracted with ethyl acetate (100 mL x 3). The combined extracts were concentrated and the crude residue was purified by flash column chromatography on silica gel (eluting with EtOAc in PE: 0-100% for 30 min) to afford tert-butyl N-[3-(4-iodopyrazol-1-yl)propyl]carbamate (8000 mg, 22.8 mmol, 88.4 % yield) as a yellow oil.LCMS (Method 4): LC retention time = 1.77 min. MS (ESI) m / z 352.0 [M+H]+. Step 2. tert-butyl N-[3-[4-(2-bromophenyl)pyrazol-1-yl]propyl]carbamate

[215] To a solution of tert-butyl N-[3-(4-iodopyrazol-1-yl)propyl]carbamate (5000 mg, 14.2 mmol) in 1,4-dioxane (50 mL) and water (10 mL) were added (2-bromophenyl)boronic acid (719 mg, 28.5 mmol), potassium carbonate (5903 mg, 42.7 mmol), and tetrakis(triphenylphosphine)palladium (0) (3290 mg, 2.85 mmol). The mixture was stirred at 85 °C overnight under N2. After cooling to room temperature, the reaction mixture was filtered, and the solids washed with EA (30 mL). The combined filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluting with EtOAc in PE, 0-50% for 50 min) to obtain tert-butyl N-[3-[4-(2-bromophenyl)pyrazol-1-yl]propyl]carbamate (2000 mg, 5.26 mmol, 36.9 % yield) as a yellow oil.LCMS (Method 4): LC retention time = 1.58 min. MS (ESI) m / z 380.0, 382.0 [M+H]+.Intermediate 6A:tert-Butyl N-[3-[4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrazol-1-yl]propyl]carbamate

[216] Intermediate 6A was synthesized by following procedures similar to those employed in the synthesis of Intermediate 2A, except using Intermediate 6 as a starting material.LCMS (Method 4): LC retention time = 1.99min. MS (ESI) m / z 428.0 [M+H]+.Intermediate 7:2-(2-Bromophenyl)-N-(2-(1,3-dioxoisoindolin-2-yl)ethyl)ethane-1-sulfonamideStep 1. Synthesis of 2-(2-bromophenyl)ethanesulfonyl chloride

[217] To a solution of S-[2-(2-bromophenyl)ethyl]ethanethioate (10.00 g, 38.6 mmol) in MeCN (50 mL) and 2N HCl (10 mL) was added N-chlorosuccinimide (20.61 g, 154 mmol) at 0 °C. The reaction mixture was stirred at rt for 2 h, concentrated, and purified by flash column chromatography on silica gel (eluting with PE : EA = 20:1) to give 2-(2-bromophenyl)ethanesulfonyl chloride (10.00 g, 35.3 mmol, 91.4 % yield) as a white solid.LCMS (Method 3): LC retention time = 2.02 min. No MS signal was observed.Step 2. Synthesis of 2-(2-bromophenyl)-N-[2-(1,3-dioxoisoindolin-2-yl)ethyl]ethanesulfonamide

[218] To a solution of 2-(2-aminoethyl)isoindoline-1,3-dione hydrochloride (6.00 g, 26.4 mmol) and triethylamine (7.4 mL, 52.9 mmol) in DCM (50 mL) was added 2-(2-bromophenyl)ethanesulfonyl chloride (5.00 g, 17.6 mmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 1 h, diluted with water (30 mL) and extracted with DCM (30 mL × 3). The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluting with PE : EA = 1:1) to give 2-(2-bromophenyl)-N-[2-(1,3-dioxoisoindolin-2-yl)ethyl]ethanesulfonamide (5.30 g, 12.1 mmol, 68.7 % yield) as a white solid.LCMS (Method 3): LC retention time = 1.90 min. MS (ESI) m / z 437.1, 439.1 [M+H]+.Intermediate 8:tert-Butyl N-[6-(3-bromo-2-thienyl)hexyl]carbamate Step 1. Synthesis of2-[6-(3-bromo-2-thienyl)hex-5-ynyl]isoindoline-1,3-dione

[219] To a solution of 2-hex-5-ynylisoindoline-1,3-dione (30 mg, 0.132 mmol) and 3-bromo-2-iodo-thiophene (76 mg, 0.264 mmol) in THF (2 mL) was added bis(triphenylphosphine)palladium (II) chloride (9.3 mg, 0.0132 mmol), copper (I) iodide (2.5 mg, 0.0132 mmol), and triethylamine (0.046 mL, 0.330 mmol). The mixture was stirred at rt for 4 h and poured into water (5 mL). The resulting suspension was extracted with EA (15 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was first purified by reverse-phase flash chromatography (C18, 0.1%TFA in water, 10-100% MeCN), followed by another reverse-phase flash chromatography run (C18, 0.1% NH4HCO3 in water, 10-100% MeCN) to give 2-[6-(3-bromo-2-thienyl)hex-5-ynyl]isoindoline-1,3-dione (2.0 mg, 0.00515 mmol, 3.9 % yield) as a white solid.LCMS (Method 4): LC retention time = 2.03 min. MS (ESI) m / z 388 and 390 [M+H]+. Step 2. Synthesis of2-[6-(3-bromo-2-thienyl)hexyl]isoindoline-1,3-dione

[220] A mixture of 2-[6-(3-bromo-2-thienyl)hex-5-ynyl]isoindoline-1,3-dione (350 mg, 0.901 mmol),p-toluenesulfonhydrazide (2518 mg, 13.5 mmol) and sodium acetate (1109 mg, 13.5 mmol) in 1,2-dimethoxyethane and water (5:1, v / v) was stirred at 90 °C for 16 h. To this mixture was added water (10 mL). The aqueous solution was extracted with EA (15 mL × 3). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluting with PE : EA = 5:1) to give 2-[6-(3-bromo-2-thienyl)hexyl]isoindoline-1,3-dione (170 mg, 0.433 mmol, 48.1 % yield) as a colorless oil.LCMS (Method 1): LC retention time = 2.19 min. No MS (ESI) signal was observed.Step 3. Synthesis of6-(3-bromo-2-thienyl)hexan-1-amine

[221] 6-(3-bromo-2-thienyl)hexan-1-amine was synthesized (in 72.4% yield) by following essentially the same procedure as in Step 3 of the synthesis of Intermediate 4.LCMS (Method 1): LC retention time = 1.51 min. MS (ESI) m / z 262 and 264 [M+H]+.Step 4. Synthesis oftert-butyl N-[6-(3-bromo-2-thienyl)hexyl]carbamatetert-Butyl N-[6-(3-bromo-2-thienyl)hexyl]carbamate was synthesized (in 52.8% yield) by following essentially the same procedure as in Step 2 of the synthesis of Intermediate 4,.LCMS (Method 1): LC retention time = 1.59 min. MS (ESI) m / z 306 and 308 [M+H-tBu]+.Intermediate 8A:tert-Butyl N-[6-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl]hexyl]carbamate

[222] Intermediate 8A was synthesized in 29.5% yield by following essentially the same procedure as in the synthesis of Intermediate 2A, except using Intermediate 8 as a starting material.LCMS (Method 1): LC retention time = 2.49 min. MS (ESI) m / z 354.2 [M+H-tBu]+.Intermediate A-1:4-(2-Bromophenyl)thiazol-2-amineStep 1.Synthesis of 2-bromo-1-(2-bromophenyl)ethanone

[223] To a solution of 1-(2-bromophenyl)ethanone (1.00 eq, 150.00 g, 754 mmol) in acetonitrile (1500 mL) was added pyridine hydrobromide perbromide (1.00 eq, 241.02 g, 754 mmol). The mixture was stirred at room temperature for 4 h. The reaction was quenched with water. The aqueous solution was extracted with EA. The organic phase was washed sequentially with saturated aqueous NaHCO3, aqueous Na2S2O3, brine, and then dried over Na2SO4, filtered, and concentrated under reduced pressure to yield the title compound (200.00 g, 720 mmol, 95.5 % yield) as a brown oil.LCMS (Method 1): LC retention time = 1.93 min. MS (ESI) m / z 277, 279 [M+H]+.Step 2. Synthesis of 4-(2-bromophenyl)thiazol-2-amine

[224] To a solution of 2-bromo-1-(2-bromophenyl)ethanone (1.00 eq, 100 mg, 0.360 mmol) in ethanol (1 mL) was added thiourea (1.00 eq, 27 mg, 0.360 mmol). The reaction was heated at reflux for 2 h. The reaction was quenched with saturated aqueous NH4Cl (10 mL). The aqueous phase was extracted with EA (10 mL × 3). The combined EA extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (0-60% EA in heptane) to yield the title compound as a pale-yellow solid.LCMS (Method 2): LC retention time = 1.02 min. MS (ESI) m / z 255, 257 [M+H]+.Intermediate A-1a:4-(2-Bromo-6-methyl-phenyl)thiazol-2-amine

[225] Intermediate A-1a was prepared in essentially the same manner as Intermediate A-1starting from 1-(2-bromo-6-methylphenyl)ethan-1-one.LCMS (Method 3): LC retention time = 1.57 min. MS (ESI) m / z 269, 271 [M+H]+.Intermediate A-2:2-(2-Aminothiazol-4-yl)phenol

[226] Intermediate A-2 was prepared in essentially the same manner as Intermediate A-1starting from 1-(2-hydroxyphenyl)ethan-1-one.LCMS (Method 1): LC retention time = 1.74 min. MS (ESI) m / z 193.0 [M+H]+.Intermediate A-3:5-Bromo-6-(2-vinylphenyl)pyridin-2-amineStep 1. Synthesis of 5-bromo-6-(2-vinylphenyl)pyridin-2-amine

[227] To a solution of (2-vinylphenyl)boronic acid (1.00 eq, 5874 mg, 39.7 mmol) in 1,4-dioxane (100 mL) and water (10 mL) were added 5,6-dibromopyridin-2-amine (1.00 eq, 10000 mg, 39.7 mmol), potassium carbonate (3.95 eq, 21667 mg, 157 mmol), and tetrakis(triphenylphosphine)palladium (0) (0.0218 eq, 1000 mg, 0.865 mmol) under N2. The reaction was stirred at 90 °C for 12 h. The mixture was concentrated to give a residue which was purified by flash column chromatography (petroleum ether : ethyl acetate = 3 : 1) to obtain the title compound (5.50 g, 19.0 mmol, 47.8 % yield) as a light-yellow solid.LCMS (Method 4): LC retention time = 1.78 min. MS (ESI) m / z 275.0, 277.0 [M+H]+.Intermediate A-4:6-Chloro-5-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridin-2-amineStep 1. Synthesis of 6-chloro-5-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridin-2-amine

[228] To a solution of 3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)-1H-pyrazole (1.00 eq, 208 mg, 0.999 mmol) in DMF (5 mL) were added 6-chloro-5-iodo-pyridin-2-amine (1.50 eq, 381 mg, 1.50 mmol), copper (I) iodide (0.500 eq, 95 mg, 0.500 mmol), N,N'-dimethylethane-1,2-diamine (0.500 eq, 44 mg, 0.500 mmol), and potassium acetate (3.00 eq, 294 mg, 3.00 mmol). The mixture was stirred at 100 °C for 8 hours under N2. The reaction mixture was poured into water (30 mL) while stirring. The aqueous solution was extracted with ethyl acetate (30 mL × 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography, eluting with 35% ethyl acetate in petroleum ether to give the title compound (50 mg, 0.149 mmol, 15.0 % yield) as a yellow solid.LCMS (Method 1): LC retention time = 1.89 min. MS (ESI) m / z 335.0 [M+H]+.Intermediate A-5:tert-Butyl N-[6-chloro-5-[6-(trifluoromethoxy)-2-pyridyl]-2-pyridyl]carbamateStep 1. Synthesis oftert-butyl N-[6-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]carbamate

[229] To a solution of tert-butyl N-(5-bromo-6-chloro-2-pyridyl)carbamate (1.00 eq, 15.00 g, 48.8 mmol) in 1,4-dioxane (150 mL) were added 1,1'-bis(diphenylphosphino)ferrocenedichloro palladium (II) dichloromethane complex (0.10 eq, 3.57 g, 4.88 mmol), bis(pinacolato)diboron (1.30 eq, 16.10 g, 63.4 mmol), and potassium acetate (2.50 eq, 11.97 g, 122 mmol) at rt. Then the mixture was stirred at 100 °C for 3 h under Ar. The reaction mixture was diluted with water (100 mL). the resulting aqueous solution was extracted with EA (100 mL × 3). The organic extracts were washed with brine (100 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography (330 g silica gel column, eluting with 0-5% ethyl acetate in petroleum) to give the title compound (17.00 g, 47.9 mmol, 98.3 % yield)LCMS (Method 2): LC retention time = 2.23 min. MS (ESI) m / z 355.0 [M+H]+.Step 2. Synthesis of tert-butyl N-[6-chloro-5-[6-(trifluoromethoxy)-2-pyridyl]-2-pyridyl]carbamate 

[230] To a solution of tert-butyl N-[6-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]carbamate (1.00 eq, 300 mg, 0.846 mmol) in 1,4-dioxane (6 mL) and water (0.6 mL) was added 1,1'-bis(diphenylphosphino)ferrocenedichloro palladium (II) dichloromethane complex (0.100 eq, 62 mg, 0.0846 mmol), 2-chloro-6-(trifluoromethoxy)pyridine (1.20 eq, 201 mg, 1.02 mmol), and potassium carbonate (2.50 eq, 292 mg, 2.11 mmol) at rt. The reaction was stirred at 100 °C for 2 h under Ar. The mixture was diluted with water (10 mL). The resulting aqueous solution was extracted with EA (10 mL × 3). The organic extracts were washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography (25 g silica gel column, eluting with 0-10% ethyl acetate in petroleum) to give the title compound (80 mg, 0.205 mmol, 24.3 % yield).LCMS (Method 2): LC retention time = 2.20 min. MS (ESI) m / z 334.0 [M+H-tBu]+.Intermediate A-6:6-Chloro-5-(3-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-amineStep 1. Synthesis of4,4,5,5-tetramethyl-2-[3-(2,2,2-trifluoroethoxy)phenyl]-1,3,2-dioxaborolane

[231] To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1000 mg, 4.54 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2109 mg, 9.09 mmol) in THF (5 mL) was added sodium (545 mg, 0.136 mmol) at 0 °C under a nitrogen atmosphere. The mixture was stirred at room temperature for 3 h, quenched with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with water (50 mL x 2) and brine (50 mL x 2), dried over anhydrous sodium sulphate, filtered, and concentrated. The residue was purified by flash chromatography (25 g silica gel column, eluting with 0-5% ethyl acetate in petroleum ether) to give 4,4,5,5-tetramethyl-2-[3-(2,2,2-trifluoroethoxy)phenyl]-1,3,2-dioxaborolane (910 mg, 3.01 mmol, 66.3 % yield).LCMS (Method 4): LC retention time = 2.01 min. MS (ESI) m / z 303.3 [M+H]+.Step 2. Synthesis of6-chloro-5-[3-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-amine

[232] To a solution of 6-chloro-5-iodo-pyridin-2-amine (1.00 g, 3.93 mmol) in 1,4-dioxane (15 mL) and water (1.5 mL) was added 1,1'-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (144 mg, 0.196 mmol), 4,4,5,5-tetramethyl-2-[3-(2,2,2-trifluoroethoxy)phenyl]-1,3,2-dioxaborolane (1187 mg, 3.93 mmol) and potassium carbonate (1086 mg, 7.86 mmol). The reaction mixture was stirred at 80 °C for 3 h under N2, then poured into water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 25% EtOAc in petroleum ether to give 6-chloro-5-[3-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-amine (800 mg, 2.64 mmol, 67.3 % yield) as a white solid.LCMS (Method 4): LC retention time = 1.79 min. MS (ESI) m / z 303.0 [M+H]+.Intermediate A-7:6-Chloro-5-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyrazin-2-amineStep 1. Synthesis of 6-chloro-5-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyrazin-2-amine

[233] To a solution of 3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)-1H-pyrazole (5000 mg, 24.0 mmol) in DMF (50 mL) were added 5-bromo-6-chloro-pyrazin-2-amine (7509 mg, 36.0 mmol), potassium carbonate (9958 mg, 72.1 mmol), copper(I) iodide (915 mg, 4.80 mmol), and N,N'-dimethylethane-1,2-diamine (847 mg, 9.61 mmol). The mixture was stirred at 80 °C for 2 days and quenched with water (30 mL). The aqueous solution was extracted with EA (30 mL × 3), washed with brine (30 mL), dried over Na2SO4, then concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 0-50% EA in PE) to give 6-chloro-5-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyrazin-2-amine (3000 mg, 8.85 mmol, 36.8 % yield) as a yellow solid. LCMS (Method 4): LC retention time = 1.80 min. MS (ESI) m / z 336.1 [M+H]+.Intermediate A-8:4-Chloro-5-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridin-2-amineStep 1. Synthesis of 4-chloro-5-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridin-2-amine

[234] To a solution of 5-bromo-4-chloro-pyridin-2-amine (1000 mg, 4.82 mmol) in DMF (10 mL) were added 3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)-1H-pyrazole (2007 mg, 9.64 mmol), copper (I) iodide (184 mg, 0.964 mmol), potassium carbonate (1999 mg, 14.5 mmol), and N,N'-dimethylethane-1,2-diamine (4249 mg, 48.2 mmol). The mixture was stirred at 100 °C overnight under Ar. After cooling to room temperature, the reaction mixture was filtered and the solids were washed with EA (50 mL). The combined filtrates were concentrated under vacuum. The crude product was purified by prep-HPLC (NH4HCO3) and freeze-dried to obtain 4-chloro-5-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridin-2-amine (800 mg, 2.39 mmol, 49.6 % yield) as a yellow solid.LCMS (Method 4): LC retention time = 1.85 min. MS (ESI) m / z 335.0 [M+H]+.Intermediate A-9 to Intermediate A-12:

[235] The following intermediates were synthesized similarly by following the synthetic protocols for synthesis of IntermediateA-6 and Intermediate A-7.IntermediateStructureNameAnalyticalA-96-Chloro-5-(3-(3,3-dimethylbutoxy)phenyl)pyrazin-2-amineLCMS (Method 1): LC retention time = 2.12 min. MS (ESI) m / z , 306 [M+H]+A-106-Chloro-5-[3-(2,2-difluoro-3,3-dimethyl-butoxy)phenyl]pyrazin-2-amineLCMS (Method 1): LC retention time = 2.17 min. MS (ESI) m / z 342.1 [M+H]+A-116-Chloro-5-[3-(3,3-dimethylbutoxy)phenyl]pyridin-2-amineLCMS (Method 2): Rt 2.12 min. MS (ESI) m / z 305.1 [M+H]+A-122'-Chloro-6-(trifluoromethoxy)-[2,3'-bipyridin]-6'-amineLCMS (Method 1): LC retention time = 1.91 min. MS (ESI) m / z 290.0 [M+H]+Intermediate B-1:(3-(3,3-Dimethylbutoxy)-5-fluorophenyl)boronic acidStep 1. Synthesis of 1-bromo-3-(3,3-dimethylbutoxy)-5-fluorobenzene

[236] To a solution of 3-bromo-5-fluorophenol (4.80 g, 25.1 mmol) in NMP (22 mL) was added Cs2CO3 (16.4 g, 50.3 mmol) and 3,3-dimethylbutyl 4-methylbenzenesulfonate (7.73 g, 30.2 mmol). The mixture was stirred at 138 °C overnight. The volatiles were removed under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE) to afford the title compound (6.554 g, 93.5%) as a colorless oil.LCMS (Method 1): LC retention time = 2.18 min. Molecular ion not observed.Step 2. Synthesis of (3-(3,3-dimethylbutoxy)-5-fluorophenyl)boronic acid

[237] To a cooled (-78 °C) and stirred solution of 1-bromo-3-(3,3-dimethylbutoxy)-5-fluorobenzene(6.55 g, 23.8 mmol) in anhydrous THF (65 mL) was added dropwise n-BuLi (2.5M in hexane, 26.2 mmol) . The reaction mixture was stirred for 30 min. Triisopropyl borate (6.72 g, 35.7 mmol,) was added dropwise while keeping the temperature of the reaction at -78 °C. The reaction was allowed to warm to rt and stirred at rt for 2 h. To the reaction mixture was added water and 2N aqueous HCl (50 mL) and stirring continued for 2 h. After reaction completion, ethyl acetate (60 mL) and water (40 mL) were added. The resulting two liquid phases were separated, and the organic phase was dried over MgSO4, and concentrated to afford the title compound (5.3 g).LCMS (Method 1): LC retention time = 2.12 min. MS (ESI) m / z 241 [M+H]+. Intermediate B-2:[3- (3,3-Dimethylbutoxy)phenyl]boronic acid

[238] Intermediate B-2 was prepared in essentially the same manner as Intermediate B-1starting from 3-bromophenol.LCMS: LC retention time = 1.99 min. MS (ESI) m / z 223 [M+H]+.Intermediate B-2a:2-[3-(3,3-Dimethylbutoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneStep 1. Synthesis of 2-[3-(3,3-dimethylbutoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[239] To a solution of 1-bromo-3-(3,3-dimethylbutoxy)benzene (prepared similarly to Intermediate B-1, Step 1) (1.00 eq, 960 mg, 3.73 mmol) in 1,4-dioxane (10 mL) were added 1,1'-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (0.0198 eq, 54 mg, 0.0738 mmol) , bis(pinacolato)diboron (1.19 eq, 1.13 g, 4.45 mmol), and potassium acetate (3.00 eq, 1.10 g, 11.2 mmol). The reaction was stirred at 100 ℃ for 12 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and quenched with water (100 mL). The aqueous solution was extracted with ethyl acetate (100 mL × 3). The combined organic extracts were washed with water (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (40 g silica gel column @ 50 mL / min, eluting with petroleum ether) to give the title compound (750 mg, 2.47 mmol, 66.0 % yield).LCMS (Method 1): LC retention time = 2.25 min. MS (ESI) m / z 305.2 [M+H]+ .Intermediate B-3 to Intermediate B-13:

[240] The following intermediates (Intermediate B-3 to Intermediate B-13) were prepared similarly by following the procedures detailed in preparation of Intermediate B-1 and Intermediate B-2a:Intermediate IDStructureNameIntermediate B-3 2-(2-Fluoro-5-(neopentyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Intermediate B-4 4,4,5,5-Tetramethyl-2-(3-(neopentyloxy)phenyl)-1,3,2-dioxaborolane Intermediate B-5 2-(3-Fluoro-5-(2,2,2-trifluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Intermediate B-6 (3-Fluoro-5-(neopentyloxy)phenyl)boronic acid Intermediate B-7 2-(4-Chloro-3-(neopentyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Intermediate B-8 (4-Fluoro-3-(3,3,3-trifluoro-2,2-dimethylpropoxy)phenyl)boronic acid Intermediate B-9 2-(3-((4-(tert-Butyl)cyclohexyl)oxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Intermediate B-10a 2-[3-(3,3-Dimethylcyclopentoxy)-5-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Intermediate B-10b 2-(3-((3,3-Dimethylcyclopentyl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Intermediate B-11 1-Bromo-3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)benzene Intermediate B-12 4,4,5,5-Tetramethyl-2-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)phenyl)-1,3,2-dioxaborolane Intermediate B-13 2-(4-(Difluoromethoxy)-3-(3,3-dimethylbutoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Intermediate B-14:2-(3-(2,2-Difluoro-3,3-dimethylbutoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneStep 1.Synthesis of 1-(3-bromophenoxy)-3,3-dimethylbutan-2-ol

[241] To a solution of 3-bromophenol (1.9 g, 11.0 mmol) in DMF (20 mL) were added 2-(tert-butyl)oxirane(1.65 g, 16.5 mmol) and cesium carbonate (7.16 g, 22.0 mmol) at room temperature. The resulting mixture was stirred at 80 °C overnight. The mixture was cooled to room temperature, diluted with water (150 mL), and extracted with ethyl acetate (40 mL × 3). The organic extracts were washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 9 % ethyl acetate in petroleum ether) to give the title compound (2.46 g, 82.0% yield) as a colorless oil.LCMS (Method 1): LC retention time = 2.24 min. MS (ESI) m / z 273, 275.0 [M+H]+.1HNMR (400 MHz, chloroform-d) δ 7.17-7.06 (m, 3 H), 6.87-6.84 (m, 1 H), 4.10-4.07 (m, 1 H), 3.85 (t, J = 9.2 Hz, 1 H) 3.69-3.66 (m, 1 H), 2.36 (d, J = 3.2 Hz, 1 H), 1.01 (s, 9 H) ppm. Step 2. Synthesis of 1-(3-bromophenoxy)-3,3-dimethylbutan-2-one

[242] To a solution of 1-(3-bromophenoxy)-3,3-dimethylbutan-2-ol (2.46 g, 9.01 mmol) in dichloromethane (30 mL) was added (1,1-diacetoxy-3-oxo-1lambda5,2-benziodoxol-1-yl) acetate (5.73 g, 13.5 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (eluting with 10% ethyl acetate in petroleum ether) to give the title compound as a colorless oil (2.18 g, 89% yield).LCMS: LC retention time = 2.18 min. MS (ESI) m / z 271, 273 [M+H]+.1HNMR (400 MHz, chloroform-d) δ 7.16-7.10 (m, 2 H), 7.02 (s, 1 H), 6.81 (d, J = 7.2 Hz, 1 H), 4.85 (s, 2 H), 1.25 (s, 9 H) ppm. Step 3. Synthesis of 1-bromo-3-(2,2-difluoro-3,3-dimethylbutoxy)benzene

[243] To a solution of 1-(3-bromophenoxy)-3,3-dimethylbutan-2-one (2.18 g, 8.04 mmol) in anhydrous dichloromethane (20 mL) was added N-ethyl-N-(trifluoro-lambda4-sulfanyl)ethanamine (5.18 g, 32.2 mmol) dropwise at 0 °C under an argon atmosphere. The resulting mixture was stirred at room temperature for 65 h. The reaction was quenched with saturated aqueous sodium bicarbonate solution. After CO2 evolution ceased, the solution was extracted with dichloromethane (30 mL × 3). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with petroleum ether) to give the title compound (1.56 g, 66.1 % yield) as a colorless oil.LCMS (Method 1): LC retention time = 2.35 min. MS (ESI) signal not observed.1HNMR (400 MHz, chloroform-d) δ 7.18-7.10 (m, 3 H), 6.88 (m, 1 H), 4.23 (t, J = 13.2 Hz, 2 H), 1.14 (s, 9 H) ppm.Step 4. Synthesis of 2-(3-(2,2-difluoro-3,3-dimethylbutoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[244] To a solution of 1-bromo-3-(2,2-difluoro-3,3-dimethylbutoxy)benzene (1.56 g, 5.32 mmol) in anhydrous 1,4-dioxane (20.0 mL) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.03 g, 7.99 mmol), potassium acetate (1.56 g, 15.96 mmol), and [1,1'-bis (diphenylphosphino)ferrocene]dichloropalladium (II) (389 mg, 0.532 mmol). The reaction was stirred at 90 °C overnight under an argon atmosphere. The solids were filtered off. The filtrate was diluted with water (120 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 3% ethyl acetate in petroleum ether) to give the title compound (1.343 g, 74% yield) as a colorless oil.LCMS (Method 1): LC retention time = 2.42 min. MS (ESI) m / z 341.1[M+H]+.Intermediate B-15:(3-(3,3-Dimethylcyclopentyl)phenyl)boronic acidStep 1. Synthesis of 3,3-dimethylcyclopent-1-en-1-yl trifluoromethanesulfonate and 4,4-dimethylcyclopent-1-en-1-yl trifluoromethanesulfonate

[245] To a cooled (0 °C) solution of diisopropylamine (5.2 g, 51.4 mmol) in anhydrous THF (40 mL) was added n-BuLi (2.5M in hexane, 18.8 mL, 47.1 mmol) under Ar. The solution was stirred at 0 °C for 15 min, and then cooled to -78 °C. To the above reaction solution was added a solution of 3,3-dimethylcyclopentanone (7.37 g, 40 mmol) in anhydrous THF (40 mL). The mixture was stirred at -78 °C for 2 h. A solution of bis(trifluoromethanesulfonyl)aniline (16.80 g, 47.1 mmol) in anhydrous THF (80 mL) was added, and the mixture was warmed to 0 °C and stirred overnight. The mixture was poured into saturated aqueous NH4Cl and extracted with Et2O. The combined organic extracts were washed with water, brine, dried, and concentrated to give the title compound (8.00 g, 76.6%) as a colorless oil.1H NMR (400 MHz, chloroform-d) δ 5.56-5.49 (m, 1H), 2.66-2.62 (m, 1H), 2.42-2.40 (m, 1H), 2.23-2.21 (m, 1H), 1.85 (t, J = 8.1 Hz, 1H), 1.15 (s, 3H), 1.14 (s, 3H) ppm.Step 2. Synthesis of 1-(3,3-dimethylcyclopent-1-en-1-yl)-3-nitrobenzene and 1-(4,4-dimethylcyclopent-1-en-1-yl)-3-nitrobenzene

[246] To a solution of 3,3-dimethylcyclopent-1-en-1-yl trifluoromethanesulfonate in toluene / EtOH / water (60 mL / 30 mL / 15 mL) were added 4,4-dimethylcyclopent-1-en-1-yl trifluoromethanesulfonate (2.00 g, 8.18 mmol), (3-nitrophenyl)boronic acid (1.71 g, 10.2 mmol), tetrakis (triphenylphosphine) palladium (236 mg, 0.205 mmol), and sodium carbonate (2.60 g, 24.6 mmol). The mixture was stirred at 90 ℃ for 16 h and concentrated. The residue was suspended in water (50 mL) and extracted with ethyl acetate (50 mL × 2). The organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with PE) to obtain the title compound (1.3 g, 73.1%) as a yellow oil.1HNMR (400 MHz, chloroform-d) δ 8.23-8.20 (m, 1H), 8.06-8.03 (m, 1H), 7.72-7.69 (m, 1H), 7.48 (t, J = 8.0 Hz, 1H), 6.24-6.14 (m, 1H), 2.80-2.76 (m, 1H), 2.57-2.55 (m, 1H), 2.40-2.39 (m, 1H), 1.89 (t, J = 7.2 Hz, 1H), 1.19 (s, 3H), 1.16 (s, 3H) ppm.Step 3. Synthesis of 3-(3,3-dimethylcyclopentyl)aniline

[247] To a solution of 1-(3,3-dimethylcyclopent-1-en-1-yl)-3-nitrobenzene and 1-(4,4-dimethylcyclopent-1-en-1-yl)-3-nitrobenzene (1.30 g, 6.00 mmol) in MeOH (50 mL) was added 10 wt % Pd / C (130 mg) under an Ar atmosphere at room temperature. The flask was flushed with hydrogen and the mixture stirred under a hydrogen atmosphere for 16 h. The reaction mixture was filtered, and the filtrate was concentrated to obtain the title compound (700 mg, 62.0 % yield) as a yellow oil.LCMS (Method 1): LC retention time =1.95 min. MS (ESI) m / z 190.0 [M+H]+.1HNMR (400 MHz, chloroform-d) δ 7.09 (t, J = 7.6 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 6.59 (s, 1H), 6.52-6.49 (m, 1H), 3.59 (br, 2H), 3.14-3.09 (m, 1H), 2.10-2.06 (m, 1H), 1.85-1.47 (m, 5H), 1.16 (s, 3H), 1.14 (s, 3H) ppm.Step 4. Synthesis of 1-bromo-3-(3,3-dimethylcyclopentyl)benzene

[248] To a solution of 3-(3,3-dimethylcyclopentyl)aniline (700 mg, 3.33 mmol) in anhydrous MeCN (20 mL) were added CuBr2 (445 mg, 2.00 mmol) and tert-butyl nitrite (343 mg, 3.33 mmol) at room temperature. The resulting mixture was stirred at reflux for 15 min. The reaction was quenched with water (80 mL). The aqueous layer was extracted with ethyl acetate (80 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluting with PE : EA = 50 : 1) to give the title compound (478 mg, 53.9 %) as a yellow oil.1HNMR (400 MHz, chloroform-d): δ 7.41-7.13 (m, 4H), 3.57-3.12 (m, 1H), 2.17-1.50 (m, 6H), 1.12 (s, 3H), 1.10 (s, 3H) ppm.Step 5. Synthesis of (3-(3,3-dimethylcyclopentyl)phenyl)boronic acid

[249] To a cooled and stirred solution of 1-bromo-3-(3,3-dimethylcyclopentyl)benzene(470 mg, 1.67 mmol) in anhydrous tetrahydrofuran (20 mL) was added n-butyllithium (1.34 mL, 3.34 mmol, 2.5 M solution in hexanes) dropwise at -78 °C. After completion of the addition, the reaction mixture was stirred at -78 °C for 0.5 h. Next, trimethyl borate (347 mg, 3.34 mmol) was added dropwise at -78 °C. The resulting mixture was stirred at -78 °C for 1 h. The reaction was then gradually warmed to room temperature over 2 h. To this solution was added hydrochloric acid (6.0 N, 5 mL) at 0 °C. The resulting mixture was stirred at room temperature overnight. The reaction was diluted with water (50 mL). The aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic extracts were washed with brine (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (400 mg, crude) as a yellow solid.1HNMR (400 MHz, chloroform-d): δ 7.68-7.23 (m, 4H), 3.20-3.15 (m, 1H), 2.07-1.30 (m, 6H), 1.16 (s, 3H), 1.14 (s, 3H) ppm.Intermediate B-16:4,4,5,5-Tetramethyl-2-(6-neopentyl-3,6-dihydro-2H-pyran-4-yl)-1,3,2-dioxaborolaneStep 1.Synthesis of 6-neopentyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate

[250] To a stirred solution of 3,3-dimethylbutanal(1.0 g, 9.98 mmol) in dry dichloromethane (50.0 mL) was added dropwise at 0 °C trifluoromethanesulfonic acid (1.8 g, 12.0 mmol) , followed by but-3-yn-1-ol (1.05 g, 15.0 mmol) . The reaction mixture was stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was treated with saturated aqueous sodium bicarbonate solution (100 mL) and extracted with DCM (80 mL × 2). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated to dryness. The residue was purified by flash column chromatography (eluting with PE: EA= 10: 1) to give the title compound (1.70 g, 56.3%) as a yellow oil.Step 2. Synthesis of 4,4,5,5-tetramethyl-2-(6-neopentyl-3,6-dihydro-2H-pyran-4-yl)-1,3,2-dioxaborolane.

[251] A mixture of 6-neopentyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (1.7 g, 5.62 mmol), bis (pinacolato)diboron (2.14 g, 8.44 mmol), CH3COOK (1.10 g, 11.2 mmol), Pd (dppf)Cl2 (411 mg, 0.562 mmol) and 1,4-dioxane (60 mL) was heated overnight at 80 °C under Ar. The reaction mixture was concentrated to afford the crude title compound (0.87 g, 56.3%) as a yellow oil.LCMS (Method 1): LC retention time = 2.50 min. MS (ESI) m / z 281.0 [M+H]+.Intermediate B-17:(6-(3,3-Dimethylbutoxy)pyridin-2-yl)boronic acidStep 1. Synthesis of 2-bromo-6- (3,3-dimethylbutoxy)pyridine

[252] To a cooled (0 °C) and stirred solution of 3,3-dimethylbutan-1-ol (500 mg, 4.89 mmol) in dry THF (10 mL) was added NaH (293.58 mg, 7.34 mmol, 60% dispersion in oil). The reaction mixture was stirred at room temperature for 0.5 h. To the reaction mixture was added 2,6-dibromopyridine (1.16 g, 4.89 mmol), and stirring at room temperature continued for 12 h. The reaction was diluted with EA (20 mL), and washed with water (10 mL × 2). The EA extract was dried over Na2SO4, filtered, and concentrated to dryness to give the crude product which was purified by silica gel chromatography (petroleum ether eluent) to give the title compound (1.8 g, 71% two batches) as a colorless oil.LCMS (Method 1): MS (ESI) m / z 258, 260 [M + H]+Step 2. Synthesis of (6-(3,3-dimethylbutoxy)pyridin-2-yl)boronic acid

[253] To the stirred solution of 2-bromo-6- (3,3-dimethylbutoxy)pyridine(0.5 g, 1.93 mmol) in THF (6 mL) was added n-butyllithium (1.42 mL, 2.9 mmol) at -78 °C under a N2 atmosphere. The reaction was stirred at this temperature for 1 h, then triisopropyl borate (436.3 mg, 2.32 mmol) was added. The mixture was warmed to room temperature and stirred at this temperature for 13 h. TLC (silica, PE / EA = 8 / 1) showed that the starting material was consumed. To the mixture was added MeOH (3 mL), the pH adjusted to 3 with aqueous HCl (2 M), the organics removed under reduced pressure , and the pH adjusted to 7 with aqueous NaHCO3. The aqueous mixture was extracted with EA (15 mL × 3). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to dryness. The residue was suspended in PE (10 mL) and filtered to give the title compound (0.2 g, 46.3%) as a yellow solid.1H NMR (400 MHz, methanol-d) δ 8.19 (t, J = 7.8 Hz, 1H), 7.46 (d, J = 7.4 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 4.46 (t, J = 7.2 Hz, 2H), 1.97-1.81 (m, 2H), 1.06 (s, 9H) ppm.Intermediate B-18:2-(3-(1,1-Difluoro-4,4-dimethylpentyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneStep 1.Synthesis of (3,3-dimethylbutyl)magnesium bromide

[254] Magnesium turnings (2.10 g, 86.42 mmol) were added to 60 mL of Et2O. A small amount of iodine was added, followed by the slow addition of a solution of 1-bromo-3,3-dimethylbutane (17.500 g, 106 mmol) in 10 mL of Et2O . The reaction mixture was stirred under reflux for 2 h. After cooling to rt, the reaction solution containing the desired 3,3-dimethylbutyl)magnesium bromide was used directly in the next step.Step 2.Synthesis of 1-(3-bromophenyl)-4,4-dimethylpentan-1-ol

[255] To a solution of 3-bromobenzaldehyde (5.42 g, 29.3 mmol) in anhydrous Et2O (30 mL) was added under N2 at room temperature (3,3-dimethylbutyl)magnesium bromide (70 mL, 86.42 mmol) . The resulting mixture was stirred at room temperature for 2 h. The mixture was poured into a saturated aqueous ammonium chloride solution (50 mL) and extracted with DCM (30 mL × 2). The extracts were washed with brine (20 mL × 2), dried over sodium sulfate, and filtered. The filtrate was used directly in the next step.LCMS (Method 1): LC retention time =2.34 min. MS (ESI) m / z 271, 273 [M+H]+.Step 3. Synthesis of 1-(3-bromophenyl)-4,4-dimethylpentan-1-one

[256] To a stirred solution of 1-(3-bromophenyl)-4,4-dimethylpentan-1-ol (7.95 g, 29.3 mmol) in dry DCM (150 mL) was added at 0 °C under nitrogen PCC (17.60 g, 81.7 mmol) . The resulting mixture was stirred at room temperature for 12 h. The mixture was filtered, and the filtrate concentrated. The residue was purified by silica gel chromatography (eluting with PE / EA = 98 / 2) to give the title compound (6.95 g, 88 % yield over 3 steps) as a light-yellow oil.LCMS (Method 1): LC retention time = 2.33 min. MS (ESI) m / z 269, 271 [M+H]+.Step 4. Synthesis of 1-bromo-3-(1,1-difluoro-4,4-dimethylpentyl)benzene

[257] To a stirred solution of 1-(3-bromophenyl)-4,4-dimethylpentan-1-one (1.74 g, 6.84 mmol) in DCM (20 mL) was added DAST (4.50 g, 27.9 mmol) at room temperature under nitrogen. The reaction mixture was stirred at 86 °C for 14 h. The mixture was poured into ice water. The pH of the aqueous phase was adjusted to 8. The aqueous phase was extracted with EA (10 mL × 3). The organic extracts were combined, dried over Na2SO4, filtered and concentrated. The crude residue was purified via flash chromatography (eluting with PE) to afford the title compound (1.59 g, 79.9%) as a colorless oil.1H NMR (400 MHz, Chloroform-d) δ 7.64 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 2.11-2.03 (m, 2H), 1.35-1.30 (m, 2H), 0.90 (s, 9H) ppm.Step 5.Synthesis of (3-(1,1-difluoro-4,4-dimethylpentyl)phenyl)boronic acid 

[258] A mixture of 1-bromo-3-(1,1-difluoro-4,4-dimethylpentyl)benzene (266 mg, 0.913 mmol), potassium acetate (270mg, 2.75 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (255 mg, 1.0 mmol), tricyclohexylphosphane (27 mg, 0.096 mmol) and Pd2 (dba)3 (84 mg, 0.092 mmol) in 1,4-dioxane (10 mL) was stirred at 85 °C under N2 for 20 h. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated to give the title compound (235 mg, 100%) as a colorless oil.LCMS: LC retention time = 2.19 min. MS (ESI) m / z 256.8 [M+H]+.Intermediate B-19:3-(3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(trifluoromethyl)isoxazoleStep 1. Synthesis of 1-(3-bromophenyl)-4,4,4-trifluoro-butane-1,3-dione

[259] Sodium (347 mg, 15.1 mmol) was dissolved in ethanol (10 mL) under nitrogen. To this solution was added a solution of ethyl 2,2,2-trifluoroacetate (2.86 g, 20.1 mmol) in ethanol (10 mL), followed by a solution of 1-(3-bromophenyl)ethanone (2.00 g, 10.0 mmol) in ethanol (10 mL). The reaction mixture was refluxed at 85 °C overnight. After the completion of the reaction, the reaction was quenched with aqueous HCl (1 N) (30 mL). The aqueous mixture was extracted with ethyl acetate (50 mL). The EA extract was washed with brine (50 mL × 2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluting with 15 % ethyl acetate in petroleum ether) to afford the title compound(2.12 g, 7.19 mmol, 71.9% yield) as a red oil.LCMS (Method 1): LC retention time = 1.18 min. MS (ESI) m / z 295, 296 [M+H]+.Step 2. Synthesis of 3-(3-bromophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-5-ol

[260] To a solution of hydroxylamine hydrochloride (236 mg, 3.39 mmol) in aqueous NaOH (142 mg, 3.56 mmol) was added 1-(3-bromophenyl)-4,4,4-trifluoro-butane-1,3-dione (1 g, 3.39 mmol) over 1 h at 20-30 °C. The resulting mixture was refluxed for 45 min. After cooling to room temperature, the mixture was poured into ice water (50 mL). The precipitate was filtered off. The filtrate was extracted with ethyl acetate (30 mL), the EA extract dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford the title compound (810 mg, 77.1 % yield).LCMS (Method 1): LC retention time = 2.02 min. MS (ESI) m / z 310, 312 [M+H]+.Step 3. Synthesis of 3-(3-bromophenyl)-5-(trifluoromethyl)isoxazole

[261] A solution of 3-(3-bromophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-5-ol (810 mg, 3.36 mmol) in trifluoroacetic acid (20 mL) was refluxed overnight. After completion of the reaction, the reaction was quenched with saturated aqueous NaHCO3 (40 mL). The aqueous phase was extracted with ethyl acetate (40 mL). The organic extract was then washed with water (30 mL), dried over anhydrous Na2SO4 and filtered. The resulting solution was concentrated under reduced pressure to yield the crude product which was purified by silica gel chromatography (11 % ethyl acetate in petroleum ether) to afford the title compound (190 mg).LCMS: LC retention time = 1.54 min. MS (ESI) m / z: no signal observed.Step 4. Synthesis of 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(trifluoromethyl)isoxazole

[262] To a solution of 3-(3-bromophenyl)-5-(trifluoromethyl)isoxazole (200 mg, 0.685 mmol) in 1,4-dioxane (10 mL) were added under a nitrogen atmosphere 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (174 mg, 0.685 mmol), Pd(dppf)Cl2 (25.1 mg, 0.034 mmol) and potassium acetate (134 mg, 1.37 mmol) . The reaction was stirred at 80 °C overnight. After completion of the reaction, the mixture was filtered, and the filtrate was extracted with ethyl acetate (25 mL). The organic extract was washed with water (25 mL) and brine (25 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound as a brown oil.LCMS (Method 1): LC retention time = 1.59 min. MS (ESI) m / z 340 [M+H]+.Intermediate B-20:4,4,5,5-Tetramethyl-2-(3-((1S)-3-(trifluoromethoxy)cyclopentyl)phenyl)-1,3,2-dioxaborolaneStep 1. Synthesis of (S)-3-(3-bromophenyl)cyclopentan-1-one

[263] To a solution of (3-bromophenyl)boronic acid (6.84 g, 34.2 mmol) in 40 mL of dioxane and 4 mL of H2O were added under nitrogen acetylacetonatobis(ethylene)rhodium (I) (188.6 mg, 0.74 mmol), S-BINAP (455 mg, 0.74 mmol), and cyclopent-2-en-1-one (2.0 g, 24.4 mmol) . After refluxing for 5.0 h, the reaction mixture was cooled and concentrated. The residue was partitioned between 100 mL of EA and 100 mL of 1N aqueous NaHCO3. After phase separation, the organic layer was washed with 100 mL of brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (eluting with PE : EA = 5 : 1) to afford the title compound (4.70 g, 80.6 % yield) as a light-yellow solid.LCMS (Method 1): LC retention time = 2.14 min. MS (ESI) m / z 239, 241 [M+H]+.Step 2. Synthesis of (3S)-3-(3-bromophenyl)cyclopentan-1-ol

[264] A solution of (S)-3-(3-bromophenyl)cyclopentan-1-one (4.58 g, 19.2 mmol) in anhydrous tetrahydrofuran (40.0 mL) was cooled to -78 °C under an argon atmosphere. To this solution was added DIBAL (1M in toluene) (76.7 mL) while maintaining the original temperature. The reaction mixture was allowed to warm slowly to room temperature and stirring continued at room temperature overnight. Saturated potassium sodium tartrate tetrahydrate solution (80 mL) was added and stirred for another 1 h. The mixture was filtered through a Celite plug. The filtrate was concentrated under reduced pressure to give the crude product which was purified by reverse phase column chromatography to afford the title compound (3.25 g, 70.4 %) as a colorless oil.LCMS (Method 1): LC retention time = 2.05 min. MS (ESI) m / z 223, 225 [M-H2O]+.Step 3. Synthesis of 1-bromo-3-((1S)-3-(trifluoromethoxy)cyclopentyl)benzene 

[265] A flask was charged with silver trifluoromethanesulfonate (3.20 g, 12.4 mmol), Select-F® (2.20 g, 6.22 mmol), KF (964 mg, 16.6 mmol), and (3S)-3-(3-bromophenyl)cyclopentan-1-ol (1.0 g, 4.15 mmol). The flask was purged with argon, then ethyl acetate (20 mL) was added, followed by TMSCF3 (1.77g, 12.4 mmol) and 2-fluoropyridine (1.21 g, 12.4 mmol). The reaction mixture was stirred overnight at room temperature under argon. The reaction mixture was filtered through a Celite pad. The filtrate was concentrated. The residue was purified by silica gel column chromatography (eluting with PE) to afford the title compound (402 mg, 31.4 %) as a colorless oil.1H NMR (400 MHz, chloroform-d) δ 7.36 (m, 2H), 7.16 (m, 2H), 4.85 (m,, 1H), 3.39-2.95 (m, 1H), 2.61-2.21 (m, 2H), 2.16-1.59 (m, 5H) ppm.Step 4. Synthesis of 4,4,5,5-tetramethyl-2-[3-[(1S)-3-(trifluoromethoxy)cyclopentyl] phenyl]-1,3,2-dioxaborolane

[266] To a solution of 1-bromo-3-[(1S)-3-(trifluoromethoxy) cyclopentyl]benzene (1.0 g, 3.23 mmol) in dioxane (20 mL) were added 2,4,4,5,5-pentamethyl-1,3,2-dioxaborolane (1.38 g, 4.85 mmol), KOAc (793 mg, 8.09 mmol), and Pd(dppf)Cl2 (70.9 mg, 9.70 x 10-5 mol). The reaction was stirred at 90°C overnight under argon. The mixture was concentrated and extracted with EA (10 mL × 3), the combined organic extracts were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with PE: EA = 10: 1) to give the title compound (720 mg, 62.5% yield) as a light oil.LCMS (acidic): LC retention time = 2.41, MS (ESI): m / z 357 [M+H]+.Intermediate B-21:1-Bromo-3-((1R)-3-(trifluoromethoxy)cyclopentyl)benzene 

[267] Intermediate B-21 was prepared in the same manner as Intermediate B-20, except using R-BINAP in Step 1 instead of S-BINAP.Intermediate B-22:2-(3-(3-(1,1-Difluoroethyl)cyclopentyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneStep 1.Synthesis of methyl 3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-ene-1-carboxylate

[268] To a solution of methyl 3-oxocyclopentane-1-carboxylate (2.56 g, 18.0 mmol) in toluene (50 mL) was added at room temperature under a N2 atmosphere DIEA (9.35 g, 72.3 mmol) . The solution was then chilled to 0 °C and triflic anhydride (12.80 g, 45.4 mmol) added . The resulting mixture was stirred at 50 °C for 2 h. The mixture was poured into water (400 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic extracts were washed with water (100 mL × 2), dried over sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography (eluting with PE : EA = 10 : 1) to afford the title compound (4.93 g, 100 %) as a yellow oil.1H NMR (400 MHz, chloroform-d) δ 5.74-5.61 (m, 1H), 3.75 (s, 3H), 3.82-3.62 (m, 1H), 3.35-2.96 (m, 1H), 2.87-2.64 (m, 2H), 2.37-2.30 (m, 1H) ppm.Step 2.Synthesis of methyl 3-(3-(benzyloxy)phenyl)cyclopent-2-ene-1-carboxylate

[269] To a solution of methyl 3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-ene-1-carboxylate (4930 mg, 18.0 mmol) in 1,2-dimethoxyethane / H2O (60 mL, v / v = 5 / 1) were added (3-(benzyloxy)phenyl)boronic acid (4.18 g, 18.3 mmol), Pd(Ph3P)4 (520 mg, 0.45 mmol), and NaHCO3 (4.57 g, 54.49 mmol). The resulting mixture was stirred at 80 °C under an argon atmosphere for 16 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was suspended in water (200 mL). The aqueous mixture was extracted with ethyl acetate (20 mL × 2). The EA extracts were combined, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel chromatography (eluting with PE : EA = 10 : 1) to afford the title compound (2.63 g, 47.5% yield over 2 steps) as a yellow oil.LCMS (Method 1): LC retention time = 2.27 min. MS (ESI) m / z 309 [M+H]+.Step 3.Synthesis of methyl 3-(3-hydroxyphenyl)cyclopentane-1-carboxylate

[270] To a solution of methyl 3-(3-(benzyloxy)phenyl)cyclopent-2-ene-1-carboxylate (2.63 g, 8.53 mmol) in MeOH (150 mL) was added Pd / C (1210 mg). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 16 h. The reaction mixture was filtered through a Celite plug. The filtrate was concentrated and purified by silica gel chromatography (eluting with PE : EA = 5 : 1) to give the title compound (1450 mg, 77.2%) as a yellow oil.LCMS (Method 1): LC retention time = 1.54 min. MS (ESI) m / z 221 [M+H]+.Step 4. Synthesis of methyl 3-(3-(benzyloxy)phenyl)cyclopentane-1-carboxylate

[271] To a solution of methyl 3-(3-hydroxyphenyl)cyclopentane-1-carboxylate (1.45 g, 6.58 mmol) in acetone (30 mL) were added (bromomethyl)benzene (2220 mg, 12.98 mmol) and K2CO3 (2735 mg, 19.79 mmol). The resulting mixture was stirred at 55 °C under a N2 atmosphere for 16 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined EA extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel chromatography (eluting with PE : EA = 10 : 1) to give the title compound (2.04 g, 100 % yield) as a yellow oil.LCMS (Method 1): LC retention time = 2.26 min. MS (ESI) m / z 333 [M+Na]+.Step 5.Synthesis of 3-(3-(benzyloxy)phenyl)cyclopentane-1-carboxylic acid

[272] To a stirred solution of methyl 3-(3-(benzyloxy)phenyl)cyclopentane-1-carboxylate (2.04 g, 6.57 mmol) in THF (8 mL), MeOH (4 mL) and water (0.75 mL) was added at room temperature LiOH·H2O (2060 mg, 49.05 mmol). Stirring at room temperature was continued for 16 h. Hydrochloric acid (2N) was added to the solution until the pH reached 4. The mixture was extracted with ethyl acetate (50 mL × 2). The combined EA extracts were washed with brine (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (2.17 g, 100 % yield) as a yellow solid.LCMS (Method 1): LC retention time = 1.38 min. MS (ESI) m / z 297 [M+H]+.Step 6.Synthesis of 3-(3-(benzyloxy)phenyl)-N-methoxy-N-methylcyclopentane-1-carboxamide

[273] To a solution of 3-(3-(benzyloxy)phenyl)cyclopentane-1-carboxylic acid (2175 mg, 7.34 mmol) in DCM (40 mL) were added at room temperature HATU (5580 mg, 14.68 mmol), N,O-dimethylhydroxylamine hydrochloride (1.08 g, 11.12 mmol) and DIEA (2850 mg, 22.05 mmol) . The resulting mixture was stirred at the same temperature for 16 h. The mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL × 2). The extracts were combined and washed with water (100 mL × 2), dried over sodium sulfate, and evaporated. The crude product was purified by silica gel chromatography (eluting with PE : EA = 10 : 1) to give the title compound (2.19 g, 88.0 % yield) as a colorless oil.LCMS (Method 1): LC retention time = 2.16 min. MS (ESI) m / z 340.1 [M+H]+.Step 7.Synthesis of 1-(3-(3-(benzyloxy)phenyl)cyclopentyl)ethan-1-one

[274] To a solution of 3-(3-(benzyloxy)phenyl)-N-methoxy-N-methylcyclopentane-1-carboxamide (2690 mg, 7.92 mmol) in THF (20 mL) was added CH3MgBr (7.9 mL, 23.7 mmol, 3.0 M) under N2 at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic extracts were washed with water (100 mL × 2), dried over sodium sulfate, and concentrated. The resulting residue was purified by silica gel chromatography (eluting with PE : EA = 10 : 1) to afford the title compound (2.31 g, 99.0 % yield) as a colorless oil.LCMS (Method 1): LC retention time = 2.22 min. MS (ESI) m / z 295 [M+H]+.Step 8.Synthesis of 1-(benzyloxy)-3-(3-(1,1-difluoroethyl)cyclopentyl)benzene

[275] To a stirred solution of 1-(3-(3-(benzyloxy)phenyl)cyclopentyl)ethan-1-one (1.50 g, 5.1 mmol) in DCM (15 mL) was added DAST (4.0 mL) at 0 °C under nitrogen. The reaction mixture was stirred at room temperature for 16 h. The mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL × 2). The extracts were washed with water (100 mL × 2), dried over sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography (eluting with PE : EA = 95 : 5) to give the title compound (1.36 g, 84.9 % yield) as a colorless oil.MS (Method 1): LC retention time = 2.47 min. MS (ESI) m / z 317.0 [M+H]+.Step 9.Synthesis of 3-(3-(1,1-difluoroethyl)cyclopentyl)phenolTo a solution of 1-(benzyloxy)-3-(3-(1,1-difluoroethyl)cyclopentyl)benzene (2.04 g, 6.46 mmol) in EA (50 mL) was added Pd / C (1.04 g). The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 16 h. The mixture was filtered through a Celite plug. The filtrate was concentrated and purified by silica gel chromatography (eluting with PE : EA = 6 : 1) to give the title compound (1.25 g, 85.6% yield) as a yellow oil. LCMS (Method 1): LC retention time = 2.03 min. MS (ESI) m / z 227.0 [M+H]+.Step 10. Synthesis of 3-(3-(1,1-difluoroethyl)cyclopentyl)phenyl trifluoromethanesulfonate

[276] To a solution of 3-(3-(1,1-difluoroethyl)cyclopentyl)phenol (223 mg, 0.986 mmol) in DCM (2.5 mL) were added at 0 °C pyridine (80 mg, 1.01 mmol) and triflic anhydride (335 mg, 1.19 mmol) . The reaction mixture was stirred at room temperature overnight, and concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EA (20 mL × 3). The organic phases were combined, washed with saturated aqueous NaHCO3 (10 mL) and brine (20 mL), dried over anhydrous Na2SO4. The solvent was evaporated and the residue purified by silica gel column chromatography (eluting with 5 % EA in PE) to afford the title compound (171 mg, 48.4% yield) as a colorless oil.LCMS (Method 1): LC retention time = 2.37 min. MS (ESI) m / z 381.0 [M+Na]+.Step 11.Synthesis of 2-(3-(3-(1,1-difluoroethyl)cyclopentyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[277] To a solution of 3-(3-(1,1-difluoroethyl)cyclopentyl)phenyl trifluoromethanesulfonate (171 mg, 0.48 mmol) in dioxane (2.5 mL) were added at room temperature 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (108 mg, 0.84 mmol), TEA (145 mg, 1.43 mmol) and PdCl2(dppf) (22 mg, 0.03 mmol) . The reaction was refluxed for 16 h until TLC indicated that the starting material had been consumed. The mixture was extracted with EA (30 mL × 2). The combined organic extracts were washed with brine (30 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound (195 mg, 100% yield) as a yellow solid.LCMS (Method 1): LC retention time = 1.96 min. MS (ESI) m / z 337.0 [M+H]+.Intermediate B-23:2-(3-(3-(2,2-Difluoropropyl)cyclopentyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Step 1. Synthesis of (3-(3-(benzyloxy)phenyl)cyclopentyl)methanol

[278] To a solution of 3-(3-(benzyloxy)phenyl)cyclopentane-1-carboxylic acid(from Step 5, Intermediate B-22) (2.10 g, 7.09 mmol) in anhydrous THF (60 mL) was slowly added LiAlH4 (808 mg, 21.3 mmol) at 0 °C under an argon atmosphere. After addition, the mixture was allowed to warm to room temperature and stirred for 1 h. LCMS analysis showed that the starting material was consumed. The mixture was cooled to 0 °C, and Na2SO4·10H2O, and water were added . The mixture was stirred for another 1 h, being allowed to warm to rt. The mixture was filtered through a Celite pad. The filtrate was extracted with ethyl acetate (150 mL). The organic extract was washed with water (100 mL) and brine (150 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude which was purified by flash chromatography column (eluting with PE / EA = 5 / 1) to afford the title compound (1.66 g, 83.0% yield) as a colorless oil.LCMS (Method 1): LC retention time = 2.15 min. MS (ESI) m / z 283.0 [M+H]+.Step 2. Synthesis of (3-(3-(benzyloxy)phenyl)cyclopentyl)methyl 4-methylbenzenesulfonate

[279] To a solution of (3-(3-(benzyloxy)phenyl)cyclopentyl)methanol (1.66 g, 5.88 mmol) in DCM (30 mL) were added under an argon atmosphere at 0 °C DMAP (71.8 mg, 0.59 mmol), Et3N (1.78 g, 17.6 mmol), and TsCl (1.68 g, 8.82 mmol) . The mixture was allowed to warm to room temperature and stirred at the same temperature overnight. The mixture was poured into ice-water (100 mL) and extracted with DCM (60 mL). The DCM solution was washed with saturated aqueous NaHCO3 (30 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (2.47 g, 96.2 % yield) as a yellow oil.LCMS (Method 1): LC retention time = 2.38 min. MS (ESI) m / z 459 [M+Na]+.Step 3. Synthesis of 2-(3-(3-(benzyloxy)phenyl)cyclopentyl)acetonitrile

[280] To a solution of (3-(3-(benzyloxy)phenyl)cyclopentyl)methyl 4-methylbenzenesulfonate (2.47 g, 5.66 mmol) in DMF (30.0 mL) were added 18-Crown-6 (2.24 g, 8.49 mmol) and KCN (552 mg, 8.49 mmol). The solution was stirred at 55 °C overnight. The resulting solution was cooled to rt, diluted with ethyl acetate (150 mL), washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude was purified by flash chromatography column (eluting with PE : EA = 5 : 1) to give the title compound (1.49 g, 90.4% yield) as a colorless oil.LCMS (Method 1): LC retention time = 2.22 min. MS (ESI) m / z 292 [M+H]+.Step 4. Synthesis of 2-(3-(3-(benzyloxy)phenyl)cyclopentyl)acetic acid

[281] To a solution of 2-(3-(3-(benzyloxy)phenyl)cyclopentyl)acetonitrile (1.49 g, 5.11 mmol) in ethanol (30 mL) and H2O (3.0 mL) was added sodium hydroxide (4.09 g, 100.3 mg). The reaction was stirred at 80 °C for 12 h. The resulting mixture was concentrated under vacuum. The residue was dissolved in water (60 mL). The pH was adjusted to 4 with hydrochloric acid (1N). The mixture was extracted with ethyl acetate (100 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the title compound (1.48 g) as a light-yellow solid.LCMS (Method 1): LC retention time = 2.13 min. MS (ESI) m / z 311.1 [M+H]+. 

[282] The rest of the steps were carried out by following procedures of Steps 6 to 11, Preparation of Intermediate 22, to obtain Intermediate 23.LCMS (Method 1): LC retention time = 2.45 min. MS (ESI) m / z 351.0 [M+H]+.Intermediate B-24:1-(3-Bromo-5-fluorophenyl)-3-(tert-butyl)pyrrolidineStep 1.Synthesis of 1-(phenylsulfonyl)-1H-pyrrole

[283] To a suspension of NaH (8.05 g, 201 mmol, 60% dispersion in oil) in THF (100 mL) was added at 0 °C a solution of pyrrole (9.0 g, 134 mmol) in THF (100 mL) . After 30 min, benzenesulfonyl chloride (23.70 g, 134 mmol) in THF (50 mL) was added. The mixture was stirred at rt for 5 h. The reaction was quenched with water (200 mL). THF was evaporated under reduced pressure. The resulting suspension was filtered, and the filter cake was washed with water and dried to obtain the title compound (26.00 g, 89.8% yield) as a white solid.LCMS (Method 1): LC retention time = 2.04 min. MS (ESI) m / z 208.2 [M+H]+.Step 2.Synthesis of 3-(tert-butyl)-1-(phenylsulfonyl)-1H-pyrrole

[284] To a solution of 1-(phenylsulfonyl)-1H-pyrrole (9.0 g, 43.4 mmol) and 2-chloro-2-methylpropane (4.79 g, 52.1mmol) in DCM (150 mL) was added AlCl3 (8.68 g, 65.1 mmol) at 0 °C. After addition, the mixture was stirred at rt for 6 h. The reaction was quenched with water (150 mL). The aqueous mixture was extracted with DCM (100 mL). The organic phase was washed with water (100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with PE : EA = 2:1) to give the title compound (6.0 g, 49.8% yield) as a yellow oil.LCMS (Method 1): LC retention time = 2.25 min. MS (ESI) m / z 264.2 [M+H]+.Step 3.Synthesis of 3-(tert-butyl)-1H-pyrrole

[285] To a solution of 3-(tert-Butyl)-1-(phenylsulfonyl)-1H-pyrrole(6.0 g, 22.8 mmol) in EtOH / H2O (60 mL / 60 mL) was added KOH (12.8 g, 228 mmol). The mixture was refluxed for 5 h. The solvent was removed under reduced pressure. The residue was suspended in water (50 mL). The resulting aqueous mixture was extracted with DCM (20 mL × 3). The organic extract was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with PE : EA = 5 : 1) to give the title compound (2.20 g, 78.4% yield) as a yellow oil.Step 4.Synthesis of 3-(tert-butyl)pyrrolidine

[286] To a solution of 3-(tert-butyl)-1H-pyrrole(2.20 g, 17.9 mmol) in EtOH (100 mL) was added aqueous HCl (1N, 1.0 mL) and PtO2 (203 mg) at room temperature under an Ar atmosphere . The flask was purged with hydrogen and stirring continued at rt under a hydrogen atmosphere for 16 h. The reaction mixture was filtered and the solids washed with ether. The combined filtrate was concentrated in vacuo to afford the title compound (1.80 g, 79.2% yield) as a yellow oil.LCMS (Method 1): LC retention time = 1.43 min. MS (ESI) m / z 128.1 [M+H] +Step 5.Synthesis of 1-(3-bromo-5-fluorophenyl)-3-(tert-butyl)pyrrolidine

[287] To a solution of 1-bromo-3,5-difluorobenzene (2.0 g, 10.4 mmol) in NMP (10.0 mL) placed in a reaction tube were added 3-(tert-butyl)pyrrolidine(1.45 g, 11.4 mmol) and DIPEA (6.68 g, 51.8 mmol). The tube was sealed and heated at 100 °C while stirring overnight. Upon cooling, the reaction mixture was diluted with water and ethyl acetate (10 mL each). The aqueous layer was back extracted with ethyl acetate (30 mL × 3). The combined organic extracts were washed with H2O (150 mL), brine (150 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with PE) to obtain the title compound (2.40 g, 51.7% yield) as a colorless oil.LCMS (Method 1): LC retention time = 3.04 min. MS (ESI) m / z 300, 302.0 [M+H]+.Intermediate B-25:3-(Neopentyloxy)-1H-pyrazoleStep 1.Synthesis of 1-(3-hydroxy-1H-pyrazol-1-yl)ethan-1-one

[288] To a stirred solution of methyl (E)-3-methoxyacrylate(6.00 g, 51.72 mmol) in MeOH (50 mL) was added hydrazine hydrate (30 mL) at room temperature. The solution was stirred under reflux for 16 h. After the reaction was complete, the solvent was removed under reduced pressure. The residue was dissolved in pyridine (30 mL) and Ac2O (4.7 g, 46.12 mmol) was added slowly at 95 °C. Stirring was continued at 95 °C for 2 h. The solvent was removed under reduced pressure and the residue was suspended in Et2O (60 mL). The resulting slurry was stirred overnight at room temperature. The solid was collected via filtration and rinsed with Et2O (30 mL) to afford the title compound (4.32 g, 78% yield) as a light-yellow solid.LCMS (Method 1): MS (ESI) m / z 127.0 [M+H]+. Step 2.Synthesis of 1-(3-(neopentyloxy)-1H-pyrazol-1-yl)ethan-1-one

[289] To a stirred solution of 1-(3-hydroxy-1H-pyrazol-1-yl)ethan-1-one (4.32 g, 34.29 mmol) in THF (100 mL) were added at room temperature 2,2-dimethylpropan-1-ol (3.00 g, 34.29 mmol), PPh3 (9.88 g, 37.72 mmol) and DIAD (7.62 g, 37.72 mmol) . The mixture was stirred at room temperature for 16 h. The mixture was diluted with water (50 mL) and extracted with EA (30 mL × 3). The combined organic extracts were washed with brine (20 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with EA:PE = 1:10) to afford the title compound (3.3 g, 49% yield) as a light-yellow solid.LCMS (Method 1): MS (ESI) m / z 197 [M+H]+. Step 3.Synthesis of 3-(neopentyloxy)-1H-pyrazole

[290] To a stirred solution of 1-(3-(neopentyloxy)-1H-pyrazol-1-yl)ethan-1-one (3.3 g, 16.84 mmol) in MeOH / H2O (30 mL / 3 mL) was added NaOH (673 mg, 16.84 mmol) at room temperature. The solution was stirred at room temperature for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with EA (20 mL × 3). The combined organic extracts were washed with brine (20 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with EA : PE = 1 : 5) to afford the title compound (2.0 g, 80% yield) as a yellow oil.LCMS (Method 1): MS (ESI) m / z 155 [M+H]+.Intermediate B-26:3-(3,3-Dimethylbutoxy)-1H-pyrazole

[291] Intermediate B-26was prepared from 1-(3-hydroxy-1H-pyrazol-1-yl)ethan-1-one (from Step 1, preparation of Intermediate B-25) by following the procedures of Steps 2 and 3 above, except for using 2,2-dimethylpropan-1-ol instead of 2,2-dimethylpropan-1-ol in Step 2.LCMS (Method 1): MS (ESI) m / z 169.1 [M+H]+.Intermediate B-27:3-((4,4-Dimethylpentyl)oxy)-1H-pyrazole

[292] Intermediate B-27was prepared from 1-(3-hydroxy-1H-pyrazol-1-yl)ethan-1-one (from Step 1, preparation of Intermediate B-25) by following the procedures of Steps 2 and 3 above, except for using 4,4-dimethylpentan-1-ol instead of 2,2-dimethylpropan-1-ol in Step 2.LCMS: MS (ESI) m / z 183 [M+H]+.Intermediate B-28:3-(3,3,3-Trifluoro-2,2-dimethylpropoxy)-1H-pyrazole

[293] Intermediate B-28 was prepared from 1-(3-hydroxy-1H-pyrazol-1-yl)ethan-1-one (from Step 1, preparation of Intermediate B-25) by following the procedures of Steps 2 to 3 above, except for using 3,3,3-trifluoro-2,2-dimethylpropan-1-ol instead of 2,2-dimethylpropan-1-ol in Step 2.LCMS (Method 1): LC retention time = 1.58 min. MS (ESI) m / z 208.8 [M+H]+.1H NMR (400 MHz, chloroform-d) d 7.37 (s, 1H), 5.76 (s, 1H), 4.13 (s, 2H), 1.26 (s, 6H) ppm.Intermediate B-29:3-(3-(1,1-Difluoroethyl)cyclopentyl)-1H-pyrazoleStep 1. Synthesis of N-methoxy-N-methyl-3-oxocyclopentane-1-carboxamide

[294] To a stirred solution of 3-oxocyclopentane-1-carboxylic acid (3.50 g, 27.3 mmol) in DCM (20 mL) were added oxalyl chloride (6.93 g, 54.6 mol) and DMF (0.2 mL). After the reaction was stirred at rt for 2 h, the solvent was removed. The residue was dissolved in DCM (30 mL). To this solution were added DIPEA (7.06 g, 54.6 mol) and N,O-dimethylhydroxylamine (2.00 g, 32.8 mmol). The reaction was stirred at rt for 16 h and concentrated in vacuo to afford the title compound (4.20 g, 89.8% yield) as a yellow solid. The crude product was used immediately in the next step without further purification and characterization.Step 2. Synthesis of 3-(methoxy(methyl)carbamoyl)cyclopent-1-en-1-yl trifluoromethanesulfonate

[295] To a solution of N-methoxy-N-methyl-3-oxocyclopentane-1-carboxamide (3.6o g, 0.021 mol) in anhydrous THF (150 mL) was slowly added LDA (27 mL, 1M in THF, 27 mol) at -78 °C. The mixture was stirred at -78 °C for 2 h. A solution of 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(9.02 g, 25.2 mmol) in anhydrous THF (50 mL) was added. The mixture was warmed to 0 °C and stirred overnight. The mixture was poured into saturated aqueous NH4Cl (30 mL) and extracted with Et2O (80 mL × 3). The combined organic extracts were washed with water (50 mL) and brine (80 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to afford the title compound (5.00 g, 78.5 % yield) as a yellow solid. The crude product was used immediately in the next step without further purification and characterization.Step 3. Synthesis of N-methoxy-N-methyl-3-(1H-pyrazol-3-yl)cyclopent-2-ene-1-carboxamide

[296] To a stirred solution of 3-(methoxy(methyl)carbamoyl)cyclopent-1-en-1-yl trifluoromethanesulfonate (3.5 g, 11.5 mmol) in toluene / ethanol / H2O (175 mL, v / v / v = 4 / 2 / 1) were added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.79 g, 9.23 mmol), Pd(Ph3P)4 (1.33 g, 1.15 mmol) and K2CO3 (3.19 g, 23.1 mmol). The resulting mixture was stirred overnight at 80 °C under an argon atmosphere . The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was suspended in water (100 mL) and brine (100 mL). The aqueous mixture was extracted with ethyl acetate (100 mL × 3), the combined extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The crude product was purified by reverse phase flash column chromatography to afford the title compound(1.3 g, 50.9% over 3 steps) as a light-yellow oil.LCMS (Method 1): MS (ESI) m / z 222.0 [M+H]+.Step 4. Synthesis of N-methoxy-N-methyl-3-(1H-pyrazol-3-yl)cyclopentane-1-carboxamide

[297] To a stirred solution of N-methoxy-N-methyl-3-(1H-pyrazol-3-yl)cyclopent-2-ene-1-carboxamide (1.3 g, 5.88 mmol) in ethyl acetate (20 mL) was added Pd / C (0.0625 g, 0.588 mmol). The reaction was stirred at rt under H2 for 16 h. The solids were filtered off and the filtrate was evaporated to afford the title compound (1.1 g, 83.9% yield) as a yellow solid.LCMS (Method 1): MS m / z 224.1 [M+H]+.Step 5. Synthesis of N-methoxy-3-(1-(methoxymethyl)-1H-pyrazol-3-yl)-N-methylcyclopentane-1-carboxamide

[298] To a stirred solution of N-methoxy-N-methyl-3-(1H-pyrazol-3-yl)cyclopentane-1-carboxamide (1.1 g, 0.00493 mol) in DMF (20 mL) were added potassium carbonate (1.36 g, 9.85 mmol) and MOM-Br (0.739 g, 5.91 mmol). The reaction mixture was stirred at rt for 16 h, cooled and concentrated to dryness. The residue was purified by prep-HPLC to afford the title compound (1.20 g, 91% yield) as a yellow solid.LCMS (Method 1): MS (ESI) m / z 268.0 [M+H]+.Step 6. Synthesis of 1-(3-(1-(methoxymethyl)-1H-pyrazol-3-yl)cyclopentyl)ethan-1-one

[299] To a stirred solution of N-methoxy-3-(1-(methoxymethyl)-1H-pyrazol-3-yl)-N-methylcyclopentane-1-carboxamide (1.20 g, 4.49 mmol) in THF (50 mL) was slowly added CH3MgBr (4.49 mL, 13.5 mol) at 0 °C. The reaction mixture was stirred at rt for 4 h and concentrated to dryness. The residue was purified by prep-HPLC to afford the title compound (0.83 g, 83.0% yield) as a yellow solid.LCMS (Method 1): MS (ESI) m / z 223.0 [M+H]+.Step 7. Synthesis of 3-(3-(1,1-difluoroethyl)cyclopentyl)-1-(methoxymethyl)-1H-pyrazole

[300] To a stirred solution of 1-(3-(1-(methoxymethyl)-1H-pyrazol-3-yl)cyclopentyl)ethan-1-one (0.73 g, 3.28 mmol) in DCM (5 mL) was added DAST (2.18 g, 9.85 mol). The reaction mixture was stirred at rt for 16 h, the solvent was evaporated, and the residue was purified by prep-HPLC to afford the title compound (0.25 g, 31.0% yield) as a yellow solid.LCMS (Method 1): MS (ESI) m / z 245 [M+H]+.Step 8. Synthesis of 3-(3-(1,1-difluoroethyl)cyclopentyl)-1H-pyrazole

[301] To a stirred solution of 3-(3-(1,1-difluoroethyl)cyclopentyl)-1-(methoxymethyl)-1H-pyrazole (0.2 g, 0.819 mmol) in MeOH (5 mL) was added aqueous dilute HCl (0.5 mL). The reaction mixture was stirred at 60 °C for 16 h, concentrated, and the residue purified by prep-HPLC to afford the title compound (0.11 g, 67.1% yield) as a yellow solid.LCMS (Method 1): MS (ESI) m / z 201.0 [M+H]+.Intermediate B-30:3-(3,3-Dimethylbutoxy)piperidineStep 1. Synthesis of tert-butyl 3-(3,3-dimethylbutoxy)piperidine-1-carboxylate

[302] To a chilled (0 °C) solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (1.00 g, 5.0 mmol) in DMF (10 mL) was added NaH (400 mg, 10.0 mmol, 60% dispersion in oil). The reaction mixture was stirred at rt for 30 min and 1-iodo-3,3-dimethylbutane (1.40 g, 6.5 mmol) was added. The stirred mixture was allowed to warm from 0 °C to rt over 16 h. To the reaction mixture was added water (50 mL). The aqueous solution was extracted with EA (50 mL x 2). The organic phase was washed with brine (50 mL) and dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography using PE : EA (10 : 1) as eluent to give the title compound (130 mg, 7.0 % yield) as a colorless oil.LCMS (Method 1): MS (ESI) m / z 308 [M+Na]+.Step 2. Synthesis of 3-(3,3-dimethylbutoxy)piperidine

[303] To a stirred solution of tert-butyl 3-(3,3-dimethylbutoxy)piperidine-1-carboxylate (130 mg, 0.5 mmol) in DCM (2 mL) was added HCl in dioxane (4M, 2 mL). The reaction mixture was stirred at rt for 1 h, and concentrated to afford the title compound (80 mg, 95% yield) as a white solid.Intermediate B-31:(S)-3-(3,3-Dimethylbutoxy)pyrrolidine hydrochloride

[304] Intermediate B-31was prepared by following the procedure for the preparation of Intermediate B-30except for using tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate instead of tert-butyl 3-hydroxypiperidine-1-carboxylate in Step 1.LCMS (Method 1): MS (ESI) m / z 172.0 [M+H]+Intermediate B-32:(R)-3-(3,3-Dimethylbutoxy)pyrrolidine hydrochloride

[305] Intermediate B-32 was prepared by following the procedure for the preparation of Intermediate B-30except for using tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate instead of tert-butyl 3-hydroxypiperidine-1-carboxylate in Step 1.LCMS (Method 1): MS (ESI) m / z 172.0 [M+H]+.Intermediate B-33:2,2-Dimethyl-6-oxa-9-azaspiro[4.5]decane hydrochlorideStep 1. Synthesis of 3,3-dimethylcyclopentan-1-one

[306] To a suspension of CuI (6.85 g, 36.0 mmol) in anhydrous ether (100 mL) was added a solution of methyllithium in diethoxy methane (1.6 M, 47 mL, 75 mmol) at 0 °C over a period of 30 min. The mixture was stirred at 0 °C for 30 min. To the above mixture was added 3-methylcyclopent-2-en-1-one (2.88 g, 30.0 mmol) dropwise over a period of 30 min at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. The reaction was then quenched with saturated aqueous NH4Cl (150 mL) and filtered. The filtrate was extracted with ether (100 mL × 2). The combined organic extracts were dried over anhydrous Mg2SO4 and filtered. The filtrate was evaporated under reduced pressure to obtain the title compound. This crude product was used immediately in the next step without further purification and characterization.Step 2. Synthesis of 3,3-dimethyl-1-((trimethylsilyl)oxy)cyclopentane-1-carbonitrile

[307] To a solution of 3,3-dimethylcyclopentan-1-one (2.52 g, 22.5 mmol) in 30 mL of THF were added at 0 °C trimethylsilylformonitrile (3.35 g, 33.8 mmol) and ZnI2 (72 mg, 0.225 mmol) . The mixture was stirred for 3 hours at 0 °C and for 3 hours at 60 °C. The resulting solids were filtered off. The filtrate was concentrated to obtain the title compound. This crude product was used immediately in the next step without further purification and characterization.Step 3. Synthesis of 1-(aminomethyl)-3,3-dimethylcyclopentan-1-ol

[308] To a solution of 3,3-dimethyl-1-((trimethylsilyl)oxy)cyclopentane-1-carbonitrile (4.76 g, 22.5 mmol) in 50 mL of THF was added a solution of lithium aluminum hydride in THF (27 mL, 1 M, 27 mmol) dropwise at 0 °C under an argon atmosphere. After stirring for 16 h at room temperature, an aqueous sodium hydroxide solution (20 %) was added slowly with cooling. The solid was filtered off after dilution with ethyl acetate (30 mL). The filtrate was evaporated to give the title compound (3.23 g, 22.6 mmol, 100% yield) as a semi-solid.LCMS (Method 1): LC retention time = 1.314 min. MS (ESI) m / z 144 [M+H]+.Step 4. Synthesis of 2-chloro-N-((1-hydroxy-3,3-dimethylcyclopentyl)methyl)acetamide

[309] To a solution of potassium carbonate (6.22 g, 45.1 mmol) in water (30 mL) was added to a solution of 1-(aminomethyl)-3,3-dimethylcyclopentan-1-ol (3.23 g, 22.6 mmol) in ethyl acetate (30 mL). The mixture was cooled to 0 °C, and then treated dropwise with 2-chloroacetyl chloride (2.8 g, 24.8 mmol) . After completion of the addition, the reaction mixture was warmed to 25 °C and allowed to stir for 16 h. The aqueous solution was extracted with ethyl acetate (50 mL × 3). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound. This crude product was used immediately in the next step without further purification and characterization.Step 5. Synthesis of 2,2-dimethyl-6-oxa-9-azaspiro[4.5]decan-8-one

[310] To a suspension of tBuOK in tert-butanol (40 mL) was added 2-chloro-N-((1-hydroxy-3,3-dimethylcyclopentyl)methyl)acetamide (4.95 g, 22.5 mmol) in THF (30 mL) over 30 min. The resulting mixture was stirred at room temperature for 16 h before it was concentrated. The residue was diluted with EA and water, the organic layer was separated, washed with brine, and concentrated to give the title compound. This crude product was used immediately in the next step without further purification and characterization.Step 6. Synthesis of 2,2-dimethyl-6-oxa-9-azaspiro[4.5]decane hydrochloride

[311] To a solution of 2,2-dimethyl-6-oxa-9-azaspiro[4.5]decan-8-one (4.13 g, 22.5 mmol) in THF (50 mL) was added at room temperature borane-tetrahydrofuran (7.75 g, 90.2 mmol) . The reaction mixture was then refluxed for 2 h and cooled to room temperature. MeOH was carefully added. The mixture was concentrated under reduced pressure. To the residue was added MeOH (50 mL) and N,N,N',N'-tetramethylethylenediamine (10.5 g, 90.2 mmol), and the reaction was stirred at 78°Covernight. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate and water. The organic phase was separated, washed with brine, and concentrated in vacuo to give a crude product. To the crude product was added HCl-dioxane (5 mL) and stirring continued at rt for 1 h. Concentration of the resulting mixture afforded the title compound (566 mg, 7 % yield over 6 steps) as a yellow solid.LCMS (acidic): LC retention time = 1.421 min. MS (ESI): m / z 170 [M+H]+.Intermediate B-34:2,2,8-Trimethyl-6-oxa-9-azaspiro[4.5]decane hydrochloride

[312] Intermediate B-34 was synthesized in same manner as Intermediate B-33.Intermediate B-35:2-(Trifluoromethoxy)-6-oxa-9-azaspiro[4.5]decane hydrochlorideStep 1. Synthesis of ((cyclopent-3-en-1-yloxy)methyl)benzene

[313] To a cooled and stirred suspension of sodium hydride (2.85 g, 71.3 mmol, 60% in paraffin oil) in 30 mL dry toluene was added slowly under a N2 atmosphere a solution of cyclopent-3-en-1-ol(4.00 g, 47.6 mmol) in toluene (10 mL) . After gas evolution ceased, a solution of benzyl bromide (8.94 g, 52.3 mmol) in toluene (20 mL) was added dropwise and the resulting mixture was refluxed for 12 h. Methanol in toluene was added in small portions to decompose residual NaH. The reaction mixture was partitioned between water and ethyl acetate (20 mL each) and the two phases were separated. The organic phase was dried over sodium sulfate and the solvent was evaporated. The residue was purified by flash column chromatography on silica gel (eluting with PE) to afford the title compound (8.0 g, 96.6% yield) as a yellow oil.LCMS (acidic): LC retention time = 2.179 min; MS (ESI) signal not observed.Step 2. Synthesis of 3-(benzyloxy)-6-oxabicyclo[3.1.0]hexane

[314] To a stirred solution of [(cyclopent-3-en-1-yloxy)methyl]benzene(8.00 g, 45.9 mmol) in DCM (80 mL) at 0 °C was added meta-chloroperoxybenzoic acid (8.69 g, 50.5 mmol) in one portion. The reaction mixture was stirred at 0 °C for 2 h before it was slowly warmed to room temperature. The reaction mixture was slowly quenched with a 1:1 mixture of saturated aqueous NaHSO3 and NaHCO3 solutions (150 mL), diluted with ethyl acetate and the two phases were separated. The aqueous phase was extracted with ethyl acetate (100 mL × 2). The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with a 0-5% EA in PE gradient) to afford the title compound (7.06 g, 80.8%) as a yellow oil.LCMS (acidic): LC retention time = 1.875, 1.948 min. MS (ESI) m / z 213 [M+Na]+.Step 3. Synthesis of 3-(benzyloxy)cyclopentan-1-ol

[315] To a solution of 3-(benzyloxy)-6-oxabicyclo[3.1.0]hexane (7.06 g, 37.1 mmol) in 80 mL of THF was added a solution of LiAlH4 (44.5 mL, 44.5 mmol, 1.0 M in THF) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h and quickly warmed to room temperature over 5 min. To this mixture was added Celite / Na2SO4·10H2O (1:1, 100 g) until gas stopped evolving. The solid was dissolved in diethyl ether and filtered through a plug of Celite. The filtrate was concentrated to give the title compound (3.44 g, 48.2%) as a yellow oil.LCMS (acidic): LC retention time = 1.83 min. MS (ESI) m / z 193 [M+H]+.Step 4. Synthesis of 3-(benzyloxy)cyclopentan-1-one

[316] To a stirred solution of 3-(benzyloxy)cyclopentan-1-ol (3.44 g, 17.9 mmol) in 40 mL of THF was added Dess-Martin periodinane (15.20 g, 35.8 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 4 h. The reaction mixture was quenched slowly with a mixture of saturated aqueous NaHSO3 and NaHCO3 solutions (1:1, 100 mL), diluted with ethyl acetate, and the two phases were separated. The aqueous phase was extracted with ethyl acetate (150 mL × 2). The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to afford the title compound(2.67 g, 78.5%) as a yellow oil.LCMS (acidic): LC retention time = 1.896 min. MS (ESI) m / z 191 [M+H]+.Step 5. Synthesis of 3-(benzyloxy)-1-((trimethylsilyl)oxy)cyclopentane-1-carbonitrile

[317] To a solution of 3-(benzyloxy)cyclopentan-1-one (2.10 g, 11.0 mmol) in 25 mL of THF were added at 0 °C trimethylsilylformonitrile (1.75 g, 17.7 mmol) and ZnI2 (352 mg, 1.10 mmol) . The mixture was stirred at 0 °C for 6 h and at 60 °C for 16 h. The solids were filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluting with PE: EA = 20: 1) to give the title compound (2.25 g, 70.4%) as a yellow oil.LCMS (acidic): LC retention time = 2.66 min. MS (ESI) m / z 312 [M+Na]+.Step 6. Synthesis of 1-(aminomethyl)-3-(benzyloxy)cyclopentan-1-ol

[318] To a solution of 3-(benzyloxy)-1-((trimethylsilyl)oxy)cyclopentane-1-carbonitrile (2.25 g, 7.77 mmol) in 15 mL of tetrahydrofuran was added dropwise under an argon atmosphere at 0 °C a solution of lithium aluminum hydride in tetrahydrofuran (9.33 mL, 9.33 mmol) . After stirring for 16 h at room temperature, an aqueous sodium hydroxide solution (20 %) was added slowly with cooling. The solids were filtered off after dilution with ethyl acetate and the filtrate was concentrated to give the title compound (1.60 g, 93.0%) as a yellow oil.LCMS (acidic): LC retention time = 1.296 min. MS (ESI) m / z 222 [M+H]+.Step 7. Synthesis of N-((3-(benzyloxy)-1-hydroxycyclopentyl)methyl)-2-chloroacetamide

[319] To a solution of potassium carbonate (2.0 g, 14.5 mmol) in water (15 mL) was added to a solution of 1-(aminomethyl)-3-(benzyloxy)cyclopentan-1-ol (1.60 g, 7.23 mmol) in ethyl acetate (15 mL). The mixture was cooled to 0 °C, and then treated with 2-chloroacetyl chloride (980 mg, 8.68 mmol). After completion of the addition, the reaction mixture was warmed to 25 °C and allowed to stir for 16 h. The aqueous solution was extracted with ethyl acetate (50 mL × 3). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (1.90 g, 88.2%) as a yellow oil.LCMS (acidic): LC retention time = 1.86 min. MS (ESI) m / z 298 [M+H]+.Step 8. Synthesis of 2-(benzyloxy)-6-oxa-9-azaspiro[4.5]decan-8-one

[320] To a solution of potassium tert-butoxide (1.43 g, 12.8 mmol) in tert-butanol (15 mL) was added N-((3-(benzyloxy)-1-hydroxycyclopentyl)methyl)-2-chloroacetamide (1.90 g, 6.38 mmol) in THF (15 mL) over 10 min, and the resulting mixture was stirred for 16 h at room temperature before it was concentrated. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase was isolated, washed with brine (50 mL × 2), and concentrated to provide the title compound (1.50 g, 90.0%) as a light-yellow oil.LCMS (acidic): LC retention time = 1.81, 1.84 min (mixture of 2 diastereomers). MS (ESI) m / z 262 [M+H]+.Step 9. Synthesis of 2-(benzyloxy)-6-oxa-9-azaspiro[4.5]decane

[321] To a solution of 2-(benzyloxy)-6-oxa-9-azaspiro[4.5]decan-8-one (1.30 g, 4.97 mmol) in THF (15 mL) was added at room temperature borane-tetrahydrofuran (14.9 mL, 14.9 mmol) . The reaction mixture was refluxed for 2 h, then cooled to room temperature. MeOH was carefully added, and the solvent was evaporated under reduced pressure. To the residue was added MeOH (15 mL) and N,N,N',N'-tetramethylethylenediamine (2.31 g, 19.9 mmol). The reaction was stirred at 75 °C overnight. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (50 mL) and water (50 mL), and the two phases were separated. The organic phase was washed with brine (50 mL × 2) and concentrated in vacuo to give the title compound (1.15 g, 93.5%) as a yellow oil.LCMS (acidic): LC retention time = 1.531, 1.558 min (mixture of 2 diastereomers). MS (ESI) m / z 248 [M+H]+.Step 10. Synthesis of tert-butyl 2-(benzyloxy)-6-oxa-9-azaspiro[4.5]decane-9-carboxylate

[322] To a solution of 2-(benzyloxy)-6-oxa-9-azaspiro[4.5]decane (1.20 g, 4.85 mmol) in 1,4-dioxane (10 mL) and H2O (10 mL) were added di-tert-butyl dicarbonate (3.18 g, 14.6 mmol) and Na2CO3 (1.54 g, 14.6 mmol). The resulting mixture was stirred at room temperature overnight. The reaction solution was concentrated. The residue was dissolved in EA (50 mL). The EA solution was washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with PE: EA = 5: 1) to give the title compound (1.20 g, 71.2%) as a yellow oil.LCMS (acidic): LC retention time = 2.205, 2.242 min (mixture of 2 diastereomers). MS (ESI) m / z 292 [M-tBu]+Step 11. Synthesis of tert-butyl 2-hydroxy-6-oxa-9-azaspiro[4.5]decane-9-carboxylate

[323] To a solution of tert-butyl 2-(benzyloxy)-6-oxa-9-azaspiro[4.5]decane-9-carboxylate (1.20 g, 3.45 mmol) in ethyl acetate (25 mL) was added Pd / C. The flask was attached to a hydrogenation apparatus. The flask was agitated under a hydrogen atmosphere for 5 h. The catalyst was filtered off. The filtrate was concentrated to give the title compound (810 mg, 91.1%) as a colorless oil.LCMS (acidic): LC retention time = 1.736 min. MS (ESI) m / z 202 [M-t-Bu]+.Step 12. Synthesis of tert-butyl 2-(trifluoromethoxy)-6-oxa-9-azaspiro[4.5]decane-9-carboxylate

[324] A flask was charged with silver triflate (1.65 g, 6.41 mmol), Select-F® (1.14 g, 3.21 mmol), KF (497 mg, 8.55 mmol) and tert-butyl 2-hydroxy-6-oxa-9-azaspiro[4.5]decane-9-carboxylate (550 mg, 2.14 mmol). The flask was purged with argon. Ethyl acetate (15 mL) was added, followed by TMSCF3 (912 mg, 6.41 mmol) and 2-fluoropyridine (623 mg, 6.41 mmol). The reaction mixture was stirred at room temperature overnight under an argon atmosphere, then filtered through a Celite pad. The filtrate was concentrated and purified by flash chromatography on silica gel (eluting with PE) to afford the title compound(420 mg, 60.4 %) as a yellow oil.LCMS: LC retention time = 2.170 min. MS (ESI) m / z 270 [M-t-Bu]+.Step 13. Synthesis of 2-(trifluoromethoxy)-6-oxa-9-azaspiro[4.5]decane hydrochloride

[325] To a solution of tert-butyl 2-(trifluoromethoxy)-6-oxa-9-azaspiro[4.5]decane-9-carboxylate (650 mg, 2.0 mmol) in dioxane (1 mL) was added HCl-dioxane (10 mL). The solution was stirred at room temperature for 2 h. The mixture was concentrated to give the title compound (523 mg, 100% yield) as a yellow oil.LCMS (Method 1): LC retention time = 1.28 min. MS (ESI) m / z 226 [M+H]+.Intermediate B-36:tert-Butyl 6-oxa-2,9-diazaspiro[4.5]decane-9-carboxylateStep 1. Synthesis of 5-benzyl-1-oxa-5-azaspiro[2.4]heptane

[326] To a suspension of NaH (3.01 g, 60% dispersion in oil, 75.33 mmol) in DMSO (120 mL) was added trimethylsulfoxonium iodide (19.59 g, 89.03 mmol) followed by 1-benzylpyrrolidin-3-one(12.00 g, 68.48 mmol). The reaction mixture was stirred at room temperature for 3 h, quenched by the addition of water (500 mL) and extracted with ethyl acetate (500 mL × 2). The combined extracts were washed with water (300 mL × 2), dried over Na2SO4, filtered, and concentrated to afford the title compound (12.00 g, 92.6 %) as a brown oil.LCMS: LC retention time = 1.370 min. MS (ESI) m / z 190 [M+H]+.Step 2. Synthesis of 3-(aminomethyl)-1-benzylpyrrolidin-3-ol

[327] To a solution of 5-benzyl-1-oxa-5-azaspiro[2.4]heptane(12.00 g, 63.4 mmol) in 60 mL of MeOH was added dropwise at 0 °C 90 mL of 28% aqueous NH4OH . The reaction mixture was stirred at room temperature overnight, concentrated, and diluted with 500 mL of ethyl acetate. The two phases were separated, and the organic phase was washed with water (200 mL × 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica (eluting with a 0-10% gradient of MeOH in DCM) togivethe title compound (5.93 g, 45.3 %) as a yellow oil.LCMS (Method 1): LC retention time = 1.10 min. MS (ESI) m / z 207 [M+H]+.Step 3. Synthesis of N-((1-benzyl-3-hydroxypyrrolidin-3-yl)methyl)-2-chloroacetamide

[328] Triethylamine was added  dropwise under Ar to a stirred, chilled (-20 °C) solution of 3-(aminomethyl)-1-benzylpyrrolidin-3-ol (6.08 g, 29.5 mmol) in DCM (50 mL)  (8.95 g, 88.4 mmol) followed by 2-chloroacetyl chloride (3.33 g, 29.5 mmol). The reaction mixture was stirred at -20 °C for 0.5 h and then warmed to r.t for 1 h. The reaction mixture was diluted with DCM (100 mL) and washed with saturated aqueous NH4Cl solution (100 mL), and brine (100 mL). The organic phase was dried (Na2SO4) and concentrated in vacuo to give the crude product which was purified by flash column chromatography on silica (eluting with 0-5% MeOH in DCM) to give the title compound(4.70 g, 56% yield) as a yellow oil.LCMS (Method 1): LC retention time = 0.578 min. MS (ESI) m / z 283 [M+H]+. Step 4. Synthesis of 2-benzyl-6-oxa-2,9-diazaspiro[4.5]decan-8-one

[329] To a solution of N-((1-benzyl-3-hydroxypyrrolidin-3-yl)methyl)-2-chloroacetamide (0.35 g, 1.24 mmol, 1.0 eq) in THF (5 mL) was added at 0 °C under Ar a solution of t-BuOK in THF (1.0 M, 1.49 mL, 1.49 mmol, 1.2 eq) . The mixture was stirred at the same temperature for 15 min and then at rt for 1 h. The reaction was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined extracts were washed with brine (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give the crude product which was purified by flash chromatography on silica (eluting with 0-5% MeOH in DCM) to give the title compound (178 mg, 58.0% yield) as a white solid.LCMS (Method 1): LC retention time = 1.251 min. MS (ESI) m / z 247 [M+H]+.Step 5. Synthesis of tert-butyl 2-benzyl-6-oxa-2,9-diazaspiro[4.5]decane-9-carboxylate

[330] To a stirred solution of 2-benzyl-6-oxa-2,9-diazaspiro[4.5]decan-8-one (2.36 g, 9.58 mmol, 1.0 eq) in THF (150 mL) was added at 0 °C under Ar LiAlH4 (14.4 mL, 1 M, 14.4 mmol, 1.5 eq) in THF. The mixture was refluxed for 1 h, cooled to 0 °C and quenched by the addition of H2O (5 mL) and Na2CO3 (2.03 g, 19.2 mmol, 2.0 eq). To this solution was added (Boc)2O (4.18 g, 19.2 mmol, 2.0 eq). The mixture was stirred at rt for 3 h, then diluted with H2O (200 mL) and extracted with ethyl acetate (200 mL × 2). The combined extracts were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (eluting with 0-20% ethyl acetate in heptane) to give the title compound (2.59 g, 82.0% yield) as a colorless oil.LCMS (Method 1): LC retention time = 1.484 min. MS (ESI) m / z 333 [M+H]+.Step 6. Synthesis of tert-butyl 6-oxa-2,9-diazaspiro[4.5]decane-9-carboxylate

[331] To a solution of tert-butyl 2-benzyl-6-oxa-2,9-diazaspiro[4.5]decane-9-carboxylate (3.00 g, 9.0 mmol, 1.0 eq) in MeOH (50 mL) was added at rt Pd / C (10 wt. %, 2.0 g) and ammonium formate (4.00 g, 63.4 mmol, 7.0 eq). The mixture was refluxed for 1 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give the title compound(2.0 g, 91.5% yield) as a colorless oil.LCMS (Method 1): LC retention time = 1.417 min. MS (ESI) m / z 243 [M+H]+.Intermediate B-37:2-NeopentylmorpholineStep 1. Synthesis of 1-bromo-4,4-dimethylpentan-2-one

[332] To a chilled (0 °C) solution of 4, 4-dimethylpentan-2-one (1.0 g, 8.76 mmol) in 15 mL of MeOH was added dropwise Br2 (1.40 g, 8.76 mmol) , and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to afford the title compound (1.69 g, 100%) as a brown oil. This crude product was used immediately in the next step of the reaction without further purification and characterization.Step 2. Synthesis of 1-(benzyl(2-hydroxyethyl)amino)-4,4-dimethylpentan-2-one

[333] To a solution of 1-bromo-4,4-dimethylpentan-2-one (1.69 g, 8.75 mmol) in 40 mL of CH3CN were added 2-(benzylamino)ethanol (1.99 g, 13.1 mmol) and K2CO3 (1.81 g, 13.1 mmol). The reaction was then heated at 80 °C overnight. The reaction mixture was cooled to rt and concentrated. The residue was dissolved in ethyl acetate (100 mL), the ethyl acetate solution was washed with water (50 mL), brine (50 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by prep-TLC to afford the title compound (500 mg, 21.7%) as a yellow oil.LCMS (Method 1): LC retention time = 1.624 min. MS (ESI) m / z 264 [M+H]+.Step 3. Synthesis of 1-(benzyl(2-hydroxyethyl)amino)-4,4-dimethylpentan-2-ol

[334] To a solution of 1-(benzyl(2-hydroxyethyl)amino)-4,4-dimethylpentan-2-one (500 mg, 1.90 mmol) in 10 mL of MeOH was added NaBH4 (351mg, 9.49 mmol) in portions. The reaction mixture was stirred at room temperature for 5 h, quenched with aqueous NH4Cl , concentrated, and extracted with ethyl acetate (20 mL × 4). The combined organic extracts were washed with brine, water, dried over Na2SO4, filtered, and concentrated to afford the title compound (430 mg, 85.3%) as a yellow oil.LCMS (Method 1): LC retention time = 1.555 min. MS (ESI) m / z 266 [M+H]+.Step 4. Synthesis of 4-benzyl-2-neopentylmorpholine

[335] To a solution of 1-(benzyl(2-hydroxyethyl)amino)-4,4-dimethylpentan-2-ol (400 mg, 1.51 mmol) in 10 mL of THF was added at room temperature Ph3P (1.19 g, 4.52 mmol), followed by the dropwise addition of DIAD (913 mg, 4.52 mmol) . The reaction mixture was stirred at room temperature overnight, then quenched through the addition of aqueous NH4Cl. The aqueous mixture was extracted with ethyl acetate (20 mL × 4). The EA extracts were concentrated to dryness and redissolved in ethyl acetate (50 mL). The solid formed was filtered off. The filtrate was concentrated and purified by silica gel Prep-TLC (eluting with PE: EA = 3:1) to afford the title compound (100 mg, 26.7% yield) as a pink oil.LCMS (Method 1): LC retention time = 2.047 min. MS (ESI) m / z 248 [M+H]+. Step 5. Synthesis of 2-neopentylmorpholine

[336] To a solution of 4-benzyl-2-neopentylmorpholine(100 mg, 0.404 mmol) in 30 mL of MeOH was added Pd / C (100 mg, 10 wt. %). The reaction was stirred at room temperature under H2 for 4 h, the solids were filtered off and the filtrate concentrated to afford 2-neopentylmorpholine(45 mg, 70.8%) as a pink oil.LCMS (Method 1): LC retention time = 1.529 min. MS (ESI) m / z 158 [M+H]+.Intermediate B-38:2-(3,3-Dimethylbutyl)morpholine hydrochlorideStep 1. Synthesis of N-benzyl-2-chloro-N-(2-hydroxyethyl)acetamide

[337] To a solution of 2-(benzylamino)ethan-1-ol (20.00 g, 132 mmol) in 50 mL of DCM were added dropwise a solution of NaOH (5.29 g, 132 mmol) in 50 mL of H2O and 2-chloroacetyl chloride (14.9 g, 132 mmol) . The reaction mixture was stirred at room temperature overnight. The two phases were separated, and the organic layer was washed with water (50 mL). The organic solution was dried over Na2SO4, filtered, and concentrated to afford the title compound (29.00 g, 96%) as a yellow oil.LCMS: LC retention time = 1.523 min. MS (ESI) m / z 228 [M+H]+.Step 2. Synthesis of 4-benzylmorpholin-3-one

[338] To a suspension of t-BuOK (23.70 g, 211 mmol) in 100 mL of t-BuOH was added dropwise a solution of N-benzyl-2-chloro-N-(2-hydroxyethyl)acetamide (24.00 g, 105 mmol) in 100 mL of THF . The reaction mixture was stirred at room temperature for 2 h, and diluted with 180 mL of ethyl acetate. The ethyl acetate solution was washed with water (100 mL × 2), dried over Na2SO4, filtered, and concentrated to afford the title compound (18.00 g, 89.3%) as a yellow oil.LCMS: LC retention time = 1.512 min. MS (ESI) m / z 192 [M+H]+.Step 3. Synthesis of 4-benzyl-2-(1-hydroxy-3,3-dimethylbutyl)morpholin-3-one

[339] To a solution of 4-benzylmorpholin-3-one (5.00 g, 26.1 mmol) in 60 mL of THF was added n-BuLi (2.5M in hexane, 12.6 mL, 31.4 mmol) at -78 °C. After stirring at -78 °C for 45 min, 3,3-dimethylbutanal (3.14 g, 31.4 mmol) was added. The reaction mixture was stirred at -78 °C for 1 h, then allowed to warm to room temperature overnight. The reaction mixture was quenched by addition of aqueous NH4Cl (50 mL). The aqueous suspension was extracted with EA (100 mL × 2). The organic extract was concentrated and the residue purified by flash column chromatography on silica (eluting with a 0-100% EA in PE gradient) to afford the title compound(3.78 g, 49.1 % yield) as a yellow oil.LCMS: LC retention time = 2.006 min. MS (ESI) m / z 292 [M+H]+.Step 4. Synthesis of 1-(4-benzylmorpholin-2-yl)-3,3-dimethylbutan-1-ol

[340] To a solution of 4-benzyl-2-(1-hydroxy-3,3-dimethylbutyl)morpholin-3-one(3.48 g, 11.9 mmol) in 20 mL of THF was added BH3.THF (1M in THF, 35.8 mL, 35.8 mmol). The reaction mixture was heated at 55 °C for 2 h, cooled to room temperature, quenched with MeOH (1 mL), and concentrated. The residue was dissolved in MeOH (30 mL). To the methanol solution was added TMEDA (5.54 g, 47.8 mmol), and the solution heated at 80 °C overnight. After cooling to rt, the mixture was concentrated. The residue was dissolved in ethyl acetate (100 mL), the ethyl acetate solution was washed with brine (80 mL × 2), dried (Na2SO4), filtered, and concentrated to afford the title compound (3.0 g, 90%) as a yellow oil.LCMS (Method 1): LC retention time = 1.526 min. MS (ESI) m / z 278 [M+H]+.Step 5. Synthesis of 4-benzyl-2-(3,3-dimethylbutyl)morpholine

[341] To a solution of 1-(4-benzylmorpholin-2-yl)-3,3-dimethylbutan-1-ol (1.0 g, 3.60 mmol) in DCM (10 mL) was added DMAP (88 mg, 0.721 mmol) and TEA (728 mg, 7.21 mmol). The reaction mixture was cooled to 0 °C. Tosyl chloride (825 mg, 4.33 mmol) was added in portions. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with water (20 mL), extracted with DCM (30 mL × 2), the DCM extract was washed with water and concentrated. The residue was dissolved in THF (5 mL). To this solution wasadded LiAlH4 (1M in THF, 5.84 mL) at 0 °C. The reaction mixture was refluxed overnight, cooled to room temperature, quenchedwith aqueous Na2SO4 solution (2 mL), and filtered. The filter cake was washed with ethyl acetate. The combined filtrates were dried over Na2SO4, filtered and concentrated. The residue was purified by Prep-TLC (eluting with PE: EA = 4:1) to afford the title compound (283 mg, 55.6%) as a yellow oil.LCMS (Method 1): LC retention time =1.661 min. MS (ESI) m / z 262 [M+H]+.Step 6. Synthesis of 2-(3,3-dimethylbutyl)morpholine hydrochloride

[342] To a solution of 4-benzyl-2-(3,3-dimethylbutyl)morpholine (283 mg, 1.08 mmol) in 50 mL of MeOH was added 500 mg of Pd / C (10 wt. %). The reaction mixture was stirred overnight at room temperature under H2 . The solids were filtered off, and the filtrate was concentrated. The residue was dissolved in 2 mL of DCM and 5 mL of 4M HCl in dioxane was added. The reaction mixture was stirred at room temperature for 20 min and concentrated, to afford the title compound (200 mg, 88.9%) as a white solid.LCMS (Method 1): LC retention time = 1.488 min. MS (ESI) m / z 172 [M+H]+.Intermediate B-39:2-(4,4-Dimethylpentyl)morpholineStep 1. Synthesis of tert-butyl 2-formylmorpholine-4-carboxylate

[343] To a stirred solution of oxalyl chloride (1.93 g, 15.2 mmol) in DCM (40 mL) was slowly added DMSO (0.79 mL, 11.0 mmol) at -78 °C. The resulting mixture was stirred for 30 min at this temperature. A solution of tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (3.00 g, 13.8 mmol) in DCM (10 mL) was added slowly over 10 min and stirred for 1 h. Then TEA (6.29 g, 62.1 mmol) was added dropwise and stirring continued for 0.5 h. The reaction mixture was allowed to warm slowly to rt and quenched with water (30 mL). After extraction with DCM (20 mL × 3), the combined organic extracts were washed successively with HCl (1 M, 10 mL), saturated aqueous Na2CO3 (30 mL), and brine (30 mL). The organic phaser was dried over anhydrous Na2SO4 and concentrated in vacuo to afford the title compound as a yellow oil (2.0 g, 67.0 % yield).LCMS (Method 1): LC retention time = 1.49 min; MS (ESI) m / z 160 [M-t-Bu]+.Step 2. Synthesis of tert-butyl (E)-2-(4,4-dimethylpent-1-en-1-yl)morpholine-4-carboxylate

[344] To a chilled (0 °C) solution of (3,3-dimethylbutyl) (triphenyl)phosphonium methanesulfonate (2.05 g, 4.6 mmol) in THF (30 mL) was added sodium hydride (60% dispersion in mineral oil, 223 mg, 9.2 mmol). The mixture was stirred for 30 min. To the reaction mixture was added dropwise a solution of tert-butyl 2-formylmorpholine-4-carboxylate (1.0 g, 4.6 mmol) in THF (10 mL), and the mixture was stirred at 50 °C for 4 h. Hydrochloric acid (1N) was added, and the mixture was extracted with ethyl acetate (50 mL). The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography using PE : EA (20 : 1) as eluent to give the title compound (490 mg, 37.0% yield) as a colorless oil.LCMS: LC retention time = 2.30 min; MS (ESI) m / z 228 [M-t-Bu]+.1H NMR (400 MHz, chloroform-d) δ 5.72-7.65 (m, 1H), 5.43-5.38 (m, 1 H), 4.13 (t, J = 8.4 Hz, 1H), 3.88-3.52 (m, 4H), 2.94 (t, J = 11.2 Hz, 1H), 2.68 (s, 1H), 2.01 (d, J = 8.0 Hz, 2H), 1.47 (s, 9H), 0.90 (s, 9H) ppm. Step 3. Synthesis of (E)-2-(4,4-dimethylpent-1-en-1-yl)morpholine

[345] To a stirred solution of tert-butyl (E)-2-(4,4-dimethylpent-1-en-1-yl)morpholine-4-carboxylate (430 mg, 1.4 mmol) in DCM (3 mL) was added HCl / dioxane (4 mL). The reaction was stirred at rt for 1 h and concentrated to give the title compound (250 mg, 90% yield) as a white solid.LCMS (Method 1): LC retention time = 1.48 min. MS (ESI) m / z 184 [M+H]+. Step 4. Synthesis of 2-(4,4-dimethylpentyl)morpholine

[346] To a solution of(E)-2-(4,4-dimethylpent-1-en-1-yl)morpholine (250 mg, 0.77 mmol) in MeOH (6 mL) were added Pd / C (10%, 100 mg). The reaction mixture was stirred at rt under H2 for 1 h, the solids filtered off, and the filtrate concentrated to give the title compound (220 mg, 87% yield) as a white solid.LCMS (Method 1): LC retention time = 1.54 min. MS (ESI) m / z 186 [M+H]+.Intermediate B-40:4-(tert-Butoxy)-2-methylpyrrolidineStep 1. Synthesis of 1-benzyl 2-methyl 4-(tert-butoxy)pyrrolidine-1,2-dicarboxylate

[347] To a stirred solution of 1-benzyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (5.67 g, 20.3 mmol) in THF (60 mL) was added tert-butyl 2,2,2-trichloroethanimidate (3.6 mL). The mixture was stirred at room temperature for 3 h, then additional tert-butyl 2,2,2-trichloroethanimidate (3.6 mL) was added and stirring continued for 0.5 h. The remaining amount of tert-butyl 2,2,2-trichloroethanimidate (29.1 mL) was added portion wise. After addition was completed, the solution was stirred at room temperature for 48 h. To the reaction mixture was added DCM (60 mL). The mixture was filtered through a Celite plug and the filtrate was concentrated to dryness under reduced pressure to give the crude which was purified by reversed phase silica gel column chromatography to afford the title compound (1.75 g, 25.7 %) as a colorless oil.LCMS (Method 1): LC retention time = 2.12 min. MS (ESI) m / z 336 [M+H]+.Step 2. Synthesis of benzyl 4-(tert-butoxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

[348] To a stirred solution of 1-benzyl 2-methyl 4-(tert-butoxy)pyrrolidine-1,2-dicarboxylate (1.75 g, 4.17 mmol) in anhydrous tetrahydrofuran (40.0 mL) was added diisobutylaluminium hydride (1M in toluene, 20.9 mL) at -78 °C under an argon atmosphere. The mixture was allowed to warm slowly to room temperature and stirred overnight. Saturated aqueous potassium sodium tartrate tetrahydrate solution (40 mL) was added and stirring continued for 1 h. The mixture was filtered through a Celite plug. The filtrate was concentrated under reduced pressure. The crude was purified by flash column chromatography on silica (eluting with PE : EA = 2:1) to give the title compound (850 mg, 53.0% yield) as a light-yellow oil.LCMS: LC retention time = 1.99 min. MS (ESI) m / z 308 [M + H]+.Step 3.Synthesis of benzyl 4-(tert-butoxy)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate

[349] To a chilled (0 °C) solution of benzyl 4-(tert-butoxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate(700 mg, 2.28 mmol) in DCM (30 mL) were added mesyl chloride (521 mg, 4.55 mmol) and Et3N (690 mg, 6.83 mmol). The mixture was stirred at room temperature overnight, concentrated to dryness in vacuo, and the residue was dissolved in ethyl acetate (80 mL). The ethyl acetate solution was washed with a saturated aqueous NaHCO3 solution (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give the crude which was purified by flash column chromatography on silica (eluting with PE : EA = 2 : 1) to afford the title compound (860 mg, 98.0 %) as a colorless oil.LCMS (Method 1): LC retention time = 2.08 min. MS (ESI) m / z 386 [M+H]+.Step 4. Synthesis of benzyl 4-(tert-butoxy)-2-methylpyrrolidine-1-carboxylate

[350] To a solution of benzyl 4-(tert-butoxy)-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (860 mg, 2.23 mmol) in dioxane (30 mL) was added under an argon atmosphere (Bu4N)BH4 (2.29 g, 9.92 mmol) . The reaction mixture was stirred at 100 °C for 5 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (150 mL). The ethyl acetate solution was washed with water (80 mL) and brine (150 mL). The aqueous phase was back extracted with ethyl acetate (80 mL × 2). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the crude which was purified by silica gel chromatography (eluting with PE : EA = 5 : 1) to afford the title compound (530 mg, 81.5% yield) as a colorless oil.LCMS (Method 1): LC retention time = 2.22 min. MS (ESI) m / z 314 [M+Na]+.Step 5. Synthesis of 4-(tert-butoxy)-2-methylpyrrolidine

[351] To a solution of benzyl 4-(tert-butoxy)-2-methylpyrrolidine-1-carboxylate (530 mg, 1.82 mmol) in MeOH (20 mL) was added Pd(OH)2 (150 mg). The mixture was stirred at room temperature overnight under a hydrogen atmosphere. The mixture was diluted with MeOH (20 mL) and filtered through a Celite plug. The filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography (eluting with EA) to give the title compound (70 mg, 24.5%) as a light-yellow oil.LCMS (Method 1): LC retention time = 1.35 min. MS (ESI) m / z 158 [M+H]+.Intermediate B-41:(2R,4R)-4-(tert-Butoxy)-2-methylpyrrolidine

[352] Intermediate B-41was prepared in essentially the same way as Intermediate B-40described above except for using 1-benzyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate instead of 1-benzyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate in Step 1.Intermediate B-42:3-(3,3-Dimethylbutyl)pyrrolidin-2-oneStep 1. Synthesis of 1-benzyl-3-(3,3-dimethylbutyl)pyrrolidin-2-one

[353] To a solution of diisopropylamine (3.18 g, 31.4 mmol) in THF (50 mL) was added n-BuLi (13.7 mL, 34.2 mmol) at 0 °C and stirred for 0.5 h. The mixture was cooled to -78 °C and 1-benzylpyrrolidin-2-one (5 g, 28.5 mmol) was added. The mixture was stirred for 0.5 h, 1-bromo-3,3-dimethyl-butane (7.07 g, 42.8 mmol) was added, and the reaction was allowed to warm up slowly to rt with stirring over 16 h . The reaction was quenched with water (2 mL), extracted with ethyl acetate (50 mL). The ethyl acetate extract was washed with brine (50 mL × 2). The aqueous phase was back extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with EA in PE = 0-10%) to give the title compound (2.90 g, 39.2% yield) as a yellow oil.LCMS (Method 1): L...

Claims

1. A compound of Formula (I):(I),or a pharmaceutically acceptable salt thereof,whereinRing A is selected from the group consisting of , , , and ;wherein Ring B is selected from the group consisting of , , , , , and ;X1 is -C(H)=, -C(R4)=, or -N=;X2 is -C(H)=, -C(R4)=, or -N=;L1 is a bond or -C(=O)-;L2 is an optionally substituted C4-8 alkylene chain, wherein 1-3 methylene units are optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 1-4 instances of halogen;M is =O or =N(H);W is selected from the group consisting of -N(H)-, -N(R2)-, and ;each R1 is independently selected from the group consisting of H, halogen, optionally substituted C1-5alkyl, and optionally substituted -O-C1-8alkyl, wherein -O-C1-8alkyl is optionally substituted with 1-3 instances of halogen;R2 is selected from the group consisting of optionally substituted C1-5alkyl, optionally substituted 4-7 membered cycloalkyl, optionally substituted 4-7 membered heterocyclyl, wherein C1-5alkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of optionally substituted halogen, C1-3alkyl, optionally substituted 4-7 membered cycloalkyl, optionally substituted 4-7 membered heterocyclyl, and -C(=O)OH;each R3 is H, halogen, or optionally substituted C1-3alkyl;each R4 is H, halogen, or optionally substituted C1-3alkyl;m is selected from the group consisting of 1, 2, 3, 4, and 5;n is selected from the group consisting of 1, 2, 3, and 4; and p is 1 or 2.  2. The compound of claim 1, wherein the compound is a compound of Formula (II):(II),or a pharmaceutically acceptable salt thereof. 3. The compound of claim 1, wherein the compound is a compound of Formula (III):(III),or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein the compound is a compound of Formula (IV):(IV), or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, wherein the compound is a compound of Formula (V):(V),or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, wherein the compound is a compound of Formula (VI):(VI),or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1, wherein the compound is a compound of Formula (VII):(VII),or a pharmaceutically acceptable salt thereof.

8. The compound of any one of claims 1-7, wherein X1 is -N=.

9. The compound of any one of claims 1-7, wherein X1 is -C(R4)=.

10. The compound of claim 9, wherein X1 is -CH=.

11. The compound of claim 9, wherein X1 is -CF=.

12. The compound of any one of claims 1-11, wherein L1 is a bond.

13. The compound of any one of claims 1-11, wherein L1 is -C(=O)-.

14. The compound of any one of claims 1-13, wherein L2 is an optionally substituted C5-6alkylene chain, wherein 1 methylene unit is optionally replaced with -O- or -N(H)-, and wherein L2 is optionally substituted with 2 instances of halogen.

15. The compound of any one of claims 1-13, wherein each R1 is independently -O-C1-8alkyl, wherein -O-C1-8alkyl is optionally substituted with 1-3 instances of halogen.

16. The compound of claim 15, wherein the halogen is fluoro.

17. The compound of any one of claims 1-13, wherein each R1 is independently selected from the group consisting of -CH3, , , , , ..and .

18. The compound of any one of claims 1-17, wherein W is -NR2, wherein R2 is optionally substituted C1-5alkyl, wherein R2 is optionally substituted with 1-3 instances of a substituent independently selected from the group consisting of C1-3alkyl, 4-7 membered cycloalkyl, 4-7 membered heterocyclyl, and -C(=O)OH.

19. The compound of any one of claims 1-17, wherein W is -NR2, and wherein R2 is selected from the group consisting of -CH3, ,, , ,,,,,,, ,,,,,,,,,,,,, , , ,,, ,,,,, ,,,,,, ,,, , ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,, ,, and .

20. The compound of claim 19, wherein R2 is -CH3. 21. The compound of any one of claims 1-20, wherein at least one R3 is -CH3. 22. The compound of any one of claims 1-21, wherein at least one R3 is halogen. 23. The compound of any one of claims 1-22, wherein at least one R4 is halogen. 24. The compound of any one of claims 1-23, wherein m is 1 or 2. 25. The compound of any one of claims 1-24, wherein n is 1 or 2. 26. The compound of any one of claims 1-25, wherein p is 1. 27. The compound of any one of claims 1-26, wherein M is =O. 28. A compound selected from:Compound No.StructureIUPAC name16-[3-(3,3-dimethylbutoxy)phenyl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide26-[3-(3,3-dimethylbutoxy)phenyl]-14-oxa-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide36-[3-(3,3-dimethylbutoxy)-5-fluoro-phenyl]-9,20-dimethyl-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(24),4(26),6,8(13),9,11,21(25),22-octaene 2,2-dioxide43-[6-[3-(3,3-dimethylbutoxy)phenyl]-2,2-dioxo-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]-2,2-dimethyl-propanoic acid53-[2,2-dioxo-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]-2,2-dimethyl-propanoic acid62-[[6-[3-(3,3-dimethylbutoxy)phenyl]-2,2-dioxo-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]-2-methyl-pentanoic acid7(P1)(2R)-2-[[6-[3-(3,3-dimethylbutoxy)phenyl]-2,2-dioxo-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]-2-methyl-pentanoic acid7(P2)(2S)-2-[[6-[3-(3,3-dimethylbutoxy)phenyl]-2,2-dioxo-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]-2-methyl-pentanoic acid82-cyclohexyl-3-[6-[3-(3,3-dimethylbutoxy)phenyl]-2,2-dioxo-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]-2-methyl-propanoic acid91-[[6-[3-(3,3-dimethylbutoxy)phenyl]-2,2-dioxo-2λ6,5-dithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaen-20-yl]methyl]cyclohexanecarboxylic acid106-[3-(3,3-dimethylbutoxy)phenyl]-2λ6,5-dithia-3,20,26-triazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2-dioxide116-[3-(3,3-dimethylbutoxy)phenyl]-2λ6,5,19λ6-trithia-3,20,26-triazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2,19,19-tetraoxide126-[3-(3,3-dimethylbutoxy)phenyl]-2λ6,5,19λ6-trithia-3,20,25,26-tetrazatetracyclo[19.3.1.14,7.08,13]hexacosa-1(25),4(26),6,8,10,12,21,23-octaene 2,2,19,19-tetraoxideor a pharmaceutically acceptable salt thereof. Kindly note that the electronic filing system was unable to accept the complete Claim No. 28 due to the large size of the compound. Accordingly, the full text of Claim No. 28 has been provided in the other attachments for your reference. 29. The compound of any one of claims 1-28, wherein the compound is a CFTR corrector. 30. A pharmaceutical composition comprising a compound of any one of the preceding claims, and one or more pharmaceutically acceptable carriers or excipients. 31. The pharmaceutical composition of claim 30, further comprising one or more CFTR therapeutic agents. 32. A method of treating deficient CFTR activity in a cell, comprising contacting the cell with a compound of any one of claims 1–29, or the pharmaceutical composition of claim 30 or 31. 33. The method of claim 32, wherein contacting the cell occurs in a subject in need thereof, thereby treating a CFTR-mediated condition and / or disease. 34. The method of claim 33, wherein the disease or condition is selected from cystic fibrosis, asthma, smoke induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, I-cell disease / pseudo-Hurler, mucopolysaccharidoses, Sandhof / Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy / hyperinsulemia, Diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders, Huntington's, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, myotonic dystrophy, spongiform encephalopathies, hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, Sjogren's disease, Osteoporosis, Osteopenia, bone healing and bone growth, bone repair, bone regeneration, reducing bone resorption, increasing bone deposition, Gorham's Syndrome, chloride channelopathies, myotonia congenita, Bartter's syndrome type III, Dent's disease, hyperekplexia, epilepsy, hyperekplexia, lysosomal storage disease, Angelman syndrome, Primary Ciliary Dyskinesia (PCD), PCD with situs inversus, PCD without situs inversus and ciliary aplasia. 35. The method of claim 33 or 34, wherein the disease or condition is selected from cystic fibrosis, congenital bilateral absence of vas deferens (CBAVD), acute, recurrent, or chronic pancreatitis, disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis, chronic obstructive pulmonary disease (COPD), chronic sinusitis, dry eye disease, protein C deficiency, Abetalipoproteinemia, lysosomal storage disease, type 1 chylomicronemia, mild pulmonary disease, lipid processing deficiencies, type 1 hereditary angioedema, coagulation-fibrinolyis, hereditary hemochromatosis, CFTR-related metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, and Sjogren's syndrome. 36. The method of any one of claims 33-35, wherein the disease or condition is cystic fibrosis.

37. A method of treating cystic fibrosis in a subject, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-29, or the pharmaceutical composition of claim 30 or 31.

38. The method of claim 37, wherein the subject is human.

39. The method according to claim 37 or 38, wherein said subject is at risk of developing cystic fibrosis, and wherein said administering step is carried out prior to the onset of symptoms of cystic fibrosis in said subject.

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