5-membered heteroaryl aminosulfonamides for the treatment of conditions mediated by lack of cftr activity

Abstract

The present invention relates to heteroaryl compounds, pharmaceutically acceptable salts thereof, and pharmaceutical formulations thereof. Also described herein are compositions and uses of such compounds in methods of treating diseases and conditions mediated by a lack of CFTR activity, particularly cystic fibrosis.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority and benefit to U.S. Provisional Patent Application No. 62 / 934,293, filed November 12, 2019, which is incorporated herein by reference in its entirety. Background Technology

[0003] Cystic fibrosis (CF), an autosomal recessive disorder, is caused by a defect in the function of cAMP-activated cystic fibrosis transmembrane transport regulator (CFTR), which can lead to damage to the lungs, pancreas, and other organs. Genes encoding CFTR have been identified and sequenced (see Gregory, RJ et al. (1990) Nature 347:382-386; Rich, DP et al. (1990) Nature 347:358-362; Riordan, JR et al. (1989) Science 245:1066-1073). CFTR, a member of the ATP-binding cassette (ABC) superfamily, consists of two six-transmembrane domains (MSD1 and MSD2), two nucleotide-binding domains (NBD1 and NBD2), a regulatory region (R), and four cytoplasmic loops (CL1-4). Typically, CFTR proteins are primarily located in the apical membrane of epithelial cells, where they play a role in transducing anions, including chloride, bicarbonate, and thiocyanate, into and out of the cell. CFTRs can also regulate other electrolyte channels, including the epithelial sodium channel ENaC.

[0004] In patients with cystic fibrosis, the absence or dysfunction of the CFTR leads to exocrine gland dysfunction and multisystemic disease characterized by pancreatic insufficiency and malabsorption, as well as abnormal mucociliary clearance in the lungs, mucus accumulation, chronic lung infection and inflammation, decreased lung function, and ultimately respiratory failure.

[0005] Although over 1,900 mutations have been identified in the CFTR gene, only one subgroup is known for a detailed understanding of how each CFTR mutation can affect channel function (Derichs, European Respiratory Review, 22:127, 58-65 (2013)). The most frequent CFTR mutation is an in-frame deletion (ΔF508) of phenylalanine residue 508 in the first nucleotide-binding domain (NBD1). Over 80% of cystic fibrosis patients have a deletion at residue 508 in at least one allele. The loss of this critical phenylalanine residue renders the CFTR NBD1 domain conformationally unstable at physiological temperatures and impairs the integrity of the interdomain interface between NBD1 and the second transmembrane domain (ICL4) of CFTR. The ΔF508 mutation results in a misfolded CFTR protein that is not transported to the plasma membrane but remains in the endoplasmic reticulum and is targeted for degradation by the ubiquitin-proteasome system.

[0006] Loss of functional CFTR channels at the plasma membrane disrupts ion homeostasis and airway surface hydration, leading to decreased lung function. Reduced periciliary fluid volume and increased mucus viscosity hinder mucociliary clearance, resulting in chronic infection and inflammation. In the lungs, loss of CFTR function leads to numerous physiological effects downstream of altered anion transport, which in turn cause dysfunction in additional organs such as the pancreas, intestine, and gallbladder.

[0007] Guided in part by research into the mechanisms of CFTR misfolding and dysfunction, small-molecule CFTR modulators that can increase CFTR channel function have been identified. Although compounds that modulate CFTR have been identified, there is no cure for this deadly disease, thus necessitating the identification of new compounds and treatments, as well as novel approaches to treat cystic fibrosis and other CFTR-mediated disorders and diseases, or to alleviate their severity. Summary of the Invention

[0008] In some respects, this application relates to a compound of formula (I):

[0009]

[0010] Or its pharmaceutically acceptable salt.

[0011] in:

[0012] R 1 Is it hydrogen or C? 1-6 alkyl;

[0013] X is C 1-6Alkyl, 5-6 aryl, 4-10 heterocyclic alkyl or 5-6 heteroaryl, each represented by R 0-3 times. 2 replace;

[0014] Cy 1 It is C 3-9 Cycloalkyl, 5-6 aryl, 4-10 heterocycloalkyl or 5-6 heteroaryl, each represented by R 0-3 times. 3 replace;

[0015] Cy 2 It is C 3-9 Cycloalkyl, 5-6 aryl, 4-10 heterocycloalkyl or 5-6 heteroaryl, each represented by R 1-3 times. 4 replace;

[0016] Each R 2 Independently, it is hydroxyl, halogen, -NH2, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, 4-10 membered heterocyclic alkyl, 5-6 membered heteroaryl, C 3-9 cycloalkyl, C 3-9 Cycloalkoxy, -C(O)NH2, -N(R) a (R) 5 ), -N(R a )C(O)-R 5 -N(R) a SO2-R 5 -SO2-R 5 -C(O)N(R) a (R) 5 ), -S(O)-R 5 -N(R) a )S(O)(NH)-R 5 or -P(O)(R 5 )2, where each C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-9 Cycloalkyl or 4-10 membered heterocyclic alkyl groups are further modified by R appearing 0-3 times. 5 replace;

[0017] Each R 3 Independently, it is a halogen group, C 1-8 Alkyl, C 1-8 alkenyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-8 Halogenated alkoxy groups, C 3-9cycloalkyl, C 1-4 Alkyl-C 3-9 cycloalkyl, C 1-4 Alkoxy-C 3-9 cycloalkyl, C 3-9 Cycloalkoxy, C 3-9 Cycloalkenyl, 5-6 aryl, aralkyl, arylalkoxy, 5-6 heteroaryl, 4-10 heterocycloalkyl, -C(O)-R 7 -C(O)N(R) a (R) 7 ) or -N(R a (R) 8 ), where each C 3-9 cycloalkyl, C 3-9 Cycloalkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Alkoxy, 4-10 membered heterocyclic alkyl, 5-6 membered aryl, 5-6 membered heteroaryl, cycloalkenyl, C 1-4 Alkyl-C 3-9 cycloalkyl or C 1-4 Alkoxy-C 3-9 Cycloalkyl groups are further affected by R appearing 0-3 times. 7 replace;

[0018] Each R 4 Independently, it is a halogen group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, N(R) a )2 or 4-10 membered heterocyclic alkyl groups, wherein each 4-10 membered heterocyclic alkyl group may be further divided by 0-3 R groups. b replace;

[0019] Each R 5 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 3-9 Cycloalkyl, hydroxyl, -SO2-R 6 -CO2H, -NH2, -CO2-C 1-4 Alkyl or 4-10 membered heterocyclic alkyl, wherein each C 1-6 Alkyl, C 3-9 Cycloalkyl or 4-10 membered heterocyclic alkyl groups are further modified by R appearing 0-3 times. 6 replace;

[0020] Each R 6 Independently, it is a hydroxyl group, -NH2 group, halogen group, or C group. 1-4 Alkyl, C 1-4Halogenated alkyl, -CO2H or -CO2-(C 1-4 alkyl);

[0021] Each R 7 Independently, it is a halogen group, C 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Haloalkyl, C 1-5 Halogenated alkoxy groups, C 1-5 Haloalkenyl, C 3-7 Cycloalkyl, hydroxyl, 5-6 aryl, aralkyl, arylalkoxy, -C(O)-OC 1-4 Alkyl, -C(O)N(R) a (C) 1-4 Alkyl), 5-6-membered heteroaryl or 4-10-membered heterocyclic alkyl, wherein each C 3-7 Cycloalkyl, 5-6 aryl, or 4-10 heterocyclic alkyl groups are further modified by R appearing 0-3 times. 8 replace;

[0022] Each R 8 Independently, it is a halogen group, C 1-4 Alkyl, C 1-4 Haloalkoxy, C(O)-C 1-4 Alkyl or C(O)N(R) a (C) 1-4 alkyl);

[0023] Each R a Independently, it is H or C 1-6 Alkyl; and

[0024] Each R b It is C 1-4 alkyl;

[0025] in

[0026] a) If Cy 1 It is a phenyl group, and has R appearing three times. 3 Then each R 3 It is not a methoxy group;

[0027] b) When X and Cy 2 When each is a phenyl group, then R 2 and R 4 Not each of them is a methyl group;

[0028] c)R 3 and R 4 It can be either tert-butyl or methoxy at the same time;

[0029] d) When Cy 1 and Cy 2If X is a monosubstituted phenyl group, then X is not a thiophene group; and

[0030] e) When Cy 1 and Cy 2 When it is a monosubstituted phenyl group, then R 2 Not OH, R 3 It is not Cl, and R 4 It's not OMe.

[0031] This article discloses methods for treating CFTR activity deficiency, thereby treating diseases or disorders mediated by CFTR activity deficiency. Such diseases and disorders include, but are not limited to, cystic fibrosis, congenital bilateral vas deferens agenesis (CBAVD), acute pancreatitis, recurrent or chronic pancreatitis, disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis, congenital pneumonia, malabsorption, celiac disease, nasal polyposis, nontuberculous mycobacterial infection, pancreatic steatorrhea, intestinal atresia, chronic obstructive pulmonary disease (COPD), chronic sinusitis, xerophthalmia, protein C deficiency, abeta-lipoproteinemia, lysosomal storage disease, type 1 chylomicronemia, mild lung disease, lipid processing defects, type 1 hereditary angioedema, coagulation-fibrinolysis, hereditary hemochromatosis, CFTR-related metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, and Sjogren's syndrome. In some implementations, the disease is cystic fibrosis.

[0032] In some embodiments, the present invention provides a pharmaceutical composition suitable for use in subjects to treat or prevent diseases and disorders associated with CFTR activity deficiency, said pharmaceutical composition comprising an effective amount of any compound described herein (e.g., compounds of the present invention, such as compounds of formula (I)) and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical formulation may be used to treat or prevent diseases or disorders as described herein.

[0033] This article provides a combination therapy of compound (I) with CFTR active agent, which enhances the therapeutic benefits beyond the capabilities of primary therapy alone. Detailed Implementation

[0034] In some respects, this application relates to a compound of formula (I):

[0035]

[0036] Or its pharmaceutically acceptable salt.

[0037] in:

[0038] R 1 Is it hydrogen or C? 1-6alkyl;

[0039] X is C 1-6 Alkyl, 5-6 aryl, 4-10 heterocyclic alkyl or 5-6 heteroaryl, each represented by R 0-3 times. 2 replace;

[0040] Cy 1 It is C 3-9 Cycloalkyl, 5-6 aryl, 4-10 heterocycloalkyl or 5-6 heteroaryl, each represented by R 0-3 times. 3 replace;

[0041] Cy 2 It is C 3-9 Cycloalkyl, 5-6 aryl, 4-10 heterocycloalkyl or 5-6 heteroaryl, each represented by R 1-3 times. 4 replace;

[0042] Each R 2 Independently, it is hydroxyl, halogen, -NH2, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, 4-10 membered heterocyclic alkyl, 5-6 membered heteroaryl, C 3-9 cycloalkyl, C 3-9 Cycloalkoxy, -C(O)NH2, -N(R) a (R) 5 ), -N(R a )C(O)-R 5 -N(R) a SO2-R 5 -SO2-R 5 -C(O)N(R) a (R) 5 ), -S(O)-R 5 -N(R) a )S(O)(NH)-R 5 or -P(O)(R 5 )2, where each C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-9 Cycloalkyl or 4-10 membered heterocyclic alkyl groups are further modified by R appearing 0-3 times. 5 replace;

[0043] Each R 3 Independently, it is a halogen group, C 1-8 Alkyl, C 1-8 alkenyl, C 1-8 Alkoxy, C1-8 Haloalkyl, C 1-8 Halogenated alkoxy groups, C 3-9 cycloalkyl, C 1-4 Alkyl-C 3-9 cycloalkyl, C 1-4 Alkoxy-C 3-9 cycloalkyl, C 3-9 Cycloalkoxy, C 3-9 Cycloalkenyl, 5-6 aryl, aralkyl, arylalkoxy, 5-6 heteroaryl, 4-10 heterocycloalkyl, -C(O)-R 7 -C(O)N(R) a (R) 7 ) or -N(R a (R) 8 ), where each C 3-9 cycloalkyl, C 3-9 Cycloalkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Alkoxy, 4-10 membered heterocyclic alkyl, 5-6 membered aryl, 5-6 membered heteroaryl, cycloalkenyl, C 1-4 Alkyl-C 3-9 cycloalkyl or C 1-4 Alkoxy-C 3-9 Cycloalkyl groups are further affected by R appearing 0-3 times. 7 replace;

[0044] Each R 4 Independently, it is a halogen group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, N(R) a )2 or 4-10 membered heterocyclic alkyl groups, wherein each 4-10 membered heterocyclic alkyl group may be further divided by 0-3 R groups. b replace;

[0045] Each R 5 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 3-9 Cycloalkyl, hydroxyl, -SO2-R 6 -CO2H, -NH2, -CO2-C 1-4 Alkyl or 4-10 membered heterocyclic alkyl, wherein each C 1-6 Alkyl, C 3-9 Cycloalkyl or 4-10 membered heterocyclic alkyl groups are further modified by R appearing 0-3 times. 6 replace;

[0046] Each R 6Independently, it is a hydroxyl group, -NH2 group, halogen group, or C group. 1-4 Alkyl, C 1-4 Halogenated alkyl, -CO2H or -CO2-(C 1-4 alkyl);

[0047] Each R 7 Independently, it is a halogen group, C 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Haloalkyl, C 1-5 Halogenated alkoxy groups, C 1-5 Haloalkenyl, C 3-7 Cycloalkyl, hydroxyl, 5-6 aryl, aralkyl, arylalkoxy, -C(O)-OC 1-4 Alkyl, -C(O)N(R) a (C) 1-4 Alkyl), 5-6-membered heteroaryl or 4-10-membered heterocyclic alkyl, wherein each C 3-7 Cycloalkyl, 5-6 aryl, or 4-10 heterocyclic alkyl groups are further modified by R appearing 0-3 times. 8 replace;

[0048] Each R 8 Independently, it is a halogen group, C 1-4 Alkyl, C 1-4 Haloalkoxy, C(O)-C 1-4 Alkyl or C(O)N(R) a (C) 1-4 alkyl);

[0049] Each R a Independently, it is H or C 1-6 Alkyl; and

[0050] Each R b It is C 1-4 alkyl;

[0051] in

[0052] a) If Cy 1 It is a phenyl group, and has R appearing three times. 3 Then each R 3 It is not a methoxy group;

[0053] b) When X and Cy 2 When each is a phenyl group, then R 2 and R 4 Not each of them is a methyl group;

[0054] c)R 3 and R 4 It can be either tert-butyl or methoxy at the same time;

[0055] d) When Cy 1 and Cy 2 If X is a monosubstituted phenyl group, then X is not a thiophene group; and

[0056] e) When Cy 1 and Cy 2 When it is a monosubstituted phenyl group, then R 2 Not OH, R 3 It is not Cl, and R 4 It's not OMe.

[0057] This article discloses the compound of formula (I):

[0058]

[0059] Or its pharmaceutically acceptable salt.

[0060] in:

[0061] R 1 It is hydrogen;

[0062] X is a 5-6 aryl or 5-6 heteroaryl group, each of which is represented by R 0-3 times. 2 replace;

[0063] Cy 1 It is a 5-6 aryl, a 4-10 heterocyclic alkyl, or a 5-6 heteroaryl, each of which is represented by R 0-3 times. 3 replace;

[0064] Cy 2 It is a 5-6 aryl group, which is affected by R 1-3 times. 4 replace;

[0065] Each R 2 Independently, it is a halogen group, -NH2, C 1-6 Alkyl, C 1-8 Haloalkoxy, 5-6 membered heteroaryl, -N(R) a (R) 5 ), -N(R a )C(O)-R 5 -SO-R 5 or -SO2-R 5 ;

[0066] Each R 3 Independently, it is a halogen group, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Halogenated alkoxy groups, C 3-9 cycloalkyl, C 3-9 Cycloalkoxy or 4-10 membered heterocyclic alkyl groups, wherein each C 3-9 cycloalkyl, C3-9 Cycloalkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Alkoxy groups and 4-10 membered heterocyclic alkyl groups are further modified by R groups appearing 0-3 times. 7 replace;

[0067] Each R 4 Independently, it is a halogen group, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups;

[0068] Each R 5 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 3-9 Cycloalkyl, hydroxyl, or -CO2H, wherein each C 1-6 Alkyl or C 3-9 Cycloalkyl groups are further affected by R appearing 0-3 times. 6 replace;

[0069] Each R 6 Independently, it is a halogen group, a hydroxyl group, or a C group. 1-6 Alkyl, -CO2H or -CO2-(C 1-4 alkyl);

[0070] Each R 7 Independently, it is a halogen group, C 1-5 Alkyl, C 1-5 Halogenated alkoxy groups, C 3-7 cycloalkyl and hydroxyl; and

[0071] Each R a Independently, it is H or C 1-6 alkyl.

[0072] In some implementation schemes, R 1 It is H. In some implementations, R 1 It is C 1-6 Alkyl (e.g., methyl or ethyl).

[0073] In some implementations, X is R that appears 0-3 times. 2 Substituted aryl group. In some embodiments, X is R that appears 0-3 times. 2 Substituted phenyl. In some embodiments, X is R that appears 0 times. 2 Substituted phenyl groups.

[0074] In some implementations, X is R that appears once. 2 Substituted phenyl groups. In some embodiments, R 2 It is -NH2. In some implementations, R 2It is a hydroxyl group. In some embodiments, R 2 It is a halogenated group (e.g., fluorinated, chlorolated, or bromine-based). In some embodiments, R 2 It is a nitro group. In some implementations, R 2 It is C 1-6 Alkyl groups (e.g., methoxy, ethoxy, or isopropoxy). In some embodiments, R 2 It is R that appears 0-3 times. 5 Replacement C 1-6 Halogenated alkyl groups (e.g., trifluoromethyl, difluoromethyl, or 2,2,2-trifluoroethyl). In some embodiments, R 2 It is R that appears 0 times. 5 Replacement C 1-6 Halogenated alkyl groups (e.g., trifluoromethyl, difluoromethyl, or 2,2,2-trifluoroethyl). In some embodiments, R 2 It was R that appeared once. 5 Replacement C 1-6 Halogenated alkyl groups (e.g., trifluoromethyl, difluoromethyl, or 2,2,2-trifluoroethyl). In other embodiments, R 5 It is a hydroxyl group.

[0075] In some implementations, X is R that appears once. 2 Substituted phenyl groups. In some embodiments, R 2 It is -C(O)NH2. In some implementations, R 2 It is R that appears 0-3 times. 5 Replacement C 1-6 Halogenated alkoxy groups (e.g., trifluoromethoxy or difluoromethoxy). In some embodiments, R 2 It is R that appears 0 times. 5 Replacement C 1-6 Halogenated alkoxy groups (e.g., trifluoromethoxy or difluoromethoxy). In some embodiments, R 2 It is R that appears 0-3 times. 5 Replacement C 1-6 Alkyl (e.g., methyl or isopropyl). In some embodiments, R 2 It is R that appears 0 times. 5 Replacement C 1-6 Alkyl (e.g., methyl or isopropyl). In some embodiments, R 2 It was R that appeared once. 5 Replacement C 1-6 Alkyl (e.g., methyl or isopropyl). In some embodiments, R 5 It is a hydroxyl group. In some embodiments, R 5 It is -SO2-R 6 In some implementations, R6 It is C 1-4 Alkyl (e.g., methyl). In some embodiments, R 2 It is -S(O)-R 5 In some implementations, R 5 It is C 1-6 Alkyl (e.g., methyl). In some embodiments, R 2 It is -P(O)(R) 5 2. In some implementations, two Rs 5 All are C 1-6 Alkyl (e.g., methyl). In some embodiments, R 2 It is –N(R) a SO2-R 5 In some implementations, R a It is H, and R 5 It is C 1-6 Alkyl (e.g., methyl). In some embodiments, R a It is H, and R 5 It is C 1-6 Halogenated alkyl groups (e.g., trifluoromethyl). In some embodiments, R a It is C 1-6 Alkyl (e.g., methyl), and R 5 It is C 1-6 Alkyl (e.g., methyl). In some embodiments, R a It is C 1-6 Alkyl (e.g., methyl), and R 5 It is C 1-6 Halogenated alkyl groups (e.g., trifluoromethyl). In some embodiments, R 2 Yes - SO2R 5 In some implementations, R 5 It is -NH2.

[0076] In some implementations, X is R that appears once. 2 Substituted phenyl groups. In some embodiments, R... 2 It is R that appears 0-3 times. 5 Substituted heteroaryl groups (e.g., 1-pyrazolyl or 5-pyrazolyl). In some embodiments, R 2 It is R that appears 0 times. 5 Substituted heteroaryl groups (e.g., 1-pyrazolyl or 5-pyrazolyl). In some embodiments, R 2 It is -N(R) a (R) 5 In some implementations, R a It is H, and R 5 It is C 1-6Alkyl (e.g., methyl). In some embodiments, R a It is C 1-6 Alkyl (e.g., methyl), and R 5 It is C 1-6 Alkyl (e.g., methyl). In some embodiments, R a It is H, and R 5 It is C 1-6 Halogenated alkyl groups (e.g., trifluoromethyl or 1,1,1-trifluoroisopropyl). In some embodiments, R a It is H, and R 5 It is R that appears 0-3 times. 6 Substituted heterocyclic alkyl groups (e.g., 3-tetrahydrofuranyl). In some embodiments, R a It is H, and R 5 It is R that appears 0 times. 6 Substituted heterocyclic alkyl groups (e.g., 3-tetrahydrofuranyl). In some embodiments, R a It is H, and R 5 It is further R that appears 0-3 times. 6 Replacement C 3-9 Cycloalkyl (e.g., cyclobutyl or cyclopentyl). In some embodiments, R a It is H, and R 5 It is further R that appears 0 times. 6 Replacement C 3-9 Cycloalkyl (e.g., cyclobutyl or cyclopentyl). In some embodiments, R a It is H, and R 5 It is further R that appears once. 6 Replacement C 3-9 Cycloalkyl (e.g., cyclobutyl or cyclopentyl). In some embodiments, R 6 It is -CO2H. In some implementations, R 6 It is -C(O)2-C 1-4 Alkyl groups (e.g., -CO2Me or -CO2Et). In some embodiments, R a It is H, and R 5 It is further R that appears twice 6 Replacement C 3-9 Cycloalkyl (e.g., cyclobutyl or cyclopentyl). In some embodiments, R appears only once. 6 It is a hydroxyl group, and it appears again as C. 1-4 Alkyl (e.g., methyl).

[0077] In some implementations, X is R that appears once. 2 Substituted phenyl groups. In some embodiments, R 2 It is -N(R) a)C(O)-R 5 In some implementations, R a It is H, and R 5 It is R that appears 0-3 times. 6 Replacement C 1-6 Alkyl (e.g., methyl, ethyl, or isopropyl). In some embodiments, R a It is H, and R 5 It is R that appears 0 times. 6 Replacement C 1-6 Alkyl (e.g., methyl, ethyl, or isopropyl). In some embodiments, R a It is H, and R 5 It was R that appeared once. 6 Replacement C 1-6 Alkyl (e.g., methyl, ethyl, or isopropyl). In some embodiments, R 6 It is -NH2. In some implementations, R 6 It is a hydroxyl group. In some embodiments, R a It is H, and R 5 It is C 1-6 Halogenated alkyl groups (e.g., trifluoromethyl). In some embodiments, R a It is H, and R 5 It is R that appears 0-3 times. 6 Replacement C 3-9 Cycloalkyl (e.g., cyclopropyl). In some embodiments, R a It is H, and R 5 It is R that appears 0 times. 6 Replacement C 3-9 Cycloalkyl (e.g., cyclopropyl). In some embodiments, R a It is H, and R 5 It was R that appeared once. 6 Replacement C 3-9 Cycloalkyl (e.g., cyclopropyl). In some embodiments, R 6 It is a halogenated group (e.g., a fluorinated group). In some embodiments, R 6 It is C 1-4 Halogenated alkyl groups (e.g., trifluoromethyl groups).

[0078] In some implementation schemes, R 2 It is R that appears 0-3 times. 5 Substituted heterocyclic alkyl groups (e.g., N-pyrrolidinyl). In some embodiments, R 2 It is R that appears 0 times. 5 Substituted heterocyclic alkyl groups (e.g., N-pyrrolidinyl). In some embodiments, R 2 It was R that appeared once. 5Substituted heterocyclic alkyl groups (e.g., N-pyrrolidinyl). In some embodiments, R 5 It is R that appears 0-3 times. 6 Replacement C 1-6 Alkyl (e.g., methyl). In some embodiments, R 5 It is R that appears 0 times. 6 Replacement C 1-6 Alkyl (e.g., methyl). In some embodiments, R 2 It is -C(O)-N(R) a (R) 5 In some implementations, R a It is H, and R 5 It is R that appears 0-3 times. 6 Replacement C 1-6 Alkyl (e.g., methyl or ethyl). In some embodiments, R a It is H, and R 5 It is R that appears 0 times. 6 Replacement C 1-6 Alkyl (e.g., methyl or ethyl). In some embodiments, R a It is H, and R 5 It was R that appeared once. 6 Replacement C 1-6 Alkyl (e.g., methyl or ethyl). In some embodiments, R 6 It is a hydroxyl group. In some embodiments, R 2 It is -N(R) a )S(O)(NH)-R 5 In some implementations, R a It is H, and R 5 It is R that appears 0-3 times. 6 Replacement C 1-6 Alkyl (e.g., methyl). In some embodiments, R a It is H, and R 5 It is R that appears 0 times. 6 Replacement C 1-6 Alkyl (e.g., methyl).

[0079] In some implementations, X is

[0080] In some implementations, X is R that appears twice. 2 Substituted phenyl groups. In some embodiments, each R... 2 It is a halogen group (e.g., fluorine or chlorine). In some embodiments, each R2 It is fluorine-based. In some implementations, each R... 2 It is a chlorine group. In some implementations, an R 2 It is -NH2, and an R 2 It is a halogenated group (e.g., a fluorinated group). In some embodiments, an R 2 It is C 1-6 Alkyl (e.g., methyl), and another R 2 It is C 1-6 Halogenated alkyl groups (e.g., difluoromethyl). In some embodiments, an R 2 It is a halogen group (e.g., a fluorine group), and another R 2 It is -N(R) a (R) 5 (e.g., -NHMe). In some implementations, R a It is H, and R 5 It is C 1-6 Alkyl (e.g., methyl). In some embodiments, R a It is H, and R 5 It is further R that appears 0-3 times. 6 Replacement C 3-9 Cycloalkyl (e.g., cyclopentyl). In some embodiments, R a It is H, and R 5 It is further R that appears once. 6 Replacement C 3-9 Cycloalkyl (e.g., cyclopentyl). In some embodiments, R 6 It is C 1-6 Alkyl (e.g., methyl). In some embodiments, R a It is H, and R 5 It is further R that appears 0-3 times. 6 Substituted heterocyclic alkyl groups (e.g., 3-pyrrolidinyl). In some embodiments, R a It is H, and R 5 It is further R that appears once. 6 Substituted heterocyclic alkyl groups (e.g., 3-pyrrolidinyl). In some embodiments, R 6 It is C 1-4 Alkyl (e.g., methyl).

[0081] In some implementation schemes, X is

[0082] In some implementations, X is R that appears 3 times. 2 Substituted phenyl groups. In some embodiments, the two R groups... 2 It is a halogen group (e.g., a fluorine group), and the remaining R2 It is -NH2. In some implementations, X is...

[0083] In some implementations, X is R that appears 0-3 times. 2 Substituted 5-6 membered heteroaryl groups. In some embodiments, X is selected from R that appears 0-3 times. 2 Substituted pyridyl, pyrazolyl, isoxazolyl, pyrazolyl, indolyl, thiazolyl, thiophenyl, or furanyl.

[0084] In some implementations, X is R that appears 0-3 times. 2 Substituted 2-pyridyl group. In some embodiments, X is R that appears 0 times. 2 Substituted 2-pyridyl group.

[0085] In some implementations, X is R that appears once. 2 Substituted 2-pyridyl. In some embodiments, wherein R 2 It is -NH2. In some implementations, R 2 It is a halogenated group (e.g., fluorinated or chlorinated). In some embodiments, R 2 It is R that appears 0-3 times. 5 Replacement C 1-6 Alkyl groups (e.g., methoxy or isopropoxy). In some embodiments, R 2 It is R that appears 0 times. 5 Replacement C 1-6 Alkyl groups (e.g., methoxy, ethoxy, or isopropoxy). In some embodiments, R 2 It was R that appeared once. 5 Replacement C 1-6 Alkyl groups (e.g., methoxy, ethoxy, or isopropoxy). In some embodiments, R 5 It is R that appears 0-3 times. 6 Replacement C 3-9 Cycloalkyl (e.g., cyclopropyl or cyclobutyl). In some embodiments, R 5 It was R that appeared once. 6 Replacement C 3-9 Cycloalkyl (e.g., cyclopropyl or cyclobutyl). In some embodiments, R 6 It is C 1-4 Halogenated alkyl groups (e.g., trifluoromethyl). In some embodiments, R 5 It was R that appeared twice. 6 Replacement C 3-9 Cycloalkyl (e.g., cyclopropyl or cyclobutyl). In some embodiments, the two R... 6 They are all halogen groups (e.g., fluorine groups).

[0086] In some implementation schemes, R 2 It is -N(R) a SO2-R 5 In some implementations, R a It is H, and R 5 It is R that appears 0-3 times. 6 Replacement C 1-6 Alkyl (e.g., methyl). In some embodiments, R a It is H, and R 5 It is R that appears 0 times. 6 Replacement C 1-6 Alkyl (e.g., methyl). In some embodiments, R 2 It is -N(R) a )C(O)-R 5 In some implementations, R a It is H, and R 5 It is R that appears 0-3 times. 6 Replacement C 1-6 Alkyl (e.g., methyl or isopropyl). In some embodiments, R a It is H, and R 5 It is R that appears 0 times. 6 Replacement C 1-6 Alkyl groups (e.g., methyl or isopropyl).

[0087] In some implementation schemes, R 2 It is -N(R) a (R) 5 In some implementations, R a It is H, and R 5 It is R that appears 0-3 times. 6 Replacement C 1-6 Alkyl (e.g., methyl or neopentyl). In some embodiments, R a It is H, and R 5 It is R that appears 0 times. 6 Replacement C 1-6 Alkyl (e.g., methyl or neopentyl). In some embodiments, R a It is H, and R 5 It was R that appeared once. 6 Replacement C 1-6 Alkyl (e.g., methyl or neopentyl). In some embodiments, R 6 It is -CO2H. In some implementations, R 6 It is -CO2-C 1-4 Alkyl groups (e.g., -CO2Me or -CO2Et). In some embodiments, R a It is C 1-6Alkyl (e.g., methyl or ethyl), and R 5 It is R that appears 0-3 times. 6 Replacement C 1-6 Alkyl (e.g., methyl or isopropyl). In some embodiments, R a It is C 1-6 Alkyl (e.g., methyl or ethyl), and R 5 It is R that appears 0 times. 6 Replacement C 1-6 Alkyl (e.g., methyl or isopropyl). In some embodiments, R a It is H, and R 5 It is R that appears 0-3 times. 6 Replacement C 3-9 Cycloalkyl (e.g., cyclopropyl or cyclopentyl). In some embodiments, R a It is H, and R 5 It is R that appears 0 times. 6 Replacement C 3-9 Cycloalkyl (e.g., cyclopropyl or cyclopentyl). In some embodiments, R a It is H, and R 5 It was R that appeared once. 6 Replacement C 3-9 Cycloalkyl groups (e.g., cyclopropyl, cyclohexyl, or cyclopentyl). In some embodiments, R 6 It is -CO2H. In some implementations, R 6 It is -CO2-C 1-4 Alkyl groups (e.g., -CO2Me or -CO2Et). In some embodiments, R a It is H, and R 5 It is R that appears 0-3 times. 6 Replacement C 1-6 Halogenated alkyl groups (e.g., 1,1,1-trifluoroisopropyl). In some embodiments, R a It is H, and R 5 It is R that appears 0 times. 6 Replacement C 1-6 Halogenated alkyl groups (e.g., 1,1,1-trifluoroisopropyl). In some embodiments, R a It is C 1-6 Alkyl (e.g., methyl), and R 5 It is R that appears 0-3 times. 6 Replacement C 1-6 Halogenated alkyl groups (e.g., 2,2,2-trifluoroethyl). In some embodiments, R a It is C 1-6 Alkyl (e.g., methyl), and R 5 It is R that appears 0 times. 6 Replacement C1-6 Halogenated alkyl groups (e.g., 2,2,2-trifluoroethyl). In some embodiments, R 2 It is R that appears 0 times. 5 Replacement C 3-9 Cycloalkoxy (e.g., cyclopropoxy). In some embodiments, R 2 It is C 1-6 Haloalkoxy groups (e.g., trifluoromethyl, 2,2-difluoroethyl, 1,1,1-trifluoroisopropyl, 1,1,1-trifluorotert-butyl, or 1,3-difluoroisopropyl). In some embodiments, R 2 It is R that appears 0-3 times. 5 Replacement C 3-9 Cycloalkyl (e.g., cyclopentyl or cyclohexyl). In some embodiments, R 2 It was R that appeared once. 5 Replacement C 3-9 Cycloalkyl (e.g., cyclopentyl or cyclohexyl). In some embodiments, R 5 It is -CO2H. In some implementations, R 5 It is -CO2-R 6 In some implementations, R 6 It is C 1-4 Alkyl (e.g., methyl).

[0088] In some implementation schemes, R 2 It is R that appears 0-3 times. 5 Substituted heterocyclic alkyl groups (e.g., azahexacyclic butyl, pyrrolidinyl, piperidinyl, or morpholinyl). In some embodiments, R 2 It is R that appears 0 times. 5 Substituted heterocyclic alkyl groups (e.g., azahexacyclic butyl, pyrrolidinyl, piperidinyl, or morpholinyl). In some embodiments, R 2 It was R that appeared twice. 5 Substituted heterocyclic alkyl groups (e.g., azahexacyclic butyl, pyrrolidinyl, piperidinyl, or morpholinyl). In some embodiments, the R appears twice. 5 Both are halogen groups (e.g., fluorine groups). In some embodiments, the R appears twice. 5 All were R that appeared 0-3 times. 6 Replacement C 1-6 Alkyl (e.g., methyl). In some embodiments, the R appears twice. 5 All were R that appeared 0 times. 6 Replacement C 1-6 Alkyl (e.g., methyl). In some embodiments, R appears only once. 5 It is -CO2H, and R appears again. 5 It is further R that appears 0-3 times. 6Replacement C 1-6 Alkyl (e.g., methyl). In some embodiments, R appears only once. 5 It is -CO2H, and R appears again. 5 It is further R that appears 0 times. 6 Replacement C 1-6 Alkyl (e.g., methyl). In some embodiments, R appears only once. 5 It is -CO2-C 1-4 Alkyl groups (e.g., -CO2Me), and another R that appears 5 It is further R that appears 0-3 times. 6 Replacement C 1-6 Alkyl (e.g., methyl). In some embodiments, R appears only once. 5 It is -CO2-C 1-4 Alkyl groups (e.g., -CO2Me), and another R that appears 5 It is further R that appears 0 times. 6 Replacement C 1-6 Alkyl (e.g., methyl).

[0089] In some implementation schemes, X is

[0090]

[0091] In some implementations, X is R that appears twice. 2 Substituted 2-pyridyl. In some embodiments, an R 2 It is -NH2, and another R 2 It is a halogenated group (e.g., a fluorinated group). In some embodiments, an R 2 It is a hydroxyl group, and another R 2 It is a halogen group (e.g., a fluorine group).

[0092] In some implementation schemes, X is

[0093] In some implementations, X is R that appears 0-3 times. 2 The substituted 3-pyrazolyl group. In some embodiments, X is R that appears 0 times. 2 The substituted 3-pyrazolyl group. In some embodiments, X is replaced by R appearing only once. 2 The substituted 3-pyrazolyl group. In some embodiments, R 2 It is C 1-6 Alkyl (e.g., methyl). In some embodiments, X is...

[0094] In some implementations, X is R that appears 0-3 times. 2 The substituted 4-isooxazolyl group. In some embodiments, X is R that appears 0 times. 2 Substituted 4-isooxazolyl group.

[0095] In some implementations, X is R that appears twice. 2 The substituted 4-isooxazolyl group. In some embodiments, each R 2 C is independent 1-6 Alkyl (e.g., methyl). In some embodiments, X is...

[0096] In some implementations, X is R that appears 0-3 times. 2 Substituted 3-pyridyl group. In some embodiments, X is R that appears 0 times. 2 Substituted 3-pyridyl group.

[0097] In some implementations, X is R that appears once. 2 Substituted 3-pyridyl. In some embodiments, R 2 It is -NH2. In some implementations, R 2 It is C 1-6 Alkyl groups (e.g., methoxy groups). In some embodiments, R 2 It is -N(R) a SO2-R 5 In some implementations, R a It is H, and R 5 It is R that appears 0-3 times. 6 Replacement C 1-6 Alkyl (e.g., methyl). In some embodiments, R a It is H, and R 5 It is R that appears 0 times. 6 Replacement C 1-6 Alkyl (e.g., methyl). In some embodiments, R 2 It is R that appears 0-3 times. 5 Substituted heterocyclic alkyl groups (e.g., N-oxoheterobutylene). In some embodiments, R 2 It is R that appears 0 times. 5 Substituted heterocyclic alkyl groups (e.g., N-oxoheterobutylene). In some embodiments, R 2 It is R that appears 0 times. 5 Substituted N-oxoheterobutylene.

[0098] In some implementation schemes, X is or

[0099] In some implementations, X is R that appears 0-3 times. 2 The substituted 5-thiazolyl group. In some embodiments, X is R that appears 0 times. 2 The substituted 5-thiazolyl group. In some embodiments, X is represented by R appearing only once. 2 The substituted 5-thiazolyl group. In some embodiments, R 2 It is -NH2. In some implementations, R 2 It is a halogenated group (e.g., a chlorinated group). In some embodiments, R 2 It is -N(R) a (R) 5 In some implementations, R a It is H, and R 5 It is R that appears 0 times. 6 Replacement C 1-6 Alkyl group. In some embodiments, R 2 Yes -NHEt. In some implementations, R a It is H, and R 5 It was R that appeared once. 6 Replacement C 1-6 Alkyl (e.g., methyl or ethyl). In some embodiments, R 6 It is a hydroxyl group. In some embodiments, R 2 yes

[0100] In some implementation schemes, X is

[0101] In some implementations, X is R that appears 0-3 times. 2 The substituted 4-pyrazolyl group. In some embodiments, X is R that appears 0 times. 2 The substituted 4-pyrazolyl group. In some embodiments, X is replaced by R appearing only once. 2 The substituted 4-pyrazolyl group. In some embodiments, R 2 It is C 1-6 Halogenated alkyl groups (e.g., difluoromethyl). In some embodiments, R 2 It is R that appears 0-3 times. 5 Substituted heterocyclic alkyl groups (e.g., 3-tetrahydrofuranyl). In some embodiments, R 2 It is R that appears 0 times. 5 Substituted heterocyclic alkyl groups (e.g., 3-tetrahydrofuranyl).

[0102] In some implementation schemes, X is

[0103] In some implementations, X is R that appears twice. 2The substituted 4-pyrazolyl group. In some embodiments, each R 2 C is independent 1-6 Alkyl (e.g., methyl). In some embodiments, an R 2 It is C 1-6 Alkyl (e.g., methyl), and another R 2 It is C 1-6 Halogenated alkyl groups (e.g., 1,1,1-trifluoroisopropyl).

[0104] In some implementation schemes, X is

[0105] In some implementations, X is R that appears 0-3 times. 2 Substituted 6-indole group. In some embodiments, X is R that appears 0 times. 2 Substituted 6-indolyl.

[0106] In some implementations, X is R that appears 0-3 times. 2 Substituted 4-pyridyl group. In some embodiments, X is R that appears 0 times. 2 Substituted 4-pyridyl group.

[0107] In some implementations, X is R that appears once. 2 Substituted 4-pyridyl. In some embodiments, R 2 It is -NH2. In some implementations, R 2 It is -N(R) a (R) 5 In some implementations, R a It is C 1-6 Alkyl (e.g., methyl), and R 5 It is R that appears 0-3 times. 6 Replacement C 1-6 Alkyl (e.g., methyl). In some embodiments, R a It is C 1-6 Alkyl (e.g., methyl), and R 5 It is R that appears 0 times. 6 Replacement C 1-6 Alkyl (e.g., methyl). In some embodiments, R 2 It is -N(R) a )C(O)-R 5 In some implementations, R a It is H, and R 5 It is R that appears 0-3 times. 6 Replacement C 1-6 Alkyl (e.g., methyl). In some embodiments, R a It is H, and R 5It is R that appears 0 times. 6 Replacement C 1-6 Alkyl (e.g., methyl). In some embodiments, R 2 It is R that appears 0-3 times. 5 Substituted heterocyclic alkyl groups (e.g., N-pyrrolidinyl). In some embodiments, R 2 It is R that appears 0 times. 5 Substituted heterocyclic alkyl groups (e.g., N-pyrrolidinyl alkyl groups).

[0108] In some implementation schemes, X is or

[0109] In some implementations, X is R that appears twice. 2 Substituted 4-pyridyl. In some embodiments, an R 2 It is -NH2, and another R 2 It is a hydroxyl group.

[0110] In some implementations, X is R that appears 0-3 times. 2 The substituted 4-thiazolyl group. In some embodiments, X is R that appears 0 times. 2 Substituted 4-thiazolyl group.

[0111] In some implementations, X is R that appears once. 2 The substituted 4-thiazolyl group. In some embodiments, R 2 It is -NH2. In some implementations, X is...

[0112] In some implementations, X is R that appears 0-3 times. 2 Substituted 3-thiazolyl group.

[0113] In some implementations, X is R that appears 0-3 times. 2 Substituted 3-thiophene group. In some embodiments, X is R that appears 0 times. 2 Substituted 3-thiophene group.

[0114] In some implementations, X is R that appears once. 2 Substituted 3-thiophene group. In some embodiments, R 2 It is a nitro group. In some implementations, R 2 It is -NH2. In some implementations, X is...

[0115] In some implementations, Cy 2 yes

[0116] In some implementations, Cy 2 It is R that appears 1-3 times 4 Substituted aryl group. In some embodiments, Cy 2 It is R that appears 1-3 times 4 Substituted phenyl groups. In some embodiments, Cy 2 It was R that appeared once. 4 Substituted phenyl groups. In some embodiments, R 4 It is C 1-6 Alkyl (e.g., methyl or isopropyl), C 1-6 Halogenated alkyl groups (e.g., trifluoromethyl, difluoromethyl, 2-fluoroisopropyl, or fluoromethyl), C 1-6 Alkoxy (e.g., methoxy, isopropoxy, or 3,3-dimethylbutoxy), C 1-6 Halogenated alkoxy groups (e.g., trifluoromethoxy groups) or C 3-6 Cycloalkyl (e.g., cyclopropyl). In some embodiments, Cy 2 yes

[0117] In some implementations, Cy 2 It was R that appeared twice. 4 Substituted phenyl groups. In some embodiments, the two R groups... 4 All are C 1-6 Alkyl (e.g., methyl). In some embodiments, the two R... 4 Both are halogen groups (e.g., fluorine or chlorine). In some embodiments, the two R groups... 4 All are C 1-6 Halogenated alkyl groups (e.g., trifluoromethyl or difluoromethyl). In some embodiments, an R 4 It is C 1-6 Alkyl (e.g., methyl), and an R 4 It is C 1-6 Alkyl groups (e.g., isopropoxy groups). In some embodiments, an R 4 It is C 1-6 Alkyl groups (e.g., isopropoxy groups), and an R 4 It is a halogen group (e.g., fluorine or chlorine). In some embodiments, an R 4 It is C 1-6 Halogenated alkoxy groups (e.g., trifluoromethoxy, 1,1,1-trifluoroisopropoxy, or difluoromethoxy), and an R 4 It is a halogenated group (e.g., fluorinated or chlorinated). In some embodiments, an R 4 It is C 1-6Alkyl (e.g., methyl), and an R 4 It is a halogenated group (e.g., fluorinated or chlorinated). In some embodiments, an R 4 It is C 1-6 Alkyl groups (e.g., isopropoxy groups), and an R 4 It is C 1-6 Alkyl (e.g., methyl). In some embodiments, an R 4 It is C 1-6 Halogenated alkyl group (e.g., trifluoromethyl, difluoromethyl, or 1,1,1-trifluoropropane-2-yl), and an R 4 It is a halogenated group (e.g., fluorinated or chlorinated). In some embodiments, an R 4 It is C 1-6 Alkyl groups (e.g., isopropoxy or 3,3-dimethylbutoxy), and an R 4 It is C 1-6 Halogenated alkyl groups (e.g., trifluoromethyl). In some embodiments, an R 4 It is C 1-6 Alkyl (e.g., methyl), and an R 4 It is C 1-6 Halogenated alkyl groups (e.g., trifluoromethyl or difluoromethyl). In some embodiments, an R 4 It is -N(R) a )2 (e.g., -N(CH3)2), and an R 4 It is a halogenated group (e.g., a fluorinated group). In some embodiments, Cy 2 yes

[0118] In some implementations, Cy 2 It was R that appeared 3 times. 4 Substituted phenyl groups. In some embodiments, the two R groups... 4 It is C 1-6 Alkyl (e.g., methyl), and an R 4 It is C 1-6 Halogenated alkyl groups (e.g., trifluoromethyl). In some embodiments, Cy 2 yes

[0119] In some implementations, Cy 2 It is R that appears 1-3 times 4 Substituted 5-6 membered heteroaryl groups. In some embodiments, Cy 2 It is R that appears 1-3 times 4 Substituted 3-pyridyl. In some embodiments, Cy 2 It was R that appeared once. 4 Substituted 3-pyridyl. In some embodiments, R4 It is R that appears 0-3 times. b Substituted 4-10 membered heterocyclic alkyl groups. In some embodiments, R 4 It is R that appears 0-3 times. b Substituted N-pyrroloalkyl. In some embodiments, R 4 It was R that appeared 3 times. b (e.g., methyl)-substituted N-pyrrolidinyl. In some embodiments, Cy 2 yes

[0120] In some implementations, Cy 2 It is R that appears 1-3 times 4 The substituted 3-pyrazolyl group. In some embodiments, Cy 2 It was R that appeared once. 4 The substituted 3-pyrazolyl group. In some embodiments, R 4 It is C 1-6 Alkyl groups (e.g., isopropyl). In some embodiments, Cy 2 It was R that appeared twice. 4 The substituted 3-pyrazolyl group. In some embodiments, an R 4 It is C 1-6 Alkyl (e.g., isopropyl), and an R 4 It is C 1-6 Halogenated alkyl groups (e.g., trifluoroalkyl groups). In some embodiments, Cy 2 yes

[0121] In some implementations, Cy 1 It is R that appears 0-3 times. 3 Substituted aryl group. In some embodiments, Cy 1 It is R that appears 0-3 times. 3 Substituted phenyl groups. In some embodiments, Cy 1 It is R that appears 0 times. 3 Substituted phenyl groups. In some embodiments, Cy 1 It was R that appeared once. 3 Substituted phenyl groups. In some embodiments, R 3 It is R that appears 0 times. 7 Replacement C 1-8 Alkyl (e.g., o-isopropyl). In some embodiments, R 3 It is R that appears 0 times. 7 Replacement C 1-8Halogenated alkyl groups (e.g., m-trifluoromethyl, m-1,1-difluoro-3,3-dimethylbutyl, or m-1,1-difluoro-4,4-dimethylpentyl). In some embodiments, R 3 It is R that appears 0 times. 7 Replacement C 1-8 Alkoxy groups (e.g., m-methoxy, m-3,3-dimethylbutoxy, p-3,3-dimethylbutoxy, m-neopentyloxy, m-2-ethylbutoxy, m-(4,4-dimethylpentan-2-yl)oxy, or m-(3,3-dimethylpentyl)oxy). In some embodiments, Cy 1 yes

[0122] In some implementation schemes, R 3 It was R that appeared once. 7 Replacement C 1-8 Alkyl groups (e.g., methoxy or ethoxy). In some embodiments, R 3 It was R that appeared once. 7 Substituted methoxy group. In some embodiments, R 7 It is further R that appears 0 times. 8 Substituted 5-6-membered heteroaryl groups (e.g., 5-thiazolyl). In some embodiments, R 7 It was R that appeared once. 8 Substituted 4-10 membered heterocyclic alkyl groups (e.g., 2-azacyclobutane). In some embodiments, R 8 It is C 1-4 Alkyl (e.g., isopropyl), C(O)(C) 1-4 Alkyl groups (e.g., C(O)-tert-butyl) or C(O)N(R) a (C) 1-4 Alkyl groups (e.g., C(O)-NH-tert-butyl). In some embodiments, R 3 It was R that appeared once. 7 Substituted ethoxy group. In some embodiments, R 7 It is R that appears 0 times. 8 Substituted heterocyclic alkyl groups (e.g., N-morpholino). In some embodiments, Cy 1 yes

[0123] In some implementation schemes, R 3 It is R that appears 0 times. 7 Replacement C 1-8Halogenated alkoxy groups (e.g., m-trifluoromethoxy, m-2,2,2-trifluoroethoxy, m-3,3,3-trifluoropropoxy, m-3,3,3-trifluoro-2-methylpropoxy, m-4,4,4-trifluoro-3-methylbutoxy, m-3,3,3-trifluoro-2,2-dimethylpropoxy, m-2-fluoro-3,3-dimethylbutoxy, m-1,1-difluoro-3,3-dimethylbutoxy, or m-2,2-difluoro-3,3-dimethylbutoxy). In some embodiments, R 3 It is further R that appears 0-3 times. 7 Replacement C 3-9 Cycloalkyl (e.g., cyclopentyl). In some embodiments, Cy 1 yes

[0124] In some implementation schemes, R 3 It was R that appeared once. 7 Substituted meta-cyclopentyl or para-cyclopentyl. In some embodiments, R 7 It is C 1-4 Halogenated alkoxy groups (e.g., trifluoromethoxy). In some embodiments, R 7 It is C 1-4 Halogenated alkyl groups (e.g., 1,1-difluoroethyl or 2,2-difluoropropyl). In some embodiments, R 3 It was R that appeared twice. 7 Substituted meta-cyclopentyl. In some embodiments, the two R... 7 All are C 1-4 Alkyl groups (e.g., methyl groups). In some embodiments, Cy 1 yes

[0125] In some implementation schemes, R 3 It is further R that appears 0-3 times. 7 Replacement C 3-9 Cycloalkoxy (e.g., cyclopentoxy). In some embodiments, R 3 It was R that appeared once. 7 Substituted meta-cyclopentyloxy group. In some embodiments, R 7 It is C 1-4 Alkyl (e.g., methyl). In some embodiments, R 3 It was R that appeared twice. 7 Substituted meta-cyclopentyloxy group. In some embodiments, the two R groups... 7 All are C 1-4 Alkyl groups (e.g., methyl groups). In some embodiments, Cy 1 yes

[0126] In some implementation schemes, R 3 It is R that appears 0-3 times. 7 Replacement C 1-4 Alkyl-C 3-9 Cycloalkyl groups (e.g., cyclopentylmethyl). In some embodiments, R 3 It was R that appeared 3 times. 7 Substituted cyclopentylmethyl. In some embodiments, the two R... 7 It is a halogen group (e.g., a fluorine group), and another R 7 It is a hydroxyl group. In some embodiments, R 3 It is R that appears 0-3 times. 7 Replacement C 1-4 Alkoxy-C 3-9 Cycloalkyl groups (e.g., cyclohexylmethoxy, cyclopropylmethoxy, or 2-cyclopropylethoxy). In some embodiments, R 3 It was R that appeared once. 7 Substituted cyclopropyl methoxy. In some embodiments, R 7 It is C 1-4 Alkyl (e.g., methyl). In some embodiments, R 7 It is C 1-4 Halogenated alkyl groups (e.g., trifluoromethyl). In some embodiments, R 3 It was R that appeared once. 7 Substituted 2-cyclopropylethoxy. In some embodiments, R 7 It is C 1-4 Halogenated alkyl groups (e.g., trifluoromethyl). In some embodiments, R 3 It was R that appeared twice. 7 Substituted cyclohexylmethoxy. In some embodiments, the two R... 7 All are halogenated (e.g., fluorinated). In some embodiments, Cy 1 yes or

[0127] In some implementation schemes, R 3 It is R that appears 0-3 times. 7 Substituted heteroaryl groups (e.g., 3-isooxazolyl). In some embodiments, R 3 It is R that appears 0 times. 7 Substituted heteroaryl groups (e.g., 3-isooxazolyl). In some embodiments, R 3 It was R that appeared once. 7 Substituted heteroaryl groups (e.g., 3-isooxazolyl). In some embodiments, R 7 It is C 1-4Halogenated alkyl groups (e.g., trifluoromethyl). In some embodiments, R 3 It is -C(O)-R 7 In some implementations, R 7 It is R that appears 0-3 times. 8 Substituted heterocyclic alkyl groups (e.g., N-pyrrolidinyl). In some embodiments, R 7 It is R that appears 0 times. 8 Substituted heterocyclic alkyl groups (e.g., N-pyrrolidinyl). In some embodiments, R 7 It was R that appeared once. 8 Substituted heterocyclic alkyl groups (e.g., N-pyrrolidinyl). In some embodiments, R 8 It is C 1-4 Halogenated alkoxy groups (e.g., trifluoromethoxy). In some embodiments, R 7 It was R that appeared twice. 8 Substituted heterocyclic alkyl groups (e.g., N-pyrrolidinyl alkyl groups). In some embodiments, each R 8 It is a halogenated group (e.g., a fluorinated group). In some embodiments, Cy 1 yes or

[0128] In some implementations, Cy 1 It was R that appeared twice. 3 Substituted phenyl groups. In some embodiments, an R... 3 It is a halogen group (e.g., fluorine or chlorine), and another R 3 It is further R that appears 0 times. 7 Replacement C 1-8 Alkoxy groups (e.g., methoxy, ethoxy, 3,3-dimethylbutoxy, 2,3-dimethylbutoxy, neopentyloxy, (3-methylbutyl-2-yl)oxy, 2,3,3-trimethylbutoxy, or (4,4-dimethylpentan-2-yl)oxy). In some embodiments, Cy 1 yes

[0129] In some implementations, an R 3 It is a halogen group (e.g., fluorine or chlorine), and another R 3 It was R that appeared once. 7 Replacement C 1-8 Alkyloxy (e.g., isopentyloxy, 2,3,3'-trimethylbutoxy, or 2,3'-dimethylbutoxy). In some embodiments, R 7 It is a hydroxyl group. In some embodiments, Cy 1 yes or

[0130] In some implementations, an R 3 It is a halogen group (e.g., fluorine or chlorine), and another R 8 It was R that appeared twice. 7 Replacement C 1-8 Alkyl groups (e.g., propoxy or 2,3-dimethylbutoxy). In some embodiments, the two R groups... 7 All are hydroxyl groups. In some embodiments, one R 7 It is a hydroxyl group, and another R 7 It is -C(O)-OC 1-4 Alkyl groups (e.g., -CO2Me). In some embodiments, Cy 1 yes

[0131] In some implementations, an R 3 It is a halogen group (e.g., fluorine or chlorine), and another R 3 It is R that appears 0 times. 7 Replacement C 1-8 Alkyl groups (e.g., methyl, ethyl, isobutyl, or neopentyl). In some embodiments, Cy 1 yes

[0132] In some implementations, an R 3 It is a halogen group (e.g., fluorine or chlorine), and another R 3 It is R that appears 0 times. 7 Replacement C 1-8 Halogenated alkoxy groups (e.g., trifluoromethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy, 2,2-difluoro-3,3-dimethylbutoxy, or 3,3,3-trifluoro-2-methylpropoxy). In some embodiments, Cy 1 yes or

[0133] In some implementations, an R 3 It is a halogen group (e.g., fluorine or chlorine), and another R 3 It was R that appeared once. 7 Replacement C 1-8 Halogenated alkoxy groups (e.g., 3,3,3-trifluoropropoxy, (1,1,1-trifluoropropane-2-yl)oxy, or 4,4,4-trifluoro-3-methylbutoxy). In some embodiments, R 7 It is a hydroxyl group. In some embodiments, R 7 It is C 1-4Alkyl groups (e.g., methoxy groups). In some embodiments, R 7 It is an arylalkoxy group (e.g., benzyloxy). In some embodiments, Cy 1 yes

[0134] In some implementations, an R 3 It is a halogen group (e.g., fluorine or chlorine), and another R 3 It was R that appeared once. 7 Replacement C 3-9 Alkyloxy group (e.g., cyclopentoxy or cyclohexyloxy). In some embodiments, R 7 It is C 1-4 Halogenated alkoxy groups (e.g., trifluoromethoxy). In some embodiments, R 7 It is C 1-4 Alkyl (e.g., tert-butyl). In some embodiments, an R 3 It is a halogen group (e.g., fluorine or chlorine), and another R 3 It was R that appeared twice. 7 Replacement C 3-9 Alkyloxy group (e.g., cyclopentoxy or cyclohexyloxy). In some embodiments, the two R groups... 7 All are C 1-4 Alkyl (e.g., methyl). In some embodiments, an R 3 It is R that appears 0 times. 7 Replacement C 1-8 Halogenated alkyl groups (e.g., difluoromethyl), and another R 3 It is R that appears 0 times. 7 Replacement C 1-8 Alkyl groups (e.g., 3,3-dimethylbutoxy). In some embodiments, an R 3 It is a halogen group (e.g., fluorine or chlorine), and another R 3 It was R that appeared twice. 7 Replacement C 3-9 Cycloalkyl (e.g., cyclohexyl). In some embodiments, the two R... 7 All are C 1-4 Alkyl groups (e.g., methyl groups). In some embodiments, Cy 1 yes

[0135] In some implementations, an R 3 It is a halogen group (e.g., a fluorine group), and another R 3 It was R that appeared once. 7 Substituted aryl group (e.g., phenyl). In some embodiments, R 7 It is C 1-4Alkyl (e.g., isopropyl). In some embodiments, R 7 It is C 1-4 Halogenated alkyl groups (e.g., trifluoromethyl). In some embodiments, Cy 1 yes or

[0136] In some implementations, an R 3 It is a halogen group (e.g., a fluorine group), and another R 3 It is -C(O)R 7 In some implementations, R 7 It is R that appears 0 times. 8 Substituted heterocyclic alkyl groups (e.g., morpholino). In some embodiments, an R 3 It is a halogen group (e.g., a fluorine group), and another R 3 It is -C(O)N(R) a (R) 7 In some implementations, R a It is H, and R 7 It is C 1-5 Alkyl (e.g., tert-butyl or neopentyl). In some embodiments, an R 3 It is a halogen group (e.g., a fluorine group), and another R 3 It is an arylalkoxy group (e.g., benzyloxy). In some embodiments, Cy 1 yes or

[0137] In some implementations, an R 3 It is a halogen group (e.g., a fluorine group), and another R 3 It was R that appeared twice. 7 Replacement C 3-9 Cycloalkyl. In some embodiments, the two Rs 7 All are C 1-5 Alkyl (e.g., methyl). In some embodiments, an R 3 It is a halogen group (e.g., a fluorine group), and another R 3 It was R that appeared once. 7 Replacement C 1-4 Alkoxy-C 3-9 Cycloalkyl. In some embodiments, R 7 It is C 1-5 Halogenated alkyl groups (e.g., trifluoromethyl). In some embodiments, an R 3 It is a halogen group (e.g., a fluorine group), and another R 3 It was R that appeared twice. 7 Replacement C 1-4 Alkoxy-C 3-9Cycloalkyl (methoxycyclobutyl or methoxycyclohexyl). In some embodiments, the two R... 7 All are halogenated (e.g., fluorinated). In some embodiments, an R 3 It is a halogen group (e.g., a chloro group), and another R 3 It was R that appeared twice. 7 Replacement C 3-9 Cycloalkenyl (e.g., cyclohexenyl). In some embodiments, the two R... 7 All are C 1-5 Alkyl (e.g., methyl). In some embodiments, an R 3 It is a halogen group (e.g., a fluorine group), and another R 3 It is C 1-8 Alkenyl (e.g., 2-methylprop-1-en-1-yl). In some embodiments, an R 3 It is a halogen group (e.g., a fluorine group), and another R 3 It was R that appeared once. 7 Substituted heterocyclic alkyl groups (e.g., pyrrolidinyl alkyl groups). In some embodiments, R 7 It is C 1-5 Alkyl groups (e.g., tert-butyl groups).

[0138] In some implementations, Cy 1 yes

[0139] In some implementations, Cy 1 It was R that appeared 3 times. 3 Substituted phenyl groups. In some embodiments, the two R groups... 3 It is a halogen group (e.g., a fluorine group), and another R 3 It is R that appears 0 times. 7 Replacement C 1-8 Alkyloxy (e.g., neopentyloxy or 3,3-dimethylbutoxy). In some embodiments, the two R... 3 It is a halogen group (e.g., a fluorine group), and another R 3 It was R that appeared twice. 7 Replacement C 3-9 Cycloalkoxy (e.g., cyclopentoxy). In some embodiments, the two R... 7 All are C 1-5 Alkyl groups (e.g., methyl groups). In some embodiments, Cy 1 yes

[0140] In some implementations, Cy 1 It is R that appears 0-3 times. 3 Substituted heterocyclic alkyl groups. In some embodiments, Cy 1It is R that appears 0 times. 3 Substituted heterocyclic alkyl groups. In some embodiments, Cy 1 It was R that appeared once. 3 Substituted heterocyclic alkyl groups. In some embodiments, Cy 1 It was R that appeared once. 3 Substituted heterocyclic alkyl groups (e.g., N-azacyclobutane, N-pyrrolyl, N-morpholinyl, N-piperidinyl, N-piperidin-2-one, N-pyrrolidine-2-one, 3-tetrahydropyranyl, 3-(3,6-dihydro-2H-pyranyl), 2N-6-oxa-9-azaspiro[4.5]decyl or 2N-6-oxa-2,9-diaazaspiro[4.5]decyl). In some embodiments, R 3 It is R that appears 0 times. 7 Replacement C 1-8 Alkyl groups (e.g., neopentyl, 4,4-dimethylpentyl, 3-methylbutyl, or 3,3-dimethylbutyl). In some embodiments, R 3 It was R that appeared once. 7 Replacement C 1-8 Alkyl group (e.g., 3,3-dimethylbutyl). In some embodiments, R 7 It is a hydroxyl group. In some embodiments, R 3 It is R that appears 0 times. 7 Replacement C 1-8 Alkyloxy group (e.g., 3,3-dimethylbutoxy, neopentyloxy, or tert-butoxy). In some embodiments, R 3 It is C 1-8 Halogenated alkoxy groups (e.g., trifluoromethoxy). In some embodiments, R 3 It is -C(O)-R 7 In some implementations, R 7 It is C 1-5 Alkyl groups (e.g., tert-butoxy groups).

[0141] In some implementations, Cy 1 yes

[0142] In some implementations, Cy 1 It was R that appeared twice. 3 Substituted heterocyclic alkyl groups (e.g., N-piperidinyl, 9-(oxa-9-azaspiro[4.5]decyl) or 2-(3-oxa-1-azaspiro[4.4]non-1-enyl)). In some embodiments, an R 3 It is C 1-8 Alkyl (e.g., methyl), and another R 3 It is C 1-8Alkyl groups (e.g., tert-butoxy groups). In some embodiments, the two R groups... 3 All are C 1-8 Alkyl groups (e.g., methyl groups). In some embodiments, Cy 1 yes

[0143] In some implementations, Cy 1 It was R that appeared 3 times. 3 Substituted heterocyclic alkyl groups (e.g., 9-(oxa-9-azaspiro[4.5]decyl)). In some embodiments, the three Rs 3 It is C 1-8 Alkyl groups (e.g., methyl groups). In some embodiments, Cy 1 yes

[0144] In some implementations, Cy 1 It is R that appears 0-3 times. 3 Substituted heteroaryl groups. In some embodiments, Cy 1 It is R that appears 0 times. 3 Substituted heteroaryl groups. In some embodiments, Cy 1 It was R that appeared once. 3 Substituted heteroaryl groups. In some embodiments, Cy 1 It was R that appeared once. 3 Substituted heteroaryl groups (e.g., 4-thiazolyl, 2-pyridyl, 4-pyridyl, 1-pyrazolyl, 3-pyrazolyl, 2-thienyl, 4-pyrazolyl, or 2-(1,3,4-thiadiazolyl)). In some embodiments, R 3 It is R that appears 0 times. 7 Replacement C 1-8 Alkyl group (e.g., 3,3-dimethylbutyl). In some embodiments, R 3 It is R that appears 0 times. 7 Replacement C 1-8 Alkyloxy group (e.g., 3,3-dimethylbutoxy, neopentyloxy, or 4,4-dimethylpentyloxy). In some embodiments, R 3 It is R that appears 0 times. 7 Replacement C 1-8 Halogenated alkoxy groups (e.g., 2,2,2-trifluoroethoxy, 3,3,3-trifluoro-2,2-dimethylpropoxy, and 2,2-difluoro-3,3-dimethylbutoxy). In some embodiments, R 3 It was R that appeared once. 7 Replacement C 1-8Halogenated alkyl groups (e.g., 4,4,4-trifluoro-3,3-dimethylbutyl or 5,5,5-trifluoro-4,4-dimethylpentane-2-yl). In some embodiments, R 7 It is a hydroxyl group. In some embodiments, R 3 It was R that appeared once. 7 Substituted heterocyclic alkyl groups (e.g., N-pyrrolidinyl). In some embodiments, R 7 It is C 1-5 Halogenated alkoxy groups (e.g., trifluoromethoxy). In some embodiments, R 3 It is R that appears 0 times. 7 Replacement C 1-4 Alkoxy-C 3-9 Cycloalkyl. In some embodiments, R 3 yes In some implementation schemes, R 3 It was R that appeared 3 times. 7 Replacement C 1-4 Alkyl-C 3-9 Cycloalkyl. In some embodiments, the two Rs 7 It is a halogen group (e.g., a fluorine group), and an R 7 It is a hydroxyl group. In some embodiments, R 3 yes In some implementation schemes, R 3 It was R that appeared once. 7 Replacement C 3-9 Cycloalkyl (e.g., cyclohexyl). In some embodiments, R 7 It is C 1-5 Halogenated alkyl groups (e.g., 1,1-difluoroethyl). In some embodiments, R 7 It is C 1-5 Haloalkenyl groups (e.g., 1-fluoroethylene). In some embodiments, R 3 It is -C(O)R 7 In some implementations, R 7 It is 3,3,3-trifluoro-2,2-dimethylpropyl. In some embodiments, R 7 It was R that appeared twice. 8 Replacement C 3-7 Cycloalkyl (e.g., cyclopentyl). In some embodiments, the two R... 8 All are halogenated (e.g., fluorinated). In some embodiments, Cy 1 yes

[0145] In some implementations, Cy 1 It was R that appeared twice. 3Substituted heteroaryl groups. In some embodiments, Cy 1 It was R that appeared twice. 3 Substituted 2-pyridyl. In some embodiments, an R 3 It is a halogen group (e.g., a fluorine group), and another R 3 It is R that appears 0 times. 7 Replacement C 1-8 Alkyl groups (e.g., 3,3-dimethylbutoxy). In some embodiments, an R 3 It is R that appears 0 times. 7 Replacement C 1-8 Halogenated alkyl groups (e.g., trifluoromethyl), and another R 3 It is R that appears 0 times. 7 Replacement C 1-8 Alkoxy (e.g., 3,3-dimethylbutoxy). In some embodiments, Cy 1 It was R that appeared twice. 3 Substituted 2-thiophene group. In some embodiments, an R 3 It is a halogen group (e.g., a chloro group), and another R 3 It is R that appears 0 times. 7 Replacement C 1-8 Alkoxy (e.g., 3,3-dimethylbutoxy). In some embodiments, Cy 1 yes

[0146] In some implementations, Cy 1 It is R that appears 0-3 times. 3 Replacement C 3-9 Cycloalkyl. In some embodiments, Cy 1 It is R that appears 0 times. 3 Replacement C 3-9 Cycloalkyl (e.g., cyclohexyl). In some embodiments, Cy 1 It was R that appeared once. 3 Replacement C 3-9 Cycloalkyl (e.g., cyclohexyl or cyclopentyl). In some embodiments, R 3 It is C 1-8 Alkoxy (e.g., 3,3-dimethylbutoxy). In some embodiments, Cy 1 yes

[0147] In some embodiments, the compound of formula (I) is selected from the following compounds represented in Table 1 below:

[0148] Table 1

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323] In some embodiments, the compound of formula (I) is selected from the following compounds represented in Table 2 below:

[0324] Table 2

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342] definition

[0343] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art of this disclosure. The following references provide general definitions for many of the terms used herein: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd edition, 1994); The Cambridge Dictionary of Science and Technology (Walker, ed., 1988); The Glossary of Genetics, 5th edition, R. Rieger et al. (eds.), Springer Verlag (1991); and Hale and Marham, The Harper Collins Dictionary of Biology (1991). Unless otherwise specified, as used herein, the following terms have the meanings attributed to them.

[0344] In this disclosure, terms such as “comprises / comprising,” “containing,” and “having” may have the meanings applicable under U.S. Patent Law, and may mean “includes / including”; “consisting essentially of / consists essentially” also has the meanings applicable under U.S. Patent Law, and the terms are open-ended, thereby allowing for more content than described, as long as the basic or novel features of the described content are not altered by the presence of more content than described, but excluding prior art embodiments.

[0345] Unless explicitly stated or obvious from the context, the term "or" as used herein shall be understood as inclusive. Unless explicitly stated or obvious from the context, the terms "a / an" and "the" as used herein shall be understood as singular or plural.

[0346] The term "acyl" is well known in the art and refers to a group represented by the general formula hydrocarbon C(O)-, preferably alkyl C(O)-.

[0347] The term "acylamino" is well known in the art and refers to an amino group that has been substituted with an acyl group, and can be represented, for example, by the alkyl group C(O)NH-.

[0348] The term "acyloxy group" is well known in the art and refers to a group represented by the general formula hydrocarbon group C(O)O-, preferably alkyl group C(O)O-.

[0349] The term "alkoxy" refers to an alkyl group having an oxygen atom attached to it, preferably a lower alkyl group. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, etc.

[0350] The term "alkoxyalkyl" refers to an alkyl group that has been substituted with an alkoxy group and can be represented by the general formula alkyl-O-alkyl.

[0351] As used herein, the term "alkenyl" refers to an aliphatic group containing at least one double bond, and is intended to include both "unsubstituted alkenyl" and "substituted alkenyl," wherein the latter refers to an alkenyl moiety having substituents that replace hydrogen on one or more carbons of the alkenyl group. Such substituents may be present on one or more carbons, including or not included in one or more double bonds. Furthermore, such substituents include all those substituents considered for alkyl groups as discussed below, unless stability prohibits them. For example, consider substituting an alkenyl group with one or more alkyl, carbocyclic, aryl, heterocyclic, or heteroaryl groups.

[0352] "Alkyl" or "alkane" refers to a fully saturated straight-chain or branched non-aromatic hydrocarbon. Unless otherwise defined, straight-chain or branched alkyl groups typically have 1 to about 20 carbon atoms, preferably 1 to about 10 carbon atoms, and more preferably 1 to 6 carbon atoms. Examples of straight-chain and branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl, and octyl. C1-C6 straight-chain or branched alkyl groups are also referred to as "lower alkyl groups."

[0353] Furthermore, as used throughout the specification, examples, and claims, the term "alkyl" (or "lower alkyl") is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter referring to an alkyl moiety having substituents replacing hydrogen on one or more carbons of the hydrocarbon backbone. Unless otherwise specified, such substituents may include, for example, halogens, hydroxyl groups, carbonyl groups (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl groups (such as thioesters, thioacetates, or thiocarbamates), alkoxy groups, phosphoryl groups, phosphate esters, phosphonates, hypophosphonates, amino groups, amide groups, amidines, imines, cyano groups, nitro groups, azide groups, hydrogen sulfide groups, alkyl sulfide groups, sulfate esters, sulfonates, aminosulfonyl groups, sulfonamide groups, sulfonyl groups, heterocyclic groups, aralkyl groups, or aromatic or heteroaromatic moieties. Those skilled in the art will appreciate that, where appropriate, the portion substituted on the hydrocarbon chain may itself be substituted. For example, substituents in the substituted alkyl group may include substituted and unsubstituted forms of amino, azide, imino, amide, phosphoryl (including phosphonates and hypophosphonates), sulfonyl (including sulfates, sulfonamides, aminosulfonyls, and sulfonates), and silyl, as well as ethers, alkylthio groups, carbonyl (including ketones, aldehydes, carboxylic esters, and esters), -CF3, -CN, etc. Exemplary substituted alkyl groups are described below. Cycloalkyl groups may be further substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl groups, -CF3, -CN, etc.

[0354] Term "C" x-y "When used in conjunction with chemical motifs such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, it is intended to include groups containing x to y carbons in the chain. For example, the term 'C'..." x-y "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group containing x to y carbons in the chain, including straight-chain alkyl and branched-chain alkyl groups, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. When the group is in the terminal position, C0 alkyl indicates hydrogen; if it is in the internal position, it indicates a bond. The term "C"... 2-y "Alkenyl" and "C" 2-y "Alkyne" refers to an alkyl group that is similar to the above-mentioned alkyl groups in length and possible substitutions, but contains at least one double or triple bond of a substituted or unsubstituted unsaturated aliphatic group.

[0355] As used herein, the term "alkylamino" refers to an amino group that has been substituted with at least one alkyl group.

[0356] As used herein, the term "alkylthio" refers to a thiol group substituted with an alkyl group and can be represented by the general formula alkylS-.

[0357] As used herein, the term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom has been replaced by a halogen such as a fluorinated, chloro, bromine, or iodinated group. Exemplary haloalkyl groups include trifluoromethyl, difluoromethyl, fluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.

[0358] As used herein, the term "alkynyl" refers to an aliphatic group containing at least one triple bond, and is intended to include both "unsubstituted alkynyl" and "substituted alkynyl," the latter referring to an alkynyl moiety having substituents replacing hydrogen on one or more carbons of the alkynyl group. Such substituents may be present on one or more carbons, including or not included in one or more triple bonds. Furthermore, such substituents include all those substituents considered for alkyl groups as discussed above, unless stability prohibits them. For example, consider substituting an alkynyl group with one or more alkyl, carbocyclic, aryl, heterocyclic, or heteroaryl groups.

[0359] As used in this article, the term "amide" refers to a group.

[0360]

[0361] Each R 10 Independently representing a hydrogen or hydrocarbon group, or two Rs 10 Together with the N atoms they are attached to, they form heterocycles with 4 to 8 atoms in the ring structure.

[0362] The terms "amine" and "amino" are well known in the art and refer to both unsubstituted and substituted amines, as well as their salts, such as portions that can be represented by the following formula:

[0363]

[0364] Each R 10 Independently representing a hydrogen or hydrocarbon group, or two Rs 10 Together with the N atoms they are attached to, they form heterocycles with 4 to 8 atoms in the ring structure. As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0365] As used herein, the term "aralkyl" refers to an alkyl group that has been substituted with an aryl group.

[0366] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups, wherein each atom of the ring is a carbon. Preferably, the ring is a 5- or 6-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings, wherein at least one ring is aromatic, and other rings may be cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl, and / or heterocyclic. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, etc.

[0367] The term "carbamate" is well known in the art and refers to a group...

[0368]

[0369] Where R 9 and R 10 Independently representing hydrogen or a hydrocarbon group such as alkyl, or R 9 and R 10 Together with one or more intercalated atoms, they form a heterocycle with 4 to 8 atoms in the ring structure.

[0370] As used herein, the terms "carbocyclic" and "carbocyclic" refer to saturated or unsaturated rings in which every atom of the ring is carbon. The term carbocyclic includes both aromatic and non-aromatic carbocyclic rings. Non-aromatic carbocyclic rings include both cycloalkanes in which all carbon atoms are saturated and cycloalkenes containing at least one double bond.

[0371] The term "carbocyclic ring" includes 3-10 membered monocyclic rings and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocyclic ring may be self-saturated, unsaturated, or aromatic. A carbocyclic ring includes a bicyclic molecule in which one, two, or three or more atoms are shared between two rings. The term "fused carbocyclic ring" refers to a bicyclic carbocyclic ring in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocyclic ring may be self-saturated, unsaturated, or aromatic. In an exemplary embodiment, an aromatic ring such as a phenyl ring may be fused to a saturated or unsaturated ring such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of a carbocyclic ring, where valence permits. Exemplary "carbocyclic rings" 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 carbocyclic rings include decahydronaphthalene, 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. The “carbocyclic ring” may be substituted at any one or more positions capable of carrying hydrogen atoms.

[0372] “Cycloalkyl” is a fully saturated cyclic hydrocarbon. “Cycloalkyl” includes monocyclic and bicyclic rings. Unless otherwise defined, monocyclic cycloalkyl molecules typically have 3 to about 10 carbon atoms, more commonly 3 to 9 carbon atoms. The second ring of a bicyclic cycloalkyl molecule may be a self-saturated, unsaturated, or aromatic ring. 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 molecule in which each of the rings shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl molecule may be a self-saturated, unsaturated, or aromatic ring.

[0373] "Cycloalkenyl" is a cyclic hydrocarbon containing one or more double bonds. The cycloalkenyl ring can have 3 to 10 carbon atoms. Therefore, cycloalkenyl can be monocyclic or polycyclic. In addition to covalent substitution, the individual rings of such polycyclic cycloalkenyl groups can also have different connectivity, such as fusion, bridging, helicaling, etc. Exemplary cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentyl, cyclohexenyl, cycloheptenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, and 1,5-cyclooctadienyl.

[0374] Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornel, bicyclo[3.2.1]octyl, octahydro-cyclopentadienyl, spiro[4.5]decyl, cyclopropyl, and adamantyl.

[0375] As used herein, the term "carbocyclic alkyl" refers to an alkyl group that has been substituted with a carbocyclic group.

[0376] The term "carbonate" is well known in the art and refers to the group -OCO2-R. 10 , where R 10 It indicates a hydrocarbon group.

[0377] As used in this article, the term "carboxyl group" refers to a group represented by the formula -CO2H.

[0378] As used in this article, the term "ester" refers to the group -C(O)OR. 10 , where R 10 It indicates a hydrocarbon group.

[0379] As used herein, the term "ether" refers to a hydrocarbon group attached to another hydrocarbon group via oxygen. Therefore, the ether substituent of a hydrocarbon group can be hydrocarbon-O-. Ethers can be symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocyclic-O-heterocycles and aryl-O-heterocycles. Ethers include "alkoxyalkyl," which can be represented by the general formula alkyl-O-alkyl.

[0380] As used herein, the terms “halogen” and “halogen” refer to halogens and include chlorine, fluorine, bromine, and iodine groups.

[0381] As used herein, the term "hetaralkyl / heteroaralkyl" refers to an alkyl group that has been substituted with a heteroaryl group.

[0382] As used herein, the term "heteroalkyl" refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent.

[0383] The term "heteroaryl" refers to a ring structure comprising at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms, of a substituted or unsubstituted aromatic monocyclic structure, preferably a 3- to 10-membered ring, more preferably a 5- to 9-membered ring, such as a 5- to 6-membered ring. The term "heteroaryl" also includes polycyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings, and wherein at least one ring is heteroaromatic; for example, other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine.

[0384] In addition to covalent substitution, the individual rings of such polycyclic heteroaryl groups can also exhibit different linkages, such as fusion. Exemplary heteroaryl groups include furanyl, thiopheneyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrroleyl, 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, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, and pyrazoloyl. [3,4-b]pyridyl, terpineyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyridyl, benzo[b]thiophenyl, 5,6,7,8-tetrahydro-quinoline-3-yl, benzoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoisoxazolyl, benzoimidazolyl, thioindenyl, isothioindenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolazilyl, indolazilyl, isoquinolinyl, quinolinyl, phthalazinyl, quinoxolinyl, quinazolinyl and benzoxazinyl, etc. Generally, heteroaryl groups are usually linked to the main structure through carbon atoms.

[0385] As used herein, the term "heteroatom" refers to an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0386] The terms "heterocyclic group," "heterocyclic," and "heterocyclic" refer to a ring structure comprising at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms, a substituted or unsubstituted non-aromatic ring structure, preferably a 3- to 10-membered ring, more preferably a 3- to 7-membered ring. The terms "heterocyclic group" and "heterocyclic" also include polycyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings, and wherein at least one ring is a heterocyclic ring, for example, other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic groups. Heterocyclic groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, etc.

[0387] In addition to covalent substitution, the individual rings of such polycyclic heterocyclic alkyl groups can also have different connectivity, such as fusion, bridging, screwing, etc. Exemplary heterocyclic alkyl groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiaranyl, aziridine propane, aziridine butane, oxacyclopropane, methylenedioxy, chromenyl, malonylurea, isoxazolyl, 1,3-oxazolidine-3-yl, isothiazolyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidine-2-yl, 1,3-pyrazolidine-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, tetrahydroaziridine heptatrienyl, piperazinyl, piperazin-2-one, piperazin-3-one, chromanyl, 2 -pyrrolinyl, 3-pyrrolinyl, imidazoalkyl, 2-imidazoalkyl, 1,4-dioxanehexyl, 8-azabicyclo[3.2.1]octyl, 3-azabicyclo[3.2.1]octyl, 3,8-diazabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[4.1.0]heptyl, 3-azabicyclo[3.1.0]hexyl, 2-azaspiro[4.4]nonyl, 7-oxa-1-aza-spiro[4.4]nonyl, 7-azabicyclo[2.2.2]heptyl, octahydro-1H-indoleyl, etc. Generally, heterocyclic alkyl groups are usually attached to the main structure via carbon or nitrogen atoms.

[0388] As used herein, the term "heterocyclic alkyl" refers to an alkyl group that has been substituted with a heterocyclic group.

[0389] As used herein, the term "hydrocarbon group" refers to a group bonded by carbon atoms without =O or =S substituents and generally having at least one carbon-hydrogen bond and a predominantly carbon skeleton, but optionally including heteroatoms. Therefore, for the purposes of this application, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbon groups, but substituents such as acetyl (which has =O on the linking carbon) and ethoxy (which is linked by oxygen rather than carbon) are not considered hydrocarbon groups. Hydrocarbon groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, alkenyl, ynyl, and combinations thereof.

[0390] As used in this article, the term "hydroxyalkyl" refers to an alkyl group that has been substituted with a hydroxyl group.

[0391] The term "lower" when used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is intended to include groups in which ten or fewer non-hydrogen atoms, preferably six or fewer, are present in the substituents. "Lower alkyl" refers, for example, to an alkyl group containing ten or fewer carbon atoms, preferably six or fewer. In some embodiments, the acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents as defined herein are 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 descriptions of hydroxyalkyl and aralkyl (in which case, for example, when counting carbon atoms in the alkyl substituent, atoms in the aryl group are not counted).

[0392] The terms "polycyclic," "polycyclic," and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic) in which two or more atoms are common to two adjacent rings; for example, the ring is a "fused ring." Each ring in a polycyclic compound may be substituted or unsubstituted. In some embodiments, each ring of the polycyclic compound contains 3 to 10 atoms, preferably 5 to 7 atoms.

[0393] The term "silyl group" refers to a silicon moiety having three hydrocarbon groups attached to it.

[0394] The term “substituted” refers to a substituent that partially replaces hydrogen on one or more carbons of the carbon skeleton. It should be understood that “substitution” or “replaced by” includes the implicit condition that the substitution conforms to the permissible valence of the substituted atom and the substituent, and that the substitution produces a stable compound, such as a stable compound that does not spontaneously undergo transformations such as those achieved through rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is considered to include all permissible substituents of an organic compound. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. A suitable organic compound may have one or more permissible substituents, and they may be the same or different. For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents conforming to the valence of the heteroatom in the organic compound described herein. Substituents may include any substituents described herein, such as halogens, hydroxyl groups, carbonyl groups (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl groups (such as thioesters, thioacetic acids, or thiocarbamates), alkoxy groups, phosphoryl groups, phosphate esters, phosphonates, hypophosphonates, amino groups, amide groups, amidine groups, imine groups, cyano groups, nitro groups, azide groups, hydrogen sulfide groups, alkyl sulfide groups, sulfate esters, sulfonates, aminosulfonyl groups, sulfonamide groups, sulfonyl groups, heterocyclic groups, aralkyl groups, or aromatic or heteroaromatic moieties. Those skilled in the art will understand that substituents themselves may be substituted, where appropriate. Unless specifically stated as “unsubstituted,” references to the chemical part herein should be understood to include substituted variants. For example, references to an “aryl” group or part implicitly include both substituted and unsubstituted variants.

[0395] The term "sulfate group" is well known in the art and refers to the group -OSO3H or its pharmaceutically acceptable salt.

[0396] The term "sulfonamide" is well known in the art and refers to a group represented by the following general formula:

[0397]

[0398] Where R 9 and R 10 Independently representing hydrogen or a hydrocarbon group such as alkyl, or R 9 and R 10 Together with one or more intercalated atoms, they form a heterocycle with 4 to 8 atoms in the ring structure.

[0399] The term "sulfoxide" is well known in the art and refers to the group -S(O)-R. 10 , where R 10 It indicates a hydrocarbon group.

[0400] The term "sulfonic acid group" is well known in the art and refers to the group SO3H or its pharmaceutically acceptable salt.

[0401] The term "sulfone" is well known in the art and refers to the group -S(O)2-R. 10 , where R 10 It indicates a hydrocarbon group.

[0402] As used herein, the term "thioalkyl" refers to an alkyl group that has been substituted with a thiol group.

[0403] As used in this article, the term "thioester" refers to the group -C(O)SR. 10 or -SC(O)R 10 , where R 10 It indicates a hydrocarbon group.

[0404] As used in this article, the term "thioether" is equivalent to ether, in which oxygen is replaced by sulfur.

[0405] The term "urea" is well known in the art and can be represented by the following general formula:

[0406]

[0407] Where R 9 and R 10 Independently representing hydrogen or a hydrocarbon group such as alkyl, or any of the R that appears. 9 Together with R 10 Together with one or more intercalated atoms, they form a heterocycle with 4 to 8 atoms in the ring structure.

[0408] The term "protecting group" refers to an atomic group that, when attached to a reactive functional group in a molecule, masks, reduces, or prevents the reactivity of that functional group. Typically, protecting groups can be selectively removed during the synthetic process as needed. 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”), triphenylmethyl and substituted triphenylmethyl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratroloxycarbonyl (“NVOC”), etc. Representative hydroxyl protecting groups include, but are not limited to, those in which the hydroxyl group is acylated (esterified) or alkylated, such as benzyl and triphenylmethyl 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.

[0409] This invention also includes various isomers and mixtures thereof. Certain compounds of this invention can exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are paired stereoisomers whose mirror images are not superimposed, most typically because they contain asymmetrically substituted carbon atoms that act as chiral centers. "Enantiomer" means one of a pair of molecules that are mirror images of each other and are not superimposed. Diastereomers are stereoisomers that are not related as mirror images, most typically because they contain two or more asymmetrically substituted carbon atoms. "R" and "S" denote the configuration of the substituents surrounding one or more chiral carbon atoms. When the chiral center is not determined to be R or S, pure enantiomers or mixtures of the two configurations exist.

[0410] "Raceous compound" or "racemic mixture" refers to a compound of two enantiomers in equimolar amounts, wherein such mixtures do not exhibit optical activity; that is, they do not rotate the plane of polarization. In some embodiments, the compounds of the present invention may be racemic.

[0411] In some embodiments, the compounds of the present invention may be enriched with one enantiomer. For example, the compounds of the present invention 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 some embodiments, the compounds of the present invention may have more than one stereocenter. In some such embodiments, the compounds of the present invention may be enriched with one or more diastereomers. For example, the compounds of the present invention 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.

[0412] In some embodiments, the therapeutic formulation may be enriched to primarily provide one enantiomer of the compound (e.g., compound of formula (I)). The enantiomer-enriched mixture may contain, for example, at least about 60 mol% of one enantiomer, or more preferably at least about 75, about 90, about 95, or even about 99 mol%. In some embodiments, the compound enriched in one enantiomer is substantially free of the other enantiomer, where substantially free means, for example, that in the composition or compound mixture, the substance in question accounts for 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% relative to the amount of the other enantiomer. For example, if the composition or compound mixture contains about 98 grams of the first enantiomer and about 2 grams of the second enantiomer, then it will be said to contain about 98 mol% of the first enantiomer and only about 2% of the second enantiomer.

[0413] In some embodiments, the therapeutic formulation may be enriched to primarily provide a diastereomer of the compound (e.g., compound of formula (I)). The diastereomer enrichment mixture may contain, for example, at least about 60 mol% of a diastereomer, or more preferably at least about 75, about 90, about 95, or even about 99 mol%.

[0414] The compounds of the present invention can be prepared into individual isomers by isomer-specific synthesis or by resolution from a mixture of isomers. Conventional resolution techniques include using an optically active acid to form a salt of the free base of each isomer in an isomer pair (followed by fractional crystallization and regeneration of the free base); using an optically active amine to form a salt of the acid form of each isomer in an isomer pair (followed by fractional crystallization and regeneration of the free acid); using an optically pure acid, amine, or alcohol to form an ester or amide of each of the isomers in an isomer pair (followed by chromatographic separation and removal of chiral auxiliaries); or using various well-known chromatographic methods to resolve mixtures of isomers of starting materials or final products.

[0415] When the stereochemistry of a disclosed compound is named or described structurally, the named or described stereoisomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure by weight relative to other stereoisomers. When a single enantiomer is named or described structurally, the described or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% optically pure by weight. The percentage of optical purity by weight is the ratio of the weight of the present enantiomer to the combined weight of the present enantiomer and its optical isomer.

[0416] In the illustrations of the compounds presented in this application, the thickened tapered lines ( ) indicates substituents above the plane of the ring to which the asymmetric carbon belongs, while the dotted line ( () indicates a substituent below the plane of the ring to which the asymmetric carbon belongs.

[0417] As used herein, the compounds of the present invention may be in the form of possible isomers, rotational isomers, tautomers, tautomers, or mixtures thereof, for example, in the form of substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates, or mixtures thereof.

[0418] The isotopically labeled form of the disclosed compounds has one or more atoms in the compound that have been replaced by one or more atoms whose atomic mass or mass number differs from that of atoms that are normally found in greater natural abundance. Examples of isotopes readily available commercially and that can be incorporated into the disclosed compounds by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. The isotopically labeled compounds provided herein can generally be prepared by performing the procedures disclosed herein, replacing non-isotopically labeled reactants with isotopically labeled reactants.

[0419] The concentration of such heavy isotopes, particularly deuterium, can be defined by the isotope enrichment factor. As used herein, the term "isotope enrichment factor" refers to the ratio between the isotopic abundance of a specified isotope and its natural abundance. If the hydrogen atoms in the compounds of the present invention are replaced by deuterium, then the compound has an isotopic enrichment factor of at least 3500 (52.5% deuterium doping at each specified deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping) for each specified deuterium atom.

[0420] The isotopically labeled compounds provided herein can be used in many advantageous ways. Compounds with incorporated 14C are suitable for drug and / or substrate tissue distribution assays. Tritium (3H) and carbon-14 (14C) are preferred isotopes due to their ease of preparation and excellent detectability. Heavy isotopes such as deuterium (2H) offer therapeutic advantages due to their higher metabolic stability. Metabolism is influenced by first-order kinetic isotopic effects, where heavy isotopes have lower ground-state energies and result in reduced rate-limiting bond breaking. Slowing metabolism can lead to increased half-life in vivo, reduced dose requirements, or improved therapeutic index.

[0421] For further discussion, see S.L. Harbeson and R.T. Gung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417; Foster, AB, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends in Pharmacological Sciences, 5: 524-527 (1984); and Foster, AB, "Deuterium Isotope Effects in the Metabolism of Drugs and Xenobiotics: Implications for Drug Design," Advances in Drug Research, 14: 1-40 (1985).

[0422] Metabolic stability can be affected by the processing of compounds in different organs of the body. For example, compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism. Currently available in vitro liver microsomal assays provide valuable information about this type of oxidative metabolism, which in turn helps in the rational design of deuterated compounds such as those disclosed herein. Improvements can be measured in many assays known in the art, such as increases in in vivo half-life (t1 / 2), concentration at maximum therapeutic effect (Cmax), area under the dose-response curve (AUC), and bioavailability; as well as reductions in clearance, dosage, and material costs.

[0423] Another function of deuterated compounds is to reduce or eliminate unwanted toxic metabolites. For example, if a toxic metabolite is produced by the cleavage of an oxidative carbon-hydrogen (C-H) bond, then a deuterated analogue will have a slower reaction time and slow down the production of unwanted metabolites, even if the specific oxidation is not a rate-determining step. See, for example, Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990; Reider et al., J. Org. Chem. 52, 3326-3334, 1987; Foster, Adv. Drug Res. 14, 1-40, 1985; Gillette et al., Biochemistry 33(10) 2927-2937, 1994; and Jarman et al., Carcinogenesis 16(4), 683-688, 1993.

[0424] The term "subject" as considered for administration includes, but is not limited to, humans (i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) 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, quails, and / or turkeys. Humans are preferred subjects.

[0425] As used herein, a "preventive" treatment for a disease or ailment refers to a compound that, in a statistical sample, reduces the occurrence of the disease or ailment in a treated sample relative to an untreated control sample, or delays the onset of one or more symptoms of the disease or ailment or reduces the severity of one or more symptoms relative to an untreated control sample.

[0426] The term "treatment" means reducing, inhibiting, weakening, diminishing, halting, or stabilizing the development or progression of a disease (such as the disease or condition described herein), alleviating the severity of said disease, or improving symptoms associated with said disease. Treatment includes treating the symptoms of a disease, condition, or disorder. Without being bound by any theory, in some implementations, treatment includes increasing deficient CFTR activity. If treatment is administered before the clinical manifestation of a non-desired disease (such as a subject's disease or other non-desired state), then the treatment is preventative (i.e., it protects the subject from the manifestation of the non-desired disease), and if treatment is administered after the manifestation of the non-desired disease, then the treatment is therapeutic (i.e., it intends to diminish, improve, or stabilize the existing non-desired disease or its side effects).

[0427] As used herein, the term "prodrug" refers to a pharmacological derivative of a parent drug molecule that requires spontaneous or enzymatic biotransformation in vivo to release the active drug. For example, a prodrug is a variant or derivative of the compound of the present invention having groups that can be cleaved under certain metabolic conditions, upon which it transforms into the compound of the present invention. Such prodrugs then acquire pharmaceutical activity in vivo when subjected to solvent degradation or enzymatic degradation under physiological conditions. Depending on the number of biotransformation steps required to release the active drug in vivo and the number of functional groups present in the prodrug-type form, prodrug compounds herein may be referred to as single, dual, triple, etc. Prodrug forms often offer advantages in solubility, tissue compatibility, or delayed release in mammalian organisms (see Bundgard, Design of Prodrugs, pp. 7–9, 21–24, Elsevier, Amsterdam 1985; and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352–401, Academic Press, San Diego, CA, 1992). Prodrugs commonly known in the art include well-known acid derivatives, such as esters prepared by reacting a parent acid with a suitable alcohol, amides prepared by reacting a parent acid compound with an amine, and basic groups reacting to form acylated base derivatives. Of course, other prodrug derivatives can be combined with other features disclosed herein to enhance bioavailability.

[0428] Therefore, those skilled in the art will understand that certain currently disclosed compounds having a free amino, amide, hydroxyl, or carboxyl group can be converted into prodrugs. Prodrugs comprise compounds having an amino acid residue or a polypeptide chain having two or more (e.g., two, three, or four) amino acid residues covalently bonded to a free amino, hydroxyl, or carboxylic acid group of the currently disclosed compound via peptide bonds. The amino acid residues include 20 naturally occurring amino acids typically designated by three-letter symbols, and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, valine, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. Prodrugs also include compounds having a carbonate, carbamate, amide, or alkyl ester moiety covalently bonded to any of the substituents disclosed herein.

[0429] As used in this article, "therapeutic effective amount" refers to an amount sufficient to achieve the desired therapeutic effect. For example, a therapeutic effective amount may refer to an amount sufficient to improve at least one sign or symptom of cystic fibrosis.

[0430] A “response” to treatment may include a reduction or improvement of negative symptoms, a decrease in the progression of the disease or its symptoms, an increase in beneficial symptoms or clinical outcomes, a reduction in side effects, stabilization of the disease, partial or complete treatment of the disease, and other responses.

[0431] As used in this article, “CFTR” refers to the transmembrane transport regulator of cystic fibrosis. CFTR ion channel dysfunction is caused by loss-of-function mutations in the CFTR. These mutations lead to exocrine gland dysfunction, impaired mucociliary clearance, and cystic fibrosis. The most common CFTR mutation in cystic fibrosis (CF) patients results in a specific deletion of three nucleotides in the codon for phenylalanine at position 508. This mutation, found in approximately 70% of CF patients worldwide, is called “ΔF508”. The ΔF508 mutation reduces the stability of the CFTR NBD1 domain and restricts interdomain assembly of the CFTR. Because CF is an autosomal recessive disease, CF patients with the ΔF508 CFTR mutation must also carry a second defective copy of CFTR. Approximately 2000 different CFTR mutations causing CF have been identified in CF patients. CF patients with the ΔF508 CFTR mutation can be homozygous for that mutation (ΔF508 / ΔF508). If a CF patient carries a second CFTR allele that alternatively contains a different loss-of-function CFTR mutation, then such patients may also be ΔF508 heterozygous. These CFTR mutations include, but are not limited to, G542X, G551D, N1303K, W1282X, R553X, R117H, R1162X, R347P, G85E, R560T, A455E, ΔI507, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, and G1349D.

[0432] As used herein, the term "CFTR modulator" refers to a compound that increases the activity of CFTR. In some respects, CFTR modulators are CFTR correctors or CFTR enhancers, or dual-action compounds with both corrector and enhancer activities. These dual-action compounds are useful when mutations result in the absence or reduction of synthetic CFTR protein.

[0433] As used herein, the term "CFTR corrector" refers to a compound that increases the amount of functional CFTR protein at the cell surface, thereby enhancing ion transport via CFTR. CFTR correctors partially "rescue" the misfolding of the CFTR protein, particularly misfolding caused by mutations within the CFTR, thereby allowing CFTR to mature and be functionally expressed on the cell surface. CFTR correctors can promote alterations in the cellular folding environment that influence the way CFTR folds and include compounds that directly interact with the CFTR protein to alter its folding, conformational maturation, or stability. Examples of corrective agents include, but are not limited to, compounds described in US20190248809A1, VX-809, VX-661, VX-152, VX-440, VX-445, VX-659, VX-121, VX-983, GLPG2222, GLPG2737, GLPG3221, GLPG2851, FDL169, FDL304, FDL2052160, FD2035659, and PTI-801.

[0434] As used herein, the term "CFTR enhancer" refers to a compound that increases the ion channel activity of the CFTR protein located on the cell surface, thereby resulting in enhanced ion transport. CFTR enhancers restore the function of defective channels caused by CFTR mutations or otherwise increase the activity of CFTR at the cell surface. Examples of enhancers include, but are not limited to, ivacaftor (VX770), deuterated ivacaftor (CPT 656, VX-561), PTI-808, QBW251, GLPG1837, GLPG2451, ABBV-3067, ABBV-974, ABBV-191, FDL176, and genistein.

[0435] As used in this article, “CFTR disease or disorder” refers to a disease or disorder associated with a deficiency of CFTR activity, such as cystic fibrosis, congenital bilateral vas deferens agenesis (CBAVD), acute pancreatitis, recurrent or chronic pancreatitis, disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis, smoking-related lung diseases such as chronic obstructive pulmonary disease (COPD), rhinosinusitis, congenital pneumonia, malabsorption, celiac disease, nasal polyposis, nontuberculous mycobacterial infection, pancreatic steatorrhea, intestinal atresia, xerophthalmia, protein C deficiency, abeta-lipoproteinemia, lysosomal storage disease, type 1 chylomicronemia, mild lung disease, lipid processing defects, type 1 hereditary angioedema, coagulation-fibrinolysis, hereditary hemochromatosis, CFTR-associated metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, and Sjögren's syndrome.

[0436] How to use

[0437] This article discloses a method for treating CFTR deficiency in cells, the method comprising contacting the cells with a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the cell contact occurs in a subject in need, thereby treating a disease or condition mediated by CFTR deficiency.

[0438] Furthermore, this document discloses methods for treating diseases or conditions mediated by a lack of CFTR activity, said methods 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 related to the regulation of fluid volume across the epithelial membrane, particularly obstructive airway diseases such as CF or COPD.

[0439] These 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 vas deferens agenesis (CBAVD), mild lung disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), congenital pneumonia, malabsorption, celiac disease, nasal polyposis, nontuberculous mycobacterial infection, pancreatic steatorrhea, intestinal atresia, liver disease, hereditary emphysema, and hereditary diseases. Hemochromatosis, coagulation-fibrinolysis defects, protein C deficiency, type 1 hereditary angioedema, lipid processing defects, familial hypercholesterolemia, type 1 chylomicronemia, abeta-lipoproteinemia, lysosomal storage diseases, I-cell disease / pseudo-Hurler disease, mucopolysaccharidosis, Sandhof / Tay-Sachs disease, type II Crigler-Najjar disease Type II), multiple endocrine disorders / hyperinsulinemia, diabetes, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, type I glycogenopathies (CDG), congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neurohypophyseal DI, renal 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. Diseases, several polyglutamine neuropathies, Huntington's disease, type I spinocerebellar ataxia, spinobulbar muscular atrophy, dentate nucleus, rubra pallidus, hypothalamic nucleus atrophy, myotonic dystrophy, spongiform encephalopathy, hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry eye disease, Sjögren's disease, osteoporosis, osteopenia, bone healing and bone growth, bone repair, bone regeneration, reducing bone resorption, increasing bone deposition, Gorham's syndrome, chloride channel disorders, congenital myotonia, Bartter's syndrome type III.III) Dent's disease, startle reflex, epilepsy, startle reflex, lysosomal storage disease, Angelman syndrome, primary ciliary dyskinesia (PCD), PCD with paralysis, PCD without paralysis, and ciliary dysplasia.

[0440] These diseases and disorders include, but are not limited to, cystic fibrosis, congenital bilateral agenesis of the vas deferens (CBAVD), acute pancreatitis, recurrent or chronic pancreatitis, disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis, chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis, congenital pneumonia, malabsorption, celiac disease, nasal polyposis, nontuberculous mycobacterial infection, pancreatic steatorrhea, intestinal atresia, xerophthalmia, protein C deficiency, abeta-lipoproteinemia, lysosomal storage disease, type 1 chylomicronemia, mild lung disease, lipid processing defects, type 1 hereditary angioedema, coagulation-fibrinolysis, hereditary hemochromatosis, CFTR-related metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, and Sjögren's syndrome. In some implementations, the disease is cystic fibrosis.

[0441] This document provides methods for treating cystic fibrosis, the methods comprising administering to a subject in need a compound as disclosed herein or a pharmaceutically acceptable salt thereof. This document also provides methods for reducing the severity of cystic fibrosis, the methods comprising administering to a subject in need a compound as disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is a human being. In some embodiments, the subject is at risk of developing cystic fibrosis, and the administration is performed prior to the onset of symptoms of cystic fibrosis in the subject.

[0442] This document provides for the use of compounds as disclosed herein for the treatment of diseases or disorders mediated by a lack of CFTR activity. This document also provides for the use of compounds as disclosed herein in the manufacture of medicaments for the treatment of diseases or disorders mediated by a lack of CFTR activity.

[0443] The compounds and methods described herein can be used to treat subjects lacking CFTR activity and with CFTR mutations such as ΔF508. ΔF508 mutations impair normal CFTR folding, stability, transport, and function by reducing the stability of the NBD1 domain of CFTR, the ability of CFTR domain-domain assembly, or both. Due to their effects on the ICL4 interface, CFTR correctors with ICL4-directing mechanisms can be effective in subjects with mutations such as ΔF508-CFTR (>70% of all CF patients have at least one copy) and mutations that cause ICL4 interface instability, such as G85E, H139R, H1054D, L1065P, L1077P, R1066C, and other CFTR mutations in which ICL4 interface stability is compromised.

[0444] This document provides a kit for measuring the activity of CFTR or a fragment thereof in a biological sample, either in vitro or in vivo. The kit may contain: (i) a compound as disclosed herein or a pharmaceutical composition comprising a disclosed compound, and (ii) instructions regarding: a) contacting said compound or composition with a biological sample; and b) measuring the activity of said CFTR or a fragment thereof. In some embodiments, the biological sample is biopsy material obtained from a mammal or an extract thereof; blood, saliva, urine, feces, semen, tears, other bodily fluids, or extracts thereof. In some embodiments, the mammal is a human.

[0445] Combination therapy

[0446] As used herein, the term “combination therapy” means administering two or more CFTR modulators, or CFTR modulators and agents such as antibiotics, ENaC inhibitors, GSNO (S-nitrosothiol s-nitroglutathione) reductase inhibitors, and CRISPR Cas corrective therapies or systems (as described in US 2007 / 0022507, etc.).

[0447] In some embodiments, a method of treating or preventing a disease or ailment mediated by a lack of CFTR activity includes administering a compound as disclosed herein in combination with one or more other therapeutic agents. In some embodiments, one other therapeutic agent is administered. In other embodiments, at least two other therapeutic agents are administered.

[0448] Additional therapeutic agents include, for example, ENaC inhibitors, mucolytics, bronchodilators, antibiotics, anti-infectives, anti-inflammatory agents, ion channel modulators, therapeutic agents used in gene therapy, agents that reduce airway surface fluid and / or reduce airway surface pH, CFTR correctors and CFTR enhancers, or other agents that modulate CFTR activity.

[0449] In some implementations, at least one additional therapeutic agent is selected from one or more CFTR modulators, one or more CFTR correctors, and one or more CFTR enhancers.

[0450] Non-limiting examples of CFTR modifiers, correctors, and synergists include VX-770 (evaccato), VX-809 (Lumacaftor, 3-(6-(I-(2,2-5-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)cyclopropanecarbamate)-3-methylpyridin-2-yl)benzoic acid), and VX-661 (tizacattor, I-(2,2-difluoro-1,3-benzodioxacyclopenten-5-yl)-N- [I-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-5-yl]-cyclopropanecarboxamide), VX-983, VX-152, VX-440, VX-445, VX-659, VX-371, VX-121, Orkambi, and the compounds described in US20190248809A1, Ataluren (PTC) 124)(3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid), PTI-130 (Proteostasis), PTI-801, PTI-808, PTI-428, N91115.74 (cavosonstat), QBW251 (Novartis), compounds described in WO2011113894, and compound N30 Pharmaceuticals (e.g., WO 2014 / 186704), deuterated ivacartole (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 Discoverylab), FDL 176, FDL438, FDL304, FD2052160, FD1881042, FD2027304, FD2035659, FD2033129, FD1860293, CFFT-Pot01, CFFT-Pot-02, P-1037, glycerol, phenylbutyrate, etc.Non-limiting examples of anti-inflammatory agents include N6022 (3-(5-(4-(IH-imidazol-I-yl)10phenyl)-I-(4-carbamoyl-2-methylphenyl)-'H-pyrrolo-2-yl)propionic acid), ibuprofen, Lenabasum (anabasum), Acebilustat (CTX-4430), LAU-7b, POL6014, docosahexaenoic acid, α-1 antitrypsin, and sildenafil. Additional therapeutic agents include, but are not limited to, mucolytics, mucorheology modifiers (such as hypertonic saline, mannitol, and oligosaccharide-based therapies), bronchodilators, anti-infectives (such as tazobactam, piperacillin, rifampin, meropenum, ceftazidime, aztreonam, tobramycin, fosfomycin, azithromycin, vancomycin, gallium, and colistin), anti-inflammatory agents, CFTR modifiers other than those of the present invention, and nutritional agents. Additional therapeutic agents may include treatments for comorbidities of cystic fibrosis, such as exocrine pancreatic insufficiency that can be treated with pancreatic lipase or liprotamase.

[0451] Examples of CFTR synergists include, but are not limited to, ivacartool (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 synergists are also disclosed in the following publications: U.S. patent applications WO2005120497, WO2008147952, WO2009076593, WO2010048573, WO2006002421, WO2008147952, WO2011072241, WO2011113894, WO2013038373, WO2013038378, WO2013038381, WO2013038386, WO2013038390, WO2014180562, WO2015018823 and Serial Nos. 14 / 271,080, 14 / 451,619 and 15 / 164,317.

[0452] Non-limiting examples of corrective agents include rumacator (VX-809), 1-(2,2-difluoro-1,3-benzodioxane-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropane-2-yl)-1H-indol-5-yl}cyclopropaneformamide (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 corrective agents are also disclosed in U.S. applications US20160095858A1, US20190248809A1, and serial numbers 14 / 925,649 and 14 / 926,727.

[0453] In some implementations, the additional therapeutic agent is a CFTR enhancer. CFTR enhancers enhance the effects of known CFTR modulators such as synergists and correctors. Examples of CFTR enhancers include PTI130 and PTI-428. Examples of enhancers are also disclosed in publications WO2015138909 and WO2015138934.

[0454] In some embodiments, the additional therapeutic agent is an agent that reduces the activity of epithelial sodium channel blockers (ENaCs) either directly by blocking the channel or indirectly by modulating proteases that cause increased ENaC activity (e.g., serine proteases, channel-activating proteases). Examples of such agents include carmostat (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 epithelial sodium channel blockers (ENaCs) can be found, for example, in PCT Publications WO2009074575 and WO2013043720; and U.S. Patent No. 8,999,976.

[0455] In one embodiment, the ENaC inhibitor is VX-371. In another embodiment, the ENaC inhibitor is SPX-101 (S18).

[0456] In some implementations, 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.

[0457] In some embodiments, the combination of the compound of formula (I) with the second therapeutic agent may have a synergistic effect in the treatment of cancer and other diseases or conditions mediated by adenosine. In other embodiments, the combination may have an additive effect.

[0458] Pharmaceutical Composition

[0459] The compositions and methods of the present invention can be used to treat subjects in need. In some embodiments, the subject is a mammal, such as a human or a non-human mammal. When administered to a subject such as a human, the composition or compound is preferably administered in the form of a pharmaceutical composition comprising, for example, a compound of the present invention 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 mediators such as glycols, glycerols, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are used for human administration, particularly for invasive routes of administration (i.e., routes of transport or diffusion bypassing the epithelial barrier, such as injection or implantation), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients may be selected, for example, to achieve delayed release of the agent or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition may be in the form of dosage units, such as tablets, capsules (including dispensing capsules and gelatin capsules), granules, hydrophilic colloids for decongestion, powders, solutions, syrups, suppositories, injections, etc. The composition may also be present in a percutaneous delivery system such as a skin patch. The composition may also be present in solutions suitable for surface application, such as eye drops.

[0460] Pharmaceutically acceptable carriers may contain physiologically acceptable agents, such as those that stabilize compounds like those of the present invention, increase the solubility of said compounds, or increase the absorption of said compounds. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose, or dextran; 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 physiologically acceptable agents depends, for example, on the route of administration of the composition. The formulation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) may also be a liposome or other polymer matrix in which compounds, such as those of the present invention, may be present. Liposomes, for example, containing phospholipids or other lipids, are relatively simple to prepare and administer, and are non-toxic, physiologically acceptable, and metabolizable carriers.

[0461] The phrase “pharmaceutically acceptable” is used in this document to refer to compounds, materials, compositions, and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for contact with a subject’s tissues without excessive toxicity, irritation, allergic response, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0462] As used herein, the phrase “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” in the sense that it is compatible with other components of the formulation and does not cause harm to the subject. Some examples of materials that 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 gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; and (9) oils, such as peanut oil and cottonseed oil. (10) Safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (11) Diols, such as propylene glycol; (12) Polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (13) Esters, such as ethyl oleate and ethyl laurate; (14) Agar; (15) Buffers, such as magnesium hydroxide and aluminum hydroxide; (16) Alginate; (17) Atherless water; (18) Isotonic saline; (19) Ringer's solution; (20) Ethanol; (21) Phosphate buffer solution; and (22) Other non-toxic and compatible substances used in pharmaceutical preparations.

[0463] The pharmaceutical composition (formulation) can be administered to a subject via any of a number of routes of administration, including, for example, oral (e.g., oral enemas, tablets, capsules (including sprinkle capsules and gelatin capsules), pellets, powders, granules, pastes for application to the tongue, as in aqueous or non-aqueous solutions or suspensions); absorption via the oral mucosa (e.g., sublingual); anal, rectal, or vaginal (e.g., in the form of vaginal suppositories, creams, or foams); parenteral (including intramuscular, intravenous, subcutaneous, or intrathecal, in the form of, for example, sterile solutions or suspensions); nasal; intraperitoneal; subcutaneous; percutaneous (e.g., in the form of patches applied to the skin); and surface (e.g., in the form of creams, ointments, or sprays applied to the skin, or in the form of eye drops). The compound can also be formulated for inhalation. In some embodiments, the compound may simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable for said routes of administration can be found, for example, in U.S. Patent No. 6,110,973 , 5,763,493 , 5,731,000 , 5,541,231 , 5,427,798 , 5,358,970 and 4,172,896 The number and the patents cited therein.

[0464] The formulation may be provided in unit dosage form and may be prepared by any method known in the pharmaceutical industry. The amount of active ingredient that can be combined with a carrier material to produce a single-dose form will vary depending on the treated subject and the specific administration method. The amount of active ingredient that can be combined with a carrier material to produce a single-dose form will generally be the amount of the compound that produces a therapeutic effect. Typically, in 100 parts, this amount will be in the range of about 1% to about 99% of the active ingredient, preferably about 5% to about 70%, and most preferably about 10% to about 30%.

[0465] Methods for preparing these formulations or compositions include the step of associating an active compound, such as the compound of the present invention, with a carrier and optionally one or more auxiliary components. Generally, formulations are prepared by uniformly and tightly associating the compound of the present invention with a liquid carrier or a finely dispersed solid carrier, or both, followed by shaping the product if necessary.

[0466] Formulations of the present invention suitable for oral administration may be in the form of capsules (including sprinkled capsules and gelatin capsules), flat capsules, pills, tablets, sugar lozenges (using a flavored base, typically sucrose and gum arabic or tragacanth), hydrophilic colloids, powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil emulsions, or elixirs or syrups, or soft lozenges (using an inert base, such as gelatin and glycerin, or sucrose and gum arabic), and / or mouthwashes, each containing a predetermined amount of the compound of the present invention as an active ingredient. The compositions or compounds may also be administered in the form of large pills, medicated sugars, or pastes.

[0467] To prepare solid dosage forms (capsules (including sprinkled capsules and gelatin capsules), tablets, pills, sugar-coated tablets, powders, granules, etc.) for oral administration, 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 starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) humectants. (3) Disintegrants, such as glycerin; (4) Disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates and sodium carbonate; (5) Dissolution inhibitors, such as paraffin; (6) Absorption accelerators, such as quaternary ammonium compounds; (7) Wetting agents, such as cetyl alcohol and glyceryl monostearate; (8) Absorbents, such as kaolin and bentonite; (9) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, 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 composition may also contain a buffer. Similar types of solid compositions may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycol.

[0468] Tablets can be prepared by compression or molding, optionally together with one or more excipients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0469] Optionally, tablets and other solid dosage forms of pharmaceutical compositions, such as sugar-coated tablets, capsules (including spreadable capsules and gelatin capsules), pills, and granules, may be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulation. They may also be formulated using, for example, different proportions of hydroxypropyl methylcellulose, other polymer matrices, liposomes, and / or microspheres to provide the desired release profile in order to provide a slow or controlled release of the active ingredient therein. They may be sterilized, for example, by filtration through a bacterial trap filter, or by a sterilizing agent in the form of a sterile solid composition that can be immediately dissolved in sterile water or some other sterile injectable medium before use. These compositions may also optionally contain a light-blocking agent and may have a composition in which they optionally release one or more active ingredients in a delayed manner, either only or preferably in a portion of the gastrointestinal tract. Examples of encapsulation compositions that may be used include polymeric substances and waxes. If appropriate, the active ingredient may also be microencapsulated together with one or more of the excipients described above.

[0470] Liquid dosage forms suitable for oral administration include pharmaceutically acceptable emulsions, hydrophilic colloids for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents; cyclodextrins and their derivatives; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, methyl benzoate, propylene glycol, 1,3-butanediol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuranol, polyethylene glycol, and fatty acid esters of sorbitol; and mixtures thereof.

[0471] In addition to inert diluents, oral compositions may also include excipients such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, aroma agents and preservatives.

[0472] In addition to the active compound, the suspension may also contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyethylene glycol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth gum, and mixtures thereof.

[0473] Formulations of pharmaceutical compositions for rectal, vaginal, or urethral administration may be provided as suppositories, which may be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers, including, for example, cocoa butter, polyethylene glycol, suppository wax, or salicylates, and are solid at room temperature but liquid at body temperature, and thus will melt and release the active compound in the rectal or vaginal cavity.

[0474] Formulations of pharmaceutical compositions for application to the oral cavity may be provided as mouthwashes, oral sprays, or oral ointments.

[0475] Alternatively, the composition may be formulated for delivery via catheter, stent, thread, or other endoluminal device. Delivery via such devices may be particularly useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

[0476] Preparations suitable for vaginal application also include vaginal suppositories, tampons, creams, gels, pastes, foams or sprays containing such carriers as are known in the art as appropriate.

[0477] Dosage forms for topical or transdermal application include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. Active compounds can be mixed with pharmaceutically acceptable carriers, and with any necessary preservatives, buffers, or propellants, under aseptic conditions.

[0478] In addition to active compounds, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth gum, cellulose derivatives, polyethylene glycol, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0479] In addition to the active compound, powders and sprays may also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Sprays may also contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0480] Transdermal patches offer the added advantage of providing controlled delivery of the compounds of the present invention into the body. Such dosage forms can be prepared by dissolving or dispersing the active compounds in a suitable medium. Absorption enhancers can also be used to increase the flux of the compounds across the skin. The rate of this flux can be controlled by providing a rate-controlled membrane or by dispersing the compounds in a polymer matrix or gel.

[0481] Ophthalmic preparations, ophthalmic ointments, powders, solutions, etc., are also considered to be within the scope of this invention. Exemplary ophthalmic preparations are described in U.S. Publications 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. Liquid ophthalmic preparations may, if desired, have properties similar to, or be compatible with, tears, aqueous humor, or vitreous fluid. A preferred route of administration is topical application (e.g., surface application, such as eye drops, or application via an implant).

[0482] As used herein, the phrases “parenteral administration” and “administered via a parenteral route” refer to administration methods that are normally achieved by injection, other than enteral and topical administration, and include, but are not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intra-bursal, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.

[0483] Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions; or combinations of sterile powders that can be reconstituted into sterile injectable solutions or dispersions just before use, said combinations may contain antioxidants, buffers, antimicrobial agents, solutes that cause the formulation to be isotonic with the blood of the intended recipient, or suspending agents or thickeners.

[0484] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Suitable flowability can be maintained, for example, by using a coating material such as lecithin, in the case of a dispersion, by maintaining the desired particle size, and by using a surfactant.

[0485] These compositions may also contain excipients such as preservatives, humectants, emulsifiers, and dispersants. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, and sorbic acid. Isotonic agents such as sugars and sodium chloride may also be included in the composition if desired. Furthermore, prolonged absorption of injectable drug formulations can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0486] In some cases, to prolong the action of a drug, it may be desirable to slow the absorption of subcutaneously or intramuscularly injected drugs. This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility. The absorption rate of the drug then depends on its dissolution rate, which in turn may depend on the crystal size and crystal form. Alternatively, delayed absorption of parenteral drug forms can be achieved by dissolving or suspending the drug in an oil medium.

[0487] Injectable reservoir formulations are prepared by forming the subject compound into a microencapsulated matrix of a biodegradable polymer such as poly(lactide-polyglycolic acid). The drug release rate can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Injectable reservoir formulations are also prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissues.

[0488] For use in the methods of the present invention, the active compound may be administered either as the active compound itself or as a pharmaceutical composition comprising, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0489] Introduction methods can also be provided through refillable or biodegradable devices. In recent years, various slow-release polymeric devices have been developed and tested in vivo for the controlled delivery of drugs, including protein biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), encompassing both biodegradable and non-degradable polymers, can be used to form implants for the sustained release of compounds at specific target sites.

[0490] The actual dose level of the active ingredient in a pharmaceutical composition can be altered to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic response for a specific patient, composition, and administration mode, while being non-toxic to the patient.

[0491] The chosen dose level will depend on a number of factors, including the specific compound or combination of compounds used, or the activity of their esters, salts or amides; the route of administration; the time of administration; the excretion rate of one or more specific compounds used; the duration of treatment; other drugs, compounds and / or materials used in combination with one or more specific compounds used; the age, sex, weight, condition, general health and medical history of the subject being treated; and similar factors well known in the medical field.

[0492] A physician or veterinarian with common skills in the art can readily determine and specify the desired therapeutically effective amount of a pharmaceutical composition. For example, a physician or veterinarian may start with a dose of the pharmaceutical composition or compound below the level required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. "Therapeutically effective amount" means the concentration of the compound sufficient to induce the desired therapeutic effect. It is generally understood that the effective amount of a compound will vary depending on the subject's weight, sex, age, and medical history. Other factors affecting the effective amount may include, but are not limited to, the severity of the subject's illness, the condition being treated, the stability of the compound, and, if necessary, another type of therapeutic agent administered with the compound of the present invention. A larger total dose can be delivered by multiple administrations of the agent. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine, 13th edition, 1814-1882, incorporated herein by reference).

[0493] Generally, the suitable daily dose of the active compound used in the compositions and methods of the present invention will be the amount of the compound that is the lowest dose at which it effectively produces a therapeutic effect. This effective dose will typically depend on the factors described above.

[0494] If desired, the effective daily dose of the active compound may be administered, optionally in sub-dose form, once, twice, three times, four times, five times, six times, or more, at appropriate intervals throughout the day. In some embodiments of the invention, the active compound may be administered twice or three times daily. In a preferred embodiment, the active compound is administered once daily.

[0495] In some implementations, dosing follows a 3+3 design. The traditional 3+3 design does not require dose-toxicity curve modeling, going beyond the classic assumption of dose-increasing toxicity for cytotoxic drugs. This rule-based design is conducted in a cohort of three patients; the first cohort is treated with a starting dose deemed safe based on extrapolation from animal toxicology data, and subsequent cohorts are treated with pre-fixed escalating dose levels. In some implementations, the three doses of the compound of formula (I) are in the range of 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. When not taken with food, dosing may be three times a day, or twice a day when taken with food. In some embodiments, the three doses of the compound of formula (I) are in the range of about 400 mg to about 800 mg twice a day, 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. In some preferred embodiments, the dose is administered twice a day at a dose greater than about 600 mg.

[0496] If none of the three patients in the cohort experience dose-limiting toxicity, the remaining three patients will be treated at a higher dose level. However, if one of the first three patients experiences dose-limiting toxicity, the next three patients will be treated at the same dose level. Dose escalation continues until at least two patients in the cohort of three to six experience dose-limiting toxicity (i.e., ≥33% of patients experience dose-limiting toxicity at that dose level). The recommended dose for Phase II trials is typically determined to be the dose level below this toxicity level.

[0497] In some implementations, the dosing time may be approximately 40 mg / m². 2 Approximately 100 mg / m 2 Such as approximately 50 mg / m 2Approximately 80 mg / m 2 Furthermore, such as approximately 70 mg / m 2 Approximately 90 mg / m 2 Administered intravenously (IV) for 3 weeks out of a 4-week cycle.

[0498] In some embodiments, the compounds of the present invention may be used alone or in combination with another type of therapeutic agent. As used herein, the phrase "combined administration" refers to any form of administration of two or more different therapeutic compounds such that a second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., both compounds are effective in the subject simultaneously, which may include the synergistic effect of the two compounds). For example, different therapeutic compounds may be administered in parallel or sequentially, either in the same formulation or as separate formulations. In some embodiments, different therapeutic compounds may be administered within one hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or one week of each other. Thus, an individual receiving such treatment may benefit from the combined effect of the different therapeutic compounds.

[0499] In some embodiments, combined administration of the compound of the invention with one or more additional therapeutic agents (e.g., one or more additional chemotherapeutic agents) provides improved efficacy relative to individual administration of the compound of the invention (e.g., compound of formula I or Ia) or one or more additional therapeutic agents. In some such embodiments, combined administration provides an additive effect, wherein the additive effect refers to the sum of the effects of each of the individual applications of the compound of the invention and one or more additional therapeutic agents.

[0500] This invention includes the use of pharmaceutically acceptable salts of the compounds of this invention in the compositions and methods of this invention. The salts of the compounds of this invention are formed between an acid and a basic group of the compound, such as an amino functional group, or between 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.

[0501] "Pharmaceutically acceptable salt" means any non-toxic salt that, when administered to a recipient, can directly or indirectly provide the compounds of the present invention. "Pharmaceutically acceptable counterion" is the non-toxic ionic portion of a salt that is released from the salt when administered to a recipient.

[0502] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, as well as organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartrate, ascorbic acid, maleic acid, benzenesulfonic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, as well as related inorganic and organic acids. Therefore, pharmaceutically acceptable salts of this class include sulfates, pyrosulfates, bisulfates, sulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, decanoates, heptanoates, propynates, oxalates, malonates, succinates, octanoates, sebates, transbutenedioates, maleate, and butyn-1,4-dicarboxylic acid. Salts, hexyn-1,6-diacidates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleic acid salts, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, 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.

[0503] In some embodiments, the salts of the present invention considered include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkylammonium salts. In some embodiments, the salts of the present invention considered include, but are not limited to, L-arginine, phenethylbenzylamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylreduced glucosamine, hydrabamine, 1H-imidazolium, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, thiamethoxam, and zinc salts. In some embodiments, the salts of the present invention considered include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts.

[0504] Pharmaceutically acceptable acid addition salts can also exist in various solvate forms, such as with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates can also be prepared. The source of this solvate can be from the solvent of crystallization, it can be inherent in the solvent of preparation or crystallization, or it can be foreign to this solvent.

[0505] Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, releasing agents, coating agents, sweeteners, flavoring agents and aroma agents, preservatives and antioxidants may also be present in the composition.

[0506] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as palmitic acid ascorbate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0507] Although specific embodiments of this disclosure are described hereby with reference to preparations and schemes, it should be understood that such embodiments are merely illustrative and represent only a few of the many possible specific embodiments illustrating the application of the principles of this disclosure. In view of the benefits of this disclosure, various changes and modifications will be apparent to those skilled in the art and are considered to be within the spirit and scope of this disclosure as further defined in the appended claims.

[0508] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Although other compounds or methods may be used in practice or testing, certain preferred methods are described hereinstantly in the context of the following preparation and scheme.

[0509] Many synthetic schemes are used to produce the compounds described herein. These synthetic schemes (see below) have common overlap and can be used alternatively to synthesize the compounds described herein.

[0510] Example

[0511] General Scheme

[0512] The compound and intermediate of formula (I) can be prepared by the general procedures described in schemes 1-9.

[0513] Option 1.

[0514]

[0515] Scheme 1 describes the synthesis of intermediate A as an aryl methyl ketone. Any commercially available starting material that can be converted into an aryl methyl ketone can be used in this case using conventional chemical reactions well known in the art. For example, acid 1 can be converted (step 1a) into Weinreb amide (3) by coupling said acid with a methoxy(methyl)amine (2). Then, a methyl anion source such as a Grignard reagent or lithium methyl can be added to the Weinreb amide (step 2a) to form the desired aryl methyl ketone, i.e., intermediate A. Alternatively, an aryl halide derivative (4) can be subjected to Stille coupling (step 1b) to form aryl methyl ketone intermediate A. Alternatively, an aldehyde can be converted into an alcohol (7) in a reaction with a Grignard reagent or lithium methyl (step 1c), followed by oxidation (step 2b).

[0516] Option 2.

[0517]

[0518] In Scheme 2, arylmethyl ketone (intermediate A) can be converted to arylbromomethyl ketone (8) by treating intermediate A with a brominating agent such as pyridinium tribromide (step 1d). 8 is then condensed with thiourea in a polar solvent such as ethanol at room temperature or high temperature to produce arylaminothiazole 9 (step 2d). A halogen (X = bromine or iodine) substituent can be introduced into position 5 of the arylaminothiazole by treating 9 with a suitable halogenating agent such as NBS or NIS (step 3d) to produce intermediate B.

[0519] Option 3.

[0520]

[0521] Scheme 3 describes a method for preparing an arylaminothiazole (intermediate C). At high temperature, using a catalyst such as X-phos-Pd, an arylmethyl ketone (intermediate A) is coupled with an aryl bromide (10) to produce ketone 11 (step 1e). The aryl bromide 10 is obtained by a suitable reaction, such as alkylation of a substituted phenol with an alkyl halide or alkyl trifluoromethanesulfonate (see “Preparation of Intermediates” for illustrative examples). 11 is condensed with a thiourea (step 2e) to produce intermediate C.

[0522] Option 4.

[0523]

[0524] In scheme 4, arylbromine 10 is converted into arylboronic acid or pinacol boryl ester (intermediate D1 or D2) by conventional chemical reactions well known in the art (step 1f). D1 and D2 are interchangeable in the synthesis of intermediate C.

[0525] Option 5.

[0526]

[0527] Scheme 5 describes an alternative method for preparing intermediate C by coupling intermediate B with boric acid or pinacol boryl ester (D1 or D2) (step 1g).

[0528] Option 6.

[0529]

[0530] In scheme 6, the amino group in intermediate C is converted into the bromine substituent in intermediate G by a CuBr2 catalytic reaction carried out at high temperature (step 1h).

[0531] Option 7.

[0532]

[0533] Scheme 7 describes the preparation of intermediate G, wherein the substituent Cy 1 It contains a nitrogen-linking group. In step 1i, the amino group in the thiazole (intermediate B) can be removed by a reaction mediated by tert-butyl nitrite to avoid complicating the 5-position halogen substitution reaction in the next step. After the halogen at the 5-position is replaced by the amino group (step 2i), the halogen at the 2-position can be reintroduced by a simple bromination or iodination reaction (step 3i) to obtain intermediate G.

[0534] Scheme 8. Synthesis of compound (I), method 1.

[0535]

[0536] Scheme 8 describes a method 1 for synthesizing compound (I) by a direct sulfonamide formation reaction of aminothiazole (intermediate C) with arylsulfonyl chloride (step 1j).

[0537] Scheme 9. Synthesis of compound (I), method 2.

[0538]

[0539] Scheme 9 describes method 2 for synthesizing compound (I) via a Buchwald coupling reaction (step 1k) of a bromine derivative (intermediate G) and a sulfonamide (intermediate R). For the synthesis of sulfonamides (intermediate R) that are not commercially available, see the section entitled "Preparation of Intermediates".

[0540] Analysis program

[0541] Unless otherwise instructed, 1¹H NMR spectra were run at 400 MHz on a Gemini 400 or Varian Mercury 400 spectrometer with an ASW 5 mm probe, and typically at ambient temperature in deuterated solvents such as D₂O, DMSO-D₆, or CDCl₃. Chemical shift values ​​(δ) are indicated in parts per million (ppm) with tetramethylsilane (TMS) as an internal standard.

[0542] High-performance liquid chromatography-mass spectrometry (LCMS) experiments used to determine retention time (RT) and associated mass ions are performed using one of the following methods.

[0543] Mass spectrometry (MS) was performed using a Micromass mass spectrometer. Typically, positive electrospray ionization was used, with scan masses ranging from 100 to 1000 m / z. Liquid chromatography was performed on a Hewlett Packard 1100 series binary pump and degasser; the auxiliary detectors used were a Hewlett Packard 1100 series UV detector at 220 nm and a SedereSEDEX 75 evaporative light scattering (ELS) detector at 46 °C and N2 pressure of 4 bar.

[0544] LCT: Gradient (AcN + 0.05% TFA): (H2O + 0.05% TFA) = 5:95 (0 min) to 95:5 (2.5 min) to 95:5 (3 min). Column: YMC Jsphere 33×2 4μM, 1ml / min

[0545] MUX: Column: YMC Jsphere 33×2, 1ml / min

[0546] Gradient (AcN + 0.05% TFA): (H2O + 0.05% TFA) = 5:95 (0 min) to 95:5 (3.4 min) to 95:5 (4.4 min).

[0547] LCT2: YMC Jsphere 33×2 4μM, (AcN+0.05%TFA): (H2O+0.05%TFA)=5:95 (0min) to 95:5 (3.4min) to 95:5 (4.4min).

[0548] QU: YMC Jsphere 33×2 1ml / min, (AcN+0.08% formic acid):(H2O+0.1% formic acid)=5:95(0min) to 95:5(2.5min) to 95:5(3.0min).

[0549] Preparation of intermediates

[0550] This section, “Preparation of Intermediates,” describes the synthesis of common intermediates used in the preparation of the examples. It is not intended to list all intermediates. Rather, the procedures shown herein are for illustrative purposes only. This should not impose any limitation or constraint on the methods used in the synthesis examples.

[0551] Intermediate A-1

[0552] 1-(2-Isopropylphenyl)ethyl-1-one

[0553]

[0554] Step 1.

[0555]

[0556] At room temperature, HATU (6.42 g, 16.89 mmol), N,O-dimethylhydroxylamine hydrochloride (1.25 g, 12.88 mmol), and TEA (2.57 g, 25.46 mmol) were added to a solution of 2-isopropylbenzoic acid (1.39 g, 8.45 mmol) in DMF (13 mL). The resulting mixture was stirred for 3 h at the same temperature. The mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL × 2). The extract was washed with water (100 mL × 2), dried over sodium sulfate, and evaporated. The crude product obtained was purified by silica gel chromatography (PE / EA = 5 / 1) to produce 2-isopropyl-N-methoxy-N-methylbenzamide (1.50 g, 85.5%) as a colorless oil.

[0557] LCMS: MS(ESI): m / z 208[M+H] + .

[0558] Step 2.

[0559]

[0560] At 0 °C and under N2, MeMgBr (8.5 mL, 25.5 mmol, 3.0 M) was added to a solution of 2-isopropyl-N-methoxy-N-methylbenzamide (1.75 g, 8.44 mmol) in THF (17 mL). The resulting mixture was stirred for 2 h at room temperature. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL × 2). The extract was washed with water (40 mL × 2), dried over sodium sulfate, and evaporated. The resulting residue was purified by silica gel chromatography (PE / EA = 10 / 1) to provide 1-(2-isopropylphenyl)ethyl-1-one (1.25 g, 91.3%) as a colorless oil.

[0561] LCMS: MS(ESI): m / z 163[M+H] + .

[0562] Intermediate A-2

[0563] 1-(2-Isopropoxy-6-methylphenyl)ethyl-1-one

[0564]

[0565] Step 1.

[0566]

[0567] A mixture of 2-hydroxy-6-methylbenzoic acid (5.0 g, 32.9 mmol), potassium carbonate (18.16 g, 131.6 mmol), and 2-iodopropane (19.58 g, 115 mmol) in DMF (90 mL) was stirred overnight at 50 °C. LCMS indicated that 2-hydroxy-6-methylbenzoic acid remained, so 2-iodopropane (11.19 g, 65.8 mmol) and potassium carbonate (9.08 g, 65.8 mmol) were added at room temperature, and the reaction mixture was stirred again at 50 °C for 4 h. After cooling to room temperature, water (250 mL) was added, and the mixture was extracted with ethyl acetate (80 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (8% ethyl acetate / petroleum ether) to produce the product 2-isopropoxy-6-methylbenzoate (7.648 g, 99% yield) as a colorless oil.

[0568] LCMS: Retention time 2.24 min. MS(ESI) m / z 237 [M+H] + .

[0569] Step 2.

[0570]

[0571] Potassium hydroxide (54.5 g, 971 mmol) was added to a mixture of isopropyl 2-isopropoxy-6-methylbenzoate (7.65 g, 32.4 mmol) in dimethyl sulfoxide (27 mL) and water (30 mL) at room temperature. The mixture was stirred overnight at 100 °C. The mixture was diluted with water (30 mL), acidified to pH 2 with 6N HCl at 0 °C, extracted with ethyl acetate (80 mL × 3), washed with brine (80 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to produce a crude product of 2-isopropoxy-6-methylbenzoic acid (5.28 g), which was a pale yellow oil.

[0572] 1 ¹H NMR (400MHz, chloroform-d) δ 7.30 (t, J = 8.0Hz, 1H), 6.90 (d, J = 7.6Hz, 1H), 6.86 (d, J = 8.0Hz, 1H), 4.69 (m, 1H), 2.54 (s, 3H), 1.41 (d, J = 6.0Hz, 6H) ppm.

[0573] LCMS: Retention time 1.84 min. MS (ESI) m / z 177 [M-OH] + .

[0574] Step 3.

[0575]

[0576] At 0 °C under an argon atmosphere, a borane-dimethyl sulfide complex (52.5 mL, 105 mmol, 2.0 M) was added dropwise to a solution of 2-isopropoxy-6-methylbenzoic acid (5.1 g, 26.3 mmol) in tetrahydrofuran (45 mL). The resulting mixture was stirred at 60 °C for 3 h. After cooling to room temperature, the reaction mixture was adjusted to approximately pH 8 with 2.0 M sodium hydroxide solution, diluted with water (100 mL), extracted with diethyl ether (80 mL × 3), and the combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a crude product (2-isopropoxy-6-methylphenyl)methanol (4.21 g) as a yellow oil, which was used directly in the next step without further purification.

[0577] LCMS: LC retention time 1.95 min. MS (ESI) m / z 163 [M-OH] + .

[0578] Step 4.

[0579]

[0580] Active manganese dioxide (40.7 g, 468 mmol) was added to a stirred solution of (2-isopropoxy-6-methylphenyl)methanol (4.21 g, 23.4 mmol) in dichloromethane (50 mL). The resulting mixture was stirred at 50 °C for 3 h. Additional active manganese dioxide (40.7 g, 468 mmol) and dichloromethane (10 mL) were added. The resulting mixture was stirred at 50 °C for 18 h. The manganese dioxide was filtered off with diatomaceous earth, washed with ethyl acetate, and the filtrate was evaporated under reduced pressure to produce a crude product, 2-isopropoxy-6-methylbenzaldehyde (3.6 g), which was a yellow oil.

[0581] LCMS: LC retention time 2.15 min. MS(ESI) m / z 179 [M+H] + .

[0582] Step 5.

[0583]

[0584] At 0 °C under an argon atmosphere, methyl magnesium bromide (20.2 mL, 3.0 M ether solution, 60.6 mmol) was added to a solution of 2-isopropoxy-6-methylbenzaldehyde (3.60 g, 20.2 mmol) in tetrahydrofuran (30.0 mL). The resulting mixture was stirred for 3 h at room temperature. The mixture was quenched with a saturated aqueous ammonium chloride solution (30 mL), diluted with water (120 mL), and extracted with ethyl acetate (60 mL × 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to produce a crude product, 1-(2-isopropoxy-6-methylphenyl)ethyl-1-ol (3.82 g), which was a pale yellow oil.

[0585] LCMS: LC retention time 2.07 min. MS (ESI) m / z 177 [M-OH] +

[0586] Step 6.

[0587]

[0588] Active manganese dioxide (44 g, 506 mmol) was added to a solution of 1-(2-isopropoxy-6-methylphenyl)ethyl-1-ol (3.82 g, 19.7 mmol) in dichloromethane (50 mL). The resulting mixture was stirred at 50 °C for 14 h, and then active manganese dioxide (17 g, 195.5 mmol) and dichloromethane (10 mL) were added. The resulting mixture was stirred at 50 °C for 3 h. The manganese dioxide was filtered through diatomaceous earth, washed with ethyl acetate, and the solvent was evaporated under reduced pressure to produce a crude product, which was purified by silica gel chromatography (5% ethyl acetate / petroleum ether) to produce 1-(2-isopropoxy-6-methylphenyl)ethyl-1-one (3.14 g, 62% yield, in 4 steps) as a pale yellow oil.

[0589] LCMS: LC retention time 2.12 min. MS(ESI) m / z 193 [M+H] + .

[0590] 1¹H NMR (400MHz, chloroform-d) δ 7.17 (t, J = 8.0Hz, 1H), 6.73–6.77 (m, 2H), 4.56 (m, 1H), 2.49 (s, 3H), 2.22 (s, 3H), 1.32 (d, J = 6.0Hz, 6H) ppm.

[0591] Intermediate A-3

[0592] 1-(2-Isopropoxy-4-(trifluoromethyl)phenyl)ethyl-1-one

[0593]

[0594] Step 1.

[0595]

[0596] N,O-dimethylhydroxylamine (1.18 g, 12.1 mmol), HATU (4.61 g, 12.1 mmol), and DIPEA (7.82 g, 60.6 mmol) were added to a solution of 2-hydroxy-4-(trifluoromethyl)benzoic acid (2.50 g, 12.1 mmol) in THF (30 mL). The mixture was stirred at room temperature for 2 h. It was then diluted with EtOAc (50 mL) and H2O (50 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by SGC (PE / EA = 5 / 1) to provide the desired compound 2-hydroxy-N-methoxy-N-methyl-4-(trifluoromethyl)benzamide (2.40 g, 79.4%) as a colorless oil.

[0597] LC retention time: 1.77 min. MS (ESI) m / z: 250 [M+H] + .

[0598] Step 2.

[0599]

[0600] To a solution of 2-hydroxy-N-methoxy-N-methyl-4-(trifluoromethyl)benzamide (3.80 g, 15.2 mmol) in THF (50 mL), 2-iodopropane (2.59 g, 15.2 mmol) and K₂CO₃ (4.21 g, 30.5 mmol) were added. The mixture was stirred overnight at 40 °C. It was then extracted twice with EA (50 mL) and with H₂O (50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel chromatography (PE / EA = 20 / 1) to provide 2-isopropoxy-N-methoxy-N-methyl-4-(trifluoromethyl)benzamide (3.60 g, 81%) as a pale yellow oil.

[0601] LC retention time: 2.03 min. MS (ESI) m / z: 292 [M+H] + .

[0602] Step 3.

[0603]

[0604] MeMgBr (3.42 mL, 10.3 mmol) was added to a solution of 2-isopropoxy-N-methoxy-N-methyl-4-(trifluoromethyl)benzamide (2.00 g, 6.87 mmol) in THF (20 mL). The mixture was stirred at room temperature for 2 h. The mixture was then quenched with an aqueous solution of NH4Cl (50 mL) and extracted with EA (50 mL × 2). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography (PE / EA = 20 / 1) to provide the title intermediate (1.20 g, 71%) as a pale yellow oil.

[0605] LCMS: LC retention time 2.22 min. MS(ESI) m / z 247 [M+H] + .

[0606] Intermediate A-4

[0607] 1-(2-Cyclopropylphenyl)ethyl-1-one

[0608]

[0609] Step 1.

[0610]

[0611] Under a nitrogen atmosphere, palladium acetate (113 mg, 0.5 mmol) was added to a solution of 1-(2-bromophenyl)ethyl-1-one (2.00 g, 10.0 mmol), cyclopropylboronic acid (1.12 g, 13.0 mmol), K3PO4 (7.46 g, 35.0 mmol), and tricyclohexylphosphine (280 mg, 1.0 mmol) in toluene (40 mL) and water (4.0 mL). The mixture was heated to 100 °C and stirred at the same temperature for 3 h, then cooled to room temperature. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to produce a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 10 / 1) to produce the title intermediate (1.40 g, 87.0% yield) as a yellow oil.

[0612] LCMS: LC retention time 2.02 min. MS(ESI) m / z 161 [M+H] + .

[0613] Intermediate A-5

[0614] 1-(2-Methyl-6-(trifluoromethyl)phenyl)ethyl-1-one

[0615]

[0616] Step 1.

[0617]

[0618] A mixture of 2-bromo-1-methyl-3-(trifluoromethyl)benzene (2.00 g, 8.37 mmol), tributyl(1-ethoxyvinyl)stanane (4.30 g, 11.9 mmol), and Pd(PPh3)4 (194 mg, catalytic amount) in toluene (50 mL) was stirred for 16 h at 120 °C under N2 atmosphere. The mixture was concentrated, and the residue was purified by SGC (PE / EA = 10 / 1) to produce a light-colored oily intermediate. This intermediate was then treated with THF (40 mL) and 6N HCl aqueous solution (80 mL), and stirred for 6 h at room temperature. The mixture was extracted with EA (50 mL × 3). The organic layers were combined, washed with brine (50 mL × 2), dried over Na2SO4, and concentrated to produce a yellow oily 1-(2-methyl-6-(trifluoromethyl)phenyl)ethyl-1-one (1.50 g, 88.7%).

[0619] Intermediate A-6

[0620] 1-(2-(difluoromethyl)-6-methylphenyl)ethyl-1-one

[0621]

[0622] Step 1.

[0623]

[0624] At 0 °C, LiAlH4 (1.87 g, 49.1 mmol) was added to a solution of methyl 2-bromo-3-methylbenzoate (7.50 g, 32.7 mmol) in THF (53.6 mL). The mixture was stirred for 3 h at room temperature. Then, H2O / 15% NaOH / H2O (1:1:3) was added. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The mixture was purified by reversed-phase column chromatography to provide the title product (2-bromo-3-methylphenyl)methanol (6.00 g, 91.1%).

[0625] LC-MS (acid): LC retention time 2.01 min. MS (ESI) m / z 200 [M+H] + .

[0626] Step 2.

[0627]

[0628] At 0 °C, Dess-Martin periodide (12.7 g, 29.8 mol) was added to a solution of (2-bromo-3-methyl-phenyl)methanol (6.00 g, 0.0298 mol) in CH2Cl2 (60.0 mL). The mixture was stirred for 3 h at room temperature. It was then washed with ammonium bicarbonate solution. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by reversed-phase column chromatography to provide the title product 2-bromo-3-methylbenzaldehyde (5.60 g, 94.2%).

[0629] LC-MS (acid): LC retention time 2.09 min. MS (ESI) m / z 199 [M+H] + .

[0630] Step 3.

[0631]

[0632] DAST (6.79 g, 42.2 mmol) was added to a solution of 2-bromo-3-methylbenzaldehyde (5.60 g, 28.1 mmol) in CH2Cl2 (30.0 mL) at 0 °C. The mixture was stirred for 3 h at room temperature. The DCM solution was then washed with ammonium bicarbonate solution. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by SGC (PE) to provide the title product 2-bromo-1-(difluoromethyl)-3-methylbenzene (4.00 g, 64.3%).

[0633] LC-MS (acid): LC retention time 2.09 min. MS (ESI) m / z 221 [M+H] + .

[0634] Step 4.

[0635]

[0636] Pd(PPh3)4 (1.05 g, 0.905 mmol) and tributyl(1-ethoxyvinyl)stanane (7.84 g, 21.7 mmol) were added to a solution of 2-bromo-1-(difluoromethyl)-3-methylbenzene (4.00 g, 18.1 mmol) in toluene (20.0 mL). The mixture was stirred for 3 h at room temperature. Then, an aqueous solution of potassium fluoride was added. The mixture was stirred for 3 h at room temperature. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. A THF solution of HCl (12 N) was added to the mixture, and the mixture was stirred for 3 h. The mixture was then diluted with water (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The mixture was purified by SGC (PE) to provide the title product 1-(2-(difluoromethyl)-6-methylphenyl)ethyl-1-one (3.00 g).

[0637] LC-MS (acid): LC retention time 1.97 min. MS (ESI) m / z 184 [M+H] + .

[0638] Intermediate A-7

[0639] 1-(2,6-Dimethyl-4-(trifluoromethyl)phenyl)ethyl-1-one

[0640]

[0641] Step 1.

[0642]

[0643] Methylboric acid (3.37 g, 56.2 mmol), Pd(dppf)Cl2·DCM (613 mg, 0.750 mmol), and Cs2CO3 (18.3 g, 56.2 mmol) were added to a solution of 2-bromo-4-(trifluoromethyl)aniline (9.0 g, 37.5 mmol) in 1,4-dioxane (100 mL) and H2O (50 mL). The mixture was stirred at 100 °C for 16 h. Water (200 mL) was added to the mixture. The aqueous solution was then extracted with ethyl acetate (200 mL × 2). The organic layer was washed with brine (200 mL), dried over sodium sulfate, and concentrated under vacuum to obtain 2-methyl-4-(trifluoromethyl)aniline (5.20 g, 63.3%) as a yellow oil.

[0644] LCMS: LC retention time 1.92 min. MS(ESI) m / z 176 [M+H] + .

[0645] Step 2.

[0646]

[0647] NBS (6.27 g, 35.6 mmol) was added to a solution of 2-methyl-4-(trifluoromethyl)aniline (5.20 g, 23.8 mmol) in CH3CN (100 mL). The mixture was stirred at room temperature for 16 h. Water (100 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic layer was washed with brine (100 mL), dried over sodium sulfate, and concentrated under vacuum to produce 2-bromo-6-methyl-4-(trifluoromethyl)aniline (5.10 g, 71.8% yield) as a yellow oil.

[0648] LCMS: LC retention time 2.19 min. MS(ESI) m / z 256 [M+H] + .

[0649] Step 3.

[0650]

[0651] Methylboric acid (1.81 g, 30.1 mmol), Pd(dppf)Cl2·DCM (328 mg, 0.402 mmol), and Cs2CO3 (9.82 g, 30.1 mmol) were added to a solution of 2-bromo-6-methyl-4-(trifluoromethyl)aniline (5.1 g, 20.1 mmol) in 1,4-dioxane (100 mL) and H2O (50 mL). The mixture was stirred at 100 °C for 16 h. Water (200 mL) was added to the mixture, followed by extraction with ethyl acetate (200 mL × 2). The organic layer was washed with brine (200 mL), dried over sodium sulfate, and concentrated under vacuum to produce 2,6-dimethyl-4-(trifluoromethyl)aniline (3.60 g, 75.8% yield) as a yellow oil. The crude product was used directly in the next step without further purification.

[0652] LCMS: LC retention time 2.01 min. MS(ESI) m / z 190 [M+H] + .

[0653] Step 4.

[0654]

[0655] A solution of 2,6-dimethyl-4-(trifluoromethyl)aniline (3.6 g, 19.0 mmol) in HCl (50 mL) and water (50 mL) was cooled at 0 °C. Sodium nitrite (3.94 g, 57.1 mmol) aqueous solution was added dropwise. The mixture was stirred at the current temperature for 20 min. KI (6.32 g, 38.1 mmol) aqueous solution was added dropwise. The mixture was stirred at room temperature for 3 h. Water (100 mL) was added to the mixture, and extraction was performed with ethyl acetate (100 mL × 2). The organic layer was washed with brine (200 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by SGC (PE / EA = 10:1) to produce 2-iodo-1,3-dimethyl-5-(trifluoromethyl)benzene (3.00 g, 52.5% yield) as a yellow oil.

[0656] Step 5.

[0657]

[0658] Tributyl(1-ethoxyvinyl)stanane (5.42 g, 15.0 mmol) and Pd(PPh3)4 (119 mg, 0.1 mmol) were added to a solution of 2-iodo-1,3-dimethyl-5-(trifluoromethyl)benzene (3.0 g, 10.0 mmol) in toluene (80 mL). The mixture was stirred for 16 h at 100 °C under Ar conditions. The reaction was then cooled to room temperature and concentrated HCl (20.0 mL) was added. The mixture was stirred for 6 h at room temperature and extracted with Et2O (100 mL). The organic layer was washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE) to provide the title compound (1.70 g, 77.9%) as a colorless oil.

[0659] 1 ¹H NMR (400MHz, chloroform-d): δ 7.29 (s, 2H), 2.49 (s, 3H), 2.30 (s, 6H) ppm.

[0660] Intermediate A-8

[0661] 1-(2-chloro-6-(trifluoromethyl)phenyl)ethyl-1-one

[0662]

[0663] Step 1.

[0664]

[0665] At 0 °C under an argon atmosphere, a borane-dimethyl sulfide complex (44.6 mL, 89.2 mmol, 2.0 M) was added dropwise to a solution of 2-chloro-6-(trifluoromethyl)benzoic acid (5.0 g, 22.3 mmol). The resulting mixture was stirred at 60 °C for 27 h. LC-MS indicated that there was reactant remaining. Then, a borane-dimethyl sulfide complex (33.5 mL, 66.9 mmol, 2.0 M) was added dropwise at 0 °C. The resulting mixture was allowed to react at 60 °C for 65 h. After cooling to room temperature, the reaction mixture was adjusted to approximately pH 11 with 2.0 M sodium hydroxide solution, diluted with water (200 mL), and extracted with diethyl ether (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the product (2-chloro-6-(trifluoromethyl)phenyl)methanol (6.23 g) as a brown solid.

[0666] LCMS: LC retention time 1.89 min. MS(ESI) m / z 193 [M-17] + .

[0667] Step 2.

[0668]

[0669] At room temperature, Dysmartin periodide (18.9 g, 44.6 mmol) was added to a solution of (2-chloro-6-(trifluoromethyl)phenyl)methanol (6.23 g, 22.3 mmol) in dichloromethane (50 mL). The resulting reaction mixture was stirred for 19 h at room temperature. The solvent was removed under reduced pressure, and the residue was suspended in diethyl ether (50 mL) and stirred for 10 min. The resulting white solid was then filtered through diatomaceous earth, washed with diethyl ether, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (6% ethyl acetate / petroleum ether) to produce 2-chloro-6-(trifluoromethyl)benzaldehyde (3.47 g, 75% yield, two steps), a pale yellow oil.

[0670] LCMS: LC retention time 1.95 min. MS (ESI) m / z not observed.

[0671] 1 ¹H NMR (400MHz, chloroform-d) δ 10.50 (s, 1H), 7.72–7.66 (m, 2H), 7.58 (t, J = 8.0 Hz, 1H) ppm.

[0672] Step 3.

[0673]

[0674] MeMgBr (27.8 mL, 3.0 M ether solution, 83.4 mmol) was added dropwise to a solution of 2-chloro-6-(trifluoromethyl)benzaldehyde (3.47 g, 16.7 mmol) in anhydrous tetrahydrofuran (40.0 mL) at 0 °C under an argon atmosphere. The resulting mixture was stirred overnight at room temperature. The mixture was quenched with a saturated aqueous solution of ammonium chloride (40 mL) and diluted with water (30 mL), then extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (70 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to produce the desired product, 1-(2-chloro-6-(trifluoromethyl)phenyl)ethanol-1-ol (3.78 g), which was a pale yellow oil.

[0675] LCMS: LC retention time 2.08 min. MS (ESI) m / z 207 [M–OH] + .

[0676] Step 4.

[0677]

[0678] At 0 °C, Dysmartin periodide (14.2 g, 33.4 mmol) was added fractionally to a solution of 1-(2-chloro-6-(trifluoromethyl)phenyl)ethyl-1-one (3.78 g, crude product, 16.7 mmol) in dichloromethane (40.0 mL). The resulting reaction mixture was stirred for 3 h at room temperature. The solvent was removed under reduced pressure. The residue was suspended in diethyl ether (40 mL). The resulting mixture was stirred for 10 min. The resulting white solid was then filtered through diatomaceous earth and washed with diethyl ether. The filtrate was evaporated under reduced pressure. The crude product was purified by silica gel chromatography (10% ethyl acetate / petroleum ether) to produce 1-(2-chloro-6-(trifluoromethyl)phenyl)ethyl-1-one (2.63 g, 71% yield, two steps), a pale yellow oil.

[0679] LCMS: LC retention time 2.15 min. MS(ESI) m / z 223 [M+H] + .

[0680] Intermediate A-9

[0681] 1-(2-Isopropoxyphenyl)ethyl-1-one

[0682]

[0683] Step 1.

[0684]

[0685] A mixture of 1-(2-hydroxyphenyl)ethyl-1-one (4.0 g, 29.4 mmol), 2-iodopropane (6.49 g, 38.2 mmol), and K₂CO₃ (8.12 g, 58.8 mmol) in DMF (60 mL) was stirred for 16 h at 80 °C. The mixture was quenched with brine (300 mL), extracted with ethyl acetate (150 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel chromatography (PE / EA = 10 / 1) to produce the desired compound 1-(2-isopropoxyphenyl)ethyl-1-one (4.41 g, 84.2%) as a pale yellow oil.

[0686] 1 ¹H NMR (400MHz, chloroform-d) δ 7.72 (dd, J = 7.9, 1.8Hz, 1H), 7.42 (td, J = 8.1, 1.8Hz, 1H), 6.95 (t, J = 7.6Hz, 2H), 4.69 (dt, J = 12.1, 6.1Hz, 1H), 2.622 (s, 3H), 1.40 (d, J = 6.1Hz, 1H) ppm.

[0687] Intermediate B-1

[0688] 5-Iodo-4-(2-isopropylphenyl)thiazolyl-2-amine

[0689]

[0690] Step 1.

[0691]

[0692] Add pyridine hydrobromide perbromide (1.64 g, 5.15 mmol) to a solution of 1-(2-isopropylphenyl)ethyl-1-one (835 mg, 5.15 mmol) in DCM (8.0 mL). Stir the resulting mixture at room temperature for 2 h. Pour the mixture into water (50 mL) and extract with DCM (50 mL × 2). Wash the extract with water (40 mL × 2), dry over sodium sulfate and evaporate. Purify the crude product by silica gel chromatography (PE / EA = 10 / 1) to provide 2-bromo-1-(2-isopropylphenyl)ethyl-1-one (1167 mg, 93.9%) as a colorless oil.

[0693] LCMS: MS(ESI): m / z 243[M+H] + .

[0694] Step 2.

[0695]

[0696] Thiourea (741 mg, 9.74 mmol) was added to a solution of 2-bromo-1-(2-isopropylphenyl)ethyl-1-one (1.17 g, 4.84 mmol) in ethanol (12 mL). The resulting mixture was stirred overnight at room temperature. The mixture was alkalized to pH 12 with aqueous NaOH (2.0 M) and extracted with ethyl acetate (10 mL × 4). The combined organic phases were washed with aqueous Na₂S₂O₃ (20 mL × 2), H₂O (20 mL), and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (PE / EA = 5 / 1) to provide 4-(2-isopropylphenyl)thiazol-2-amine (1.00 g, 94.7%) as a pale yellow solid.

[0697] LCMS: Retention time 2.24 min; MS (ESI): m / z 219 [M+H] + .

[0698] Step 3.

[0699]

[0700] At room temperature, NIS (1.48 mg, 6.61 mmol) and AIBN (150 mg, 0.914 mmol) were added to a solution of 4-(2-isopropylphenyl)thiazol-2-amine (1250 mg, 5.73 mmol) in DCM (20 mL). The reaction mixture was then stirred for 3 h at the same temperature. The mixture was extracted with EA (200 mL × 2), washed with brine (200 mL), and dried over anhydrous Na₂SO₄. The filtrate was concentrated and purified by silica gel chromatography (PE / EA = 5 / 1) to provide 5-iodo-4-(2-isopropylphenyl)thiazol-2-amine (1286 mg, 65.2%) as a yellow solid.

[0701] LCMS: MS(ESI) m / z 345 [M+H] +

[0702] Intermediate B-2a

[0703] 5-Bromo-4-(2,6-dimethylphenyl)thiazol-2-amine

[0704]

[0705] Intermediate B-2b

[0706] 4-(2,6-Dimethylphenyl)-5-iodothiazole-2-amine

[0707]

[0708] Step 1.

[0709]

[0710] 1-(2,6-dimethylphenyl)ethyl-1-one (5.00 g, 33.78 mmol) was dissolved in acetonitrile (60 mL). Pyridinium tribromide (10.81 g, 33.78 mmol) was added to this solution. The mixture was stirred overnight at room temperature until the solution turned pale yellow or colorless. The solvent was extracted with dichloromethane (200 mL) and washed with water (300 mL). The organic layers were combined and concentrated under vacuum to provide 2-bromo-1-(2,6-dimethylphenyl)ethyl-1-one (7.29 g, 82.1%) as a yellow oil.

[0711] LCMS: LC retention time 2.06 min. MS(ESI) m / z 229 [M+H] + .

[0712] Step 2.

[0713]

[0714] Thiourea (2.44 g, 32.11 mmol) was added to a solution of 2-bromo-1-(2,6-dimethylphenyl)ethyl-1-one (7.29 g, 32.11 mmol) in ethanol (75 mL), and the reaction mixture was refluxed for 2 h. After removing the solvent, the resulting white precipitate was suspended in water / saturated NaHCO3 aqueous solution (30 / 70, 250 mL) and washed for 1 h. The solution was extracted with ethyl acetate (200 mL × 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to produce a crude substance, which was purified by silica gel chromatography (PE / EA = 1 / 1) to produce 4-(2,6-dimethylphenyl)thiazol-2-amine (5.30 g, 80.8%) as a yellow solid.

[0715] LCMS: LC retention time 1.45 min. MS(ESI) m / z 205 [M+H] + .

[0716] Step 3a.

[0717]

[0718] NBS (872.5 mg, 4.90 mmol) was added to a solution of 4-(2,6-dimethylphenyl)thiazol-2-amine (1.0 g, 4.90 mmol) in anhydrous tetrahydrofuran (20 mL). After stirring overnight at room temperature, the mixture was partitioned between ethyl acetate (100 mL) and water (80 mL). The organic phase was washed with water (150 mL × 2), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to produce a crude substance, which was purified by silica gel chromatography (PE / EA = 3 / 1) to produce 5-bromo-4-(2,6-dimethylphenyl)thiazol-2-amine (0.964 g, 69.5%) as a pale yellow solid.

[0719] LCMS: LC retention time 1.92 min. MS(ESI) m / z 285 [M+H] + .

[0720] Step 3b.

[0721]

[0722] N-iodosuccinimide (551 mg, 2.45 mmol) was added to a solution of 4-(2,6-dimethylphenyl)thiazol-2-amine (500 mg, 2.45 mmol) in tetrahydrofuran (5.0 mL), and the resulting mixture was allowed to react at room temperature for 3 h. The reaction was quenched by adding water (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated under vacuum (at approximately 40 °C), and purified by silica gel column chromatography (PE / EA = 5 / 1) to provide the title compound 4-(2,6-dimethylphenyl)-5-iodothiazol-2-amine (600 mg, 74%) as a brown solid.

[0723] LCMS: LC retention time 1.85 min. MS(ESI) m / z 331 [M+H] + .

[0724] Intermediate B-3

[0725] 4-(2,6-Dimethyl-4-(trifluoromethyl)phenyl)-5-iodothiazole-2-amine

[0726]

[0727] Step 1.

[0728]

[0729] Add pyridinium tribromide (2.01 g, 6.29 mmol) to a solution of 1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)ethyl-1-one (intermediate A-7) (1.7 g, 6.29 mmol) in acetonitrile (60 mL). Stir the mixture overnight at room temperature. Remove the solvent under vacuum; extract the residue with dichloromethane (50 mL × 2) and wash with water (100 mL). Combine the organic layers and concentrate under vacuum to provide crude 2-bromo-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)ethyl-1-one (1.90 g).

[0730] Step 2.

[0731]

[0732] Thiourea (377 mg, 4.96 mmol) was added to a solution of 2-bromo-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)ethyl-1-one (1.90 g, 4.51 mmol) in ethanol (50.0 mL), and the mixture was refluxed for 4 h. After removing the solvent under vacuum, the residue was stirred with a saturated aqueous sodium bicarbonate solution (40 mL) for 20 min. The mixture was then extracted with ethyl acetate (50 mL × 2). The combined organic solutions were washed with brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (silica gel, PE / EA = 3:1) to obtain the title compound 4-(2,6-dimethyl-4-(trifluoromethyl)phenyl)thiazol-2-amine (1.10 g, 89.6% yield) as a colorless solid.

[0733] LCMS: LC retention time 1.68 min. MS(ESI) m / z 273 [M+H] + .

[0734] Step 3.

[0735]

[0736] NIS (1.07 g, 4.77 mmol) was added to a solution of 4-(2,6-dimethyl-4-(trifluoromethyl)phenyl)thiazole-2-amine (1.30 g, 4.77 mmol) in CH3CN (60 mL). The mixture was stirred at room temperature for 16 h. The solvent was then removed by rotary evaporation. Water (100 mL) was added to the residue, and the mixture was extracted with EA (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and purified by silica gel column chromatography (PE / EA = 3:1) to obtain 4-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-5-iodothiazole-2-amine (1.30 g, 61.5%) as a yellow solid.

[0737] LCMS: LC retention time 2.15 min. MS(ESI) m / z 399 [M+H] + .

[0738] Intermediate B-4

[0739] 5-Iodo-4-(2-methyl-6-(trifluoromethyl)phenyl)thiazolyl-2-amine

[0740]

[0741] Step 1.

[0742]

[0743] At 0 °C, pyridinium tribromide (2.37 g, 7.42 mmol) was slowly added to a mixture of 1-[2-methyl-6-(trifluoromethyl)phenyl]ethyl ketone (intermediate A5) (1.50 g, 7.42 mmol) in CH3CN (40 mL). The resulting mixture was stirred for 12 h at room temperature and then concentrated. The residue was diluted with brine (70 mL), extracted with EA (50 mL × 3), dried over Na2SO4, and concentrated to produce 2-bromo-1-[2-methyl-6-(trifluoromethyl)phenyl]ethyl ketone (1.80 g, 86.3%) as a brown solid.

[0744] LCMS: LC retention time 2.109 min. MS(ESI) m / z 281 [M+H] + .

[0745] Step 2.

[0746]

[0747] A solution of 2-bromo-1-[2-methyl-6-(trifluoromethyl)phenyl]ethyl ketone (1.8 g, 6.4 mmol) and thiourea (487 mg, 6.4 mmol) in ethanol (30 mL) was stirred for 16 h at 80 °C. The mixture was concentrated, and the residue was purified by SGC (PE / EA = 2 / 1) to produce 4-[2-methyl-6-(trifluoromethyl)phenyl]thiazol-2-amine (700 mg, 42.3%) as a yellow solid.

[0748] LCMS: LC retention time 1.85 min. MS(ESI) m / z 259 [M+H] + .

[0749] Step 3.

[0750]

[0751] At room temperature, NIS (732 mg, 3.25 mmol) was added to a solution of 4-[2-methyl-6-(trifluoromethyl)phenyl]thiazol-2-amine (700 mg, 2.71 mmol) in THF (20 mL). After addition, the mixture was stirred for 12 h. The mixture was dried by purging with N2. The residue was diluted with brine (60 mL), extracted with EA (40 mL × 3), the organic layers were combined and washed with brine (40 mL × 3), dried over Na2SO4, and concentrated to produce 5-iodo-4-(2-methyl-6-(trifluoromethyl)phenyl)thiazol-2-amine (960 mg, 92.2%) as a brown solid.

[0752] LCMS: LC retention time 1.686 min. MS(ESI) m / z 385 [M+H] + .

[0753] Intermediate B-5

[0754] 5-Bromo-4-(2-(difluoromethyl)-6-methylphenyl)thiazolyl-2-amine

[0755]

[0756] Step 1.

[0757]

[0758] Add pyridinium tribromide (3.19 g, 0.0179 mol) to a solution of 1-[2-(difluoromethyl)-6-methylphenyl]ethyl ketone (intermediate A-6) (3.00 g, 0.0163 mol) in CH2Cl2 (30.0 mL). Stir the mixture at room temperature for 1 h. Dilute the mixture with water (10 mL). Extract the aqueous solution with EtOAc (10 mL × 2). Dry the combined organic phases over anhydrous sodium sulfate, filter, and concentrate under vacuum to provide the title compound 2-bromo-1-(2-(difluoromethyl)-6-methylphenyl)ethyl-1-one (3.70 g).

[0759] LC-MS (acid): LC retention time 2.03 min. MS (ESI) m / z 262 [M+H] + .

[0760] Step 2.

[0761]

[0762] Thiourea (1.07 g, 14.1 mmol) was added to a solution of 2-bromo-1-(2-(difluoromethyl)-6-methylphenyl)ethyl-1-one (3.70 g, 14.1 mmol) in EtOH (30.0 mL). The mixture was stirred at room temperature for 1 h. The mixture was diluted with water (10 mL). The aqueous solution was extracted with EtOAc (10 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by SGC (PE / EA = 3 / 1) to provide the title product 4-(2-(difluoromethyl)-6-methylphenyl)thiazol-2-amine (2.70 g).

[0763] LC-MS (acid): LC retention time 1.60 min. MS (ESI) m / z 241 [M+H] + .

[0764] Step 3.

[0765]

[0766] NBS (2.00 g, 11.2 mmol) was added to a solution of 4-[2-(difluoromethyl)-6-methylphenyl]thiazol-2-amine (2.70 g, 0.0112 mol) in THF (30.0 mL). The mixture was stirred for 1 h at room temperature. The mixture was diluted with water (10 mL). The aqueous solution was extracted with EtOAc (10.0 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by SGC (PE / EA = 3 / 1) to provide the title product 5-bromo-4-(2-(difluoromethyl)-6-methylphenyl)thiazol-2-amine (2.20 g, 61.3%).

[0767] LC-MS (acid): LC retention time 2.04 min. MS (ESI) m / z 320 [M+H] + .

[0768] Intermediate B-6

[0769] 5-Iodo-4-(2-isopropoxy-6-methylphenyl)thiazolyl-2-amine

[0770]

[0771] Step 1.

[0772]

[0773] At room temperature, pyridinium tribromide (5.21 g, 16.3 mmol) was added to a solution of 1-(2-isopropoxy-6-methylphenyl)ethyl-1-one (3.14 mg, 16.3 mmol) in acetonitrile (30 mL). The resulting mixture was stirred at room temperature for 17 h. LCMS indicated that 1-(2-isopropoxy-6-methylphenyl)ethyl one was in excess, and pyridinium tribromide (1.56 g, 4.89 mmol) was added again at room temperature. The resulting mixture was stirred at room temperature for another 3 h. The reaction was quenched with saturated aqueous sodium bicarbonate solution (30 mL), diluted with water (50 mL), and extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a crude product of 2-bromo-1-(2-isopropoxy-6-methylphenyl)ethyl-1-one (4.882 g) as a yellow oil.

[0774] LCMS: LC retention time 2.20 min. MS(ESI) m / z 273 [M+H] + .

[0775] Step 2.

[0776]

[0777] Thiourea (1.87 g, 24.6 mmol) was added to a solution of 2-bromo-1-(2-isopropoxy-6-methylphenyl)ethyl-1-one (4.88 g, crude, 16.4 mmol) in ethanol (25 mL). The resulting mixture was stirred at 80 °C for 3 h. The solvent was removed under reduced pressure, and the mixture was diluted with water (30 mL) and a saturated aqueous solution of sodium bicarbonate (40 mL). The aqueous solution was extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (35% ethyl acetate / petroleum ether) to produce 4-(2-isopropoxy-6-methylphenyl)thiazol-2-amine (3.21 g, 80% yield, in 2 steps) as a white solid.

[0778] LCMS: LC retention time 2.05 min. MS(ESI) m / z 387 [M+H] +

[0779] 1 ¹H NMR (400MHz, chloroform-d) δ 7.16 (t, J = 8.0Hz, 1H), 6.84 (d, J = 7.6Hz, 1H), 6.80 (d, J = 8.4Hz, 1H), 6.40 (s, 1H), 4.96 (s, 2H), 4.32 (m, 1H), 2.21 (s, 3H), 1.19 (d, J = 6.0Hz, 6H) ppm.

[0780] Step 3.

[0781]

[0782] At 0 °C, 1-iodopyrrolidine-2,5-dione (2.9 g, 12.9 mmol) was added to a solution of 4-(2-isopropoxy-6-methylphenyl)thiazol-2-amine (3.21 g, 12.9 mmol) in tetrahydrofuran (30 mL). The resulting mixture was stirred at room temperature for 1.5 h, and additional 1-iodopyrrolidine-2,5-dione (0.871 g, 3.87 mmol) was added at room temperature. The resulting reaction mixture was stirred again at room temperature for 40 min. The reaction was quenched with saturated sodium bicarbonate aqueous solution (30 mL), diluted with water (40 mL), and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with saturated sodium bicarbonate aqueous solution (60 mL) and brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to produce the product 5-iodo-4-(2-isopropoxy-6-methylphenyl)thiazol-2-amine (5.54 g), which was a brown solid.

[0783] LCMS: LC retention time 1.79 min. MS(ESI) m / z 375 [M+H] + .

[0784] 1 ¹H NMR (400MHz, chloroform-d) δ 7.22 (t, J = 8.0Hz, 1H), 6.85 (d, J = 7.6Hz, 1H), 6.79 (d, J = 8.4Hz, 1H), 5.36 (br, 2H), 4.38 (m, 1H), 2.09 (s, 3H), 1.22 (d, J = 5.2Hz, 6H) ppm.

[0785] Intermediate B-7

[0786] 4-(2-chloro-6-(trifluoromethyl)phenyl)-5-iodothiazole-2-amine

[0787]

[0788] Step 1.

[0789]

[0790] At room temperature, pyridinium tribromide (4.53 g, 14.2 mmol) was added to a solution of 1-(2-chloro-6-(trifluoromethyl)phenyl)ethyl-1-one (2.625 g, 11.8 mmol) in acetonitrile (20.0 mL). The resulting mixture was stirred overnight at room temperature. The solvent was removed. A saturated aqueous solution of sodium bicarbonate (50 mL) and water (40 mL) were added. The aqueous solution was then extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the product 2-bromo-1-(2-chloro-6-(trifluoromethyl)phenyl)ethyl-1-one (3.32 g) as a yellow oil.

[0791] LCMS: LC retention time 2.17 min. MS(ESI) m / z 301 [M+H] + .

[0792] Step 2.

[0793]

[0794] Thiourea (1.26 g, 16.5 mmol) was added to a solution of 2-bromo-1-(2-chloro-6-(trifluoromethyl)phenyl)ethyl-1-one (3.32 g, 11.0 mmol) in ethanol (24 mL). The reaction was stirred at 80 °C for 70 h. The solvent was removed under reduced pressure and diluted with water (70 mL) and a saturated aqueous solution of sodium bicarbonate (40 mL). The aqueous solution was extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (33% ethyl acetate / petroleum ether) to produce 4-(2-chloro-6-(trifluoromethyl)phenyl)thiazol-2-amine (2.17 g, 67% yield, in two steps) as a brown solid.

[0795] LCMS: LC retention time 1.81 min. MS(ESI) m / z 279 [M+H] + .

[0796] 1 ¹H NMR (400MHz, chloroform-d) δ 7.65–7.63 (m, 2H), 7.42 (m, 1H), 6.49 (s, 1H), 5.06 (s, 2H) ppm.

[0797] Step 3.

[0798]

[0799] At 0 °C, 1-iodopyrrolidine-2,5-dione (2.11 g, 9.37 mmol) was added to a solution of 4-(2-chloro-6-(trifluoromethyl)phenyl)thiazol-2-amine (2.18 g, 7.81 mmol) in tetrahydrofuran (20 mL). The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched with saturated aqueous sodium bicarbonate solution (30 mL), diluted with water (30 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to produce a brown solid, which was suspended in petroleum ether (30 mL) and dichloromethane (0.5 mL) and stirred for 30 min at room temperature. After filtration, the product 4-(2-chloro-6-(trifluoromethyl)phenyl)-5-iodothiazol-2-amine (3.14 g) was obtained as a brown solid.

[0800] LCMS: LC retention time = 2.04 min. MS(ESI) m / z = 405 [M+H] + .

[0801] 1 ¹H NMR (400MHz, chloroform-d) δ 7.68 (m, 2H), 7.48 (t, J = 8.0Hz, 1H), 5.22 (br, s, 2H) ppm.

[0802] Intermediate B-8

[0803] 5-Bromo-4-(2-isopropoxyphenyl)thiazol-2-amine

[0804]

[0805] Step 1.

[0806]

[0807] Add pyridinium tribromide (3.20 g, 10 mmol) to a solution of 1-(2-isopropoxyphenyl)ethyl-1-one (1.78 g, 10 mmol) in acetonitrile (50 mL). Stir the mixture overnight at room temperature until the solution turns pale yellow or colorless. Extract the solution with dichloromethane (100 mL × 3). Wash the DCM solution with water (80 mL). Combine the organic layers and concentrate under vacuum to provide 2-bromo-1-(2-isopropoxyphenyl)ethyl-1-one (2.41 g, 93.8%) as a yellow oil.

[0808] LCMS: LC retention time 2.10 min. MS(ESI) m / z 257 [M+H] + .

[0809] Step 2.

[0810]

[0811] Thiourea (742 mg, 9.75 mmol) was added to a solution of 2-bromo-1-(2-isopropoxyphenyl)ethyl-1-one (2.41 g, 9.38 mmol) in ethanol (50 mL), and the reaction mixture was refluxed for 2 h. After removing the solvent, the resulting white precipitate was suspended in saturated aqueous NaHCO3 solution (100 mL) and washed for 1 h. The solution was extracted with ethyl acetate (80 mL × 3). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to produce the desired compound 4-(2-isopropoxyphenyl)thiazol-2-amine (2.20 g, 100% yield) as a yellow oil.

[0812] LCMS: LC retention time 1.56 min. MS(ESI) m / z 235 [M+H] + .

[0813] Step 3.

[0814]

[0815] NBS (1.67 g, 9.4 mmol) was added to a solution of 4-(2-isopropoxyphenyl)thiazol-2-amine (2.20 g, 9.4 mmol) in anhydrous tetrahydrofuran (50 mL). After stirring overnight at room temperature, the mixture was partitioned between ethyl acetate (200 mL) and water (150 mL). The organic phase was washed with water (150 mL × 2), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure to produce a crude substance, which was purified by silica gel chromatography (PE / EA = 3 / 1) to produce the desired compound 5-bromo-4-(2-isopropoxyphenyl)thiazol-2-amine (1.70 g, 58%) as a reddish-brown oil.

[0816] LCMS: LC retention time 1.85 min. MS(ESI) m / z 315 [M+H] + .

[0817] Intermediate B-9

[0818] 5-Iodo-4-(2-(trifluoromethyl)phenyl)thiazol-2-amine

[0819]

[0820] Intermediate B-9 was prepared in essentially the same manner as intermediate B-7.

[0821] Intermediate B-10

[0822] 4-(2,2-Dimethylcyclopentyl)thiazol-2-amine

[0823]

[0824] Step 1.

[0825]

[0826] At 100 °C, over 2 h, 2-methylcyclohexane-1-one (10.00 g, 89.2 mol) was added dropwise to a stirred suspension of NaH (5.12 g, 134 mmol of 60% mineral oil dispersion) in anhydrous toluene (180 mL). At 60 °C, over 2 h, CH3I (19.00 g, 134 mol) was added dropwise to this mixture. The mixture was then stirred at 60 °C for another 2 h. After cooling, a mixture of NaOMe (10.60 g, 196 mmol) and HCO2Me (11.2 g, 152 mmol) was added to the mixture at 5 °C, and the reaction mixture was stirred at room temperature for 12 h, then poured into ice water (100 mL). The aqueous layer was acidified with 10% HCl aqueous solution and extracted with diethyl ether. The combined organic phases were washed with brine, dried over MgSO4 and concentrated to provide (E)-6-(hydroxymethylene)-2,2-dimethylcyclohexane-1-one (9.00 g, 65%) as a brown oil.

[0827] LCMS: LC retention time 2.09 min. MS(ESI) m / z 155 [M+H] + .

[0828] Step 2.

[0829]

[0830] 30% H₂O₂ (6.06 g, 53.5 mmol) was added dropwise to a solution of (E)-6-(hydroxymethylene)-2,2-dimethylcyclohexane-1-one (7.50 g, 48.6 mmol) in 13 mL of t-BuOH. The reaction mixture was stirred overnight at room temperature. The resulting solution was heated at 100 °C for 4 h. The reaction mixture was cooled to room temperature. 80 mL of water was added to this solution, followed by extraction with diethyl ether. The organic phase was washed with 2N NaOH solution (200 mL × 5). The extract was acidified with 4N HCl, followed by extraction with Et₂O (150 mL × 2), dried over Na₂SO₄, filtered, and concentrated to provide 2,2-dimethylcyclopentane-1-carboxylic acid (5.5 g, 79%) as a yellow oil.

[0831] 1¹H NMR (400MHz, chloroform-d) δ 2.09–1.49 (m, 7H), 1.21 (s, 3H), 0.96 (s, 3H) ppm.

[0832] Step 3.

[0833]

[0834] The reaction mixture of 2,2-dimethylcyclopentane-1-carboxylic acid (2.50 g, 17.6 mmol) in SOCl2 (10 mL) was heated for 2 h at 50 °C. The reaction mixture was then concentrated. The resulting residue was dissolved in CH3CN (10 mL). 2 M diazonylmethyl(trimethyl)silane (22 mL, 44 mmol) was added to this solution. The reaction mixture was stirred for 2 h at room temperature, cooled to 0 °C, and 40% HBr in AcOH solution (10.50 g, 52.7 mmol) was added dropwise. The mixture was stirred for 20 min at 0 °C. The mixture was filtered, and the filtrate was concentrated. The resulting residue was dissolved in EtOH (12 mL). Thiourea (1.34 g, 17.6 mmol) was added to this solution. The reaction mixture was heated for 1 h at 70 °C. The reaction mixture was concentrated and diluted with water, and the pH was adjusted with NaHCO3. The aqueous solution was extracted with EtOAc (50 mL × 2). The ethyl acetate solution was concentrated and purified by preparative TLC (DCM:MeOH = 10:1) to provide 4-(2,2-dimethylcyclopentyl)thiazol-2-amine (750 mg, 21%) as a brown oil.

[0835] LCMS: LC retention time 1.32 min. MS(ESI) m / z 197 [M+H] + .

[0836] Intermediate C-1

[0837] 5-(3-(3,3-dimethylbutoxy)phenyl)-4-(2-isopropylphenyl)thiazol-2-amine

[0838]

[0839] Step 1.

[0840]

[0841] To a solution of 3-bromophenol (5.00 g, 28.9 mmol) in 1,4-dioxane (80 mL), 1-bromo-3,3-dimethylbutane (6.20 g, 37.6 mmol) and Cs₂CO₃ (14.1 g, 43.4 mmol) were added. The resulting mixture was stirred overnight at 100 °C under an Ar atmosphere. The reaction mixture was cooled to room temperature and extracted with EA (20 mL × 3). The organic layers were combined, washed with brine (20 mL), and dried over anhydrous Na₂SO₄. The combined organic layers were concentrated under vacuum. The crude product thus obtained was purified by silica gel chromatography (100% PE) to provide 1-bromo-3-(3,3-dimethylbutoxy)benzene (7.40 g, 99.6%) as a yellow oil.

[0842] LCMS: LC retention time 2.73 min. MS(ESI) m / z 280 [M+Na] +

[0843] Step 2.

[0844]

[0845] To a solution of 1-bromo-3-(3,3-dimethylbutoxy)benzene (1.80 g, 7.0 mmol) in toluene (20 mL), 1-(2-isopropylphenyl)ethyl ketone (1.14 g, 7 mmol) was added, followed by the addition of t-BuOK (1.57 g, 14 mmol) and X-phos-Pd (55.2 mg, 0.07 mmol). The resulting mixture was stirred for 4 h at 65 °C under an Ar atmosphere. The reaction mixture was cooled to room temperature and quenched with NH4Cl (30 mL). The mixture was extracted with EA (10 mL × 3). The organic layers were combined, washed with brine (20 mL), and dried over anhydrous Na2SO4. The combined organic layers were concentrated under vacuum. The crude product was purified by silica gel chromatography (PE / EA = 4%) to provide 2-[3-(3,3-dimethylbutoxy)phenyl]-1-(2-isopropylphenyl)ethyl ketone (1.80 g, 76.0%) as a yellow oil.

[0846] LCMS: LC retention time 2.6 min. MS(ESI) m / z 339 [M+H] + .

[0847] Step 3.

[0848]

[0849] Thiourea (486 mg, 6.38 mmol) was added to a solution of 2-[3-(3,3-dimethylbutoxy)phenyl]-1-(2-isopropylphenyl)ethyl ketone (1.80 g, 5.32 mmol) in DMF (20 mL), followed by the addition of KHCO3 (638 mg, 6.38 mmol) and BrCCl3 (2.11 g, 10.6 mmol). The resulting mixture was stirred for 2 h at 80 °C under an Ar atmosphere. The reaction mixture was cooled and quenched with an aqueous solution of NH4Cl (30 mL) and extracted with EA (10 mL × 3). The organic layers were combined, washed with brine (20 mL), and dried over anhydrous Na2SO4. The organic layers were concentrated under vacuum. The crude substance was purified by silica gel chromatography (PE / EA = 40%) to provide 5-(3-(3,3-dimethylbutoxy)phenyl)-4-(2-isopropylphenyl)thiazol-2-amine (800 mg, 38.1%) as a brown oil.

[0850] LCMS: LC retention time 2.6 min. MS(ESI) m / z 395 [M+H] + .

[0851] Intermediate C-2

[0852] 5-(3-(2,2-difluoro-3,3-dimethylbutoxy)-4-fluorophenyl)-4-(2-isopropylphenyl)thiazol-2-amine

[0853]

[0854] Step 1.

[0855]

[0856] At room temperature, 2-tert-butyloxetane (3.93 g, 39.3 mmol) and cesium carbonate (17.08 g, 52.4 mmol) were added to a solution of 5-bromo-2-fluorophenol (5.00 g, 26.2 mmol) in N,N-dimethylformamide (60 mL). The resulting mixture was stirred overnight at 80 °C. The mixture was cooled to room temperature, diluted with water (350 mL), extracted with ethyl acetate (80 mL × 3), washed with water (100 mL × 2) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5% ethyl acetate / petroleum ether) to yield 1-(5-bromo-2-fluorophenoxy)-3,3-dimethylbut-2-ol (4.068 g, 53% yield) as a colorless oil.

[0857] LCMS: LC retention time 2.19 min. MS (ESI) m / z 275 [M-OH] +

[0858] 1 ¹H NMR (400MHz, chloroform-d) δ 7.11–7.08 (m, 1H), 7.06–7.02 (m, 1H), 69.8–6.93 (m, 1H), 4.16–4.13 (m, 1H), 3.91 (t, J = 8.8 Hz, 1H), 3.73–3.71 (m, 1H), 2.47 (s, 1H), 1.01 (s, 9H) ppm.

[0859] Step 2.

[0860]

[0861] At 0 °C, acetic acid (1,1-diacetoxy-3-oxo-1λ5,2-benzoiodazocyclopenten-1-yl) ester (8.89 g, 21 mmol) was added to a solution of 1-(5-bromo-2-fluorophenoxy)-3,3-dimethylbut-2-one (4.07 g, 14 mmol) in dichloromethane (60 mL). The resulting reaction mixture was stirred for 18 h at room temperature. The solvent was removed under reduced pressure. Diethyl ether (60 mL) was added to the residue, and the resulting mixture was stirred for 3 h at room temperature. The mixture was filtered through diatomaceous earth and washed with diethyl ether. The filtrate was concentrated, and the residue was purified by silica gel chromatography (5% ethyl acetate / petroleum ether) to produce 1-(5-bromo-2-fluorophenoxy)-3,3-dimethylbut-2-one (3.50 g, 87% yield) as a yellow oil.

[0862] LCMS: LC retention time 2.28 min. MS(ESI) m / z 291 [M+H] + .

[0863] 1 ¹H NMR (400MHz, chloroform-d): δ 7.07–7.03 (m, 1H), 6.99–6.94 (m, 2H), 4.94 (s, 2H), 1.25 (s, 9H) ppm.

[0864] Step 3.

[0865]

[0866] At 0 °C and under an argon atmosphere, N-ethyl-N-(trifluoro-λ4-thioalkyl)ethylamine (9.76 g, 60.5 mmol) was added to a solution of 1-(5-bromo-2-fluorophenoxy)-3,3-dimethylbut-2-one (3.5 g, 12.1 mmol) in anhydrous dichloromethane (40 mL). The resulting mixture was stirred for 40 h at room temperature. The reaction was quenched with a saturated aqueous sodium bicarbonate solution. After CO2 evaporation ceased, the aqueous phase was extracted with dichloromethane (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% ethyl acetate / petroleum ether) to yield a crude product, 4-bromo-2-(2,2-difluoro-3,3-dimethylbutoxy)-1-fluorobenzene (2.83 g, 75% yield), as a yellow oil.

[0867] LCMS: LC retention time 2.36 min. MS (ESI) m / z not observed.

[0868] Step 4.

[0869]

[0870] To a solution of 4-bromo-2-(2,2-difluoro-3,3-dimethylbutoxy)-1-fluorobenzene (1.00 g, 3.24 mmol) in anhydrous toluene (12 mL), 1-(2-isopropylphenyl)ethyl ketone (500 mg, 3.09 mmol) and potassium tert-butoxide (830 mg, 6.2 mmol) were added, followed by the addition of XPhos precatalyst (25 mg, 0.0309 mmol). The reaction was stirred for 6 h at 60 °C under a nitrogen atmosphere in a sealed tube. After cooling to room temperature, the mixture was filtered through diatomaceous earth. The filtrate was concentrated. The residue was purified by silica gel chromatography (10% ethyl acetate / petroleum ether) to yield the desired product, 2-(3-(2,2-difluoro-3,3-dimethylbutoxy)-4-fluorophenyl)-1-(2-isopropylphenyl)ethyl-1-one (977 mg, 81% yield), as a pale yellow oil.

[0871] LCMS: LC retention time 2.41 min. MS(ESI) m / z 393 [M+H] + .

[0872] Step 5.

[0873]

[0874] Thiourea (227 mg, 2.99 mmol), potassium bicarbonate (324 mg, 3.24 mmol), and chloroform (0.49 mL, 4.98 mmol) were added to a solution of 2-(3-(2,2-difluoro-3,3-dimethylbutoxy)-4-fluorophenyl)-1-(2-isopropylphenyl)ethyl-1-one (977 mg, 2.49 mmol) in DMF (8.0 mL). The reaction mixture was stirred at 70 °C for 4 h. After cooling to room temperature, the reaction mixture was diluted with water (80 mL) and a saturated sodium bicarbonate solution (80 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to provide the product 5-(3-(2,2-difluoro-3,3-dimethylbutoxy)-4-fluorophenyl)-4-(2-isopropylphenyl)thiazol-2-amine (195 mg, 18% yield) as a white solid.

[0875] LCMS: LC retention time 2.16 min. MS(ESI) m / z 449 [M+H] + .

[0876] Intermediate C-3

[0877] 5-(3-(2,2D-difluoro-3,3-dimethylbutoxy)phenyl)-4-(2-isopropylphenyl)thiazol-2-amine

[0878]

[0879] Step 1.

[0880]

[0881] DAST (5.18 g, 3.22 mmol) was added to a cooled (0 °C) and stirred solution of 1-(3-bromophenoxy)-3,3-dimethylbut-2-one (4.36 g, 1.61 mmol) in DCM (50 mL). The mixture was heated to room temperature and stirred overnight. LCMS showed that the starting material was consumed. Saturated NaHCO3 (50 mL) was added to the mixture, and extraction was performed with DCM (120 mL). The mixture was washed with water (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude material was purified by silica gel column chromatography (PE / EA = 20 / 1) to produce a mixture of compounds, 1-bromo-3-(2,2-difluoro-3,3-dimethylbutoxy)benzene, as a colorless oil containing approximately 50% of the desired compound (1.22 g, 25.9%).

[0882] LCMS: LC retention time 2.39 min. MS(ESI) m / z 294 [M+H] + .

[0883] Step 2.

[0884]

[0885] To a solution of 1-bromo-3-(2,2-difluoro-3,3-dimethylbutoxy)benzene (1.22 g, 4.16 mmol) in toluene (15 mL), 1-(2-isopropylphenyl)ethyl-1-one (743 mg, 4.58 mmol) and t-BuOK (932 mg, 8.32 mmol) were added, followed by X-phos-Pd (30.8 mg, 0.04 mmol). The reaction was stirred for 5 h at 60 °C under Ar conditions. After cooling to room temperature, a saturated aqueous solution of NH4Cl (50 mL) was added. The resulting solution was stirred thoroughly. The mixture was poured into water (100 mL) and extracted with ethyl acetate (80 mL × 3). The combined organic washings were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to produce a crude product. The crude material was purified by silica gel chromatography (PE / EA = 20 / 1) to produce the desired compound 2-(3-(2,2-difluoro-3,3-dimethylbutoxy)phenyl)-1-(2-isopropylphenyl)ethyl-1-one (1.23 g, 78.9%), which was a pale yellow oil.

[0886] LCMS: LC retention time 2.46 min. MS(ESI) m / z 397 [M+Na] + .

[0887] Step 3.

[0888]

[0889] Thiourea (300 mg, 3.94 mmol), KHCO3 (394 mg, 3.94 mmol), and BrCCl3 (1.30 g, 6.57 mmol) were added to a solution of 2-(3-(2,2-difluoro-3,3-dimethylbutoxy)phenyl)-1-(2-isopropylphenyl)ethyl-1-one (1.23 g, 3.28 mmol) in DMF (40 mL). The reaction mixture was heated to 80 °C and stirred for 2 h. After cooling to room temperature, the mixture was poured into water (80 mL), extracted with ethyl acetate (80 mL × 3), washed with brine (150 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to produce a crude substance, which was then purified by preparative HPLC to produce the desired compound 5-(3-(2,2-difluoro-3,3-dimethylbutoxy)phenyl)-4-(2-isopropylphenyl)thiazol-2-amine (320 mg, 22.6% yield) as a white solid.

[0890] LCMS: LC retention time 2.08 min. MS(ESI) m / z 431 [M+H] + .

[0891] Intermediate C-4

[0892] 5-(3-(3,3-dimethylbutoxy)phenyl)-4-(2-(trifluoromethyl)phenyl)thiazol-2-amine

[0893]

[0894] Step 1.

[0895]

[0896] 3-Bromophenol (3.43 g, 19.83 mmol) and Cs₂CO₃ (12.93 g, 39.69 mmol) were added to a stirred solution of 1-bromo-3,3-dimethylbutane (3.64 g, 22.06 mmol) in DMF (10 mL). The resulting mixture was stirred at room temperature for 20 h. The reaction mixture was then diluted with water (100 mL) and extracted with EA (200 mL × 2). The organic solution was washed with brine (200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (EA / PE = 1 / 10) to provide 1-bromo-3-(3,3-dimethylbutoxy)benzene as a colorless oil (4.61 g; 90.4%).

[0897] LCMS: LC retention time 2.64 min. MS(ESI) m / z 282 [M+Na] + .

[0898] 1 ¹H NMR (400MHz, chloroform-d): 7.15 (t, J = 8.4Hz, 1H), 7.10–7.07 (m, 2H), 6.86–6.83 (m, 1H), 4.02 (t, J = 7.6Hz, 2H), 1.74 (t, J = 7.6Hz, 2H), 1.01 (s, 9H) ppm.

[0899] Step 2.

[0900]

[0901] XPhos precatalyst (22 mg, 0.029 mmol) and C4H9OK (662 mg, 5.91 mmol) were added to a test tube equipped with a stir bar. The test tube was sealed with a screw cap lined with Teflon septum and evacuated / backfilled with argon. 1-(2-(trifluoromethyl)phenyl)ethyl-1-one (558 mg, 2.96 mmol), 1-bromo-3-(3,3-dimethylbutoxy)benzene (756 mg, 2.94 mmol), and toluene (6.0 mL) were added sequentially to the reaction vessel using a syringe. The reaction mixture was heated to 60 °C for 5 h. After cooling to room temperature, saturated NH4Cl aqueous solution (4.0 mL) was added to the reaction mixture, and the mixture was vigorously shaken. The mixture was then poured into a separatory funnel and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with brine, dried over sodium sulfate, and evaporated. The resulting residue was purified by silica gel chromatography (PE / EA = 10 / 1) using a Biotage instrument to provide 2-(3-(3,3-dimethylbutoxy)phenyl)-1-(2-(trifluoromethyl)phenyl)ethyl-1-one (820 mg, 76.6%) as a pale yellow oil.

[0902] LCMS: LC retention time 2.34 min. MS(ESI) m / z 387 [M+Na] + .

[0903] Step 3.

[0904]

[0905] To a solution of 2-(3-(3,3-dimethylbutoxy)phenyl)-1-(2-(trifluoromethyl)phenyl)ethyl-1-one (820 mg, 2.25 mmol) in DMF (5 mL), KHCO3 (339 mg, 3.39 mmol), thiourea (259 mg, 3.4 mmol), and CBrCl3 (852 mg, 4.3 mmol) were added. The mixture was stirred at 70 °C for 1 h. The mixture was diluted with water (50 mL) and extracted with EA (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (EA / PE = 1 / 1) to provide 5-(3-(3,3-dimethylbutoxy)phenyl)-4-(2-(trifluoromethyl)phenyl)thiazol-2-amine (130 mg, 13.7%) as a pale yellow solid.

[0906] LCMS: LC retention time 2.22 min. MS(ESI) m / z 421 [M+H] + .

[0907] Intermediate C-5

[0908] 4-(2,6-Dimethylphenyl)-5-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)phenyl)thiazole-2-amine

[0909]

[0910] Intermediate C-5 was prepared using essentially the same method as intermediate C-3.

[0911] Intermediate C-6a

[0912] 5-(3-(3,3-dimethylbutoxy)-5-fluorophenyl)-4-(2,6-dimethylphenyl)thiazol-2-amine

[0913]

[0914] Intermediate C-6a was prepared using essentially the same method as intermediate C-3.

[0915] Intermediate C-6b

[0916] 5-(3-(3,3-dimethylbutoxy)phenyl)-4-(2,6-dimethylphenyl)thiazol-2-amine

[0917]

[0918] Intermediate C-6b was prepared using essentially the same method as intermediate C-3.

[0919] Intermediate C-7

[0920] 5-(3-(3,3-dimethylbutoxy)-5-fluorophenyl)-4-(2-isopropylphenyl)thiazol-2-amine

[0921]

[0922] Step 1.

[0923]

[0924] To a solution of (3-(3,3-dimethylbutoxy)-5-fluorophenyl)boronic acid (intermediate D-1) (512 mg, 2.13 mmol) in toluene (40 mL), EtOH (20 mL), and water (10 mL), Na₂CO₃ (106 mg, 4.87 mmol) and 5-iodo-4-(2-isopropylphenyl)thiazol-2-amine (intermediate B-1) (555 mg, 1.61 mmol) were added. The mixture was bubbled with N₂ for 5 min. Then, Pd(Ph₃P)₄ (188 mg, 0.163 mmol) was added. The mixture was stirred at 80 °C for 12 h, then cooled to room temperature. The mixture was partitioned between EtOAc and water. The organic layer was dried and filtered. The filtrate was concentrated and purified by silica gel chromatography (PE / EA = 5 / 1) to produce 5-(3-(3,3-dimethylbutoxy)-5-fluorophenyl)-4-(2-isopropylphenyl)thiazol-2-amine (500 mg; 75.3%) as a yellow solid.

[0925] LCMS: MS(ESI): m / z 413[M+H] + .

[0926] Intermediate C-8

[0927] 5-(3-(3,3-dimethylbutoxy)-5-fluorophenyl)-4-(2-methyl-6-(trifluoromethyl)phenyl)thiazol-2-amine

[0928]

[0929] Step 1.

[0930]

[0931] At 80 °C and under a nitrogen atmosphere, a mixture of 5-iodo-4-[2-methyl-6-(trifluoromethyl)phenyl]thiazol-2-amine (intermediate B-4) (960 mg, 2.5 mmol), (3-(3,3-dimethylbutoxy)-5-fluorophenyl)boronic acid (intermediate D-1) (720 mg, 3 mmol), Pd(PPh3)4 (579 mg, catalytic amount) and Na2CO3 (795 mg, 7.5 mmol) in toluene (20 mL), ethanol (10 mL), and water (5 mL) was stirred for 12 h. The mixture was concentrated, and the residue was purified by SGC (PE / EA = 2 / 1) to yield the title intermediate (400 mg, 36%) as a yellow solid.

[0932] LCMS: LC retention time 2.234 min. MS(ESI) m / z 453 [M+H] + .

[0933] Intermediate C-9

[0934] 5-(3-(3,3-dimethylbutoxy)phenyl)-4-(2-methyl-6-(trifluoromethyl)phenyl)thiazol-2-amine

[0935]

[0936] Intermediate C-9 was prepared in the same manner as intermediate C-8.

[0937] Intermediate C-10

[0938] 4-(2,6-Dimethylphenyl)-5-(3-fluoro-5-(neopentyloxy)phenyl)thiazolyl-2-amine

[0939]

[0940] Step 1.

[0941]

[0942] To a stirred solution of (3-fluoro-5-(neopentyloxy)phenyl)boronic acid (intermediate D-6) (800 mg, 2.42 mmol) in toluene / ethanol / H₂O (30 / 15 / 7.5 mL), 4-(2,6-dimethylphenyl)-5-iodothiazol-2-amine (intermediate B-2b) (602 mg, 2.67 mmol), Pd(Ph₃P)₄ (280 mg, 0.24 mmol), and Na₂CO₃ (770 mg, 7.27 mmol) were added. The resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EA = 1 / 1) to provide the product 4-(2,6-dimethylphenyl)-5-(3-fluoro-5-(neopentyloxy)phenyl)thiazol-2-amine (510 mg, 55%) as a brown oil.

[0943] LC retention time: 2.27 min. MS (ESI) m / z: 385 [M+H] + .

[0944] Intermediate C-11

[0945] 5-(3-(3,3-dimethylbutoxy)-5-fluorophenyl)-4-(2,6-dimethylphenyl)thiazol-2-amine

[0946]

[0947] Step 1.

[0948]

[0949] To a solution of 5-bromo-4-(2,6-dimethylphenyl)thiazol-2-amine (intermediate B-2a) (964 mg, 3.41 mmol) in toluene / ethanol / H₂O (52.5 mL, v / v / v = 4 / 2 / 1), 3-(3,3-dimethylbutoxy)-5-fluorophenyl)boronic acid (intermediate D-1) (981 mg, 4.09 mmol), Pd(Ph₃P)₄ (393 mg, 0.34 mmol), and Na₂CO₃ (1.08 g, 10.22 mmol) were added. The resulting mixture was stirred for 16 h at 80 °C under an argon atmosphere. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum. The residue was dissolved in water (150 mL) and brine (150 mL). The aqueous solution was extracted with ethyl acetate (80 mL × 3), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure until dry to produce a crude substance, which was purified by silica gel chromatography (PE / EA = 3 / 1) to produce the desired compound 5-(3-(3,3-dimethylbutoxy)-5-fluorophenyl)-4-(2,6-dimethylphenyl)thiazol-2-amine (670 mg, 49.4%) as a yellow solid.

[0950] LCMS: LC retention time 2.49 min. MS(ESI) m / z 400 [M+H] + .

[0951] Intermediate C-12

[0952] 5-(3-(2,2-difluoro-3,3-dimethylbutoxy)phenyl)-4-(2-isopropoxy-6-methylphenyl)thiazolyl-2-amine

[0953]

[0954] This intermediate was prepared in the same manner as intermediate C-11.

[0955] Intermediate D-1

[0956] (3-(3,3-dimethylbutoxy)-5-fluorophenyl)boronic acid

[0957]

[0958] Step 1.

[0959]

[0960] Cs₂CO₃ (16.4 g, 50.3 mmol) and 3,3-dimethylbutyl 4-methylbenzenesulfonic acid (7.73 g, 30.2 mmol) were added to a solution of 3-bromo-5-fluorophenol (4.80 g, 25.1 mmol) in NMP (22 mL). The mixture was stirred overnight at 138 °C. Volatiles were removed under reduced pressure. The residue was purified by SGC (PE = 100%) to provide 1-bromo-3-(3,3-dimethylbutoxy)-5-fluorobenzene (6.55 g, 93.5%) as a colorless oil.

[0961] LCMS: LC retention time 2.18 min. Molecular ions not observed.

[0962] Step 2.

[0963]

[0964] n-BuLi (2.5 M, in hexane, 26.2 mmol) was added dropwise 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). The reaction mixture was stirred for 30 min. Triisopropyl borate (6.72 g, 35.7 mmol) was added dropwise while maintaining the reaction temperature at -78 °C. The reaction was heated to room temperature and stirred for 2 h. Water and 2N HCl (50 mL) were added to the reaction mixture, and the mixture was stirred for another 2 h. After the reaction was complete, ethyl acetate (60 mL) and water (40 mL) were added. The two layers were separated, and the organic solution was dried over MgSO4 and concentrated to provide (3-(3,3-dimethylbutoxy)-5-fluorophenyl)boronic acid (5.30 g).

[0965] LCMS: LC retention time 2.12 min. MS(ESI) m / z 241 [M+H] + .

[0966] Intermediate D-2

[0967] [3-(3,3-dimethylbutoxy)phenyl]boronic acid

[0968]

[0969] Step 1.

[0970]

[0971] A mixture of 3-bromophenol (7 g, 40.5 mmol), 1-bromo-3,3-dimethylbutane (8.68 g, 52.6 mol), and K₂CO₃ (11.2 g, 80.9 mol) in DMF (80 mL) was stirred for 12 h at 100 °C. The mixture was filtered and diluted with brine (400 mL), followed by extraction with ethyl acetate (200 mL × 3). The organic solution was washed with brine (200 mL), dried over Na₂SO₄, and concentrated. The residue was purified by combi-flash elution (using PE / EA = 20 / 1) to produce 1-bromo-3-(3,3-dimethylbutoxy)benzene (6.90 g, 66.3%) as a light-colored oil.

[0972] LCMS: LC retention time 2.47 min. MS(ESI) m / z 257 [M+H] + .

[0973] Step 2.

[0974]

[0975] 1-Bromo-3-(3,3-dimethylbutoxy)benzene (3.0 g, 11.7 mmol) was dissolved in 30 mL of tetrahydrofuran, and the solution was cooled to -70 °C in a cooling bath (acetone / dry ice). Under argon atmosphere, n-butyllithium solution (5.13 mL, 2.5 M, in hexane) was added dropwise, ensuring the temperature did not rise above -60 °C. After stirring at -70 °C for 1.5 h, trimethyl borate (3.64 g, 35 mmol) was added dropwise, ensuring the temperature did not rise above -60 °C. After cold stirring for 1 h, the mixture was heated to 25 °C over 2 h. 500 mL of hydrochloric acid (6 N) was added to the reaction solution. The mixture was stirred at 25 °C for 15 h. The mixture was then extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated on a rotary evaporator. The residue was purified by silica gel column chromatography (PE / EA = 5 / 1 on silica gel) to obtain the title compound [3-(3,3-dimethylbutoxy)phenyl]boronic acid (1.67 g, 64.5%) as a white solid.

[0976] LCMS: LC retention time 1.99 min. MS(ESI) m / z 223 [M+H] + .

[0977] Intermediate D-3

[0978] 2-(2-fluoro-5-(neopentyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane

[0979]

[0980] Step 1.

[0981]

[0982] K₂CO₃ (2.90 g, 20.94 mmol) was added to a solution of 3-bromo-4-fluorophenol (2.00 g, 10.47 mmol) and neopentyl 4-methylbenzenesulfonate (3.00 g, 12.56 mmol) in NMP (10 mL). The reaction was stirred overnight at 150 °C. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with EA (50 mL). The organic solution was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (EA / PE = 1 / 50) to provide 2-bromo-1-fluoro-4-(neopentyloxy)benzene (2.40 g, 88%) as a colorless oil.

[0983] LCMS: MS(ESI) m / z 261 [M+H] + .

[0984] Step 2.

[0985]

[0986] Add 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborane) (1.46 g, 5.75 mmol), KOAc (1.13 g, 11.49 mmol), and Pd(dppf)Cl2 (280 mg, 0.38 mmol) to a stirred solution of 2-bromo-1-fluoro-4-(neopentyloxy)benzene (1.0 g, 3.83 mmol) in 1,4-dioxane (10 mL) as follows: The solution was stirred at 80 °C for 3 h. Water (50 mL) was added to the reaction mixture, followed by extraction with EA (50 mL). The organic solution was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE) to provide 2-(2-fluoro-5-(neopentyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (960 mg, crude) as a colorless oil.

[0987] LCMS: MS(ESI) m / z 309 [M+H] + .

[0988] The following intermediates are synthesized in a similar manner using the procedure detailed above:

[0989] Intermediate D-4

[0990] 4,4,5,5-Tetramethyl-2-(3-(neopentyloxy)phenyl)-1,3,2-dioxaborane

[0991]

[0992] Intermediate D-5

[0993] 2-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane

[0994]

[0995] Intermediate D-6

[0996] (3-Fluoro-5-(neopentyloxy)phenyl)boronic acid

[0997]

[0998] Intermediate D-7

[0999] 2-(4-chloro-3-(neopentyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane

[1000]

[1001] Intermediate D-8

[1002] (4-Fluoro-3-(3,3,3-trifluoro-2,2-dimethylpropoxy)phenyl)boronic acid

[1003]

[1004] Intermediate D-9

[1005] 2-(3-((4-(tert-butyl)cyclohexyl)oxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane

[1006]

[1007] Intermediate D-10

[1008] 1-Bromo-3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)benzene

[1009]

[1010] Step 1.

[1011]

[1012] At room temperature, under an argon atmosphere, a borane-dimethyl sulfide complex (29.2 mL, 2.0 M THF solution, 58.4 mmol) was added to a stirred solution of 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (6.0 g, 38.96 mmol) in anhydrous tetrahydrofuran (35 mL). The resulting reaction mixture was stirred at 40 °C for 18 h. The reaction was quenched by adding saturated aqueous ammonium chloride solution (120 mL). The resulting solid was filtered off. The filtrate was extracted with diethyl ether (50 mL × 3). The combined organic solutions were washed with saturated aqueous sodium bicarbonate solution (100 mL) and brine (100 mL). The organic solutions were then dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to produce (1-(trifluoromethyl)cyclopropyl)methanol (5.11 g), which was a pale yellow oil.

[1013] LCMS: MS(ESI) m / z not observed.

[1014] 1 ¹H NMR (400MHz, chloroform-d) δ 3.73 (s, 2H), 1.05–1.02 (m, 2H), 0.78 (m, 2H) ppm.

[1015] Step 2.

[1016]

[1017] Triethylamine (16.3 mL, 116.9 mmol) was added to a stirred solution of (1-(trifluoromethyl)cyclopropyl)methanol (5.11 g, 38.96 mmol) in anhydrous dichloromethane (80 mL) at 0 °C under an argon atmosphere, followed by the addition of 4-methylbenzenesulfonyl chloride (9.62 g, 50.6 mmol) and 4-dimethylaminopyridine (436 mg, 3.9 mmol). The reaction mixture was stirred for 15 h at room temperature. The reaction mixture was diluted with dichloromethane (80 mL), and the organic layer was washed with 2 M HCl (90 mL), saturated sodium bicarbonate aqueous solution (80 mL), and brine (80 mL). The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated to produce methyl 4-methylbenzenesulfonic acid (1-(trifluoromethyl)cyclopropyl) ester (7.30 g, 64%, in two steps), a pale yellow oil.

[1018] LCMS: LC retention time 2.08 min. MS(ESI) m / z 295 [M+H] + .

[1019] 1¹H NMR (400MHz, chloroform-d) δ 7.79 (d, J = 8.0Hz, 2H), 7.36 (d, J = 8.0Hz, 2H), 4.10 (s, 2H), 2.46 (s, 3H), 1.12 (m, 2H), 0.84 (m, 2H) ppm.

[1020] Step 3.

[1021]

[1022] A mixture of methyl 4-methylbenzenesulfonic acid (1-(trifluoromethyl)cyclopropyl) ester (3.00 g, 10.2 mmol), potassium cyanide (0.995 g, 15.3 mmol), and 18-crown-6 (4.04 g, 15.3 mmol) in DMF (30 mL) was stirred for 18 h at 55 °C. The resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with water (80 mL × 2) and brine (80 mL). The organic solution was then dried over sodium sulfate, filtered, and concentrated under reduced pressure to produce 1.31 g of 2-(1-(trifluoromethyl)cyclopropyl)acetonitrile, which was a yellow oil.

[1023] LCMS: LC retention time 2.08 min. MS (ESI) m / z not observed.

[1024] 1 ¹H NMR (400MHz, chloroform-d) δ 2.81 (s, 2H), 1.18 (m, 2H), 0.94 (m, 2H) ppm.

[1025] Step 4.

[1026]

[1027] At 80 °C, a mixture of 2-(1-(trifluoromethyl)cyclopropyl)acetonitrile (1.31 g, 8.79 mmol) and sodium hydroxide (7.03 g, 176 mmol) in ethanol (30 mL) and water (10 mL) was stirred for 18 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (20 mL). The pH was adjusted to 2.0 with hydrogen chloride (4 N). The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to produce 2-(1-(trifluoromethyl)cyclopropyl)acetic acid (1.31 g) as a brown oil.

[1028] LCMS: LC retention time 2.50 min. MS (ESI) m / z not observed.

[1029] 1 ¹H NMR (400MHz, chloroform-d) δ 2.60 (s, 2H), 1.12 (m, 2H), 0.86 (m, 2H) ppm.

[1030] Step 5.

[1031]

[1032] At 0 °C under an argon atmosphere, a borane-dimethyl sulfide complex (7.8 mL, 2.0 M THF solution, 15.6 mmol) was added to a solution of 2-(1-(trifluoromethyl)cyclopropyl)acetic acid (1.31 g, 7.79 mmol) in anhydrous tetrahydrofuran (15 mL). The resulting reaction mixture was stirred at 40 °C for 18 h. The reaction was quenched with a saturated aqueous solution of ammonium chloride (50 mL). After cooling to room temperature, the resulting solid was filtered off. The filtrate was extracted with diethyl ether (30 mL × 3), washed with a saturated aqueous solution of sodium bicarbonate (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to produce 1.21 g of 2-(1-(trifluoromethyl)cyclopropyl)ethanol-1-ol, a pale yellow oil.

[1033] LCMS: LC retention time 2.56 min. MS (ESI) m / z not observed.

[1034] 1 ¹H NMR (400MHz, chloroform-d) δ 3.79 (t, J = 7.2Hz, 2H), 1.84 (t, J = 7.2Hz, 2H), 0.98 (m, 2H), 0.67 (m, 2H) ppm.

[1035] Step 6.

[1036]

[1037] Triethylamine (1.79 g, 17.7 mmol) was added to a stirred solution of 2-(1-(trifluoromethyl)cyclopropyl)ethanol-1-ol (0.91 g, crude, 5.9 mmol) in anhydrous dichloromethane (12 mL) at 0 °C under an argon atmosphere, followed by the addition of 4-methylbenzenesulfonyl chloride (1.69 g, 8.86 mmol) and 4-dimethylaminopyridine (72 mg, 0.59 mmol). The reaction mixture was stirred at room temperature for approximately 65 h. The reaction mixture was diluted with dichloromethane (50 mL), and the organic layer was washed with 2 M HCl (40 mL), saturated sodium bicarbonate aqueous solution (50 mL), and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to produce 1.26 g of 2-(1-(trifluoromethyl)cyclopropyl)ethyl 4-methylbenzenesulfonic acid, which was a yellow oil.

[1038] LCMS: LC retention time 2.14 min. MS(ESI) m / z 331 [M+Na] +

[1039] 1 ¹H NMR (400MHz, chloroform-d) δ 7.79 (d, J = 8.0Hz, 2H), 7.36 (d, J = 8.0Hz, 2H), 4.16 (t, J = 7.2Hz, 2H), 2.46 (s, 3H), 1.94 (t, J = 7.2Hz, 2H), 0.97 (m, 2H), 0.65 (m, 2H) ppm.

[1040] Step 7

[1041]

[1042] Add 3-bromophenol (916 mg, 5.3 mmol) and cesium carbonate (3.98 g, 12.2 mmol) to a solution of 2-(1-(trifluoromethyl)cyclopropyl)ethyl 4-methylbenzenesulfonic acid (1.26 g, crude, 4.07 mmol) in DMF (15 mL). Stir the reaction overnight at 120 °C. Dilute the reaction mixture with water (120 mL). Extract the aqueous phase with ethyl acetate (30 mL × 3). Wash the combined organic layers with water (50 mL × 2) and brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography (petroleum ether) to produce 1-bromo-3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)benzene (757 mg, 36% yield, in 5 steps) as a yellow oil.

[1043] LCMS: LC retention time 2.40 min. MS(ESI) m / z 309 [M+H] + .

[1044] 1 ¹H NMR (400MHz, chloroform-d) δ 7.16–7.03 (m, 3H), 6.82–6.80 (m, 1H), 4.08 (t, J = 7.2 Hz, 2H), 1.03 (t, J = 7.2 Hz, 2H), 1.03 (m, 2H), 0.73 (m, 2H) ppm.

[1045] Intermediate D-11a

[1046] 2-[3-(3,3-dimethylcyclopentoxy)-5-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane

[1047]

[1048] Step 1.

[1049]

[1050] At 0 °C, under argon atmosphere, 3,3-dimethylcyclopentanol (500 mg, 4.38 mmol) and triphenylphosphine (1.72 g, 6.57 mmol) were added to a solution of 3-bromo-5-fluorophenol (836 mg, 4.38 mmol) in THF (50 mL), followed by the addition of diisopropyl azodicarbonate (1.29 mL, 6.57 mmol). The resulting mixture was allowed to react overnight at room temperature. The solvent was removed under vacuum. The residue was purified by FCC (PE = 100%) to provide the desired compound 1-bromo-3-(3,3-dimethylcyclopentoxy)-5-fluorobenzene (890 mg, 71%) as a colorless oil.

[1051] LCMS: LC retention time 2.67 min. MS(ESI) m / z 287 [M+H] + .

[1052] Step 2.

[1053]

[1054] Pd(dppf)Cl2 (62 mg, catalytic amount) and potassium acetate (491 mg, 5.01 mmol) were added to a solution of 1-bromo-3-(3,3-dimethylcyclopentoxy)-5-fluorobenzene (480 mg, 1.67 mmol), bis(pinacol)diboron (509 g, 2.01 mmol), in DMSO (10 mL). The reaction mixture was heated at 80 °C under Ar for 3 h. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with AcOEt (40 mL × 2). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum. The residue was purified by FCC (PE / EA = 10 / 1) to provide the desired compound 2-[3-(3,3-dimethylcyclopentoxy)-5-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (730 mg, 71%) as a colorless oil.

[1055] 1H NMR (400MHz, chloroform-d) δ7.12–7.01(m,2H),6.66(dt,J=10.9,2.4Hz,1H),4.82(tt,J=6.9,3.6Hz,1H),2.25–2.10(m,1H),1. 90(dd,J=13.8,6.9Hz,2H),1.69(dt,J=10.1,6.7Hz,2H),1.53–1.41(m,1H),1.35(s,12H),1.14(s,3H),1.05(s,3H)ppm.

[1056] Intermediate D-11b

[1057] 2-(3-((3,3-dimethylcyclopentyl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane

[1058]

[1059] Intermediate D-11b was prepared using essentially the same method as intermediate D-11a.

[1060] Intermediate D-12

[1061] (3-(3,3-dimethylcyclopentyl)phenyl)boronic acid

[1062]

[1063] Step 1.

[1064]

[1065] Under Ar conditions, a solution of diisopropylamine (5.2 g, 51.4 mmol) in anhydrous THF (40 mL) was cooled to 0 °C, and n-BuLi (2.5 M, in hexane, 18.8 mL, 47.1 mmol) was added. The solution was stirred at 0 °C for 15 min, then cooled to -78 °C. A solution of 3,3-dimethylcyclopentanone (7.37 g, 40 mmol) in anhydrous THF (40 mL) was added, and the mixture was stirred at -78 °C for 2 h. A solution of PhNTf2 (16.80 g, 47.1 mmol) in anhydrous THF (80 mL) was added, and the mixture was heated to 0 °C and stirred overnight. The mixture was poured into a saturated aqueous NH4Cl solution and extracted with Et2O. The combined organic layers were washed with water and brine, dried, and concentrated to produce a mixture (8.00 g, 76.6%) of 3,3-dimethylcyclopent-1-en-1-yl trifluoromethanesulfonate and 4,4-dimethylcyclopent-1-en-1-yl trifluoromethanesulfonate, which were colorless oils.

[1066] 1 ¹H NMR (400MHz, 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.

[1067] Step 2.

[1068]

[1069] To a solution of 3,3-dimethylcyclopent-1-en-1-yl trifluoromethanesulfonate in toluene / EtOH / water (60 mL / 30 mL / 15 mL), 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) were added. The mixture was stirred at 90 °C for 16 h. The mixture was then concentrated. The residue was dissolved in water (50 mL) and extracted with ethyl acetate (50 mL × 2). The organic layer was washed with brine (100 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE) to obtain 1-(3,3-dimethylcyclopent-1-en-1-yl)-3-nitrobenzene and 1-(4,4-dimethylcyclopent-1-en-1-yl)-3-nitrobenzene (1.30 g, 73.1%) as yellow oils.

[1070] 1 HNMR (400MHz, chloroform-d) δ8.23-8.20(m,1H),8.06-8.03(m,1H),7.72-7.69(m,1H),7.48(t,J=8.0Hz,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=7.2Hz,1H),1.19(s,3H),1.16(s,3H)ppm.

[1071] Step 3.

[1072]

[1073] At room temperature and under an Ar atmosphere, 10 wt% Pd / C (130 mg) was added to a solution of 1-(3,3-dimethylcyclopentan-1-en-1-yl)-3-nitrobenzene and 1-(4,4-dimethylcyclopentan-1-en-1-yl)-3-nitrobenzene (1.30 g, 6.00 mmol) in MeOH (50 mL). The flask was purged with hydrogen and stirred for 16 h under a hydrogen atmosphere (1 atm). The reaction mixture was filtered, and the filtrate was concentrated to obtain 3-(3,3-dimethylcyclopentanyl)aniline (700 mg, 62%) as a yellow oil.

[1074] LCMS: LC retention time 1.953 min. MS(ESI) m / z 190 [M+H] + .

[1075] 1 ¹H NMR (400MHz, chloroform-d) δ 7.09 (t, J = 7.6Hz, 1H), 6.67 (d, J = 7.6Hz, 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.

[1076] Step 4.

[1077]

[1078] At room temperature, CuBr2 (445 mg, 2.00 mmol) and tert-butyl nitrite (343 mg, 3.33 mmol) were added to a solution of 3-(3,3-dimethylcyclopentyl)aniline (700 mg, 3.33 mmol) in anhydrous MeCN (20 mL). The resulting mixture was stirred under reflux for 15 min. Aliquots examined by LCMS analysis indicated the completion of the reaction. The reaction was quenched by adding water (80 mL). The aqueous phase 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 to dryness to produce a crude product, which was purified by silica gel column chromatography (PE / EA = 50 / 1) to produce the desired compound 1-bromo-3-(3,3-dimethylcyclopentyl)benzene (478 mg, 53.9%) as a yellow oil.

[1079] 1¹H NMR (400MHz, 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.

[1080] Step 5.

[1081]

[1082] At -78 °C, n-butyllithium (1.34 mL, 3.34 mmol, 2.5 M hexane solution) was added dropwise to a cooled and stirred solution of 1-bromo-3-(3,3-dimethylcyclopentyl)benzene (470 mg, 1.67 mmol) in anhydrous tetrahydrofuran (20 mL). After the addition, the reaction mixture was stirred at -78 °C for 0.5 h. Then, trimethyl borate (347 mg, 3.34 mmol) was added dropwise at -78 °C, and the resulting mixture was stirred at -78 °C for 1 h. The reaction was then gradually heated to room temperature over 2 h. Hydrochloric acid (6.0 N, 5 mL) was added to this solution at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (50 mL). The aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to produce a product (3-(3,3-dimethylcyclopentyl)phenyl)boronic acid (400 mg, crude substance) as a yellow solid.

[1083] 1 ¹H NMR (400MHz, 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.

[1084] Intermediate D-13

[1085] 4,4,5,5-Tetramethyl-2-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)phenyl)-1,3,2-dioxaboranecyclopentane

[1086]

[1087] Step 1.

[1088]

[1089] At 0 °C, LiAlH4 (4.87 g, 128 mmol) was added to a cooled, stirred solution of 3,3,3-trifluoro-2,2-dimethylpropionic acid (10.0 g, 64.1 mmol) in Et2O (150 mL). The mixture was stirred overnight at room temperature. When the reaction was complete, it was quenched with H2O (5 mL), NaOH (15% (5 mL), and H2O (15 mL). The mixture was filtered through a diatomaceous earth mat. The filtrate was concentrated to produce 3,3,3-trifluoro-2,2-dimethylprop-1-ol (8.40 g, 92.3%), which is a yellow oil.

[1090] Step 2.

[1091]

[1092] To a solution of 3,3,3-trifluoro-2,2-dimethylprop-1-ol (8.4 g, 59.1 mmol) in Et₂O (100 mL), NaOH (4.73 g, 118 mmol) was added, followed by the addition of 4-methylbenzenesulfonyl chloride (12.4 g, 65.0 mmol). The resulting mixture was stirred overnight at the specified temperature. The two layers were separated, and the organic layer was washed with water (120 mL × 3) and NaHCO₃ (50 mL). The organic solution was concentrated under vacuum, and the residue was purified by silica gel column chromatography using PE:EA (5:1) as eluent to produce 3,3,3-trifluoro-2,2-dimethylpropane 4-methylbenzenesulfonic acid (12.6 g, 71.9% yield) as a yellow oil.

[1093] LC-MS (acidic): LC retention time 2.130 min. MS (ESI) m / z 297 [M+H] + .

[1094] Step 3.

[1095]

[1096] 3-bromophenol (3.50 g, 20.2 mmol) and Cs₂CO₃ (19.8 g, 60.7 mmol) were added to a solution of 3,3,3-trifluoro-2,2-dimethylpropyl 4-methylbenzenesulfonic acid (6.00 g, 20.2 mmol) in DMSO (60 mL). The mixture was heated overnight at 130 °C with stirring. When the reaction was complete, the mixture was cooled to room temperature and diluted with EA (100 mL). The organic solution was washed with H₂O (100 mL × 3). The organic solution was concentrated under vacuum and purified by silica gel column chromatography using PE as eluent to produce 1-bromo-3-(3,3,3-trifluoro-2,2-dimethylpropoxy)benzene (4.20 g, 69.8%) as a yellow oil.

[1097] LCMS (acidic): LC retention time 2.337 min. MS (ESI) m / z: Not observed.

[1098] Step 4.

[1099]

[1100] To a solution of 1-bromo-3-(3,3,3-trifluoro-2,2-dimethylpropoxy)benzene (4 g, 13.5 mmol) in 1,4-dioxane (50 mL), bis(pinacolyl)diborane (5.13 g, 20.2 mmol), CH3COOK (3.30 g, 33.7 mmol), and Pd(dppf)Cl2 (985 mg, 1.35 mmol) were added. The reaction mixture was heated overnight at 80 °C under argon. The reaction mixture was concentrated and purified by SGC (PE:EA = 10:1) to yield 4,4,5,5-tetramethyl-2-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)phenyl)-1,3,2-dioxaborane (2.93 g, 63.2% yield) as a yellow oil.

[1101] LC-MS (acidic): LC retention time 2.539 min. MS (ESI) m / z 345 [M+H] + .

[1102] Intermediate D-14

[1103] 2-(3-(2,2-difluoro-3,3-dimethylbutoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane

[1104]

[1105] Step 1.

[1106]

[1107] At room temperature, 2-(tert-butyl)oxetine (1.65 g, 16.5 mmol) and cesium carbonate (7.16 g, 22.0 mmol) were added to a solution of 3-bromophenol (1.9 g, 11.0 mmol) in DMF (20 mL). The resulting mixture was stirred overnight at 80 °C. The mixture was cooled to room temperature, diluted with water (150 mL), and extracted with ethyl acetate (40 mL × 3). The organic solution was washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (9% ethyl acetate / petroleum ether) to produce 1-(3-bromophenoxy)-3,3-dimethylbut-2-ol (2.46 g, 82% yield) as a colorless oil.

[1108] LCMS: LC retention time 2.24 min. MS(ESI) m / z 275 [M+H] + .

[1109] 1 ¹H NMR (400MHz, chloroform-d) δ 7.17–7.06 (m, 3H), 6.87–6.84 (m, 1H), 4.10–4.07 (m, 1H), 3.85 (t, J = 9.2Hz, 1H), 3.69–3.66 (m, 1H), 2.36 (d, J = 3.2Hz, 1H), 1.01 (s, 9H) ppm.

[1110] Step 2.

[1111]

[1112] At room temperature, acetic acid (1,1-diacetoxy-3-oxo-1λ5,2-benzodiazepine-1-yl) ester (5.73 g, 13.5 mmol) was added to a solution of 1-(3-bromophenoxy)-3,3-dimethylbut-2-ol (2.46 g, 9.01 mmol) in dichloromethane (30 mL). The resulting reaction mixture was stirred for 18 h at room temperature. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (10% ethyl acetate / petroleum ether) to produce 1-(3-bromophenoxy)-3,3-dimethylbut-2-one (2.18 g, 89% yield) as a colorless oil.

[1113] LCMS: LC retention time 2.18 min. MS(ESI) m / z 273 [M+H] + .

[1114] 1¹H NMR (400MHz, chloroform-d) δ 7.16–7.10 (m, 2H), 7.02 (s, 1H), 6.81 (d, J = 7.2 Hz, 1H), 4.85 (s, 2H), 1.25 (s, 9H) ppm.

[1115] Step 3.

[1116]

[1117] At 0 °C under an argon atmosphere, N-ethyl-N-(trifluoro-λ4-thioalkyl)ethylamine (5.18 g, 32.2 mmol) was added dropwise to a solution of 1-(3-bromophenoxy)-3,3-dimethylbut-2-one (2.18 g, 8.04 mmol) in anhydrous dichloromethane (20 mL). The resulting mixture was stirred for 65 h at room temperature. The reaction was quenched with a saturated aqueous sodium bicarbonate solution. After CO2 evaporation ceased, the solution was extracted with dichloromethane (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether) to produce 1-bromo-3-(2,2-difluoro-3,3-dimethylbutoxy)benzene (1.56 g, 66% yield) as a colorless oil.

[1118] LCMS: LC retention time 2.35 min. MS (ESI) m / z not observed.

[1119] 1 ¹H NMR (400MHz, chloroform-d) δ 7.18–7.10 (m, 3H), 6.88 (m, 1H), 4.23 (t, J = 13.2 Hz, 2H), 1.14 (s, 9H) ppm.

[1120] Step 4.

[1121]

[1122] Add 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxane) (2.03 g, 7.99 mmol), potassium acetate (1.56 g, 15.96 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (389 mg, 0.532 mmol) to a solution of 1-bromo-3-(2,2-difluoro-3,3-dimethylbutoxy)benzene (1.56 g, 7.32 mmol) in anhydrous 1,4-dioxane (20.0 mL) to a solution of 1-bromo-3-(2,2-difluoro-3,3-dimethylbutoxy)benzene (1.56 g, 7.99 mmol), potassium acetate (1.56 g, 15.96 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (389 mg, 0.532 mmol) to the solution of 1-bromo-3-(2,2-difluoro-3,3-dimethylbutoxy)benzene (1.56 g, 5.32 mmol), to a solution of 1-bromo-3-(2,2-difluoro-3,3-dimethylbutoxy)benzene (2 ...dioxane (20.0 mL), to a solution of 1-dioxane (20.0 mL), to a solution of 1-dioxane (20.0 mL), to a solution of 1-dioxane (2.56 g, 2.5 mmol), to a The residue was purified by silica gel chromatography (3% ethyl acetate / petroleum ether) to produce 2-(3-(2,2-difluoro-3,3-dimethylbutoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (1.34 g, 74% yield) as a colorless oil.

[1123] LCMS: LC retention time 2.42 min. MS(ESI) m / z 340 [M+H] + .

[1124] Intermediate D-15

[1125] 2-(4-(difluoromethoxy)-3-(3,3-dimethylbutoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane

[1126]

[1127] Step 1.

[1128]

[1129] 2-methylpropyl-2-amine (14.4 g, 197 mmol) and magnesium sulfate (33.2 g, 276 mmol) were added to a solution of 4-bromo-2-fluorobenzaldehyde (8.0 g, 39.4 mmol) in dichloromethane (60 mL). The resulting mixture was stirred at room temperature for 43 h. The solution was filtered and concentrated to produce (E)-1-(4-bromo-2-fluorophenyl)-N-(tert-butyl)methylimine (10.2 g), which was a yellow oil.

[1130] LCMS: LC retention time 2.04 min. MS(ESI) m / z 258 [M+H] + .

[1131] Step 2.

[1132]

[1133] At 0 °C and under an argon atmosphere, a solution of 3,3-dimethylbut-1-ol (4.84 g, 47.4 mmol) in DMF (30 mL) was added dropwise to a suspension of sodium hydride (60 wt%, in mineral oil, 4.74 g, 119 mmol) in DMF (40 mL). The resulting mixture was stirred for 30 min at room temperature, followed by the dropwise addition of (E)-1-(4-bromo-2-fluorophenyl)-N-(tert-butyl)methylimine (10.2 g, 39.5 mmol) in DMF (30 mL) at 0 °C. The resulting reaction mixture was stirred overnight at room temperature. The reaction was quenched with water (30 mL) at 0 °C, diluted with water (250 mL), and extracted with tert-butyl methyl ether (3 × 100 mL). The combined organic layers were washed with water (150 mL) and brine (150 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to produce a yellow solid, which was treated with tetrahydrofuran (50 mL), water (50 mL), and acetic acid (12 mL). After 18 h, the solution was made alkaline with a saturated aqueous sodium carbonate solution and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (4% ethyl acetate / petroleum ether) to produce 4-bromo-2-(3,3-dimethylbutoxy)benzaldehyde (9.54 g, 85% yield, in 2 steps) as a white solid.

[1134] LCMS: LC retention time 2.56 min. MS(ESI) m / z 287 [M+H] + .

[1135] 1 ¹H NMR (400MHz, chloroform-d) δ 10.4 (s, 1H), 7.70–7.68 (m, 1H), 7.17–7.15 (m, 2H), 4.13 (t, J = 7.2Hz, 2H), 1.80 (t, J = 7.2Hz, 2H), 1.02 (s, 9H) ppm.

[1136] Step 3.

[1137]

[1138] 3-Chloroperoxybenzoic acid (85 wt%, 7.37 g, 36.3 mmol) was added to a solution of 4-bromo-2-(3,3-dimethylbutoxy)benzaldehyde (6.9 g, 24.2 mmol) in dichloromethane (70 mL). After stirring for 15 h, a saturated aqueous solution of sodium sulfite was added at 0 °C, and the solution was stirred until the aqueous phase was Kl negative. The aqueous phase was then extracted with dichloromethane (100 mL × 2). The combined organic layers were washed with a saturated sodium bicarbonate solution (100 mL), concentrated, and treated with methanol (40 mL) and 1N sodium hydroxide (70 mL) at 0 °C. The resulting mixture was stirred at room temperature for 4 h. The reaction mixture was acidified with 1M potassium bisulfate solution (pH approximately 4), followed by extraction with dichloromethane (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (4% ethyl acetate / petroleum ether) to produce 4-bromo-2-(3,3-dimethylbutoxy)phenol (5.77 g, 87% yield), which was a yellow oil.

[1139] LCMS: LC retention time 2.34 min. MS (ESI) m / z not observed.

[1140] 1 ¹H NMR (400MHz, chloroform-d) δ 6.98–6.96 (m, 2H), 6.79 (d, J = 8.8 Hz, 1H), 5.57 (s, 1H), 4.07 (t, J = 7.2 Hz, 2H), 1.75 (t, J = 7.2 Hz, 2H), 1.00 (s, 9H) ppm.

[1141] Step 4.

[1142]

[1143] A solution of KOH (5.0 g, 89.1 mmol) in H₂O (27 mL) was added to a solution of 4-bromo-2-(3,3-dimethylbutoxy)phenol (1.25 g, 4.58 mmol) in MeCN (27 mL). The mixture was immediately cooled in a -78 °C bath, and diethyl (bromodifluoromethyl)phosphonate (2.44 g, 9.15 mmol) was added. The flask was sealed, and the cooling bath was removed. The mixture was stirred for 5 h. The reaction mixture was diluted with EtOAc, and the layers were separated. The aqueous layer was extracted with EtOAc, and the combined organic phases were washed with 1 M NaOH, H₂O, and brine, then dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by preparative TLC (100% PE) to provide 4-bromo-1-(difluoromethoxy)-2-(3,3-dimethylbutoxy)benzene (1.30 g, 87.9%) as a colorless oil.

[1144] 1 ¹H NMR (400MHz, chloroform-d): δ 7.10–7.05 (m, 3H), 6.71–6.34 (t, 1H), 4.08–4.05 (m, 2H), 1.80–1.76 (m, 2H), 1.02 (s, 9H) ppm.

[1145] 19 F NMR (400MHz, chloroform-d): δ-81.709ppm.

[1146] Step 5.

[1147]

[1148] Add 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3,2-dioxaborhexacyclopentane (1.26 g, 4.95 mmol), KOAc (729 mg, 7.43 mmol), and Pd(dppf)Cl2 (90.5 mg, 0.124 mmol) to a solution of 4-bromo-1-(difluoromethoxy)-2-(3,3-dimethylbutoxy)benzene (800 mg, 2.48 mmol) in 25 mL of dioxane. Heat the reaction mixture at 90 °C under Ar for 5 h. Cool the reaction mixture to room temperature and then filter. The filtrate was concentrated to provide 2-(4-(difluoromethoxy)-3-(3,3-dimethylbutoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (917 mg, 100% yield) as a brown oil.

[1149] LCMS: LC retention time 1.955 min. MS(ESI) m / z 371.2 [M+H] + .

[1150] Intermediate D-16

[1151] 4,4,5,5-Tetramethyl-2-(6-neopentyl-3,6-dihydro-2H-pyran-4-yl)-1,3,2-dioxaboranecyclopentane

[1152]

[1153] Step 1.

[1154]

[1155] Trifluoromethanesulfonic acid (1.8 g, 12.0 mmol) was added dropwise to a stirred solution of 3,3-dimethylbutyraldehyde (1.0 g, 9.98 mmol) in anhydrous dichloromethane (50.0 mL) at 0 °C, 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 the reaction was complete, the reaction mixture was treated with saturated sodium bicarbonate solution (100 mL). Then, it was extracted with DCM (80 mL × 2). The organic layer was washed with brine and dried over anhydrous Na₂SO₄. The organic phase was then concentrated to dryness. The residue was purified by FCC (PE:EA = 10:1) to produce 6-neopentyl-3,6-dihydro-2H-pyran-4-yl ester of trifluoromethanesulfonic acid (1.70 g, 56.3%), which was a yellow oil.

[1156] Step 2.

[1157]

[1158] The reaction mixture of 6-neopentyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (1.7 g, 5.62 mmol), bis(pinacolyl)diboron (2.14 g, 8.44 mmol), CH3COOK (1.10 g, 11.2 mmol), and Pd(dppf)Cl2 (411 mg, 0.562 mmol) in 1,4-dioxane (60 mL) was heated overnight at 80 °C under Ar conditions. The reaction mixture was concentrated to provide 4,4,5,5-tetramethyl-2-(6-neopentyl-3,6-dihydro-2H-pyran-4-yl)-1,3,2-dioxaborhecyclopentane.

[1159] LCMS: LC retention time 2.50 min. MS(ESI) m / z 281 [M+H] + .

[1160] Intermediate D-17

[1161] (6-(3,3-dimethylbutoxy)pyridin-2-yl)boronic acid

[1162]

[1163] Step 1.

[1164]

[1165] At 0 °C, NaH (293.58 mg, 7.34 mmol, 60%) was added to a stirred solution of 3,3-dimethylbut-1-ol (500 mg, 4.89 mmol) in anhydrous THF (10 mL). The reaction mixture was stirred at room temperature for 0.5 h. 2,6-Dibromopyridine (1.16 g, 4.89 mmol) was added to the reaction mixture. The mixture was then stirred at room temperature for 12 h. The reaction mixture was diluted with EA (20 mL) and washed with water (10 mL × 2). The organic phase was dried over Na2SO4, filtered, and concentrated to dryness to produce a crude product, which was purified by silica gel chromatography (petroleum ether) to produce 2-bromo-6-(3,3-dimethylbutoxy)pyridine (1.8 g, 71%, two batches) as a colorless oil.

[1166] LCMS: MS(ESI) m / z 260 [M+H] +

[1167] Step 2.

[1168]

[1169] At -78°C under a nitrogen atmosphere, n-butyllithium (1.42 mL, 2.9 mmol) was added to a stirred solution of 2-bromo-6-(3,3-dimethylbutoxy)pyridine (0.5 g, 1.93 mmol) in THF (6 mL). The reaction was stirred at this temperature for 1 h, followed by the addition of triisopropyl borate (436.3 mg, 2.32 mmol). The mixture was heated to room temperature and stirred at this temperature for 13 h. TLC (PE / EA = 8 / 1) showed that the starting material was consumed. MeOH (3 mL) was added to the mixture, and the pH was adjusted to 3 with HCl (2 M). The organic solvent was evaporated to remove the solvent, the pH was adjusted to 7 with NaHCO3, and the mixture was extracted with EA (15 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The residue was suspended in PE (10 mL) and filtered to produce (6-(3,3-dimethylbutoxy)pyridin-2-yl)boronic acid (0.20 g, 46.29%) as a yellow solid.

[1170] 1 ¹H NMR (400MHz, 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.

[1171] Intermediate D-18

[1172] 2-(3-(1,1-difluoro-4,4-dimethylpentyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane

[1173]

[1174] Step 1.

[1175]

[1176] Initially, magnesium scrap (2.10 g, 86.42 mmol) was placed in 60 mL of Et₂O. A spatula tip 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 room temperature, the reaction solution (3,3-dimethylbutyl)magnesium bromide was used directly in the next step.

[1177] Step 2.

[1178]

[1179] At room temperature and under N2, (3,3-dimethylbutyl)magnesium bromide (70 mL, 86.42 mmol) was added to a solution of 3-bromobenzaldehyde (5.42 g, 29.3 mmol) in Et2O (30 mL). The resulting mixture was stirred at room temperature for 2 h. The mixture was poured into an ammonium chloride solution (50 mL) and extracted with DCM (30 mL × 2). The extract was washed with brine (20 mL × 2) and dried over sodium sulfate. The filtrate of 1-(3-bromophenyl)-4,4-dimethylpentane-1-ol was used directly in the next step.

[1180] LCMS: LC retention time 2.34 min. MS(ESI) m / z 272 [M+H + .

[1181] Step 3.

[1182]

[1183] PCC (17.60 g, 81.7 mmol) was added to a stirred solution of 1-(3-bromophenyl)-4,4-dimethylpentane-1-ol (7.95 g, 29.3 mmol) in anhydrous DCM (150 mL) at 0 °C under nitrogen atmosphere for 2 h. The resulting mixture was stirred for 12 h at room temperature. The mixture was filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography (PE / EA = 98 / 2) to produce 1-(3-bromophenyl)-4,4-dimethylpentane-1-one (6.95 g, 88.1% in three steps), which was a pale yellow oil.

[1184] LCMS: LC retention time 2.33 min. MS(ESI) m / z 271 [M+H] + .

[1185] Step 4.

[1186]

[1187] At room temperature, under nitrogen atmosphere, DAST (4.50 g, 27.9 mmol) was added to a stirred solution of 1-(3-bromophenyl)-4,4-dimethylpentan-1-one (1.74 g, 6.84 mmol) in DCM (20 mL). The reaction mixture was stirred at 86 °C for 14 h. The mixture was poured into ice water. The aqueous layer was adjusted to pH 8. The aqueous phase was then extracted with EA. The organic layer was then dried over Na2SO4, filtered, and concentrated. The crude residue was purified by rapid chromatography (PE) to provide 1-bromo-3-(1,1-difluoro-4,4-dimethylpentyl)benzene (1.59 g, 79.9%) as a colorless oil.

[1188] 1 ¹H NMR (400MHz, 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.

[1189] Step 5.

[1190]

[1191] A mixture of 1-bromo-3-(1,1-difluoro-4,4-dimethylpentyl)benzene (266 mg, 0.913 mmol), AcOK (270 mg, 2.75 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborhexacyclopentane) (255 mg, 1.0 mmol), tricyclohexylphosphine (27 mg, 0.096 mmol), and Pd2(dba)3 (84 mg, 0.092 mmol) in 1,4-dioxane (10 mL) was stirred for 20 h at 85 °C under N2 protection. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated to produce 2-(3-(1,1-difluoro-4,4-dimethylpentyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (235 mg, 100%), which is a colorless oil.

[1192] LCMS: LC retention time 2.19 min. MS(ESI) m / z 256.8 [M+H] + .

[1193] Intermediate D-19

[1194] 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-5-(trifluoromethyl)isoxazole

[1195]

[1196] Step 1.

[1197]

[1198] Sodium (347 mg, 15.1 mmol) was dissolved in ethanol (10 mL) under inert conditions. A solution of 2,2,2-trifluoroethyl acetate (2.86 g, 20.1 mmol) in ethanol (10 mL) was added to this solution, followed by a solution of 1-(3-bromophenyl)ethyl ketone (2.00 g, 10.0 mmol) in ethanol (10 mL). The reaction mixture was refluxed overnight at 85 °C. After the reaction was complete, it was quenched with an aqueous HCl solution (1 N) (30 mL). The solution was extracted with ethyl acetate (50 mL) and washed with brine (50 mL × 2). The solution was dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (15% ethyl acetate / petroleum ether) to provide 1-(3-bromophenyl)-4,4,4-trifluorobutane-1,3-dione (4.12 g) as a red oil.

[1199] LCMS: LC retention time 1.18 min. MS(ESI) m / z 297 [M+H] + .

[1200] Step 2.

[1201]

[1202] At 20–30 °C, 1-(3-bromophenyl)-4,4,4-trifluorobutane-1,3-dione (1 g, 3.39 mmol) was added to a solution of hydroxylamine hydrochloride (236 mg, 3.39 mmol) in an aqueous solution of NaOH (142 mg, 3.56 mmol) over 1 h. The resulting mixture was heated under reflux for 45 min. After cooling to room temperature, the mixture was poured into ice water (50 mL). The precipitate was filtered off. The solution was extracted with ethyl acetate (30 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure to give 3-(3-bromophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-5-ol (810 mg).

[1203] LCMS: LC retention time 2.02 min. MS(ESI) m / z 311 [M+H] + .

[1204] Step 3.

[1205]

[1206] 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 at 80 °C. After the reaction was complete, the reaction was quenched with an aqueous solution of NaHCO3 (40 mL). The aqueous solution was extracted with ethyl acetate (40 mL). The organic solution was then washed with water (30 mL). The solution was dried over anhydrous Na2SO4 and filtered. The solution was concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (11% ethyl acetate / petroleum ether) to provide the product (190 mg).

[1207] LCMS: LC retention time 1.54 min. MS (ESI) m / z not observed.

[1208] Step 4.

[1209]

[1210] A mixture of 3-(3-bromophenyl)-5-(trifluoromethyl)isoxazole (200 mg, 0.685 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3,2-dioxaborhexacyclopentane (174 mg, 0.685 mmol), Pd(dppf)Cl2 (25.1 mg, 0.034 mmol), and potassium acetate (134 mg, 1.37 mmol) in 1,4-dioxane (10 mL) was heated overnight at 80 °C under a nitrogen atmosphere. After the reaction was complete, the mixture was filtered. The filtrate was extracted with ethyl acetate (25 mL). The organic solution was washed with water (25 mL) and brine (25 mL). The solution was dried over anhydrous Na2SO4 and filtered. The solution was concentrated under reduced pressure to obtain 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)-5-(trifluoromethyl)isoxazole, which was a brown oil.

[1211] LCMS: LC retention time 1.59 min. MS(ESI) m / z 340 [M+H] + .

[1212] Intermediate D-20

[1213] 4,4,5,5-Tetramethyl-2-(3-((1S)-3-(trifluoromethoxy)cyclopentyl)phenyl)-1,3,2-dioxaboranecyclopentane

[1214]

[1215] Step 1.

[1216]

[1217] Under nitrogen atmosphere, 2.0 g (24.4 mmol) of cyclopentan-2-en-1-one was added to a mixture of 6.84 g (34.2 mmol) of (3-bromophenyl)boric acid, 188.6 mg (0.74 mmol) of acetylacetone bis(ethylene)rhodium(I), and 455 mg (0.74 mmol) of S-BINAP in 40 mL of dioxane and 4 mL of H₂O. After reflux for 5.0 h, the reaction was concentrated. The residue was partitioned between 100 mL of EtOAc and 100 mL of 1N NaHCO₃. After separation of the phases, the organic layer was washed with 100 mL of brine, dried over Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 5 / 1) to provide 4.70 g of (S)-3-(3-bromophenyl)cyclopentan-1-one as a pale yellow solid.

[1218] LCMS: LC retention time 2.14 min. MS(ESI) m / z 241 [M+H] + .

[1219] Step 2.

[1220]

[1221] 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, and at the same temperature, DIBAL (1 M, in toluene) (76.7 mL) was added under an argon atmosphere. The mixture was then slowly heated to room temperature and stirred overnight at room temperature. A saturated sodium potassium tartrate tetrahydrate solution (80 mL) was then added and stirred for another 1 h, and the mixture was filtered through a diatomaceous earth stopper. The filtrate was concentrated under reduced pressure to produce a crude product, which was purified by rapid reverse-phase column chromatography to produce (3S)-3-(3-bromophenyl)cyclopentan-1-ol (3.25 g, 70.4%) as a colorless oil.

[1222] LCMS: LC retention time 2.05 min. MS (ESI) m / z 225 [M-H2O] + .

[1223] Step 3.

[1224]

[1225] Add AgOTf (3.20 g, 12.4 mmol) to the flask. (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) were purged with argon, followed by the addition of EtOAc (20 mL), then TMSCF3 (1.77 g, 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 diatomaceous earth mat. The filtrate was concentrated and purified by silica gel column chromatography (100% PE) to provide 1-bromo-3-((1S)-3-(trifluoromethoxy)cyclopentanyl)benzene (402 mg, 31.4%) as a colorless oil.

[1226] 1¹H NMR (400MHz, chloroform-d) δ 7.36 (dd, J = 16.2, 9.0 Hz, 2H), 7.16 (dd, J = 15.8, 6.8 Hz, 2H), 4.85 (d, J = 28.0 Hz, 1H), 3.39–2.95 (m, 1H), 2.61–2.21 (m, 2H), 2.16–1.59 (m, 5H) ppm.

[1227] Step 4.

[1228]

[1229] Add 2,4,4,5,5-pentamethyl-1,3,2-dioxaborhexacyclopentane (1.38 g, 4.85 mmol), KOAc (793 mg, 8.09 mmol), and Pd(dppf)Cl2 (70.9 mg, 9.70 × 10⁻⁶) to a reaction mixture of 1-bromo-3-[(1S)-3-(trifluoromethoxy)cyclopentyl]benzene (1.0 g, 3.23 mmol) in dioxane (20 mL) to a reaction mixture of 1-bromo-3-[(1S)-3-(trifluoromethoxy)cyclopentyl]benzene (1.0 g, 3.23 mmol), to dioxane (20 mL), to a reaction mixture of 1-bromo-3-[(1S)-3-(trifluoromethoxy)cyclopentyl]benzene (1.0 g, 3.23 mmol), to dioxane (20 mL), to a reaction mixture of 2,4,4,5,5-pentamethyl-1,3,2-dioxaborhexacyclopentane (1.38 g, 4.85 mmol), to dioxane (793 mg, 8.09 mmol), to dioxane (70.9 mg, 9.70 × 10⁻⁶), to dioxane (20 mL ... -5 The mixture was stirred overnight at 90°C under argon. The mixture was concentrated and extracted with EA (10 mL × 3). The organic phase was washed with brine (20 mL). The organic phase was concentrated and purified by SGC (PE:EA = 10:1) to produce 4,4,5,5-tetramethyl-2-[3-[(1S)-3-(trifluoromethoxy)cyclopentyl]phenyl]-1,3,2-dioxaboranecyclopentane (720 mg, 62.5% yield) as a light-colored oil.

[1230] LC-MS (acidic): LC retention time 2.41, MS (ESI): m / z 357 [M+H] + .

[1231] Intermediate D-21

[1232] 1-Bromo-3-((1R)-3-(trifluoromethoxy)cyclopentyl)benzene

[1233]

[1234] Step 1.

[1235]

[1236] At room temperature and under an argon atmosphere, cyclopent-2-en-1-one (1.0 g, 12.2 mmol) was added to a mixture of (3-bromophenyl)boronic acid (2.94 g, 14.6 mmol), acetylacetone bis(ethylene)rhodium(I) (189 mg, 0.731 mmol), and (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (758 mg, 1.22 mmol) in 1,4-dioxane (20 mL) and water (2.0 mL). The resulting reaction mixture was stirred at 105 °C for 5.5 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. Add saturated sodium bicarbonate aqueous solution (100 mL) and extract with ethyl acetate (3 × 30 mL). Wash the combined organic layers with brine (60 mL), dry with sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to provide (R)-3-(3-bromophenyl)cyclopentan-1-one (2.55 g, 88% yield) as a pale yellow oil.

[1237] LCMS: LC retention time 2.00 min. MS(ESI) m / z 239 [M+H] +

[1238] 1 ¹H NMR (400MHz, chloroform-d) δ 7.40–7.37 (m, 2H), 7.23–7.17 (m, 2H), 3.43–3.35 (m, 1H), 2.70–2.63 (m, 1H), 2.51–2.41 (m, 2H), 2.35–2.26 (m, 2H), 2.02–1.92 (m, 1H) ppm.

[1239] Step 2.

[1240]

[1241] At -78 °C under an argon atmosphere, diisobutylaluminum hydride (6.3 mL, 1 M toluene solution, 6.3 mmol) was added to a solution of (R)-3-(3-bromophenyl)cyclopentan-1-one (1.0 g, 4.18 mmol) in anhydrous tetrahydrofuran (10.0 mL), and the resulting reaction mixture was stirred for 2.0 h at the same temperature. The reaction was quenched by dropwise addition of methanol (5.0 mL) at -78 °C. The mixture was then heated to room temperature, and a saturated aqueous solution of sodium potassium tartrate tetrahydrate (50 mL) was added. The resulting mixture was stirred overnight at room temperature. Extracted with ethyl acetate (30 mL × 3), the combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30% ethyl acetate / petroleum ether) to produce (3R)-3-(3-bromophenyl)cyclopentan-1-ol (798 mg, 79% yield) as a colorless oil.

[1242] LCMS: LC retention time 1.97 min. MS(ESI) m / z 223 [M–H2O] +

[1243] 1 ¹H NMR (400MHz, chloroform-d) δ 7.44–7.37 (m, 1H), 7.33–7.30 (m, 1H), 7.23–7.14 (m, 2H), 4.55–4.43 (m, 1H), 3.41–2.97 (m, 1H), 2.49–2.07 (m, 2H), 1.95–1.79 (m, 2H), 1.74–1.58 (m, 2H) ppm.

[1244] Step 3.

[1245]

[1246] At room temperature and under an argon atmosphere, (trifluoromethyl)trimethylsilane (1.41 g, 9.93 mmol) was added to a mixture of (3R)-3-(3-bromophenyl)cyclopentane-1-ol (798 mg, 3.31 mmol), silver trifluoromethanesulfonate (2.55 g, 9.93 mmol), 1-chloromethyl-4-fluoro-1,4-diazamonium bicyclo[2.2.2]octanebis(tetrafluoroborate) salt (1.758 g, 4.97 mmol), and potassium fluoride (0.768 g, 13.24 mmol) in ethyl acetate (15.0 mL), followed by the addition of 2-fluoropyridine (0.963 g, 9.93 mmol). The resulting reaction mixture was stirred at room temperature for 94 h. The filtrate was filtered through a diatomaceous earth pad, concentrated, and purified by silica gel chromatography (100% petroleum ether) to provide 1-bromo-3-((1R)-3-(trifluoromethoxy)cyclopentyl)benzene (468 mg, 46% yield) as a colorless oil.

[1247] LCMS: LC retention time 2.74 min. Not observed in MS (ESI).

[1248] 1 ¹H NMR (400MHz, chloroform-d) δ 7.40–7.33 (m, 2H), 7.19–7.13 (m, 2H), 4.90–4.79 (m, 1H), 3.37–2.98 (m, 1H), 2.59–2.32 (m, 1H), 2.29–1.63 (m, 5H) ppm.

[1249] Intermediate D-22

[1250] 2-(3-(3-(1,1-difluoroethyl)cyclopentyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane

[1251]

[1252] Step 1.

[1253]

[1254] At room temperature, DIEA (9.35 g, 72.3 mmol) was added to a solution of methyl 3-oxocyclopentane-1-carboxylate (2.56 g, 18.0 mmol) in toluene (50 mL), followed by the addition of Tf₂O (12.80 g, 45.4 mmol) at 0 °C under a nitrogen atmosphere. 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 extract was washed with water (100 mL × 2), dried over sodium sulfate, filtered, and evaporated. The crude product obtained was purified by silica gel chromatography (PE / EA = 10 / 1) to yield methyl 3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-ene-1-carboxylate (4.93 g, 100%) as a yellow oil.

[1255] 1 ¹H NMR (400MHz, 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.

[1256] Step 2.

[1257]

[1258] 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), 3-(phenylmethyloxy)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) were added. The resulting mixture was stirred for 16 h at 80 °C under an argon atmosphere, filtered, and concentrated under vacuum. The residue was washed with water (200 mL) and brine (200 mL), extracted with ethyl acetate (20 mL × 2), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product obtained therefrom was purified by silica gel chromatography (PE / EA = 10:1) on silica gel to produce methyl 3-(3-(benzylmethyloxy)phenyl)cyclopent-2-ene-1-carboxylate (2.63 g; 47.5%, two steps), which is a yellow oil.

[1259] LCMS: LC retention time 2.27 min. MS(ESI) m / z 309 [M+H] + .

[1260] Step 3.

[1261]

[1262] Pd / C (1210 mg) was added to a solution of methyl 3-(3-(benzylmethyloxy)phenyl)cyclopent-2-ene-1-carboxylate (2.63 g, 8.53 mmol) in MeOH (150 mL). The resulting mixture was stirred for 16 h at room temperature. The reaction mixture was filtered through a diatomaceous earth stopper. The filtrate was concentrated and purified by silica gel chromatography (PE / EA = 5 / 1) to yield methyl 3-(3-hydroxyphenyl)cyclopentane-1-carboxylate (1.45 g, 77.2%) as a yellow oil.

[1263] LCMS: LC retention time 1.54 min. MS(ESI) m / z 221 [M+H] + .

[1264] Step 4.

[1265]

[1266] A solution of methyl 3-(3-hydroxyphenyl)cyclopentane-1-carboxylate (1.45 g, 6.58 mmol) in acetone (30 mL) was treated with (bromomethyl)benzene (2220 mg, 12.98 mmol) and K₂CO₃ (2735 mg, 19.79 mmol). The mixture was stirred for 16 h at 55 °C under a nitrogen atmosphere. The mixture was extracted with ethyl acetate (50 mL × 2), washed with water (50 mL) and brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel chromatography (PE / EA = 10 / 1) to yield methyl 3-(3-(phenylmethyloxy)phenyl)cyclopentane-1-carboxylate (2.04 g, 100%) as a yellow oil.

[1267] LCMS: LC retention time 2.26 min. MS(ESI) m / z 333 [M+Na] + .

[1268] Step 5.

[1269]

[1270] At room temperature, LiOH·H₂O (2060 mg, 49.05 mmol) was slowly added to a stirred solution of methyl 3-(3-(phenylmethyloxy)phenyl)cyclopentane-1-carboxylic acid (2.04 g, 6.57 mmol) in THF (8 mL), MeOH (4 mL), and water (0.75 mL). The reaction was stirred at room temperature for 16 h. Hydrochloric acid (2N) was added to the solution until pH 4 was reached. The mixture was then extracted with ethyl acetate (50 mL × 2), washed with brine (50 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure to yield 3-(3-(phenylmethyloxy)phenyl)cyclopentane-1-carboxylic acid (2.17 g; 100%) as a yellow solid.

[1271] LCMS: LC retention time 1.38 min. MS(ESI) m / z 297 [M+H] + .

[1272] Step 6.

[1273]

[1274] 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) were added to a solution of 3-(3-(benzylmethyloxy)phenyl)cyclopentane-1-carboxylic acid (2175 mg, 7.34 mmol) in DCM (40 mL). The resulting mixture was stirred for 16 h at the same temperature. The mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL × 2). The extract was washed with water (100 mL × 2), dried over sodium sulfate, and evaporated. The crude product obtained was purified by silica gel chromatography (PE / EA = 10 / 1) to produce 3-(3-(benzylmethyloxy)phenyl)-N-methoxy-N-methylcyclopentane-1-carboxamide (2.19 g, 88%) as a colorless oil.

[1275] LCMS: LC retention time 2.16 min. MS(ESI) m / z 340 [M+H] + .

[1276] Step 7.

[1277]

[1278] MeMgBr (7.9 mL, 23.7 mmol, 3.0 M) was added to a solution of 3-(3-(benzylmethyloxy)phenyl)-N-methoxy-N-methylcyclopentane-1-carboxamide (2690 mg, 7.92 mmol) in THF (20 mL) at 0 °C under N2. The resulting mixture was stirred for 2 h at room temperature. The mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL × 2). The extract was washed with water (100 mL × 2), dried over sodium sulfate, and evaporated. The resulting residue was purified by silica gel chromatography (PE / EA = 10 / 1) to provide 1-(3-(3-(benzylmethyloxy)phenyl)cyclopentyl)ethyl-1-one (2.31 g, 99%) as a colorless oil.

[1279] LCMS: LC retention time 2.22 min. MS(ESI) m / z 295 [M+H] + .

[1280] Step 8.

[1281]

[1282] DAST (4.0 mL) was added to a stirred solution of 1-(3-(3-(benzylmethyloxy)phenyl)cyclopentyl)ethyl-1-one (1.50 g, 5.1 mmol) in DCM (15 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 16 h at room temperature. The mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL × 2). The extract was washed with water (100 mL × 2), dried over sodium sulfate, and evaporated. The crude product obtained was purified by silica gel chromatography (PE / EA = 95 / 5) to produce 1-(benzylmethyloxy)-3-(3-(1,1-difluoroethyl)cyclopentyl)benzene (1.36 g, 84.9%) as a colorless oil.

[1283] LCMS: LC retention time 2.47 min. MS(ESI) m / z 317 [M+H] + .

[1284] Step 9.

[1285]

[1286] Pd / C (1.04 g) was added to a solution of 1-(benzylmethyloxy)-3-(3-(1,1-difluoroethyl)cyclopentyl)benzene (2.04 g, 6.46 mmol) in EA (50 mL). The resulting mixture was stirred for 16 h at room temperature. The reaction solution was filtered through a diatomaceous earth stopper. The filtrate was concentrated and purified by silica gel chromatography (PE / EA = 6 / 1) to produce 3-(3-(1,1-difluoroethyl)cyclopentyl)phenol (1.25 g, 85.6%) as a yellow oil.

[1287] LCMS: LC retention time 2.03 min. MS(ESI) m / z 227 [M+H] + .

[1288] Step 10.

[1289]

[1290] At 0 °C, pyridine (80 mg, 1.01 mmol) and Tf₂O (335 mg, 1.19 mmol) were added to a solution of 3-(3-(1,1-difluoroethyl)cyclopentyl)phenol (223 mg, 0.986 mmol) in DCM (2.5 mL). After the addition was complete, the reaction mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure. The residue was extracted with EA (20 mL × 3). The organic solutions were combined, washed with NaHCO₃ (10 mL) and brine (20 mL), and dried over anhydrous Na₂SO₄. The solvent was evaporated and purified by SGC (PE / EA = 5%) to provide 3-(3-(1,1-difluoroethyl)cyclopentyl)phenyl trifluoromethanesulfonic acid (171 mg, 48.4%) as a colorless oil.

[1291] LCMS: LC retention time 2.37 min. MS(ESI) m / z 381 [M+Na] + .

[1292] Step 11.

[1293]

[1294] At room temperature, 4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (108 mg, 0.84 mmol), TEA (145 mg, 1.43 mmol), and PdCl2 (dppf) (22 mg, 0.03 mmol) were added to a solution of 3-(3-(1,1-difluoroethyl)cyclopentyl)trifluoromethanesulfonic acid (171 mg, 0.48 mmol) in dioxane (2.5 mL). The reaction was heated under reflux for 16 h until TLC indicated that the starting material was consumed. The mixture was extracted with EA (30 mL × 2). The organic solution was washed with brine (30 mL × 2) and dried over anhydrous Na2SO4. The filtrate was concentrated to produce 2-(3-(3-(1,1-difluoroethyl)cyclopentyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (195 mg, 100%), a yellow solid.

[1295] LCMS: LC retention time 1.96 min. MS(ESI) m / z 337 [M+H] + .

[1296] Intermediate D-23

[1297] 2-(3-(3-(2,2-difluoropropyl)cyclopentyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane

[1298]

[1299] Step 1.

[1300]

[1301] LiAlH4 (808 mg, 21.3 mmol) was slowly added to a solution of 3-(3-(phenylmethyloxy)phenyl)cyclopentane-1-carboxylic acid (2.10 g, 7.09 mmol) in anhydrous THF (60 mL) at 0 °C under an argon atmosphere. After the addition, the mixture was heated to room temperature and stirred at the same temperature for 1 h. LCMS showed that the starting material was consumed. Na2SO4·10H2O and water were added to the mixture at 0 °C, and the mixture was stirred for another 1 h. The mixture was filtered through a diatomaceous earth mat. The filtrate was extracted with ethyl acetate (150 mL). The organic solution 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 produce a crude substance, which was then purified by passing it through a rapid chromatographic column (PE / EA = 5 / 1) to produce the desired compound (3-(3-(benzyloxy)phenyl)cyclopentyl)methanol (1.66 g, 83.0%) as a colorless oil.

[1302] LCMS: LC retention time 2.15 min. MS(ESI) m / z 283 [M+H] + .

[1303] Step 2.

[1304]

[1305] At 0 °C under an argon atmosphere, DMAP (71.8 mg, 0.59 mmol), Et3N (1.78 g, 17.6 mmol), and TsCl (1.68 g, 8.82 mmol) were added to a solution of (3-(3-(benzyloxy)phenyl)cyclopentyl)methanol (1.66 g, 5.88 mmol) in DCM (30 mL). The mixture was heated to room temperature and stirred overnight at the same temperature. The mixture was poured into ice water and extracted with DCM (60 mL). The DCM solution was washed with NaHCO3 (30 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to produce methyl 4-methylbenzenesulfonic acid (3-(3-(benzyloxy)phenyl)cyclopentyl)methyl ester (2.47 g), which was a yellow oil.

[1306] LCMS: LC retention time 2.38 min. MS(ESI) m / z 459 [M+Na] + .

[1307] Step 3.

[1308]

[1309] 18-crown-6 (2.24 g, 8.49 mmol) and KCN (552 mg, 8.49 mmol) were added to a solution of 4-methylbenzenesulfonic acid (3-(3-(benzyloxy)phenyl)cyclopentyl)methyl ester (2.47 g, 5.66 mmol) in DMF (30.0 mL). The solution was stirred overnight in an oil bath at 55 °C. The resulting solution was cooled to room temperature, diluted with ethyl acetate (150 mL), washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to produce a crude substance, which was purified by passing it through a rapid chromatographic column (PE / EA = 5 / 1) to produce 2-(3-(3-(benzyloxy)phenyl)cyclopentyl)acetonitrile (1.49 g, 90.4%) as a colorless oil.

[1310] LCMS: LC retention time 2.22 min. MS(ESI) m / z 292 [M+H] + .

[1311] Step 4.

[1312]

[1313] Sodium hydroxide (4.09 g, 100.3 mg) was added to a solution of 2-(3-(3-(phenylmethyloxy)phenyl)cyclopentyl)acetonitrile (1.49 g, 5.11 mmol) in ethanol (30 mL) and H₂O (3.0 mL). 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 hydrogen chloride (1 N). 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 2-(3-(3-(phenylmethyloxy)phenyl)cyclopentyl)acetic acid (1.48 g) as a pale yellow solid.

[1314] LCMS: LC retention time 2.13 min. MS(ESI) m / z 311 [M+H] + .

[1315] Step 5.

[1316]

[1317] N-methoxymethylamine hydrochloride (698 mg, 7.15 mmol), HATU (2.72 g, 7.15 mmol), and DIPEA (1.85 g, 14.3 mmol) were added to a stirred solution of 2-(3-(3-(benzylmethyloxy)phenyl)cyclopentyl)acetic acid (1.48 g, 4.77 mmol) in DCM (35 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM (80 mL) and washed with brine (60 mL × 2), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 3 / 1) to provide the desired compound 2-(3-(3-(benzylmethyloxy)phenyl)cyclopentyl)-N-methoxy-N-methylacetamide (1.43 g, 84.9%) as a colorless oil.

[1318] LCMS: LC retention time 2.24 min. MS(ESI) m / z 354 [M+H] + .

[1319] Step 6.

[1320]

[1321] At 0 °C, methyl magnesium bromide (3 M, in THF, 2.70 mL, 8.09 mmol) was added dropwise to a stirred solution of 2-(3-(3-(benzyloxy)phenyl)cyclopentyl)-N-methoxy-N-methylacetamide (1.43 g, 4.05 mmol) in anhydrous tetrahydrofuran (25.0 mL). The reaction mixture was stirred for 1 h at room temperature. It was quenched with saturated ammonium chloride solution (60 mL) and extracted with ethyl acetate (80 mL × 3). The organic layer was washed with brine (100 mL), dried over anhydrous Na₂SO₄, and concentrated under vacuum. The crude material was purified by silica gel column chromatography (PE / EA = 5 / 1) to provide the title compound 1-(3-(3-(benzyloxy)phenyl)cyclopentyl)prop-2-one (1.15 g, 92.2%) as a colorless oil.

[1322] LCMS: LC retention time 2.28 min. MS(ESI) m / z 309 [M+H] + .

[1323] Step 7.

[1324]

[1325] Under an argon atmosphere, DAST (12.0 mL) was added to a cooled (0 °C) stirred solution of 1-(3-(3-(benzylmethyloxy)phenyl)cyclopentyl)prop-2-one (954 mg, 3.09 mmol) in DCM (20 mL). The mixture was then slowly heated to room temperature and stirred overnight at the same temperature. The mixture was concentrated to dryness by purging with nitrogen. The crude substance was dissolved in ethyl acetate (80 mL), washed with saturated NaHCO3 (60 mL) and brine (80 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum to dryness to obtain the desired compound 1-(benzylmethyloxy)-3-(3-(2,2-difluoropropyl)cyclopentyl)benzene (665 mg, 70.6%) as a pale yellow oil.

[1326] LCMS: LC retention time 2.42 min. MS(ESI) m / z 331 [M+H] + .

[1327] Step 8.

[1328]

[1329] Under a nitrogen atmosphere, Pd / C (600 mg) was added to a solution of 1-(benzylmethyloxy)-3-(3-(2,2-difluoropropyl)cyclopentyl)benzene (665 mg, 2.01 mmol) in EtOAc (20.0 mL). The mixture was then stirred overnight at room temperature. LCMS showed that the starting material was consumed. The mixture was filtered through a diatomaceous earth mat, and the filtrate was concentrated under reduced pressure to dryness. The crude material was diluted with ethyl acetate (150 mL), washed with water (80 mL) and brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to produce 3-(3-(2,2-difluoropropyl)cyclopentyl)phenol (315 mg) as a yellow oil.

[1330] LCMS: LC retention time 2.10 min. MS(ESI) m / z 241 [M+H] + .

[1331] Step 9.

[1332]

[1333] At 0 °C, pyridine (51.9 mg, 0.66 mmol) was added to a solution of 3-(3-(2,2-difluoropropyl)cyclopentyl)phenol (158 mg, 0.66 mmol) in DCM (3 mL), followed by the addition of trifluoromethanesulfonic anhydride (223 mg, 0.79 mmol). After the addition was complete, the reaction mixture was stirred overnight at the specified temperature. The reaction mixture was concentrated under vacuum. The residue was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with NaHCO3 (10 mL) and brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was evaporated, and the residue was purified by passing it through a rapid chromatographic column (PE / EA = 10 / 1) to produce the desired compound, 3-(3-(2,2-difluoropropyl)cyclopentyl)phenyl trifluoromethanesulfonic acid (190 mg, 77.6%), as a pale yellow oil.

[1334] 1 ¹H NMR (400MHz, chloroform-d) δ 7.35 (t, J = 7.8 Hz, 1H), 7.24 (s, 1H), 7.09 (dd, J = 11.8, 3.8 Hz, 2H), 3.11 (ddd, J = 17.6, 13.2, 8.8 Hz, 1H), 2.43–1.75 (m, 10H), 1.74–1.44 (m, 11H), 1.39–1.16 (m, 3H) ppm.

[1335] Step 10.

[1336]

[1337] Under Ar atmosphere, 4,4,5,5-tetramethyl-1,3,2-dioxaborhexane (174 mg, 0.685 mmol), potassium acetate (112 mg, 1.14 mmol), and a 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (11.2 mg, catalytic amount) were added to a solution of 3-(3-(2,2-difluoropropyl)cyclopentyl)trifluoromethanesulfonic acid (170 mg, 0.457 mmol) in 1,4-dioxane (8.0 mL). The solution was stirred overnight at 90 °C. After the reaction was complete, the solution was concentrated under vacuum. The residue was dissolved in ethyl acetate (50 mL) and filtered. The filtrate was washed with water (50 mL × 3) and brine (50 mL). The aqueous phase was back-extracted with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous Na2SO4 and concentrated to dryness to provide 2-(3-(3-(2,2-difluoropropyl)cyclopentyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (120 mg, 75.0% yield) as a yellow oil.

[1338] LCMS: LC retention time 2.45 min. MS(ESI) m / z 351 [M+H] + .

[1339] Intermediate D-24

[1340] 1-(3-bromo-5-fluorophenyl)-3-(tert-butyl)pyrrolidine

[1341]

[1342] Step 1.

[1343]

[1344] At 0 °C, a solution of pyrrole (9.0 g, 134 mmol) in THF (100 mL) was added to a suspension of NaH (8.05 g, 201 mmol) in THF (100 mL). After 30 min, 50 mL of THF containing benzenesulfonyl chloride (23.70 g, 134 mmol) was added. The mixture was stirred for 5 h at room temperature. The reaction was quenched with water (200 mL). The THF was evaporated under reduced pressure. The residue was filtered, and the solid filter cake was washed with water and dried to obtain 1-(phenylsulfonyl)-1H-pyrrole (26.00 g, 89.8%) as a white solid.

[1345] LCMS: LC retention time 2.04 min. MS(ESI) m / z 208 [M+H] +

[1346] Step 2.

[1347]

[1348] AlCl3 (8.68 g, 65.1 mmol) was added to a solution of 1-(phenylsulfonyl)-1H-pyrrole (9.0 g, 43.4 mmol) and 2-chloro-2-methylpropane (4.79 g, 52.1 mmol) in DCM (150 mL) at 0 °C. After addition, the mixture was stirred at room temperature for 6 h. The mixture was quenched with water (150 mL). The aqueous phase was extracted with DCM (100 mL). The organic layer was washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by SGC (PE / EA = 2:1) to produce 3-(tert-butyl)-1-(phenylsulfonyl)-1H-pyrrole (6.00 g, 49.8% yield) as a yellow oil.

[1349] LCMS: LC retention time 2.25 min. MS(ESI) m / z 264.2 [M+H] + .

[1350] Step 3.

[1351]

[1352] KOH (12.8 g, 228 mmol) was added to a solution of 3-(tert-butyl)-1-(phenylsulfonyl)-1H-pyrrole (6.0 g, 22.8 mmol) in EtOH / H2O (60 mL / 60 mL). The mixture was stirred under reflux for 5 h. The solvent was then removed under reduced pressure. The residue was dissolved in water (50 mL). The aqueous solution was extracted with DCM (20 mL × 3). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by SGC (PE / EA = 5:1) to produce 3-(tert-butyl)-1H-pyrrole (2.20 g, 78.4% yield) as a yellow oil.

[1353] Step 4.

[1354]

[1355] At room temperature, under an Ar atmosphere, HCl (1.0 mL, 1 N) and PtO2 (203 mg) were added to a solution of 3-(tert-butyl)-1H-pyrrole (2.20 g, 17.9 mmol) in EtOH (100 mL). The flask was purged with hydrogen and stirred under hydrogen at room temperature for 16 h. The reaction mixture was filtered and washed with diethyl ether. The filtrate was concentrated under vacuum to provide 3-(tert-butyl)pyrrole (1.80 g, 79.2%) as a yellow oil.

[1356] LCMS: LC retention time 1.43 min. MS(ESI) m / z 128 [M+H] +

[1357] Step 5.

[1358]

[1359] Add 3-(tert-butyl)pyrrolidine (1.45 g, 11.4 mmol) and DIPEA (6.68 g, 51.8 mmol) to a solution of 1-bromo-3,5-difluorobenzene (2.0 g, 10.4 mmol) in NMP (10.0 mL). Seal the tube and stir overnight at 100 °C. Dilute the reaction mixture with water and EtOAc (10 mL each) ppm. Back-extract the aqueous layer with EtOAc (30 mL × 3). Then wash the combined organic layers with H2O (150 mL) and brine (150 mL), dry to Na2SO4, filter and concentrate. Purify the residue by SGC (PE) to obtain 1-(3-bromo-5-fluorophenyl)-3-(tert-butyl)pyrrolidine (2.40 g, 51.7%) as a colorless oil. LCMS: LC retention time 3.04 min. MS(ESI)m / z 302[M+H] +

[1360] Intermediate E-1a

[1361] 3-(neopentyloxy)-1H-pyrazole

[1362]

[1363] and

[1364] Intermediate E-1b

[1365] 3-(3,3-dimethylbutoxy)-1H-pyrazole

[1366]

[1367] Step 1.

[1368]

[1369] Hydrazine hydrate (30 mL) was added to a stirred solution of (E)-3-methoxyacrylate (6.00 g, 51.72 mmol) in MeOH (50 mL) at room temperature. The mixture was stirred under reflux for 16 h. After the reaction was complete, the solvent was removed. The residue (3.69 g, 43.93 mmol) was dissolved in pyridine (30 mL), and Ac₂O (4.7 g, 46.12 mmol) was slowly added at 95 °C. The mixture was then stirred at 95 °C for 2 h. The solvent was removed under reduced pressure, and the residue was dissolved in Et₂O (60 mL). The slurry was stirred overnight at room temperature. The solid was collected by filtration and washed with Et₂O (30 mL) to provide 1-(3-hydroxy-1H-pyrazole-1-yl)ethyl-1-one (4.32 g, 78%) as a pale yellow solid.

[1370] LCMS MS(ESI) m / z 127[M+H] + .

[1371] Step 2a.

[1372]

[1373] At room temperature, 2,2-dimethylprop-1-ol (3.00 g, 34.29 mmol), PPh3 (9.88 g, 37.72 mmol), and DIAD (7.62 g, 37.72 mmol) were added to a stirred solution of 1-(3-hydroxy-1H-pyrazol-1-yl)ethyl-1-one (4.32 g, 34.29 mmol) in THF (100 mL). The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EA (30 mL × 3). The organic solution was washed with brine (20 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (EA / PE = 1 / 10) to provide 1-(3-(neopentyloxy)-1H-pyrazol-1-yl)ethyl-1-one (3.3 g, 49%) as a pale yellow solid.

[1374] LCMS MS(ESI) m / z 197[M+H] + .

[1375] Step 3a.

[1376]

[1377] To a stirred solution of 1-(3-(neopentyloxy)-1H-pyrazol-1-yl)ethyl-1-one (3.3 g, 16.84 mmol) in MeOH / H₂O (30 mL / 3 mL), NaOH (673 mg, 16.84 mmol) was added at room temperature. The mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with water (30 mL) and extracted with EA (20 mL × 3). The organic phase was washed with brine (20 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (EA / PE = 1 / 5) to provide 3-(neopentyloxy)-1H-pyrazol (2.00 g, 80%) as a yellow oil.

[1378] LCMS MS(ESI) m / z 155 [M+H] + .

[1379] Step 2b

[1380]

[1381] At room temperature, 2,2-dimethylprop-1-ol (3.69 g, 36.19 mmol), PPh3 (11.85 g, 45.24 mmol), and DIAD (9.14 g, 45.24 mmol) were added to a stirred solution of 1-(3-hydroxy-1H-pyrazol-1-yl)ethyl-1-one (3.8 g, 30.16 mmol) in THF (200 mL). The mixture was stirred at room temperature for 16 h. It was then diluted with water (50 mL) and extracted with EA (30 mL × 3). The organic solution was washed with brine (20 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to provide 1-(3-(3,3-dimethylbutoxy)-1H-pyrazol-1-yl)ethyl-1-one (8.80 g) as a yellow solid.

[1382] LCMS MS(ESI)m / z 211[M+H] + .

[1383] Step 3b.

[1384]

[1385] At room temperature, NaOH (1.68 g, 41.9 mmol) was added to a stirred solution of 1-(3-(3,3-dimethylbutoxy)-1H-pyrazol-1-yl)ethyl-1-one (8.80 g, 41.9 mmol) in MeOH / H₂O (100 mL / 10 mL). The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EA (30 mL × 3). The organic solution was washed with brine (30 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (EA / PE = 1 / 4) to provide 3-(3,3-dimethylbutoxy)-1H-pyrazol (2.6 g, 51%, two-step process) as a yellow oil.

[1386] LCMS MS(ESI) m / z 169 [M+H] + .

[1387] Intermediate E-2

[1388] 3-((4,4-dimethylpentyl)oxy)-1H-pyrazole

[1389]

[1390] Step 1.

[1391]

[1392] To a stirred solution of 4,4-dimethylpentyl-1-ol (1.5 g, 12.9 mmol) in THF (30 mL), 1-(3-hydroxy-1H-pyrazol-1-yl)ethyl-1-one (1.36 g, 10.8 mmol), Ph3P (4.24 g, 0.0162 mol), and DIAD (3.27 g, 16.2 mmol) were added. The mixture was then stirred at 60 °C for 16 h. The solvent was evaporated, and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1) to provide 1-(3-((4,4-dimethylpentyl)oxy)-1H-pyrazol-1-yl)ethyl-1-one (1.80 g, 74.4%) as a colorless oil.

[1393] LCMS: MS(ESI) m / z 225 [M+H] + .

[1394] Step 2.

[1395]

[1396] To a stirred solution of 1-(3-((4,4-dimethylpentyl)oxy)-1H-pyrazol-1-yl)ethyl-1-one (1.80 g, 8.02 mmol) in MeOH (20 mL) and water (2 mL), NaOH (0.32 g, 8.02 mmol) was added. The mixture was then stirred at room temperature for 16 h. The solvent was evaporated to provide 3-((4,4-dimethylpentyl)oxy)-1H-pyrazol (1.2 g, 82%) as a colorless oil...

Claims

1. A compound of formula (I): Or its pharmaceutically acceptable salt. in: R 1 It is hydrogen; X is a phenyl group, represented by R appearing 0-3 times. 2 replace; Cy 1 It is a phenyl group, represented by R 0-3 times. 3 replace; Cy 2 It is a phenyl group, represented by R appearing 1-3 times. 4 replace; Each R 2 Independently, it is a halogen group, -NH2, nitro group, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-9 cycloalkyl, C 3-9 Cycloalkoxy, -N(R) a (R) 5 ), -N(R a )C(O)-R 5 -N(R) a SO2-R 5 -SO2-R 5 or -C(O)N(R) a (R) 5 ), where each C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 3-9 Cycloalkyl groups are further affected by R appearing 0-3 times. 5 replace; Each R 3 Independently, it is a halogen group, C 1-8 Alkyl, C 1-8 alkenyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-8 Halogenated alkoxy groups, C 3-9 cycloalkyl, C 1-4 Alkyl-C 3-9 cycloalkyl, C 1-4 Alkoxy-C 3-9 cycloalkyl, C 3-9 Cycloalkoxy, C 3-9 Cycloalkenyl, -C(O)-R 7 -C(O)N(R) a (R) 7 ) or -N(R a (R) 8 ), where each C 3-9 cycloalkyl, C 3-9 Cycloalkoxy, C 1-8 Halogenated alkoxy groups, C 1-8 Alkoxy, cycloalkenyl, C 1-4 Alkyl-C 3-9 cycloalkyl or C 1-4 Alkoxy-C 3-9 Cycloalkyl groups are further affected by R appearing 0-3 times. 7 replace; Each R 4 Independently, it is a halogen group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl or N(R) a )2; Each R 5 C is independent 1-6 Alkyl, C 1-6 Haloalkyl, C 3-9 Cycloalkyl, hydroxyl, -SO2-R 6 -CO2H, -NH2, or -CO2-C 1-4 Alkyl, wherein each C 1-6 Alkyl or C 3-9 Cycloalkyl groups are further affected by R appearing 0-3 times. 6 replace; Each R 6 Independently, it is a hydroxyl group, -NH2 group, halogen group, or C group. 1-4 Alkyl, C 1-4 Halogenated alkyl, -CO2H or -CO2-(C 1-4 alkyl); Each R 7 Independently, it is a halogen group, C 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Haloalkyl, C 1-5 Halogenated alkoxy groups, C 1-5 Haloalkenyl, C 3-7 Cycloalkyl, hydroxyl, -C(O)-OC 1-4 Alkyl or -C(O)N(R) a (C) 1-4 Alkyl), wherein each C 3-7 Cycloalkyl groups are further affected by R appearing 0-3 times. 8 replace; Each R 8 Independently, it is a halogen group, C 1-4 Alkyl, C 1-4 Haloalkoxy, C(O)-C 1-4 Alkyl or C(O)N(R) a (C) 1-4 alkyl); Each R a Independently, it is H or C 1-6 Alkyl; and Each R b It is C 1-4 alkyl; in a) If Cy 1 R appears 3 times 3 Then each R 3 It is not a methoxy group; b) R 2 and R 4 Not all of them are methyl groups; and c) R 3 and R 4 It is neither tert-butyl nor methoxy at the same time.

2. The compound of claim 1, wherein X is R that appears 0 times. 2 Substituted phenyl groups.

3. The compound of claim 1, wherein X is R that appears once. 2 Substituted phenyl groups.

4. The compound of claim 3, wherein R 2 It is -N(R) a (R) 5 ).

5. The compound of claim 4, wherein R a Is it H or C? 1-6 Alkyl, and R 5 It is C 1-6 alkyl.

6. The compound of claim 4, wherein R a It is H, and R 5 Selected from R that appears 0 or 1 times 6 Replacement C 1-6 Halogenated alkyl groups and C 3-9 Cycloalkyl.

7. The compound of claim 6, wherein R 6 Selected from -CO2H, -C(O)2-C 1-4 Alkyl, hydroxyl and C 1-4 alkyl.

8. The compound of claim 3, wherein R 2 It is -N(R) a )C(O)-R 5 .

9. The compound of claim 8, wherein R a It is H, and R 5 Selected from C 1-6 Alkyl and C 3-9 Cycloalkyl groups, each represented by R 0-3 times. 6 replace.

10. The compound of claim 9, wherein R 6 Selected from -NH2, hydroxyl, halogen and C 1-4 Halogenated alkyl groups.

11. The compound of claim 3, wherein R 2 It is -C(O)-N(R) a (R) 5 ).

12. The compound of claim 11, wherein R a It is H, and R 5 It is R that appears 0-3 times. 6 Replacement C 1-6 alkyl.

13. The compound of claim 3, wherein R 2 It is -N(R) a SO2-R 5 .

14. The compound of claim 13, wherein R a It is H, and R 5 It is R that appears 0-3 times. 6 Replacement C 1-6 alkyl.

15. The compound of claim 2, wherein X is 。 16. The compound of claim 1, wherein X is R that appears twice. 2 Substituted phenyl groups.

17. The compound of claim 16, wherein each R 2 It is a halogen group.

18. The compound of claim 16, wherein one of R... 2 It is -NH2, and an R 2 It is a halogen group.

19. The compound of claim 16, wherein one of R... 2 It is C 1-6 Alkyl, and another R 2 It is C 1-6 Halogenated alkyl groups.

20. The compound of claim 16, wherein one of R... 2 It is a halogen, and another R 2 It is -N(R) a (R) 5 ) .

21. The compound of claim 20, wherein R a It is H, and R 5 It is R that appears 0-3 times. 6 Replacement C 3-9 Cycloalkyl.

22. The compound of claim 21, wherein R 6 It is C 1-6 alkyl.

23. The compound of claim 16, wherein X is 。 24. The compound of claim 1, wherein R 4 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 3-6 Cycloalkyl.

25. The compound of claim 24, wherein Cy 2 yes 。 26. The compound of claim 1, wherein Cy 2 R appears 2 or 3 times 4 Substituted phenyl groups.

27. The compound of claim 26, wherein R 4 Selected from halogen groups, C 1-6 Haloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and -N(R) a )2.

28. The compound of claim 27, wherein Cy 2 yes 。 29. The compound of claim 1, wherein Cy 2 yes 。 30. The compound of claim 1, wherein R 3 Selected from C 1-8 Alkyl, C 1-8 Halogenated alkyl groups and C 1-8 Alkyl group.

31. The compound of claim 30, wherein Cy 1 yes 。 32. The compound of claim 1, wherein R 3 It is C 1-8 Halogenated alkoxy or C 3-9 Cycloalkyl.

33. The compound of claim 32, wherein Cy 1 yes 。 34. The compound of claim 1, wherein R 3 It is R that appears 1-2 times 7 Substituted cyclopentyl, wherein R 7 Selected from C 1-4 Halogenated alkoxy groups, C 1-4 Halogenated alkyl groups and C 1-4 alkyl.

35. The compound of claim 34, wherein Cy 1 yes 。 36. The compound of claim 1, wherein R 3 It is R that appears 0-3 times. 7 Replacement C 3-9 Cycloalkoxy, where R 7 It is C 1-4 alkyl.

37. The compound of claim 36, wherein Cy 1 yes or .

38. The compound of claim 1, wherein R 3 It is R that appears 0-3 times. 7 Replacement C 1-4 Alkyl-C 3-9 cycloalkyl or C 1-4 Alkoxy-C 3-9 Cycloalkyl.

39. The compound of claim 38, wherein R 7 Selected from halogen groups, hydroxyl groups, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups.

40. The compound of claim 39, wherein Cy 1 yes .

41. The compound of claim 1, wherein Cy 1 It was R that appeared twice. 3 Substituted phenyl groups.

42. The compound of claim 41, wherein each R 3 Independently selected from halogen groups, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-9 cycloalkyl, C 1-8 Alkoxy, C 3-9 Cycloalkoxy, C 1-8 Halogenated alkoxy groups, C 1-4 Alkoxy-C 3-9 cycloalkyl, C 3-9 Cycloalkenyl, -C(O)R 7 and -C(O)N(R) a (R) 7 ), where C 3-9 cycloalkyl, C 1-8 Alkoxy, C 3-9 Cycloalkoxy, C 1-8 Halogenated alkoxy or C 1-4 Alkoxy-C 3-9 Cycloalkyl groups are represented by R 0-3 times. 7 replace.

43. The compound of claim 42, wherein R appears at least once. 7 Selected from hydroxyl, -C(O)-OC 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy groups.

44. The compound of claim 42 or 43, wherein Cy 1 yes 。 45. A compound selected from: Or its pharmaceutically acceptable salt.

46. ​​A compound selected from: Or its pharmaceutically acceptable salt.

47. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

48. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or excipient.

49. The pharmaceutical composition of claim 48, wherein the pharmaceutical composition further comprises one or more CFTR therapeutic agents.

50. Use of the compound of claim 1 in the manufacture of a medicament for treating CFTR deficiency in cells.

51. The use as described in claim 50, wherein contact with the cells occurs in a subject in need, thereby treating a CFTR-mediated disorder and / or disease.

52. The use as claimed in claim 51, wherein the disease or ailment is selected from cystic fibrosis, asthma, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral vas deferens agenesis (CBAVD), mild lung disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), congenital pneumonia, malabsorption, celiac disease, nasal polyposis, nontuberculous mycobacterial infection, pancreatic steatorrhea, intestinal atresia, liver disease, hereditary emphysema, and hereditary diseases. Hemochromatosis, coagulation-fibrinolysis defect, protein C deficiency, type 1 hereditary angioedema, lipid processing defect, familial hypercholesterolemia, type 1 chylomicronemia, abeta-lipoproteinemia, lysosomal storage disease, I-cell disease / pseudo-Huller's disease, mucopolysaccharidosis, Sandhof / Tai-Sachs disease, type II Krieger-Najjar disease, polyendocrine disorders / hyperinsulinemia, diabetes mellitus, Laren dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, 1 Glycosaminoglycanopathy (CDG), congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), Chuck-Maridus syndrome, Perizoys-Metzbach disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy, Pick's disease, several polyglutamine neuropathies, Huntington's disease, type I spinocerebellar ataxia, spinobulbar muscular atrophy, dentate nucleus, globus pallidus, hypothalamic nucleus atrophy, myotonic dystrophy Malnutrition, spongiform encephalopathy, hereditary Kreutzfeldt-Jacob disease, Fabry disease, Stösler-Schenck syndrome, COPD, dry eye disease, Sjögren's disease, osteoporosis, osteopenia, bone healing and bone growth, bone repair, bone regeneration, reduced bone resorption, increased bone deposition, High Ham syndrome, chloride channel disorders, congenital myotonia, type III Barth syndrome, Dent disease, startle reflex, epilepsy, Angelman syndrome, primary ciliary dyskinesia (PCD), and ciliary dysplasia.

53. The use as claimed in claim 51, wherein the disease or disorder is selected from cystic fibrosis, congenital bilateral vas deferens agenesis (CBAVD), acute pancreatitis, recurrent pancreatitis or chronic pancreatitis, disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis, congenital pneumonia, malabsorption, celiac disease, nasal polyposis, nontuberculous mycobacterial infection, pancreatic steatorrhea, intestinal atresia, chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis, dry eye disease, protein C deficiency, abeta-lipoproteinemia, lysosomal storage disease, type 1 chylomicronemia, mild lung disease, lipid processing defects, type 1 hereditary angioedema, coagulation-fibrinolysis, hereditary hemochromatosis, CFTR-related metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, and Sjögren's syndrome.

54. The use as claimed in claim 53, wherein the disease or ailment is cystic fibrosis.

55. Use of the compound of claim 1 in the manufacture of a medicament for treating cystic fibrosis or its symptoms in a subject.

56. The use as described in claim 55, wherein the subject is a human.

57. The use according to claim 56, wherein the subject is at risk of developing cystic fibrosis, and wherein the drug is administered to the subject prior to the onset of symptoms of cystic fibrosis in the subject.

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