5-membered heteroarylaminosulfonamides for treating conditions mediated by deficient CFTR activity

Abstract

To provide compounds, compositions, and methods for treating diseases and conditions mediated by deficient CFTR activity, in particular cystic fibrosis.SOLUTION: Provided are heteroaryl compounds illustrated below, pharmaceutically acceptable salts thereof, and pharmaceutical preparations thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and benefit of U.S. Provisional Patent Application No. 62 / 934,293, filed November 12, 2019, which is incorporated herein by reference in its entirety. [Background technology]

[0002] background Cystic fibrosis (CF), an autosomal recessive disease, is caused by dysfunction of the cAMP-activated plasma membrane chloride channel, the cystic fibrosis transmembrane conductance regulator (CFTR), which can cause damage to the lungs, pancreas, and other organs. The gene encoding CFTR has been identified and sequenced (see Gregory, RJ et al. (1990) Nature 347:382-386 (Non-Patent Document 1); Rich, DP et al. (1990) Nature 347:358-362 (Non-Patent Document 2); Riordan, JR et al. (1989) Science 245:1066-1073 (Non-Patent Document 3)). 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-CL4). Normally, the CFTR protein is located primarily in the apical membrane of epithelial cells, where it functions to conduct anions, including chloride, carbonate, and thiocyanate, into and out of the cell. CFTR may have a regulatory role over other electrolyte channels, including the epithelial sodium channel ENaC.

[0003] In patients with cystic fibrosis, the absence or dysfunction of CFTR leads to exocrine dysfunction and multisystem disease characterized by pancreatic insufficiency and malabsorption, as well as abnormal mucociliary clearance in the lungs, mucus congestion, chronic pulmonary infection and inflammation, decreased lung function, and ultimately respiratory failure.

[0004] Although over 1,900 mutations have been identified in the CFTR gene, detailed understanding of how each CFTR mutation may affect channel function is only known for a subset of mutations (Derichs, European Respiratory Review, 22:127, 58-65 (2013)). The most frequent CFTR mutation is an in-frame deletion of phenylalanine (ΔF508) at residue 508 in the first nucleotide-binding domain (NBD1). More than 80% of cystic fibrosis patients have a deletion at residue 508 in at least one allele. The loss of this critical phenylalanine renders the CFTR NBD1 domain conformationally unstable at physiological temperatures, compromising the integrity of the interdomain interface between NBD1 and the second transmembrane domain (ICL4) of CFTR. The ΔF508 mutation leads to the production of misfolded CFTR protein, which does not transport to the plasma membrane but instead is retained in the endoplasmic reticulum and targeted for degradation by the ubiquitin-proteasome system.

[0005] Loss of functional CFTR channels in the plasma membrane disrupts ion homeostasis and airway surface hydration, leading to decreased lung function. Decreased periciliary fluid volume and increased mucus viscosity impede mucociliary clearance, leading to chronic infection and inflammation. In the lung, loss of CFTR function causes numerous physiological effects downstream of altered anion conductance, leading to dysfunction of additional organs such as the pancreas, intestine, and gallbladder.

[0006] Guided in part by research into the mechanistic aspects of CFTR misfolding and dysfunction, small molecule CFTR modulators have been identified that can increase CFTR channel function. Despite the identification of compounds that modulate CFTR, there is no cure for this deadly disease, and there is a need for the identification of new compounds and new therapeutic methods, as well as new methods for treating or reducing the severity of cystic fibrosis and other CFTR-mediated conditions and diseases in patients. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Gregory, RJet al. (1990) Nature 347:382-386 [Non-patent document 2] Rich,DPet al.(1990)Nature 347:358-362 [Non-patent document 3] Riordan, JRet al. (1989) Science 245:1066-1073 [Non-patent document 4] Derichs,European Respiratory Review,22:127,58-65(2013) Summary of the Invention

[0008] overview In certain aspects, the present application provides a compound of formula (I): The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, During the ceremony, R 1 is hydrogen or C 1-6 is alkyl, X is C 1-6 alkyl, 5- to 6-membered aryl, 4- to 10-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which may be 0 to 3 occurrences of R 2 is replaced by Cy 1 is C 3-9 cycloalkyl, 5- to 6-membered aryl, 4- to 10-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which may be 0 to 3 occurrences of R 3 is replaced by Cy 2 is C 3-9 cycloalkyl, 5- to 6-membered aryl, 4- to 10-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which may be present in 1 to 3 occurrences of R 4 is replaced by Each R 2 are independently hydroxyl, halo, -NH2, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 haloalkoxy, 4- to 10-membered heterocycloalkyl, 5- to 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, and each C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-9 Cycloalkyl or 4- to 10-membered heterocycloalkyl may have 0 to 3 occurrences of R 5 is further replaced by Each R 3 independently, halo, C 1-8 Alkyl, C 1-8 Alkenyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, 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- to 6-membered aryl, aralkyl, aralkoxy, 5- to 6-membered heteroaryl, 4- to 10-membered heterocycloalkyl, -C(O)-R 7 , -C(O)N(Ra )(R 7 ) or -N(R a )(R 8 ) and each C 3-9 Cycloalkyl, C 3-9 Cycloalkoxy, C 1-8 Haloalkoxy, C 1-8 Alkoxy, 4- to 10-membered heterocycloalkyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, cycloalkenyl, C 1-4 Alkyl-C 3-9 Cycloalkyl or C 1-4 Alkoxy-C 3-9 Cycloalkyl is 0 to 3 occurrences of R 7 is further substituted with Each R 4 independently, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, N(R a ) 2- or 4- to 10-membered heterocycloalkyl, each 4- to 10-membered heterocycloalkyl having 0 to 3 R b may be further substituted with Each R 5 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-9 Cycloalkyl, hydroxyl, -SO2-R 6 , -CO2H, -NH2, -CO2-C 1-4 alkyl or 4- to 10-membered heterocycloalkyl, and each C 1-6 Alkyl, C 3-9 Cycloalkyl or 4- to 10-membered heterocycloalkyl may have 0 to 3 occurrences of R 6 is further replaced by Each R 6 are independently hydroxyl, -NH2, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, -CO2H or -CO2-(C 1-4 alkyl), Each R 7independently, halo, C 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Haloalkyl, C 1-5 Haloalkoxy, C 1-5 Haloalkenyl, C 3-7 Cycloalkyl, hydroxyl, 5- to 6-membered aryl, aralkyl, aralkoxy, -C(O)-OC 1-4 Alkyl, -C(O)N(R a )(C 1-4 alkyl), 5- to 6-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, each C 3-7 Cycloalkyl, 5- to 6-membered aryl, or 4- to 10-membered heterocycloalkyl may occur 0 to 3 times. 8 is further replaced by Each R 8 independently, halo, 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 are independently H or C 1-6 is alkyl, Each R b is C 1-4 is alkyl, During the ceremony, a) Cy 1 is phenyl and three occurrences of R 3 If each R 3 is not methoxy, b) X and Cy 2 are each phenyl, R 2 and R 4 are not methyl, c)R 3 and R 4 is not simultaneously tert-butyl or simultaneously methoxy, d) Cy 1 and Cy 2 is monosubstituted phenyl, X is not thienyl, e) Cy 1 and Cy2 When R is monosubstituted phenyl, 2 is not OH, but R 3 is not Cl, but R 4 is not OMe.

[0009] Disclosed herein are methods of treating a defect in CFTR activity, thereby treating a disease or condition mediated by a defect in CFTR activity. Such diseases and conditions include, but are not limited to, cystic fibrosis, congenital bilateral absence of the vas deferens (CBAVD), acute, recurrent, or chronic pancreatitis, disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis, congenital pneumonia, intestinal malabsorption, celiac disease, nasal polyposis, nontuberculous mycobacteriosis, pancreatic steatorrhea, intestinal atresia, chronic obstructive pulmonary disease (COPD), chronic sinusitis, dry eye disease, protein C deficiency, abetalipoproteinemia, lysosomal storage diseases, type 1 chylomyocarditis, mild pulmonary disease, lipid processing deficiency, hereditary angioedema type 1, coagulation-fibrinolysis, hereditary hemochromatosis, CFTR-associated metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, and Sjogren's syndrome. In some embodiments, the disease is cystic fibrosis.

[0010] In certain embodiments, the present invention provides pharmaceutical compositions suitable for use in a subject in treating or preventing diseases and conditions associated with defective CFTR activity, comprising an effective amount of any compound described herein (e.g., a compound of the present invention, such as a compound of Formula (I)) and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical preparation may be for use in treating or preventing a condition or disease described herein.

[0011] Provided herein are combination therapies of compounds of formula (I) and CFTR activators that can enhance therapeutic benefit beyond the capabilities of the primary therapy alone. [The present invention 1001] A compound of formula (I), or a pharmaceutically acceptable salt thereof: TIFF2025160375000002.tif25128 formula, R 1 is hydrogen or C 1-6 is alkyl, X is C 1-6 alkyl, 5- to 6-membered aryl, 4- to 10-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which occurs 0 to 3 times. 2 is replaced by Cy 1 But C 3-9 cycloalkyl, 5- to 6-membered aryl, 4- to 10-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which occurs 0 to 3 times. 3 is replaced by Cy 2 But C 3-9 cycloalkyl, 5- to 6-membered aryl, 4- to 10-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which occurs 1 to 3 times. 4 is replaced by Each R 2 are independently hydroxyl, halo, -NH2, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 haloalkoxy, 4- to 10-membered heterocycloalkyl, 5- to 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 and C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C3-9 cycloalkyl or 4- to 10-membered heterocycloalkyl occurs 0 to 3 times in R 5 is further replaced by Each R 3 But independently, Halo, C 1-8 Alkyl, C 1-8 Alkenyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, 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- to 6-membered aryl, aralkyl, aralkoxy, 5- to 6-membered heteroaryl, 4- to 10-membered heterocycloalkyl, -C(O)-R 7 , -C(O)N(R a )(R 7 ) or -N(R a )(R 8 ) and C 3-9 Cycloalkyl, C 3-9 Cycloalkoxy, C 1-8 Haloalkoxy, C 1-8 Alkoxy, 4- to 10-membered heterocycloalkyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, cycloalkenyl, C 1-4 Alkyl-C 3-9 Cycloalkyl or C 1-4 Alkoxy-C 3-9 Each cycloalkyl may have 0 to 3 occurrences of R 7 is further substituted with Each R 4 But independently, Halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, N(R a ) 2- or 4- to 10-membered heterocycloalkyl, each 4- to 10-membered heterocycloalkyl being selected from 0 to 3 Rb may be further substituted with Each R 5 But independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-9 Cycloalkyl, hydroxyl, -SO2-R 6 , -CO2H, -NH2, -CO2-C 1-4 alkyl or 4- to 10-membered heterocycloalkyl, C 1-6 Alkyl, C 3-9 cycloalkyl or 4- to 10-membered heterocycloalkyl occur 0 to 3 times in R 6 is further replaced by Each R 6 are independently hydroxyl, -NH2, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, -CO2H or -CO2-(C 1-4 alkyl), Each R 7 But independently, Halo, C 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Haloalkyl, C 1-5 Haloalkoxy, C 1-5 Haloalkenyl, C 3-7 Cycloalkyl, hydroxyl, 5- to 6-membered aryl, aralkyl, aralkoxy, -C(O)-OC 1-4 Alkyl, -C(O)N(R a )(C 1-4 alkyl), 5- to 6-membered heteroaryl or 4- to 10-membered heterocycloalkyl; 3-7 R is a group in which 0 to 3 occurrences of each of cycloalkyl, 5- to 6-membered aryl, or 4- to 10-membered heterocycloalkyl occur. 8 is further replaced by Each R 8 But independently, Halo, 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 Ra are independently H or C 1-6 is alkyl, Each R b But C 1-4 is alkyl, where: a) Cy 1 is phenyl and three occurrences of R 3 If each R 3 is not methoxy, b) X and Cy 2 are each phenyl, R 2 and R 4 are not methyl, c)R 3 and R 4 is neither tert-butyl nor methoxy at the same time, d) Cy 1 and Cy 2 is monosubstituted phenyl, X is not thienyl, and e) Cy 1 and Cy 2 When R is monosubstituted phenyl, 2 is not OH, but R 3 is not Cl, but R 4 is not OMe. [The present invention 1002] R 1 1001. The compound of the present invention, wherein is H. [The present invention 1003] R 1 But C 1-6 The compound of the present invention 1001, wherein the aryl group is alkyl (eg, methyl or ethyl). [The present invention 1004] R with 0 to 3 Xs 2 The compound of any one of claims 1001 to 1003, wherein the compound is aryl (for example, phenyl) substituted with . [The present invention 1005] R where X appears 0 times 2 1004. A compound of the present invention, wherein the compound is phenyl substituted with . [The present invention 1006] R with one occurrence of X 21004. A compound of the present invention, wherein the compound is phenyl substituted with . [The present invention 1007] R 2 However, 0 to 3 Rs appear 5 1006. A compound of the present invention, wherein the compound is heteroaryl substituted with (eg, 1-pyrazolyl or 5-pyrazolyl). [The present invention 1008] R 2 But -N(R a )(R 5 ) The compound of the present invention 1006. [The present invention 1009] R a But H or C 1-6 alkyl (e.g., methyl), and R 5 But C 1-6 1008. A compound of the present invention, wherein the compound is alkyl (e.g., methyl). [The present invention 1010] R a is H and R 5 occurs 0 or 1 time 6 Replaced by C 1-6 haloalkyl (e.g., trifluoromethyl or 1,1,1-trifluoroisopropyl), heterocycloalkyl (e.g., 3-tetrahydrofuranyl), and C 3-9 1008. Compounds of the present invention selected from cycloalkyl (eg, cyclobutyl or cyclopentyl). [The present invention 1011] R 6 -CO2H, -C(O)2-C 1-4 Alkyl (e.g., -CO2Me or -CO2Et), hydroxyl, and C 1-4 The compound of the present invention 1010, wherein the alkyl (e.g., methyl) is selected from the group consisting of: [The present invention 1012] R 2 But -N(R a )C(O)-R 5 The compound of the present invention 1006, [The present invention 1013] R a is H, R 5But C 1-6 Alkyl (e.g., methyl, ethyl, or isopropyl) and C 3-9 cycloalkyl (e.g., cyclopropyl), each of which occurs 0 to 3 times. 6 is replaced by The compound of the present invention 1012. [The present invention 1014] R 6 -NH2, hydroxyl, halo (e.g., fluoro), and C 1-4 The compound of the present invention 1013 selected from haloalkyl (eg, trifluoromethyl). [The present invention 1015] R 2 However, 0 to 3 Rs appear 5 1006. A compound of the present invention, wherein the compound is heterocycloalkyl substituted with (eg, N-pyrrolidinyl). [The present invention 1016] Each R 5 However, 0 to 3 Rs appear 6 C replaced with 1-6 The compound of the present invention 1015, wherein the compound is selected from alkyl (e.g., methyl). [The present invention 1017] R 2 But -C(O)-N(R a )(R 5 ) The compound of the present invention 1006. [The present invention 1018] R a is H and R 5 However, 0 to 3 Rs appear 6 C replaced with 1-6 The compound of the present invention 1017, which is alkyl (e.g., methyl or ethyl). [The present invention 1019] R 2 But -N(R a )S(O)(NH)-R 5 The compound of the present invention 1006, [The present invention 1020] R a is H and R 5 However, 0 to 3 Rs appear 6 C replaced with1-6 The compound of the present invention 1019, which is alkyl (e.g., methyl). [The present invention 1021] X is, The compound of the present invention 1006 is TIFF2025160375000003.tif203149TIFF2025160375000004.tif33135. [The present invention 1022] R with two occurrences of X 2 1004. A compound of the present invention, which is phenyl substituted with [The present invention 1023] Each R 2 is halo (eg, fluoro or chloro). [The present invention 1024] One R 2 is -NH2 and one R 2 Compounds of the present invention 1022, wherein is halo (e.g., fluoro). [The present invention 1025] On the other hand, R 2 But C 1-6 alkyl (e.g., methyl), and the other R 2 But C 1-6 The compound of the present invention 1022, which is haloalkyl (eg, difluoromethyl). [The present invention 1026] On the other hand, R 2 is halo (e.g., fluoro), and the other R 2 But -N(R a )(R 5 ) (for example, -NHMe). [The present invention 1027] R a is H and R 5 However, 0 to 3 Rs appear 6 C replaced with 3-9 1026. A compound of the present invention which is cycloalkyl (eg, cyclopentyl). [The present invention 1028] R a is H and R 5 However, 0 to 3 Rs appear 61026. A compound of the invention which is heterocycloalkyl substituted with (eg, 3-pyrrolidinyl). [The present invention 1029] R 6 But C 1-6 Compounds of the invention 1027 or 1028, which are alkyl (eg, methyl). [The present invention 1030] X is, The compound of the present invention 1022 is TIFF2025160375000005.tif54140. [The present invention 1031] R with 3 Xs 2 1004. A compound of the present invention, which is phenyl substituted with [The present invention 1032] The Two R's 2 is halo (e.g., fluoro), and the remaining R 2 The compound of the present invention 1031, wherein is -NH2. [The present invention 1033] X is, TIFF2025160375000006.tif17128, compound of the present invention 1032. [The present invention 1034] R with 0 to 3 Xs 2 The compound of any one of 1001 to 1003 of the present invention, wherein the compound is a 5- or 6-membered heteroaryl substituted with [This invention 1035] R with 0 to 3 Xs 2 1034. A compound of the invention selected from pyridinyl, pyrazolyl, isoxazolyl, pyrazolyl, indolyl, thiazolyl, thiophenyl, or furanyl, substituted with: [The present invention 1036] X is, -NH 2 , halo (e.g., fluoro or chloro), and 0 to 3 occurrences of R 5 C replaced with 1-6 alkoxy (e.g., methoxy or isopropoxy) One R selected from 2 1034. A compound of the present invention which is 2-pyridinyl substituted with [This invention 1037] R 5 but one or two occurrences of R 6 C replaced with 3-9 1036. A compound of the present invention which is cycloalkyl (eg, cyclopropyl or cyclobutyl). [The present invention 1038] R 6 But C 1-4 1037. A compound of the invention selected from haloalkyl (eg, trifluoromethyl) and halo (eg, fluoro). [This invention 1039] R 2 But -N(R a )SO2-R 5 The compound of the present invention 1034, [The present invention 1040] R a is H and R 5 However, 0 to 3 Rs appear 6 C replaced with 1-6 1039 compounds of the present invention which are alkyl (e.g., methyl). [This invention 1041] R 2 But -N(R a )C(O)-R 5 or -N(R a )(R 5 ) Compound 1034 of the present invention. [The present invention 1042] R a is H and R 5 However, 0 to 3 Rs appear 6 C replaced with 1-6 1041. Compounds of the invention which are alkyl (eg, methyl or isopropyl or neopentyl). [This invention 1043] R a But C 1-6 alkyl (e.g., methyl or ethyl), and R 5 However, 0 to 3 Rs appear 6 C replaced with 1-6 1041. A compound of the present invention wherein the compound is alkyl (eg, methyl or isopropyl). [This invention 1044] R a is H and R 5 However, 0 to 3 Rs appear 6 C replaced with 3-9 1041. A compound of the present invention which is cycloalkyl (eg, cyclopropyl or cyclopentyl). [This invention 1045] R a is H and R 5 However, 0 to 3 Rs appear 6 C replaced with 1-6 1041. A compound of the present invention which is haloalkyl (eg, 1,1,1-trifluoroisopropyl). [The present invention 1046] R a But C 1-6 alkyl (e.g., methyl), and R 5 However, 0 to 3 Rs appear 6 C replaced with 1-6 1041. A compound of the present invention which is haloalkyl (eg, 2,2,2-trifluoroethyl). [This invention 1047] R 6 -CO2H or -CO2-C 1-4 Any of compounds 1042 to 1046 of the present invention, which is alkyl (e.g., -CO2Me or -CO2Et). [This invention 1048] R 2 However, 0 to 3 Rs appear 5 Replaced by C 3-9 cycloalkoxy (e.g., cyclopropoxy), C 1-6 haloalkoxy (e.g., trifluoromethyl, 2,2-difluoroethyl, 1,1,1-trifluoroisopropyl, 1,1,1-trifluoro-tert-butyl, or 1,3-difluoroisopropyl), and C 3-9 1034. Compounds of the invention selected from cycloalkyl (eg, cyclopentyl or cyclohexyl). [This invention 1049] R 2 However, 0 to 3 Rs appear 51034. A compound of the invention wherein the compound is heterocycloalkyl substituted with (eg, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl). [The present invention 1050] R 5 Halo (e.g., fluoro), 0-3 occurrences of R 6 C replaced with 1-6 alkyl (e.g., methyl), and R 6 -CO2H and -CO2-C 1-4 The compound of the present invention 1049 selected from alkyl (e.g., —CO2Me). [This invention 1051] X is, TIFF2025160375000007.tif169150, compound of the present invention 1034. [This invention 1052] R with two occurrences of X 2 1034. A compound of the present invention which is 2-pyridinyl substituted with [This invention 1053] R 2 is selected from -NH2, hydroxyl, and halo (e.g., fluoro). [This invention 1054] X is, TIFF2025160375000008.tif13128, compound of the present invention 1053. [This invention 1055] R with 0 to 3 Xs 2 1034. The compound of the present invention, which is 3-pyrazolyl or 4-isoxazolyl substituted with [This invention 1056] X is, TIFF2025160375000009.tif18128, compound of the present invention 1055. [This invention 1057] R with 0 to 3 Xs 2 1034. The compound of the present invention, which is 3-pyridinyl substituted with [This invention 1058] R 2 However, -NH2, -N(Ra )SO2-R 5 , C 1-6 1057. A compound of the present invention selected from alkoxy (eg, methoxy), and heterocycloalkyl (eg, N-oxetanyl). [This invention 1059] R a is H and R 5 However, 0 to 3 Rs appear 6 C replaced with 1-6 1058. Compounds of the invention which are alkyl (eg, methyl). [The present invention 1060] X is, TIFF2025160375000010.tif17128, compound of the present invention 1058. [This invention 1061] R with 0 to 3 Xs 2 The compound of the present invention 1034, which is 5-thiazolyl substituted with [This invention 1062] R 2 -NH, halo (e.g., chloro), and -N(R a )(R 5 1061. The compound of the present invention, selected from: [This invention 1063] R a is H and R 5 occurs 0 or 1 time 6 C replaced with 1-6 The compound of the present invention 1062, which is alkyl (e.g., ethyl). [This invention 1064] but, TIFF2025160375000011.tif19128, compound of the present invention 1062. [This invention 1065] R with 0 to 3 Xs 2 The compound of the present invention 1034, which is 4-pyrazolyl substituted with [The present invention 1066] R 21062. A compound of the present invention wherein is selected from haloalkyl (eg, difluoromethyl), and heterocycloalkyl (eg, 3-tetrahydrofuranyl). [This invention 1067] X is, TIFF2025160375000012.tif26128, compound of the present invention 1066. [The present invention 1068] X is C 1-6 Alkyl (e.g., methyl) and C 1-6 two occurrences of R selected from haloalkyl (e.g., 1,1,1-trifluoroisopropyl); 2 The compound of the present invention 1034, which is 4-pyrazolyl substituted with [The present invention 1069] X is, TIFF2025160375000013.tif22128, compound of the present invention 1068. [The present invention 1070] R with 0 to 3 Xs 2 1034. The compound of the present invention, which is 6-indolyl, 3-thiazolyl, 4-thiazolyl, 3-thiophenyl, 4-pyridinyl substituted with [This invention 1071] R 2 -NH2, nitro, hydroxyl, -N(R a )(R 5 ), -N(R a )C(O)-R 5 , and 0 to 3 occurrences of R 5 1070. A compound of the present invention selected from heterocycloalkyl substituted with (eg, N-pyrrolidinyl). [This invention 1072] R a But H or C 1-6 alkyl (e.g., methyl), and R 5 However, 0 to 3 Rs appear 6 C replaced with 1-6 The compound of the present invention 1071, which is alkyl (e.g., methyl). [This invention 1073] X is, TIFF2025160375000014.tif19168, compound of the present invention 1071. [This invention 1074] Cy 2 However, 1 to 3 Rs appear 4 The compound of any one of claims 1001 to 1073, wherein the compound is aryl substituted with [This invention 1075] R 4 But C 1-6 Alkyl (e.g., methyl or isopropyl), C 1-6 haloalkyl (e.g., trifluoromethyl, difluoromethyl, 2-fluoroisopropyl, or fluoromethyl), C 1-6 Alkoxy (e.g., methoxy, isopropoxy, or 3,3-dimethylbutoxy), C 1-6 haloalkoxy (e.g., trifluoromethoxy) and C 3-6 1074. A compound of the present invention selected from cycloalkyl (eg, cyclopropyl). [This invention 1076] Cy 2 but, TIFF2025160375000015.tif46144, compound 1075 of the present invention. [This invention 1077] Cy 2 But two or three occurrences of R 4 1075 compounds of the present invention, which are phenyl substituted with [This invention 1078] R 4 halo (e.g., fluoro or chloro), C 1-6 haloalkyl (e.g., trifluoromethyl or difluoromethyl), C 1-6 Alkyl (e.g., methyl), C 1-6 Alkoxy (e.g., isopropoxy), C 1-6 haloalkoxy (e.g., trifluoromethoxy, 1,1,1-trifluoroisopropoxy, or difluoromethoxy) and —N(R a )2 (e.g., —N(CH3)2). [This invention 1079] Cy 2 but, TIFF2025160375000016.tif128132, compound of the present invention 1075. [The present invention 1080] Cy 2 However, 1 to 3 Rs appear 4 The compound of any one of claims 1001 to 1074, wherein the compound is a 5- to 6-membered heteroaryl (for example, 3-pyridinyl) substituted with [This invention 1081] R 4 However, 0 to 3 Rs appear b 1081. A compound of the present invention, wherein the compound is a 4- to 10-membered heterocycloalkyl (eg, N-pyrrolidinyl) substituted with. [This invention 1082] Cy 2 but, TIFF2025160375000017.tif20128, compound of the present invention 1081. [This invention 1083] Cy 2 But C 1-6 Alkyl (e.g., isopropyl) and C 1-6 1 to 3 occurrences of R selected from haloalkyl (e.g., trifluoroalkyl) 4 1081. A compound of the present invention which is 3-pyrazolyl substituted with [This invention 1084] Cy 2 but, TIFF2025160375000018.tif19128, compound of the present invention 1083. [This invention 1085] Cy 2 but, Any of compounds 1001 to 1074 of the present invention, which is TIFF2025160375000019.tif167148. [The present invention 1086] Cy 1 However, 0 to 3 Rs appear 3 The compound of any one of claims 1001 to 1085, wherein the compound is aryl (for example, phenyl) substituted with . [This invention 1087] R 3 But C 1-8 Alkyl (e.g., o-isopropyl), C 1-8 haloalkyl (e.g., m-trifluoromethyl, m-1,1-difluoro-3,3-dimethylbutyl, or m-1,1-difluoro-4,4-dimethylpentyl), and C 1-8 1086. Compounds of the invention selected from alkoxy (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). [This invention 1088] Cy 1 but, TIFF2025160375000020.tif59140, compound of the present invention 1087. [This invention 1089] R 3 is selected from 5- to 6-membered heteroaryl (e.g., 5-thiazolyl) and 4- to 10-membered heterocycloalkyl (e.g., 2-azetidinyl or N-morpholinyl); 7 is replaced by C 1-8 1087. A compound of the present invention which is alkoxy (eg, methoxy or ethoxy). [The present invention 1090] R 7 But C 1-4 Alkyl (e.g., isopropyl), C(O)(C 1-4 alkyl) (e.g., C(O)-t-butyl) and C(O)N(R a )(C 1-4 one R selected from alkyl) (e.g., C(O)—NH-t-butyl); 8 1089 compounds of the present invention further substituted with [This invention 1091] Cy 1 but, The compound of the present invention 1087 is TIFF2025160375000021.tif58136. [This invention 1092] R 3 But C 1-8 1087 compounds of the invention which are haloalkoxy (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) or cycloalkyl (e.g., cyclopentyl). [This invention 1093] Cy 1 but, TIFF2025160375000022.tif50137, compound of the present invention 1087. [This invention 1094] R 3 But C 1-4 haloalkoxy (e.g., trifluoromethoxy), C 1-4 haloalkyl (e.g., 1,1-difluoroethyl or 2,2-difluoropropyl) and C 1-4 one occurrence of R selected from alkyl (e.g., methyl) 7 1087. A compound of the present invention, wherein the compound is m-cyclopentyl or p-cyclopentyl, substituted with . [This invention 1095] Cy 1 but, TIFF2025160375000023.tif82130, compound 1095 of the present invention. [This invention 1096] R 3 But C 1-4 0 to 3 occurrences of R selected from alkyl (e.g., methyl) 7 C further substituted with 3-9 1087. A compound of the present invention which is cycloalkoxy (eg, cyclopentoxy). [This invention 1097] Cy 1 but, TIFF2025160375000024.tif12128, compound of the present invention 1097. [This invention 1098] R 3 However, 0 to 3 Rs appear 7 Replaced by C 1-4 Alkyl-C 3-9 cycloalkyl (e.g., cyclopentylmethyl) or C 1-4 Alkoxy-C 3-9 1087. A compound of the present invention which is cycloalkyl (eg, cyclohexylmethoxy, cyclopropylmethoxy, or 2-cyclopropylethoxy). [This invention 1099] R 7 halo (e.g., fluoro), hydroxyl, C 1-4 Alkyl (e.g., methyl) and C 1-4 1098 compounds of the present invention selected from haloalkyl (eg, trifluoromethyl). [The present invention 1100] Cy 1 but, TIFF2025160375000025.tif42154, compound of the present invention 1099. [The present invention 1101] R 3 However, 0 to 3 Rs appear 7 or -C(O)-R 7 1087. A compound of the invention which is heteroaryl substituted with (eg, 3-isoxazolyl). [The present invention 1102] R 7 However, 0 to 3 Rs appear 8 Replaced by C 1-4 The compound of the present invention 1101 which is haloalkyl (eg, trifluoromethyl) or heterocycloalkyl (eg, N-pyrrolidinyl). [The present invention 1103] R 8 But C 1-4 The compound of the present invention 1102 which is haloalkoxy (eg, trifluoromethoxy) or halo (eg, fluoro). [The present invention 1104] Cy 1 but, The compound of the present invention 1102 is TIFF2025160375000026.tif22128. [This invention 1105] Cy 1 However, there are two R 3 1087. The compound of the present invention, wherein the compound is phenyl substituted with . [The present invention 1106] Each R 3 are independently halo (e.g., fluoro or chloro), C 1-8 alkyl (e.g., methyl, ethyl, isobutyl, or neopentyl), C 1-8 haloalkyl (e.g., difluoromethyl), C 3-9 cycloalkyl (e.g., cyclohexyl), C 1-8 Alkoxy (e.g., methoxy, ethoxy, propoxy, 3,3-dimethylbutoxy, 2,3-dimethylbutoxy, neopentyloxy, (3-methylbutanyl-2-yl)oxy, 2,3,3-trimethylbutoxy, (4,4-dimethylpentan-2-yl)oxy, isopentyloxy, 2,3,3-trimethylbutoxy, or 2,3-dimethylbutoxy), C 3-9 Alkoxy (e.g., cyclopentoxy or cyclohexyloxy), C 1-8 haloalkoxy (e.g., trifluoromethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy, 2,2-difluoro-3,3-dimethylbutoxy, 3,3,3-trifluoro-2-methylpropoxy, (1,1,1-trifluoropropan-2-yl)oxy, or 4,4,4-trifluoro-3-methylbutoxy), C 1-4 Alkoxy-C 3-9 -cycloalkyl (methoxycyclobutyl or methoxycyclohexyl), C 3-9 Cycloalkenyl (e.g., cyclohexenyl), aryl (e.g., phenyl), heterocycloalkyl (e.g., pyrrolidinyl), —C(O)R 7 , and -C(O)N(R a )(R 7 1105. The compound of the present invention, selected from: [This invention 1107] R 3 But hydroxyl, -C(O)-OC 1-4 Alkyl (e.g., -CO2Me), C 1-4 Alkyl (e.g., methyl, isopropyl, t-butyl, neopentyl), C 1-8 Alkenyl (e.g., 2-methylprop-1-en-1-yl), C 1-4 Alkoxy (e.g., methoxy), aralkoxy (e.g., benzoxy), C 1-4 at least one R selected from haloalkoxy (e.g., trifluoromethoxy), and heterocycloalkyl (e.g., morpholinyl); 7 The compound of the present invention 1106 further substituted with: [This invention 1108] Cy 1 but, TIFF2025160375000027.tif104140TIFF2025160375000028.tif219145TIFF2025160375000029.tif46150, compound of the present invention 1106. [This invention 1109] Cy 1 But there are three R 3 1087. The compound of the present invention, wherein the compound is phenyl substituted with . [The present invention 1110] Each R 3 and independently halo (e.g., fluoro), C 1-8 Alkoxy (e.g., neopentyloxy or 3,3-dimethylbutoxy), and C 3-9 The compound of the present invention 1109 selected from cycloalkoxy (eg, cyclopentoxy). [The present invention 1111] R 3 But C 1-5 at least one R selected from alkyl (e.g., methyl) 7 The compound of the present invention 1110 further substituted with: [The present invention 1112] Cy 1 but, TIFF2025160375000030.tif22128, a compound of the present invention 1110. [The present invention 1113] Cy 1 However, 0 to 3 Rs appear 3 The compound of any one of claims 1001 to 1086, wherein the compound is heterocycloalkyl substituted with . [This invention 1114] 1113. A compound of the present invention wherein said heterocycloalkyl is selected from N-azetidinyl, N-pyrrolidinyl, N-morpholinyl, N-piperidinyl, N-piperidine-2-only, N-pyrrolidine-2-only, 3-tetrahydropyranyl, 3-(3,6-dihydro-2H-pyranyl), 2N-6-oxa-9-azaspiro[4.5]decanyl, 2N-6-oxa-2,9-diazaspiro[4.5]decanyl, 9-(oxa-9-azaspiro[4.5]decanyl), and 2-(3-oxa-1-azaspiro[4.4]non-1-enyl). [This invention 1115] R 3 But C 1-8 alkyl (e.g., methyl, neopentyl, 4,4-dimethylpentyl, 3-methylbutyl, or 3,3-dimethylbutyl), C 1-8 Alkoxy (e.g., 3,3-dimethylbutoxy, neopentyloxy, or tert-butoxy), C 1-8 haloalkoxy (e.g., trifluoromethoxy), and —C(O)—R 7 1114. A compound of the present invention selected from: [The present invention 1116] Cy 1 but, TIFF2025160375000031.tif101150, a compound of the present invention 1114. [This invention 1117] Cy 1 However, 0 to 3 Rs appear 3 The compound of any one of claims 1001 to 1086, wherein the compound is heteroaryl substituted with [This invention 1118] 1117. A compound of the present invention wherein said heteroaryl is selected from 4-thiazolyl, 2-pyridinyl, 4-pyridinyl, 1-pyrazolyl, 3-pyrazolyl, 2-thiophenyl, 4-pyrazolyl, and 2-(1,3,4-thiadiazolyl). [This invention 1119] R 3 halo (e.g., fluoro, chloro), C 1-8 Alkyl (e.g., 3,3-dimethylbutyl), C 1-8 haloalkyl (e.g., trifluoromethyl, 1,1-difluoroethyl, 4,4,4-trifluoro-3,3-dimethylbutyl or 5,5,5-trifluoro-4,4-dimethylpentan-2-yl), C 1-8 Alkoxy (e.g., 3,3-dimethylbutoxy, neopentyloxy, or 4,4-dimethylpentyloxy), C 1-8 haloalkoxy (e.g., 2,2,2-trifluoroethoxy, 3,3,3-trifluoro-2,2-dimethylpropoxy, and 2,2-difluoro-3,3-dimethylbutoxy), C 3-9 Cycloalkyl (e.g., cyclohexyl), heterocycloalkyl (e.g., N-pyrrolidinyl), C 1-4 Alkyl-C 3-9 Cycloalkyl, C 1-4 Alkoxy-C 3-9 cycloalkyl, TIFF2025160375000032.tif22128 and -C(O)R 7 1118. A compound of the present invention selected from: [The present invention 1120] R 3 halo (e.g., fluoro), hydroxyl, C 1-5 haloalkyl (e.g., 1,1-difluoroethyl), C 1-5 haloalkoxy (e.g., trifluoromethoxy), and C 3-7 At least one R selected from cycloalkyl (e.g., cyclopentyl) 7 1119 compounds of the present invention, wherein the compound is substituted by: [This invention 1121] Cy 1 but, TIFF2025160375000033.tif180148, compound of the present invention 1118. [This invention 1122] Cy 1 However, 0 to 3 Rs appear 3 The compound of any one of claims 1001 to 1086, wherein the compound is cycloalkyl substituted with . [This invention 1123] The cycloalkyl is cyclohexyl or cyclopentyl, and R 3 But C 1-8 The compound of the present invention 1122, which is alkoxy (eg, 3,3-dimethylbutoxy). [This invention 1124] Cy 1 but, TIFF2025160375000034.tif11128, a compound of the present invention 1123. [This invention 1125] R 1 is hydrogen, X is a 5- to 6-membered aryl or a 5- to 6-membered heteroaryl, each of which occurs 0 to 3 times. 2 is replaced by Cy 1 is a 5- to 6-membered aryl, a 4- to 10-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, each of which occurs 0 to 3 times. 3 is replaced by Cy 2 is a 5- or 6-membered aryl, and this occurs 1 to 3 times in R 4 is replaced by Each R 2 independently, halo, -NH2, C 1-6 Alkyl, C 1-8 haloalkoxy, 5- to 6-membered heteroaryl, -N(R a )(R 5 ), -N(R a )C(O)-R 5 , -SO-R 5 or -SO2-R 5 and Each R 3But independently, Halo, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-9 Cycloalkyl, C 3-9 cycloalkoxy, or 4- to 10-membered heterocycloalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkoxy, C 1-8 Haloalkoxy, C 1-8 R 2 is a group in which 0 to 3 occurrences of alkoxy and 4 to 10-membered heterocycloalkyl occur. 7 is further substituted with Each R 4 But independently, Halo, C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 is haloalkyl, Each R 5 But independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-9 cycloalkyl, hydroxyl, or -COH, and C 1-6 Alkyl or C 3-9 Each cycloalkyl occurs 0 to 3 times in R 6 is further replaced by Each R 6 are independently halo, hydroxyl, C 1-6 Alkyl, -CO2H or -CO2-(C 1-4 alkyl), Each R 7 But independently, Halo, C 1-5 Alkyl, C 1-5 Haloalkoxy, C 3-7 cycloalkyl, and hydroxyl; Each R a are independently H or C 1-6 is alkyl, 1001 compounds of the present invention. [The present invention 1126] A compound selected from any of the compounds shown in Table 1. [This invention 1127] A compound selected from any of the compounds shown in Table 2. [This invention 1128] Any of the compounds of the present invention 1001 to 1127, which is a CFTR corrector. [This invention 1129] A pharmaceutical composition comprising any one of the compounds of the present invention 1001 to 1128 and a pharmaceutically acceptable carrier or excipient. [The present invention 1130] The pharmaceutical composition of the present invention 1129 further comprising one or more CFTR therapeutic agents. [This invention 1131] A method of treating a defect in CFTR activity in a cell, the method comprising contacting the cell with any of the compounds of inventions 1001-1128. [This invention 1132] The method of claim 1131, wherein said contacting of said cells is performed in a subject in need thereof, thereby treating a CFTR-mediated condition and / or disease. [This invention 1133] The disease or condition is cystic fibrosis, asthma, smoking-induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild lung disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), congenital pneumonia, intestinal malabsorption, celiac disease, nasal polyposis, nontuberculous mycobacteriosis, pancreatic steatorrhea, intestinal atresia, liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiency, protein C deficiency, hereditary angioedema type 1, lipid processing deficiency, familial hypercholesterolemia, type 1 chylomyocarditis, abetalipoproteinemia, lysosomal storage disease, I-cell disease / pseudo-Hurler syndrome, mucopolysaccharidosis, Sandhoff / Tay-Sachs disease, Crigler's disease, Najjar disease type II, polyendocrinopathy / hyperinsulinemia, diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG1 type, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neurophyseal DI, nephrogenic DI, Charcot-Marie-Tooth syndrome, Pelizaeus-Merzbacher disease, neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, some polyglutamine neuropathies, Huntington's disease, spinocerebellar ataxia type I, spinal-bulbar muscular atrophy, dentatorubral-pallidoluysian corpus pallidoluysian, myotonic dystrophy, spongiform encephalopathy, hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry eye disease, Sjogren's syndrome, osteoporosis, osteopenia, bone healing and growth, bone repair, bone regeneration, decreased bone resorption, increased bone deposition, Gorham syndrome, chloride channelopathy, congenital myotonia, Bartter syndrome type III, Dent's disease, hyperconvulsion syndrome, epilepsy, hyperconvulsion syndrome, lysosomal storage disease, Angelman syndrome, primary ciliary dyskinesia (PCD), PCD with situs inversus, PCD without situs inversus, and ciliary aplasia. [This invention 1134] 1134. The method of claim 1132 or 1133, wherein the disease or condition is selected from cystic fibrosis, congenital bilateral absence of the vas deferens (CBAVD), acute, recurrent, or chronic pancreatitis, disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis, congenital pneumonia, intestinal malabsorption, celiac disease, nasal polyposis, nontuberculous mycobacteriosis, pancreatic steatorrhea, intestinal atresia, chronic obstructive pulmonary disease (COPD), chronic sinusitis, dry eye disease, protein C deficiency, abetalipoproteinemia, lysosomal storage diseases, type 1 chylomyocarditis, mild pulmonary disease, lipid processing deficiency, hereditary angioedema type 1, coagulation-fibrinolysis, hereditary hemochromatosis, CFTR-related metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, and Sjogren's syndrome. [This invention 1135] The method of any one of claims 1133 to 1134, wherein said disease or condition is cystic fibrosis. [This invention 1136] A method for treating cystic fibrosis or a symptom thereof in a subject, comprising administering to said subject a therapeutically effective amount of a compound of the present invention. [This invention 1137] 1136. The method of claim 1136, wherein the subject is a human. [This invention 1138] 1138. The method of any one of claims 1136 to 1137, wherein said subject is at risk of developing cystic fibrosis, and said administering step is carried out prior to the onset of symptoms of cystic fibrosis in said subject. DETAILED DESCRIPTION OF THE INVENTION

[0012] Detailed Description In certain aspects, the present application provides a compound of formula (I): The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, During the ceremony, R 1 is hydrogen or C 1-6 is alkyl, X is C 1-6alkyl, 5- to 6-membered aryl, 4- to 10-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which may be 0 to 3 occurrences of R 2 is replaced by Cy 1 is C 3-9 cycloalkyl, 5- to 6-membered aryl, 4- to 10-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which may be 0 to 3 occurrences of R 3 is replaced by Cy 2 is C 3-9 cycloalkyl, 5- to 6-membered aryl, 4- to 10-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which may be present in 1 to 3 occurrences of R 4 is replaced by Each R 2 are independently hydroxyl, halo, -NH2, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 haloalkoxy, 4- to 10-membered heterocycloalkyl, 5- to 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, and each C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-9 Cycloalkyl or 4- to 10-membered heterocycloalkyl may have 0 to 3 occurrences of R 5 is further replaced by Each R 3 independently, halo, C 1-8 Alkyl, C 1-8 Alkenyl, C 1-8 Alkoxy, C 1-8 Haloalkyl, C 1-8 Haloalkoxy, 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- to 6-membered aryl, aralkyl, aralkoxy, 5- to 6-membered heteroaryl, 4- to 10-membered heterocycloalkyl, -C(O)-R 7 , -C(O)N(R a )(R 7 ) or -N(R a )(R 8 ) and each C 3-9 Cycloalkyl, C 3-9 Cycloalkoxy, C 1-8 Haloalkoxy, C 1-8 Alkoxy, 4- to 10-membered heterocycloalkyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, cycloalkenyl, C 1-4 Alkyl-C 3-9 Cycloalkyl or C 1-4 Alkoxy-C 3-9 Cycloalkyl is 0 to 3 occurrences of R 7 is further substituted with Each R 4 independently, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, N(R a ) 2- or 4- to 10-membered heterocycloalkyl, each 4- to 10-membered heterocycloalkyl having 0 to 3 R b may be further substituted with Each R 5 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C3-9 Cycloalkyl, hydroxyl, -SO2-R 6 , -CO2H, -NH2, -CO2-C 1-4 alkyl or 4- to 10-membered heterocycloalkyl, and each C 1-6 Alkyl, C 3-9 Cycloalkyl or 4- to 10-membered heterocycloalkyl may have 0 to 3 occurrences of R 6 is further replaced by Each R 6 are independently hydroxyl, -NH2, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, -CO2H or -CO2-(C 1-4 alkyl), Each R 7 independently, halo, C 1-5 Alkyl, C 1-5 Alkoxy, C 1-5 Haloalkyl, C 1-5 Haloalkoxy, C 1-5 Haloalkenyl, C 3-7 Cycloalkyl, hydroxyl, 5- to 6-membered aryl, aralkyl, aralkoxy, -C(O)-OC 1-4 Alkyl, -C(O)N(R a )(C 1-4 alkyl), 5- to 6-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, each C 3-7 Cycloalkyl, 5- to 6-membered aryl, or 4- to 10-membered heterocycloalkyl may occur 0 to 3 times. 8 is further replaced by Each R 8 independently, halo, 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 are independently H or C 1-6 is alkyl, Each R b is C 1-4 is alkyl, During the ceremony, a) Cy 1 is phenyl and three occurrences of R 3 If each R 3 is not methoxy, b) X and Cy 2 are each phenyl, R 2 and R 4 are not methyl, c)R 3 and R 4 is not simultaneously tert-butyl or simultaneously methoxy, d) Cy 1 and Cy 2 is monosubstituted phenyl, X is not thienyl, e) Cy 1 and Cy 2 When R is monosubstituted phenyl, 2 is not OH, but R 3 is not Cl, but R 4 is not OMe.

[0013] Disclosed herein is a compound of formula (I): TIFF2025160375000036.tif25128, or a pharmaceutically acceptable salt thereof; During the ceremony, R 1 is hydrogen, X is a 5- to 6-membered aryl or a 5- to 6-membered heteroaryl, each of which may be selected from 0 to 3 occurrences of R 2 is replaced by Cy 1 is a 5- to 6-membered aryl, a 4- to 10-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, each of which may be selected from 0 to 3 occurrences of R 3 is replaced by Cy 2 is a 5- to 6-membered aryl, which is a 5- to 6-membered aryl having 1 to 3 occurrences of R 4 is replaced by Each R 2 are independently halo, -NH2, C 1-6 Alkyl, C 1-8haloalkoxy, 5- to 6-membered heteroaryl, -N(R a )(R 5 ), -N(R a )C(O)-R 5 , -SO-R 5 or -SO2-R 5 and Each R 3 independently, halo, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-9 Cycloalkyl, C 3-9 cycloalkoxy, or 4- to 10-membered heterocycloalkyl, each C 3-9 Cycloalkyl, C 3-9 Cycloalkoxy, C 1-8 Haloalkoxy, C 1-8 Alkoxy and 4- to 10-membered heterocycloalkyl are 0 to 3 occurrences of R 7 is further substituted with Each R 4 independently, halo, C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 is haloalkyl, Each R 5 independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-9 cycloalkyl, hydroxyl, or -COH, where each C 1-6 Alkyl, or C 3-9 Cycloalkyl is 0 to 3 occurrences of R 6 is further replaced by Each R 6 are independently halo, hydroxyl, C 1-6 Alkyl, -CO2H or -CO2-(C 1-4 alkyl), Each R 7 independently, halo, C 1-5 Alkyl, C 1-5 Haloalkoxy, C 3-7 cycloalkyl, and hydroxyl; Each R aare independently H or C 1-6 It is alkyl.

[0014] In some embodiments, R 1 is H. In some embodiments, R 1 But C 1-6 alkyl (for example, methyl or ethyl).

[0015] In some embodiments, X is 0 to 3 occurrences of R 2 In some embodiments, X is aryl substituted with 0 to 3 occurrences of R 2 In some embodiments, X is phenyl substituted with 0 occurrences of R 2 is a phenyl substituted with

[0016] In some embodiments, X is one occurrence of R 2 In some embodiments, R 2 is -NH2. In some embodiments, R 2 is hydroxyl. In some embodiments, R 2 is halo (e.g., fluoro, chloro, or bromo). In some embodiments, R 2 is nitro. In some embodiments, R 2 But C 1-6 In some embodiments, R is alkoxy (e.g., methoxy, ethoxy, or isopropoxy). 2 However, 0 to 3 Rs appear 5 C replaced with 1-6 haloalkyl (e.g., trifluoromethyl, difluoromethyl, or 2,2,2-trifluoroethyl). In some embodiments, R 2 However, R appears 0 times. 5 C replaced with 1-6 haloalkyl (e.g., trifluoromethyl, difluoromethyl, or 2,2,2-trifluoroethyl). In some embodiments, R 2 However, there is one R 5 C replaced with 1-6haloalkyl (e.g., trifluoromethyl, difluoromethyl, or 2,2,2-trifluoroethyl). In a further embodiment, R 5 is a hydroxyl.

[0017] In some embodiments, X is one occurrence of R 2 In some embodiments, R 2 is —C(O)NH. In some embodiments, R 2 However, 0 to 3 Rs appear 5 C replaced with 1-6 haloalkoxy (e.g., trifluoromethoxy or difluoromethoxy). In some embodiments, R 2 However, R appears 0 times. 5 C replaced with 1-6 haloalkoxy (e.g., trifluoromethoxy or difluoromethoxy). In some embodiments, R 2 However, 0 to 3 Rs appear 5 C replaced with 1-6 In some embodiments, R is alkyl (e.g., methyl or isopropyl). 2 However, R appears 0 times. 5 C replaced with 1-6 In some embodiments, R is alkyl (e.g., methyl or isopropyl). 2 However, there is one R 5 C replaced with 1-6 In some embodiments, R is alkyl (e.g., methyl or isopropyl). 5 is hydroxyl. In some embodiments, R 5 But -SO2-R 6 In some embodiments, R 6 But C 1-4 In some embodiments, R 2 But -S(O)-R 5 In some embodiments, R 5 But C 1-6 In some embodiments, R2 But -P(O)(R 5 )2. In some embodiments, both R 5 But C 1-6 In some embodiments, R 2 But -N(R a )SO2-R 5 In some embodiments, R a is H and R 5 But C 1-6 In some embodiments, R a is H and R 5 But C 1-6 haloalkyl (e.g., trifluoromethyl). In some embodiments, R a But C 1-6 alkyl (e.g., methyl), and R 5 But C 1-6 In some embodiments, R a But C 1-6 alkyl (e.g., methyl), and R 5 But C 1-6 haloalkyl (e.g., trifluoromethyl). In some embodiments, R 2 But, -SO2R 5 In some embodiments, R 5 is -NH2.

[0018] In some embodiments, X is one occurrence of R 2 In some embodiments, R 2 However, 0 to 3 Rs appear 5 In some embodiments, R is a heteroaryl substituted with , such as 1-pyrazolyl or 5-pyrazolyl. 2 However, R appears 0 times. 5 In some embodiments, R is a heteroaryl substituted with , such as 1-pyrazolyl or 5-pyrazolyl. 2 But -N(R a )(R 5 In some embodiments, R ais H and R 5 But C 1-6 In some embodiments, R a But C 1-6 alkyl (e.g., methyl), and R 5 But C 1-6 In some embodiments, R a is H and R 5 But C 1-6 haloalkyl (e.g., trifluoromethyl or 1,1,1-trifluoroisopropyl). In some embodiments, R a is H and R 5 However, 0 to 3 Rs appear 6 In some embodiments, R is a heterocycloalkyl substituted with , for example, 3-tetrahydrofuranyl. a is H and R 5 However, R appears 0 times. 6 In some embodiments, R is a heterocycloalkyl substituted with , for example, 3-tetrahydrofuranyl. a is H and R 5 However, 0 to 3 Rs appear 6 C further substituted with 3-9 cycloalkyl (e.g., cyclobutyl or cyclopentyl). In some embodiments, R a is H and R 5 However, R appears 0 times. 6 C further substituted with 3-9 cycloalkyl (e.g., cyclobutyl or cyclopentyl). In some embodiments, R a is H and R 5 However, there is one R 6 C further substituted with 3-9 cycloalkyl (e.g., cyclobutyl or cyclopentyl). In some embodiments, R 6 is —COH. In some embodiments, R 6 But -C(O)2-C 1-4 In some embodiments, R is alkyl (e.g., —COMe or —COEt).a is H and R 5 However, there are two R 6 C further substituted with 3-9 In some embodiments, one occurrence of R is cycloalkyl (e.g., cyclobutyl or cyclopentyl). 6 is hydroxyl and the other occurrences are C 1-4 It is alkyl (eg, methyl).

[0019] In some embodiments, X is one occurrence of R 2 In some embodiments, R 2 But -N(R a )C(O)-R 5 In some embodiments, R a is H and R 5 However, 0 to 3 Rs appear 6 C replaced with 1-6 alkyl (e.g., methyl, ethyl, or isopropyl). In some embodiments, R a is H and R 5 However, R appears 0 times. 6 C replaced with 1-6 alkyl (e.g., methyl, ethyl, or isopropyl). In some embodiments, R a is H and R 5 However, there is one R 6 C replaced with 1-6 alkyl (e.g., methyl, ethyl, or isopropyl). In some embodiments, R 6 is -NH2. In some embodiments, R 6 is hydroxyl. In some embodiments, R a is H and R 5 But C 1-6 haloalkyl (e.g., trifluoromethyl). In some embodiments, R a is H and R 5 However, 0 to 3 Rs appear 6 C replaced with 3-9 In some embodiments, Ra is H and R 5 However, R appears 0 times. 6 C replaced with 3-9 In some embodiments, R a is H and R 5 However, there is one R 6 C further substituted with 3-9 In some embodiments, R 6 is halo (e.g., fluoro). In some embodiments, R 6 But C 1-4 haloalkyl (eg, trifluoromethyl).

[0020] In some embodiments, R 2 However, 0 to 3 Rs appear 5 In some embodiments, R is heterocycloalkyl substituted with N-pyrrolidinyl. 2 However, R appears 0 times. 5 In some embodiments, R is heterocycloalkyl substituted with N-pyrrolidinyl. 2 However, there is one R 5 In some embodiments, R is heterocycloalkyl substituted with N-pyrrolidinyl. 5 However, 0 to 3 Rs appear 6 C replaced with 1-6 In some embodiments, R 5 However, R appears 0 times. 6 C replaced with 1-6 In some embodiments, R 2 But -C(O)-N(R a )(R 5 In some embodiments, R a is H and R 5 However, 0 to 3 Rs appear 6 C replaced with 1-6 alkyl (e.g., methyl or ethyl). In some embodiments, R ais H and R 5 However, R appears 0 times. 6 C replaced with 1-6 alkyl (e.g., methyl or ethyl). In some embodiments, R a is H and R 5 However, there is one R 6 C replaced with 1-6 alkyl (e.g., methyl or ethyl). In some embodiments, R 6 is hydroxyl. In some embodiments, R 2 But -N(R a )S(O)(NH)-R 5 In some embodiments, R a is H and R 5 However, 0 to 3 Rs appear 6 C replaced with 1-6 In some embodiments, R a is H and R 5 However, R appears 0 times. 6 C replaced with 1-6 It is alkyl (eg, methyl).

[0021] In some embodiments, X is TIFF2025160375000037.tif146150TIFF2025160375000038.tif89134.

[0022] In some embodiments, X is selected from two occurrences of R 2 In some embodiments, each R 2 is halo (e.g., fluoro or chloro). In some embodiments, each R 2 is fluoro. In some embodiments, each R 2 is chloro. In some embodiments, one R 2 is -NH2 and one R 2 is halo (e.g., fluoro). In some embodiments, one R 2 But C 1-6alkyl (e.g., methyl), and the other R 2 But C 1-6 haloalkyl (e.g., difluoromethyl). In some embodiments, one R 2 is halo (e.g., fluoro), and the other R 2 But -N(R a )(R 5 ) (e.g., —NHMe). In some embodiments, R a is H and R 5 But C 1-6 In some embodiments, R a is H and R 5 However, 0 to 3 Rs appear 6 C further substituted with 3-9 In some embodiments, R is cycloalkyl (e.g., cyclopentyl). a is H and R 5 However, there is one R 6 C further substituted with 3-9 In some embodiments, R is cycloalkyl (e.g., cyclopentyl). 6 But C 1-6 In some embodiments, R a is H and R 5 However, 0 to 3 Rs appear 6 In some embodiments, R is heterocycloalkyl (e.g., 3-pyrrolidinyl) further substituted with a is H and R 5 However, there is one R 6 In some embodiments, R is heterocycloalkyl (e.g., 3-pyrrolidinyl) further substituted with 6 But C 1-4 It is alkyl (eg, methyl).

[0023] In some embodiments, X is The file is TIFF2025160375000039.tif41149.

[0024] In some embodiments, X is selected from the group consisting of three occurrences of R2 In some embodiments, two R 2 is halo (e.g., fluoro), and the remaining R 2 In some embodiments, X is -NH. The file is TIFF2025160375000040.tif17128.

[0025] In some embodiments, X is 0 to 3 occurrences of R 2 In some embodiments, X is 0 to 3 occurrences of R 2 and wherein the substituted aryl group is selected from pyridinyl, pyrazolyl, isoxazolyl, pyrazolyl, indolyl, thiazolyl, thiophenyl, or furanyl.

[0026] In some embodiments, X is 0 to 3 occurrences of R 2 In some embodiments, X is 2-pyridinyl substituted with 0 occurrences of R 2 and 2-pyridinyl substituted with

[0027] In some embodiments, X is one occurrence of R 2 In some embodiments, R 2 is -NH2. In some embodiments, R 2 is halo (e.g., fluoro or chloro). In some embodiments, R 2 However, 0 to 3 Rs appear 5 C replaced with 1-6 In some embodiments, R is alkyl (e.g., methoxy or isopropoxy). 2 However, R appears 0 times. 5 C replaced with 1-6 In some embodiments, R is alkoxy (e.g., methoxy, ethoxy, or isopropoxy). 2 However, there is one R 5 C replaced with 1-6 In some embodiments, R is alkoxy (e.g., methoxy, ethoxy, or isopropoxy).5 However, 0 to 3 Rs appear 6 C replaced with 3-9 cycloalkyl (e.g., cyclopropyl or cyclobutyl). In some embodiments, R 5 However, there is one R 6 C replaced with 3-9 cycloalkyl (e.g., cyclopropyl or cyclobutyl). In some embodiments, R 6 But C 1-4 haloalkyl (e.g., trifluoromethyl). In some embodiments, R 5 However, there are two R 6 C replaced with 3-9 cycloalkyl (e.g., cyclopropyl or cyclobutyl). In some embodiments, both R 6 is halo (e.g., fluoro).

[0028] In some embodiments, R 2 But -N(R a )SO2-R 5 In some embodiments, R a is H and R 5 However, 0 to 3 Rs appear 6 C replaced with 1-6 In some embodiments, R a is H and R 5 However, R appears 0 times. 6 C replaced with 1-6 In some embodiments, R 2 But -N(R a )C(O)-R 5 In some embodiments, R a is H and R 5 However, 0 to 3 Rs appear 6 C replaced with 1-6 In some embodiments, R is alkyl (e.g., methyl or isopropyl). a is H and R 5 However, R appears 0 times. 6 C replaced with 1-6It is alkyl (eg, methyl or isopropyl).

[0029] In some embodiments, R 2 But -N(R a )(R 5 In some embodiments, R a is H and R 5 However, 0 to 3 Rs appear 6 C replaced with 1-6 alkyl (e.g., methyl or neopentyl). In some embodiments, R a is H and R 5 However, R appears 0 times. 6 C replaced with 1-6 alkyl (e.g., methyl or neopentyl). In some embodiments, R a is H and R 5 However, there is one R 6 C replaced with 1-6 alkyl (e.g., methyl or neopentyl). In some embodiments, R 6 is —COH. In some embodiments, R 6 But -CO2-C 1-4 In some embodiments, R is alkyl (e.g., —COMe or —COEt). a But C 1-6 alkyl (e.g., methyl or ethyl), and R 5 However, 0 to 3 Rs appear 6 C replaced with 1-6 In some embodiments, R is alkyl (e.g., methyl or isopropyl). a But C 1-6 alkyl (e.g., methyl or ethyl), and R 5 However, R appears 0 times. 6 C replaced with 1-6 In some embodiments, R is alkyl (e.g., methyl or isopropyl). a is H and R 5 However, 0 to 3 Rs appear 6 C replaced with 3-9cycloalkyl (e.g., cyclopropyl or cyclopentyl). In some embodiments, R a is H and R 5 However, R appears 0 times. 6 C replaced with 3-9 cycloalkyl (e.g., cyclopropyl or cyclopentyl). In some embodiments, R a is H and R 5 However, there is one R 6 C replaced with 3-9 cycloalkyl (e.g., cyclopropyl, cyclohexyl, or cyclopentyl). In some embodiments, R 6 is —COH. In some embodiments, R 6 But -CO2-C 1-4 In some embodiments, R is alkyl (e.g., —COMe or —COEt). a is H and R 5 However, 0 to 3 Rs appear 6 C replaced with 1-6 haloalkyl (e.g., 1,1,1-trifluoroisopropyl). In some embodiments, R a is H and R 5 However, R appears 0 times. 6 C replaced with 1-6 haloalkyl (e.g., 1,1,1-trifluoroisopropyl). In some embodiments, R a But C 1-6 alkyl (e.g., methyl), and R 5 However, 0 to 3 Rs appear 6 C replaced with 1-6 haloalkyl (e.g., 2,2,2-trifluoroethyl). In some embodiments, R a But C 1-6 alkyl (e.g., methyl), and R 5 However, R appears 0 times. 6 C replaced with 1-6 haloalkyl (e.g., 2,2,2-trifluoroethyl). In some embodiments, R 2 However, R appears 0 times. 5 C replaced with3-9 In some embodiments, R is cycloalkoxy (e.g., cyclopropoxy). 2 But C 1-6 haloalkoxy (e.g., trifluoromethyl, 2,2-difluoroethyl, 1,1,1-trifluoroisopropyl, 1,1,1-trifluoro-tert-butyl, or 1,3-difluoroisopropyl). In some embodiments, R 2 However, 0 to 3 Rs appear 5 C replaced with 3-9 cycloalkyl (e.g., cyclopentyl or cyclohexyl). In some embodiments, R 2 However, there is one R 5 C replaced with 3-9 cycloalkyl (e.g., cyclopropyl or cyclohexyl). In some embodiments, R 5 is —COH. In some embodiments, R 5 But -CO2-R 6 In some embodiments, R 6 But C 1-4 It is alkyl (eg, methyl).

[0030] In some embodiments, R 2 However, 0 to 3 Rs appear 5 In some embodiments, R is a heterocycloalkyl substituted with R (e.g., azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl). 2 However, R appears 0 times. 5 In some embodiments, R is a heterocycloalkyl substituted with R (e.g., azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl). 2 However, there are two R 5 In some embodiments, both occurrences of R are heterocycloalkyl substituted with R (e.g., azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl). 5 is halo (e.g., fluoro). In some embodiments, both occurrences of R 5 However, 0 to 3 Rs appear 6 C replaced with1-6 In some embodiments, both occurrences of R 5 However, R appears 0 times. 6 C replaced with 1-6 In some embodiments, one occurrence of R 5 is -CO2H, and the other R 5 However, 0 to 3 Rs appear 6 C further substituted with 1-6 In some embodiments, one occurrence of R 5 is -CO2H, and the other occurrence of R 5 However, R appears 0 times. 6 C further substituted with 1-6 In some embodiments, one occurrence of R 5 But -CO2-C 1-4 alkyl (e.g., -COMe), and the other occurrence of R 5 However, 0 to 3 Rs appear 6 C further substituted with 1-6 In some embodiments, one occurrence of R 5 But -CO2-C 1-4 alkyl (e.g., -COMe), and the other occurrence of R 5 However, R appears 0 times. 6 C further substituted with 1-6 It is alkyl (eg, methyl).

[0031] In some embodiments, X is The file is TIFF2025160375000041.tif169150.

[0032] In some embodiments, X is selected from two occurrences of R 2 In some embodiments, one R 2 is -NH and the other is halo (e.g., fluoro). In some embodiments, one R 2is hydroxyl and the other is halo (eg, fluoro).

[0033] In some embodiments, X is The file is TIFF2025160375000042.tif13128.

[0034] In some embodiments, X is 0 to 3 occurrences of R 2 In some embodiments, X is 3-pyrazolyl substituted with 0 occurrences of R 2 In some embodiments, X is 3-pyrazolyl substituted with one occurrence of R 2 In some embodiments, R is 3-pyrazolyl substituted with 2 But C 1-6 In some embodiments, X is alkyl (e.g., methyl). The file is TIFF2025160375000043.tif17128.

[0035] In some embodiments, X is 0 to 3 occurrences of R 2 In some embodiments, X is 4-isoxazolyl substituted with 0 occurrences of R 2 is 4-isoxazolyl substituted with

[0036] In some embodiments, X is selected from two occurrences of R 2 In some embodiments, each R 2 But independently, C 1-6 In some embodiments, X is alkyl (e.g., methyl). TIFF2025160375000044.tif14128.

[0037] In some embodiments, X is 0 to 3 occurrences of R 2 In some embodiments, X is 3-pyridinyl substituted with 0 occurrences of R 2 and 3-pyridinyl substituted with

[0038] In some embodiments, X is one occurrence of R 2 In some embodiments, R 2 is -NH2. In some embodiments, R 2 But C 1-6 In some embodiments, R 2 But -N(R a )SO2-R 5 In some embodiments, R a is H and R 5 However, 0 to 3 Rs appear 6 C replaced with 1-6 In some embodiments, R a is H and R 5 However, R appears 0 times. 6 C replaced with 1-6 In some embodiments, R 2 However, 0 to 3 Rs appear 5 In some embodiments, R is a heterocycloalkyl substituted with N-oxetanyl. 2 However, R appears 0 times. 5 In some embodiments, R is a heterocycloalkyl substituted with N-oxetanyl. 2 However, R appears 0 times. 5 and N-oxetanyl substituted with

[0039] In some embodiments, X is The file is TIFF2025160375000045.tif17128.

[0040] In some embodiments, X is 0 to 3 occurrences of R 2 In some embodiments, X is 5-thiazolyl substituted with 0 occurrences of R 2 In some embodiments, X is 5-thiazolyl substituted with one occurrence of R 2 In some embodiments, R 2is -NH2. In some embodiments, R 2 is halo (e.g., chloro). In some embodiments, R 2 But -N(R a )(R 5 In some embodiments, R a is H and R 5 However, R appears 0 times. 6 C replaced with 1-6 In some embodiments, R 2 is -NHEt. In some embodiments, R a is H and R 5 However, there is one R 6 (e.g., methyl or ethyl) 1-6 In some embodiments, R 6 is hydroxyl. In some embodiments, R 2 but, TIFF2025160375000046.tif8128.

[0041] In some embodiments, X is TIFF2025160375000047.tif19128.

[0042] In some embodiments, X is 0 to 3 occurrences of R 2 In some embodiments, X is 4-pyrazolyl substituted with 0 occurrences of R 2 In some embodiments, X is 4-pyrazolyl substituted with one occurrence of R 2 In some embodiments, R 2 But C 1-6 haloalkyl (e.g., difluoromethyl). In some embodiments, R 2 However, 0 to 3 Rs appear 5 In some embodiments, R is a heterocycloalkyl substituted with , for example, 3-tetrahydrofuranyl. 2 However, R appears 0 times. 5and heterocycloalkyl substituted with (eg, 3-tetrahydrofuranyl).

[0043] In some embodiments, X is TIFF2025160375000048.tif26128.

[0044] In some embodiments, X is selected from two occurrences of R 2 In some embodiments, each R 2 But independently, C 1-6 In some embodiments, one R 2 But C 1-6 alkyl (e.g., methyl), and the other R 2 But C 1-6 haloalkyl (eg, 1,1,1-trifluoroisopropyl).

[0045] In some embodiments, X is TIFF2025160375000049.tif21128.

[0046] In some embodiments, X is 0 to 3 occurrences of R 2 In some embodiments, X is 6-indolyl substituted with 0 occurrences of R 2 is a 6-indolyl substituted with

[0047] In some embodiments, X is 0 to 3 occurrences of R 2 In some embodiments, X is 4-pyridinyl substituted with 0 occurrences of R 2 and 4-pyridinyl substituted with

[0048] In some embodiments, X is one occurrence of R 2 In some embodiments, R 2 is -NH2. In some embodiments, R 2 But -N(R a )(R 5In some embodiments, R a But C 1-6 alkyl (e.g., methyl), and R 5 However, 0 to 3 Rs appear 6 C replaced with 1-6 In some embodiments, R a But C 1-6 alkyl (e.g., methyl), and R 5 However, R appears 0 times. 6 C replaced with 1-6 In some embodiments, R 2 But -N(R a )C(O)-R 5 In some embodiments, R a is H and R 5 However, 0 to 3 Rs appear 6 C replaced with 1-6 In some embodiments, R a is H and R 5 However, R appears 0 times. 6 C replaced with 1-6 In some embodiments, R 2 However, 0 to 3 Rs appear 5 In some embodiments, R is heterocycloalkyl substituted with N-pyrrolidinyl. 2 However, R appears 0 times. 5 and heterocycloalkyl substituted with (eg, N-pyrrolidinyl).

[0049] In some embodiments, X is TIFF2025160375000050.tif18128.

[0050] In some embodiments, X is selected from two occurrences of R 2 In some embodiments, one R 2 is -NH2, and the other R 2 is a hydroxyl.

[0051] In some embodiments, X is 0 to 3 occurrences of R 2 In some embodiments, X is 4-thiazolyl substituted with 0 occurrences of R 2 and 4-thiazolyl substituted with

[0052] In some embodiments, X is one occurrence of R 2 In some embodiments, R is 4-thiazolyl substituted with 2 In some embodiments, X is -NH. TIFF2025160375000051.tif15128.

[0053] In some embodiments, X is 0 to 3 occurrences of R 2 and 3-thiazolyl substituted with

[0054] In some embodiments, X is 0 to 3 occurrences of R 2 In some embodiments, X is 3-thiophenyl substituted with 0 occurrences of R 2 and 3-thiophenyl substituted with

[0055] In some embodiments, X is one occurrence of R 2 In some embodiments, R 2 is nitro. In some embodiments, R 2 In some embodiments, X is -NH. TIFF2025160375000052.tif12128.

[0056] In some embodiments, Cy 2 but, TIFF2025160375000053.tif170150.

[0057] In some embodiments, Cy 2 However, 1 to 3 Rs appear 4In some embodiments, Cy is an aryl substituted with 2 However, 1 to 3 Rs appear 4 In some embodiments, Cy is phenyl substituted with 2 However, there is one R 4 In some embodiments, R 4 is C 1-6 Alkyl (e.g., methyl or isopropyl), C 1-6 haloalkyl (e.g., trifluoromethyl, difluoromethyl, 2-fluoroisopropyl or fluoromethyl), C 1-6 Alkoxy (e.g., methoxy, isopropoxy, or 3,3-dimethylbutoxy), C 1-6 haloalkoxy (e.g., trifluoromethoxy) or C 3-6 In some embodiments, Cy is cycloalkyl (e.g., cyclopropyl). 2 but, The file is TIFF2025160375000054.tif43151.

[0058] In some embodiments, Cy 2 However, there are two R 4 In some embodiments, both R 4 But C 1-6 In some embodiments, both R 4 is halo (e.g., fluoro or chloro). In some embodiments, both R 4 But C 1-6 haloalkyl (e.g., trifluoromethyl or difluoromethyl). In some embodiments, one R 4 But C 1-6 alkyl (e.g., methyl), and one R 4 But C 1-6 In some embodiments, one R 4 But C 1-6 alkoxy (e.g., isopropoxy), and one R 4is halo (e.g., fluoro or chloro). In some embodiments, one R 4 But C 1-6 haloalkoxy (e.g., trifluoromethoxy, 1,1,1-trifluoroisopropoxy, or difluoromethoxy), and one R 4 is halo (e.g., fluoro or chloro). In some embodiments, one R 4 But C 1-6 alkyl (e.g., methyl), and one R 4 is halo (e.g., fluoro or chloro). In some embodiments, one R 4 But C 1-6 alkoxy (e.g., isopropoxy), and one R 4 But C 1-6 In some embodiments, one R 4 But C 1-6 haloalkyl (e.g., trifluoromethyl, difluoromethyl, or 1,1,1-trifluoropropan-2-yl), and one R 4 is halo (e.g., fluoro or chloro). In some embodiments, one R 4 But C 1-6 alkoxy (e.g., isopropoxy or 3,3-dimethylbutoxy), and one R 4 But C 1-6 haloalkyl (e.g., trifluoromethyl). In some embodiments, one R 4 But C 1-6 alkyl (e.g., methyl), and one R 4 But C 1-6 haloalkyl (e.g., trifluoromethyl or difluoromethyl). In some embodiments, one R 4 But -N(R a )2 (e.g., -N(CH3)2), and one R 4 is halo (e.g., fluoro). In some embodiments, Cy 2 but, TIFF2025160375000055.tif115151.

[0059] In some embodiments, Cy 2 But there are three R 4 In some embodiments, two R 4 But C 1-6 alkyl (e.g., methyl), and one R 4 But C 1-6 In some embodiments, Cy is a haloalkyl (e.g., trifluoromethyl). 2 but, TIFF2025160375000056.tif16128.

[0060] In some embodiments, Cy 2 However, 1 to 3 Rs appear 4 In some embodiments, Cy is a 5- to 6-membered heteroaryl substituted with 2 However, 1 to 3 Rs appear 4 In some embodiments, Cy is 3-pyridinyl substituted with 2 However, there is one R 4 In some embodiments, R 4 However, 0 to 3 Rs appear b In some embodiments, R 4 However, 0 to 3 Rs appear b In some embodiments, R is N-pyrrolidinyl substituted with 4 But there are three R b (e.g., methyl). In some embodiments, Cy 2 but, The file is TIFF2025160375000057.tif21128.

[0061] In some embodiments, Cy 2 However, 1 to 3 Rs appear 4 In some embodiments, Cy is 3-pyrazolyl substituted with 2 However, there is one R 4In some embodiments, R is 3-pyrazolyl substituted with 4 But C 1-6 In some embodiments, Cy is an alkyl (e.g., isopropyl). 2 However, there are two R 4 In some embodiments, one R 4 But C 1-6 alkyl (e.g., isopropyl), and one R 4 But C 1-6 In some embodiments, Cy is a haloalkyl (e.g., trifluoroalkyl). 2 but, TIFF2025160375000058.tif19128.

[0062] In some embodiments, Cy 1 However, 0 to 3 Rs appear 3 In some embodiments, Cy is an aryl substituted with 1 However, 0 to 3 Rs appear 3 In some embodiments, Cy is phenyl substituted with 1 However, R appears 0 times. 3 In some embodiments, Cy is phenyl substituted with 1 However, there is one R 3 In some embodiments, R 3 However, R appears 0 times. 7 C replaced with 1-8 In some embodiments, R 3 However, R appears 0 times. 7 C replaced with 1-8 haloalkyl (e.g., m-trifluoromethyl, m-1,1-difluoro-3,3-dimethylbutyl, or m-1,1-difluoro-4,4-dimethylpentyl). In some embodiments, R 3 However, R appears 0 times. 7 C replaced with 1-8alkoxy (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 but, TIFF2025160375000059.tif55151.

[0063] In some embodiments, R 3 However, there is one R 7 C replaced with 1-8 In some embodiments, R is alkoxy (e.g., methoxy or ethoxy). 3 However, there is one R 7 In some embodiments, R 7 However, R appears 0 times. 8 In some embodiments, R is a 5- to 6-membered heteroaryl (e.g., 5-thiazolyl) further substituted with 7 However, there is one R 8 In some embodiments, R is a 4- to 10-membered heterocycloalkyl (e.g., 2-azetidinyl) substituted with 8 But C 1-4 Alkyl (e.g., isopropyl), C(O)(C 1-4 alkyl) (e.g., C(O)-t-butyl) or C(O)N(R a )(C 1-4 alkyl) (e.g., C(O)—NH-t-butyl). In some embodiments, R 3 However, there is one R 7 In some embodiments, R 7 However, R appears 0 times. 8 In some embodiments, Cy is a heterocycloalkyl substituted with , such as N-morpholinyl. 1 but, The file is TIFF2025160375000060.tif47128.

[0064] In some embodiments, R 3 However, R appears 0 times. 7 C replaced with 1-8 haloalkoxy (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 However, 0 to 3 Rs appear 7 C further substituted with 3-9 In some embodiments, Cy is cycloalkyl (e.g., cyclopentyl). 1 but, TIFF2025160375000061.tif52151.

[0065] In some embodiments, R 3 However, there is one R 7 In some embodiments, R is m-cyclopentyl or p-cyclopentyl substituted with 7 But C 1-4 haloalkoxy (e.g., trifluoromethoxy). In some embodiments, R 7 But C 1-4 haloalkyl (e.g., 1,1-difluoroethyl or 2,2-difluoropropyl). In some embodiments, R 3 However, there are two R 7 In some embodiments, both R 7 But C 1-4 In some embodiments, Cy is alkyl (e.g., methyl). 1 but, TIFF2025160375000062.tif76151.

[0066] In some embodiments, R3 However, 0 to 3 Rs appear 7 C further substituted with 3-9 In some embodiments, R is cycloalkoxy (e.g., cyclopentoxy). 3 However, there is one R 7 In some embodiments, R 7 But C 1-4 In some embodiments, R 3 However, there are two R 7 In some embodiments, both R 7 But C 1-4 In some embodiments, Cy is alkyl (e.g., methyl). 1 but, TIFF2025160375000063.tif12128.

[0067] In some embodiments, R 3 However, 0 to 3 Rs appear 7 C replaced with 1-4 Alkyl-C 3-9 cycloalkyl (e.g., cyclopentylmethyl). In some embodiments, R 3 But there are three R 7 In some embodiments, two R 7 is halo (e.g., fluoro), and other R 7 is hydroxy. In some embodiments, R 3 However, 0 to 3 Rs appear 7 C replaced with 1-4 Alkoxy-C 3-9 cycloalkyl (e.g., cyclohexylmethoxy, cyclopropylmethoxy, or 2-cyclopropylethoxy). In some embodiments, R 3 However, there is one R 7 In some embodiments, R 7 But C 1-4In some embodiments, R 7 But C 1-4 haloalkyl (e.g., trifluoromethyl). In some embodiments, R 3 However, there is one R 7 In some embodiments, R 7 But C 1-4 haloalkyl (e.g., trifluoromethyl). In some embodiments, R 3 However, there are two R 7 In some embodiments, both R 7 is halo (e.g., fluoro). In some embodiments, Cy 1 but, TIFF2025160375000064.tif39128.

[0068] In some embodiments, R 3 However, 0 to 3 Rs appear 7 In some embodiments, R is a heteroaryl substituted with 3 However, R appears 0 times. 7 In some embodiments, R is a heteroaryl substituted with 3 However, there is one R 7 In some embodiments, R is a heteroaryl substituted with 7 But C 1-4 haloalkyl (e.g., trifluoromethyl). In some embodiments, R 3 But -C(O)-R 7 In some embodiments, R 7 However, 0 to 3 Rs appear 8 In some embodiments, R is heterocycloalkyl substituted with N-pyrrolidinyl. 7 However, R appears 0 times. 8 In some embodiments, R is heterocycloalkyl substituted with N-pyrrolidinyl.7 However, there is one R 8 In some embodiments, R is heterocycloalkyl substituted with N-pyrrolidinyl. 8 But C 1-4 haloalkoxy (e.g., trifluoromethoxy). In some embodiments, R 7 However, there are two R 8 In some embodiments, each R 8 is halo (e.g., fluoro). In some embodiments, Cy 1 but, TIFF2025160375000065.tif22128.

[0069] In some embodiments, Cy 1 However, there are two R 3 In some embodiments, one R 3 is halo (e.g., fluoro or chloro) and the other R 3 However, R appears 0 times. 7 C further substituted with 1-8 Alkoxy (e.g., methoxy, ethoxy, 3,3-dimethylbutoxy, 2,3-dimethylbutoxy, neopentyloxy, (3-methylbutanyl-2-yl)oxy, 2,3,3-trimethylbutoxy, or (4,4-dimethylpentan-2-yl)oxy). In some embodiments, Cy 1 but, TIFF2025160375000066.tif100158.

[0070] In some embodiments, one R 3 is halo (e.g., fluoro or chloro) and the other R 3 However, there is one R 7 C replaced with 1-8 In some embodiments, R is alkoxy (e.g., isopentoxy, 2,3,3-trimethylbutoxy, or 2,3-dimethylbutoxy). 7is hydroxyl. In some embodiments, Cy 1 but, TIFF2025160375000067.tif22128.

[0071] In some embodiments, one R 3 is halo (e.g., fluoro or chloro) and the other R 8 However, there are two R 7 C replaced with 1-8 In some embodiments, both R 7 is hydroxyl. In some embodiments, one R 7 is hydroxyl, and the other R 7 But -C(O)-OC 1-4 In some embodiments, Cy is an alkyl (e.g., -COMe). 1 but, TIFF2025160375000068.tif22128.

[0072] In some embodiments, one R 3 is halo (e.g., fluoro or chloro) and the other R 3 However, R appears 0 times. 7 C replaced with 1-8 In some embodiments, Cy is alkyl (e.g., methyl, ethyl, isobutyl, or neopentyl). 1 but, TIFF2025160375000069.tif17128.

[0073] In some embodiments, one R 3 is halo (e.g., fluoro or chloro) and the other R 3 However, R appears 0 times. 7 C replaced with 1-8haloalkoxy (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 but, TIFF2025160375000070.tif66158.

[0074] In some embodiments, one R 3 is halo (e.g., fluoro or chloro) and the other R 3 However, there is one R 7 C replaced with 1-8 haloalkoxy (e.g., 3,3,3-trifluoropropoxy, (1,1,1-trifluoropropan-2-yl)oxy, or 4,4,4-trifluoro-3-methylbutoxy). In some embodiments, R 7 is hydroxyl. In some embodiments, R 7 But C 1-4 In some embodiments, R 7 is aralkoxy (e.g., benzoxy). In some embodiments, Cy 1 but, The file is TIFF2025160375000071.tif49155.

[0075] In some embodiments, one R 3 is halo (e.g., fluoro or chloro) and the other R 3 However, there is one R 7 C replaced with 3-9 alkoxy (e.g., cyclopentoxy or cyclohexyloxy). In some embodiments, R 7 But C 1-4 haloalkoxy (e.g., trifluoromethoxy). In some embodiments, R 7 But C 1-4 In some embodiments, one R 3is halo (e.g., fluoro or chloro) and the other R 3 However, there are two R 7 C replaced with 3-9 alkoxy (e.g., cyclopentoxy or cyclohexyloxy). In some embodiments, both R 7 But C 1-4 In some embodiments, one R 3 However, R appears 0 times. 7 C replaced with 1-8 haloalkyl (e.g., difluoromethyl), and the other R 3 However, R appears 0 times. 7 C replaced with 1-8 In some embodiments, one R 3 is halo (e.g., fluoro or chloro) and the other R 3 However, there are two R 7 C replaced with 3-9 cycloalkyl (e.g., cyclohexyl). In some embodiments, both R 7 But C 1-4 In some embodiments, Cy is alkyl (e.g., methyl). 1 but, The file is TIFF2025160375000072.tif61151.

[0076] In some embodiments, one R 3 is halo (e.g., fluoro), and the other R 3 However, there is one R 7 In some embodiments, R is aryl (e.g., phenyl) substituted with 7 But C 1-4 In some embodiments, R 7 But C 1-4 In some embodiments, Cy is a haloalkyl (e.g., trifluoromethyl). 1 but, TIFF2025160375000073.tif23128.

[0077] In some embodiments, one R 3 is halo (e.g., fluoro), and the other R 3 But -C(O)R 7 In some embodiments, R 7 However, R appears 0 times. 8 In some embodiments, one R is a heterocycloalkyl (e.g., morpholinyl) substituted with 3 is halo (e.g., fluoro), and the other R 3 But -C(O)N(R a )(R 7 In some embodiments, R a is H and R 7 But C 1-5 alkyl (e.g., tert-butyl or neopentyl). In some embodiments, one R 3 is halo (e.g., fluoro), and the other R 3 is aralkoxy (e.g., benzyloxy). In some embodiments, Cy 1 but, The file is TIFF2025160375000074.tif24142.

[0078] In some embodiments, one R 3 is halo (e.g., fluoro), and the other R 3 However, there are two R 7 C replaced with 3-9 In some embodiments, both R 7 But C 1-5 In some embodiments, one R 3 is halo (e.g., fluoro), and the other R 3 However, there is one R 7 C replaced with 1-4 Alkoxy-C 3-9 In some embodiments, R 7 But C 1-5 haloalkyl (e.g., trifluoromethyl). In some embodiments, one R3 is halo (e.g., fluoro), and the other R 3 However, there are two R 7 C replaced with 1-4 Alkoxy-C 3-9 cycloalkyl (methoxycyclobutyl or methoxycyclohexyl). In some embodiments, both R 7 is halo (e.g., fluoro). In some embodiments, one R 3 is halo (e.g., chloro) and the other R 3 However, there are two R 7 C replaced with 3-9 In some embodiments, both R 7 But C 1-5 In some embodiments, one R 3 is halo (e.g., fluoro), and the other R 3 But C 1-8 alkenyl (e.g., 2-methylprop-1-en-1-yl). In some embodiments, one R 3 is halo (e.g., fluoro), and the other R 3 However, there is one R 7 In some embodiments, R is heterocycloalkyl substituted with 7 But C 1-5 In some embodiments, Cy is alkyl (e.g., tert-butyl). 1 but, The file is TIFF2025160375000075.tif74158.

[0079] In some embodiments, Cy 1 But there are three R 3 In some embodiments, two R 3 is halo (e.g., fluoro), and other R 3 However, R appears 0 times. 7 C replaced with 1-8In some embodiments, two R 3 is halo (e.g., fluoro), and other R 3 However, there are two R 7 C replaced with 3-9 In some embodiments, both R 7 But C 1-5 In some embodiments, Cy is alkyl (e.g., methyl). 1 but, TIFF2025160375000076.tif22128.

[0080] In some embodiments, Cy 1 However, 0 to 3 Rs appear 3 In some embodiments, Cy is a heterocycloalkyl substituted with 1 However, R appears 0 times. 3 In some embodiments, Cy is a heterocycloalkyl substituted with 1 However, there is one R 3 In some embodiments, Cy is a heterocycloalkyl substituted with 1 However, there is one R 3 In some embodiments, R is a heterocycloalkyl substituted with N-azetidinyl, N-pyrrolidinyl, N-morpholinyl, N-piperidinyl, N-piperidine-2-only, N-pyrrolidine-2-only, 3-tetrahydropyranyl, 3-(3,6-dihydro-2H-pyranyl), 2N-6-oxa-9-azaspiro[4.5]decanyl, or 2N-6-oxa-2,9-diazaspiro[4.5]decanyl. 3 However, R appears 0 times. 7 C replaced with 1-8 alkyl (e.g., neopentyl, 4,4-dimethylpentyl, 3-methylbutyl, or 3,3-dimethylbutyl). In some embodiments, R 3 However, there is one R 7 C replaced with 1-8In some embodiments, R is alkyl (e.g., 3,3-dimethylbutyl). 7 is hydroxyl. In some embodiments, R 3 However, R appears 0 times. 7 C replaced with 1-8 In some embodiments, R is alkoxy (e.g., 3,3-dimethylbutoxy, neopentyloxy, or tert-butoxy). 3 But C 1-8 haloalkoxy (e.g., trifluoromethoxy). In some embodiments, R 3 But -C(O)-R 7 In some embodiments, R 7 But C 1-5 In some embodiments, Cy is alkoxy (e.g., tert-butoxy). 1 but, The file is TIFF2025160375000077.tif84151.

[0081] In some embodiments, Cy 1 is a permutation R that appears twice 3 In some embodiments, one R is a heterocycloalkyl substituted with N-piperidinyl, 9-(oxa-9-azaspiro[4.5]decanyl), or 2-(3-oxa-1-azaspiro[4.4]non-1-enyl). 3 But C 1-8 alkyl (e.g., methyl), and the other R 3 But C 1-8 In some embodiments, both R 3 But C 1-8 In some embodiments, Cy is alkyl (e.g., methyl). 1 but, TIFF2025160375000078.tif18128.

[0082] In some embodiments, Cy 1 is a permutation R that appears three times 3In some embodiments, three R 3 But C 1-8 In some embodiments, Cy is alkyl (e.g., methyl). 1 but, TIFF2025160375000079.tif17128.

[0083] In some embodiments, Cy 1 However, 0 to 3 Rs appear 3 In some embodiments, Cy is heteroaryl substituted with 1 However, R appears 0 times. 3 In some embodiments, Cy is heteroaryl substituted with 1 However, there is one R 3 In some embodiments, Cy is heteroaryl substituted with 1 appears once in the substitution R 3 In some embodiments, R is a heteroaryl substituted with 4-thiazolyl, 2-pyridinyl, 4-pyridinyl, 1-pyrazolyl, 3-pyrazolyl, 2-thiophenyl, 4-pyrazolyl, or 2-(1,3,4-thiadiazolyl). 3 However, R appears 0 times. 7 C replaced with 1-8 In some embodiments, R is alkyl (e.g., 3,3-dimethylbutyl). 3 However, R appears 0 times. 7 C replaced with 1-8 In some embodiments, R is alkoxy (e.g., 3,3-dimethylbutoxy, neopentyloxy, or 4,4-dimethylpentyloxy). 3 However, R appears 0 times. 7 C replaced with 1-8 haloalkoxy (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 is an R that appears once 7 C replaced with1-8 haloalkyl (e.g., 4,4,4-trifluoro-3,3-dimethylbutyl or 5,5,5-trifluoro-4,4-dimethylpentan-2-yl). In some embodiments, R 7 is hydroxyl. In some embodiments, R 3 However, there is one R 7 In some embodiments, R is heterocycloalkyl substituted with N-pyrrolidinyl. 7 But C 1-5 haloalkoxy (e.g., trifluoromethoxy). In some embodiments, R 3 However, R appears 0 times. 7 C replaced with 1-4 Alkoxy-C 3-9 In some embodiments, R 3 but, TIFF2025160375000080.tif8128. In some embodiments, R 3 But there are three R 7 C replaced with 1-4 Alkyl-C 3-9 In some embodiments, two R 7 is halo (e.g., fluoro) and one R 7 is hydroxyl. In some embodiments, R 3 but, TIFF2025160375000081.tif20128. In some embodiments, R 3 However, there is one R 7 C replaced with 3-9 cycloalkyl (e.g., cyclohexyl). In some embodiments, R 7 But C 1-5 haloalkyl (e.g., 1,1-difluoroethyl). In some embodiments, R 7 But C 1-5 haloalkenyl (e.g., 1-fluoroethylidenyl). In some embodiments, R 3 But -C(O)R 7 In some embodiments, R 7is 3,3,3-trifluoro-2,2-dimethylpropyl. In some embodiments, R 7 However, there are two R 8 C replaced with 3-7 In some embodiments, both R 8 is halo (e.g., fluoro). In some embodiments, Cy 1 but, TIFF2025160375000082.tif149158.

[0084] In some embodiments, Cy 1 However, there are two R 3 In some embodiments, Cy is heteroaryl substituted with 1 However, there are two R 3 In some embodiments, one R 3 is halo (e.g., fluoro), and the other R 3 However, R appears 0 times. 7 C replaced with 1-8 In some embodiments, one R 3 However, R appears 0 times. 7 C replaced with 1-8 haloalkyl (e.g., trifluoromethyl), and the other R 3 However, R appears 0 times. 7 C replaced with 1-8 In some embodiments, Cy is alkoxy (e.g., 3,3-dimethylbutoxy). 1 However, there are two R 3 In some embodiments, one R 3 is halo (e.g., chloro) and the other R 3 However, R appears 0 times. 7 C replaced with 1-8 In some embodiments, Cy is alkoxy (e.g., 3,3-dimethylbutoxy). 1 but, TIFF2025160375000083.tif26128.

[0085] In some embodiments, Cy 1 However, 0 to 3 Rs appear 3 C replaced with 3-9 In some embodiments, Cy is cycloalkyl. 1 However, R appears 0 times. 3 C replaced with 3-9 In some embodiments, Cy is cycloalkyl (e.g., cyclohexyl). 1 However, there is one R 3 C replaced with 3-9 cycloalkyl (e.g., cyclohexyl or cyclopentyl). In some embodiments, R 3 But C 1-8 In some embodiments, Cy is alkoxy (e.g., 3,3-dimethylbutoxy). 1 but, The file is TIFF2025160375000084.tif11128.

[0086] In some embodiments, the compound of formula (I) is selected from the following compounds shown in Table 1 below.

[0087] (Table 1) TIFF2025160375000085.tif162160TIFF2025160375000086.tif173157TIFF2025160375000087.tif164157TIFF2025160375000088.tif205160TIFF2025160375000089.tif181157TIFF2025160375000090.tif168157TIFF2025160375000091.tif217157TIFF2025160375000092.tif208155TIFF2025160375000093.tif186155TIFF2025160375000094.tif204157TIFF2025160375000095.tif203155TIFF2025160375000096.tif217155TIFF2025160375000097.tif195152TIFF2025160375000098.tif206157TIFF2025160375000099.tif176150TIFF2025160375000100.tif188155TIFF2025160375000101.tif171157TIFF2025160375000102.tif210148TIFF2025160375000103.tif198155TIFF2025160375000104.tif162157TIFF2025160375000105.tif205150TIFF2025160375000106.tif171152TIFF2025160375000107.tif160157TIFF2025160375000108.tif163150TIFF2025160375000109.tif192157TIFF2025160375000110.tif217157TIFF2025160375000111.tif187155TIFF2025160375000112.tif204155TIFF2025160375000113.tif197152TIFF2025160375000114.tif157150TIFF2025160375000115.tif186152TIFF2025160375000116.tif195157TIFF2025160375000117.tif203157TIFF2025160375000118.tif201155TIFF2025160375000119.tif159152TIFF2025160375000120.tif162157TIFF2025160375000121.tif169152TIFF2025160375000122.tif171155TIFF2025160375000123.tif203152TIFF2025160375000124.tif176152TIFF2025160375000125.tif202157TIFF2025160375000126.tif196155TIFF2025160375000127.tif183157TIFF2025160375000128.tif193160TIFF2025160375000129.tif199157TIFF2025160375000130.tif174160TIFF2025160375000131.tif190157TIFF2025160375000132.tif165164TIFF2025160375000133.tif199164TIFF2025160375000134.tif154164TIFF2025160375000135.tif179164TIFF2025160375000136.tif178164TIFF2025160375000137.tif169164TIFF2025160375000138.tif205164TIFF2025160375000139.tif175164TIFF2025160375000140.tif155164TIFF2025160375000141.tif162164TIFF2025160375000142.tif179164TIFF2025160375000143.tif165164TIFF2025160375000144.tif186164TIFF2025160375000145.tif172164TIFF2025160375000146.tif183164TIFF2025160375000147.tif185164TIFF2025160375000148.tif169164TIFF2025160375000149.tif168164TIFF2025160375000150.tif154164TIFF2025160375000151.tif174164TIFF2025160375000152.tif168164TIFF2025160375000153.tif166164TIFF2025160375000154.tif197164TIFF2025160375000155.tif180164TIFF2025160375000156.tif188164TIFF2025160375000157.tif184164TIFF2025160375000158.tif173164TIFF2025160375000159.tif177164TIFF2025160375000160.tif184164TIFF2025160375000161.tif195164TIFF2025160375000162.tif207164TIFF2025160375000163.tif171164TIFF2025160375000164.tif184164TIFF2025160375000165.tif163164TIFF2025160375000166.tif180164TIFF2025160375000167.tif165164TIFF2025160375000168.tif194164TIFF2025160375000169.tif159154TIFF2025160375000170.tif158164TIFF2025160375000171.tif176164TIFF2025160375000172.tif158162TIFF2025160375000173.tif167162TIFF2025160375000174.tif196164TIFF2025160375000175.tif189164TIFF2025160375000176.tif180164TIFF2025160375000177.tif149164TIFF2025160375000178.tif199164TIFF2025160375000179.tif169164TIFF2025160375000180.tif167164TIFF2025160375000181.tif204164TIFF2025160375000182.tif198164TIFF2025160375000183.tif167164TIFF2025160375000184.tif156164TIFF2025160375000185.tif209164TIFF2025160375000186.tif196164TIFF2025160375000187.tif172164TIFF2025160375000188.tif210164TIFF2025160375000189.tif203164TIFF2025160375000190.tif167164TIFF2025160375000191.tif172164TIFF2025160375000192.tif198164TIFF2025160375000193.tif200164TIFF2025160375000194.tif157164TIFF2025160375000195.tif196164TIFF2025160375000196.tif176164TIFF2025160375000197.tif216164TIFF2025160375000198.tif185164TIFF2025160375000199.tif169164TIFF2025160375000200.tif183164TIFF2025160375000201.tif167164TIFF2025160375000202.tif170164TIFF2025160375000203.tif164164TIFF2025160375000204.tif183164TIFF2025160375000205.tif198164TIFF2025160375000206.tif189164TIFF2025160375000207.tif198164TIFF2025160375000208.tif194164TIFF2025160375000209.tif183164TIFF2025160375000210.tif192164TIFF2025160375000211.tif189164TIFF2025160375000212.tif200164TIFF2025160375000213.tif164164TIFF2025160375000214.tif188164TIFF2025160375000215.tif205164TIFF2025160375000216.tif161164TIFF2025160375000217.tif165164TIFF2025160375000218.tif183164TIFF2025160375000219.tif171164TIFF2025160375000220.tif175164TIFF2025160375000221.tif169164TIFF2025160375000222.tif186164TIFF2025160375000223.tif202164TIFF2025160375000224.tif168164TIFF2025160375000225.tif207164TIFF2025160375000226.tif197164TIFF2025160375000227.tif201164TIFF2025160375000228.tif197164TIFF2025160375000229.tif155164TIFF2025160375000230.tif162164TIFF2025160375000231.tif139164TIFF2025160375000232.tif147164TIFF2025160375000233.tif160164TIFF2025160375000234.tif162164TIFF2025160375000235.tif189164TIFF2025160375000236.tif179164TIFF2025160375000237.tif173164TIFF2025160375000238.tif175164TIFF2025160375000239.tif152164TIFF2025160375000240.tif191164TIFF2025160375000241.tif142164TIFF2025160375000242.tif180164TIFF2025160375000243.tif163164TIFF2025160375000244.tif183164TIFF2025160375000245.tif185164TIFF2025160375000246.tif182164TIFF2025160375000247.tif191164TIFF2025160375000248.tif178164TIFF2025160375000249.tif195164TIFF2025160375000250.tif171164TIFF2025160375000251.tif161164TIFF2025160375000252.tif195164TIFF2025160375000253.tif184164TIFF2025160375000254.tif178164TIFF2025160375000255.tif189164TIFF2025160375000256.tif199164TIFF2025160375000257.tif196164TIFF2025160375000258.tif160164TIFF2025160375000259.tif182164TIFF2025160375000260.tif150164TIFF2025160375000261.tif177164TIFF2025160375000262.tif199164TIFF2025160375000263.tif187164TIFF2025160375000264.tif198164TIFF2025160375000265.tif164164TIFF2025160375000266.tif197164TIFF2025160375000267.tif175164TIFF2025160375000268.tif159164TIFF2025160375000269.tif158164TIFF2025160375000270.tif173164TIFF2025160375000271.tif152164TIFF2025160375000272.tif193164TIFF2025160375000273.tif192164TIFF2025160375000274.tif183164TIFF2025160375000275.tif182164TIFF2025160375000276.tif173164TIFF2025160375000277.tif189164TIFF2025160375000278.tif173164TIFF2025160375000279.tif140164TIFF2025160375000280.tif201164TIFF2025160375000281.tif188164TIFF2025160375000282.tif195164TIFF2025160375000283.tif173164TIFF2025160375000284.tif148164.

[0088] In some embodiments, the compound of formula (I) is selected from the following compounds shown in Table 2 below.

[0089] (Table 2) TIFF2025160375000285.tif159164TIFF2025160375000286.tif162164TIFF2025160 375000287.tif151164TIFF2025160375000288.tif179164TIFF2025160375000289.t if199164TIFF2025160375000290.tif202164TIFF2025160375000291.tif167164TIF F2025160375000292.tif179164TIFF2025160375000293.tif186164TIFF20251603750 00294.tif161164TIFF2025160375000295.tif203164TIFF2025160375000296.tif19 9164TIFF2025160375000297.tif194164TIFF2025160375000298.tif165164TIFF202 5160375000299.tif204164TIFF2025160375000300.tif177164TIFF20251603750003 01.tif182164TIFF2025160375000302.tif188164TIFF2025160375000303.tif218164

[0090] definition Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art of this disclosure. The following references provide those skilled in the art with general definitions of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994), The Cambridge Dictionary of Science and Technology (Walker ed., 1988), The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991), and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below, unless otherwise specified.

[0091] In this disclosure, the words "comprises," "comprising," "containing," and "having" and the like may have the meaning ascribed to them in U.S. patent law, and may mean "includes," "including," and the like, and the terms "consisting essentially of" or "consisting essentially of" similarly have the meaning ascribed to them in U.S. patent law, and these terms are open-ended and permit the presence of more than what is recited, but exclude prior art embodiments, so long as the basic or novel characteristics of the recited thing are not changed by the presence of more than what is recited.

[0092] As used herein, the term "or" is understood to be inclusive unless specifically stated otherwise or clear from context. As used herein, the terms "a," "an," and "the" are understood to be singular or plural unless specifically stated otherwise or clear from context.

[0093] The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0094] The term "acylamino" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.

[0095] The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0096] The term "alkoxy" refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0097] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0098] 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," the latter of which refers to an alkenyl moiety having substituents replacing hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons included or not included in one or more double bonds. Furthermore, such substituents include all of those contemplated for alkyl groups, as discussed below, except where stability would be inhibited. For example, substitution of alkenyl groups with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[0099] An "alkyl" group or "alkane" is a fully saturated, straight-chain or branched non-aromatic hydrocarbon. Typically, a straight-chain or branched alkyl group, unless otherwise defined, has 1 to about 20 carbon atoms, preferably 1 to about 10, and more preferably 1 to 6. Examples of straight-chain and branched alkyl groups include methyl, ethyl, n-propyl, iso-propyl, 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.

[0100] Furthermore, the term "alkyl" (or "lower alkyl"), as used throughout the specification, examples, and claims, is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter of which refers to an alkyl moiety having substituents replacing hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, unless otherwise specified, can include, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, where appropriate. For example, substituents of substituted alkyls can include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfates, sulfonamides, sulfamoyl, and sulfonates), and silyl groups, as well as ethers, alkylthio, carbonyl (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN, and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, and the like.

[0101] "C x-y The term " when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups containing x to y carbons in the chain. For example, "C x-yThe term "alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups containing x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. C0 alkyl represents a hydrogen when the group is in a terminal position and a bond when the group is internal. 2-y alkenyl" and "C 2-y The term "alkynyl" refers to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double or triple bond respectively.

[0102] The term "alkylamino," as used herein, refers to an amino group substituted with at least one alkyl group.

[0103] The term "alkylthio," as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

[0104] The term "haloalkyl," as used herein, refers to an alkyl group in which at least one hydrogen has been replaced with a halogen, such as fluoro, chloro, bromo, or iodo. Exemplary haloalkyl groups include trifluoromethyl, difluoromethyl, fluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.

[0105] The term "alkynyl," as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyl" and "substituted alkynyl," the latter of which refers to an alkynyl moiety having substituents replacing hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons included or not included in one or more triple bonds. Furthermore, such substituents include all of those contemplated for alkyl groups, as discussed above, except where stability would be inhibited. For example, substitution of alkynyl groups with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[0106] The term "amide" as used herein means TIFF2025160375000304.tif19128, where each R 10 independently represent hydrogen or a hydrocarbyl group, or two R 10 together with the N atom to which they are attached complete a heterocycle with 4 to 8 atoms in the ring structure.

[0107] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, as well as salts thereof, e.g., TIFF2025160375000305.tif17128, wherein each R 10 independently represent hydrogen or a hydrocarbyl group, or two R 10 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure. The term "aminoalkyl," as used herein, refers to an alkyl group substituted with an amino group.

[0108] The term "aralkyl," as used herein, refers to an alkyl group substituted with an aryl group.

[0109] The term "aryl," as used herein, includes substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon. Preferably, the ring is a 5- to 6-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of which is aromatic, e.g., the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0110] The term "carbamate" is art-recognized and TIFF2025160375000306.tif15128, where R 9 and R 10 independently represent hydrogen or a hydrocarbyl group such as an alkyl group, or R 9 and R 10 together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0111] The terms "carbocycle" and "carbocyclic," as used herein, refer to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocycle includes both aromatic and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings in which all carbon atoms are saturated and cycloalkene rings that contain at least one double bond.

[0112] The term "carbocycle" includes 3- to 10-membered monocyclic rings and 8- to 12-membered bicyclic rings. Each ring in a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. Carbocycles include bicyclic molecules in which one, two, or three or more atoms are shared between two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each ring shares two adjacent atoms with the other ring. Each ring in a fused carbocycle can be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, can be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings, valence permitting, is included in the definition of carbocycle. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. A "carbocycle" may be substituted at any one or more positions capable of bearing a hydrogen atom.

[0113] A "cycloalkyl" group is a fully saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has 3 to about 10 carbon atoms, more typically 3 to 9 carbon atoms, unless otherwise defined. The second ring of a bicyclic cycloalkyl can be selected from saturated, unsaturated, and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two, or three or more atoms are shared between the two rings. The term "fused cycloalkyl" refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl can be selected from saturated, unsaturated, and aromatic rings.

[0114] A "cycloalkenyl" group is a cyclic hydrocarbon containing one or more double bonds. The cycloalkenyl ring can have 3 to 10 carbon atoms. Thus, cycloalkenyl groups can be monocyclic or polycyclic. The individual rings of such polycyclic cycloalkenyl groups can have different connectivity, e.g., fused, bridged, spiro, etc., in addition to covalent bond substitution. Exemplary cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentyl, cyclohexenyl, cycloheptenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, and 1,5-cyclooctadienyl.

[0115] Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornanyl, bicyclo[3.2.1]octanyl, octahydro-pentalenyl, spiro[4.5]decanyl, cyclopropyl, and adamantyl.

[0116] The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocyclic group.

[0117] The term "carbonate" is art-recognized and refers to a group -OCO-R 10 In the formula, R 10 represents a hydrocarbyl group.

[0118] The term "carboxy," as used herein, refers to a group represented by the formula -CO2H.

[0119] The term "ester" as used herein refers to the group -C(O)OR 10 In the formula, R 10 represents a hydrocarbyl group.

[0120] The term "ether," as used herein, refers to a hydrocarbyl group bonded to another hydrocarbyl group via an oxygen atom. Thus, the ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. Ethers can be symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups, which can be represented by the general formula alkyl-O-alkyl.

[0121] The terms "halo" and "halogen" as used herein mean halogen and include chloro, fluoro, bromo, and iodo.

[0122] The terms "hetaralkyl" and "heteroaralkyl," as used herein, refer to an alkyl group substituted with a hetaryl group.

[0123] The term "heteroalkyl," as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent.

[0124] The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic monocyclic ring structures, preferably 3- to 10-membered rings, more preferably 5- to 9-membered rings, e.g., 5- or 6-membered rings, which ring structures contain at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of which is heteroaromatic; e.g., the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine.

[0125] The individual rings of such polycyclic heteroaryl groups may have different connectivities, e.g., fused, etc., in addition to the covalent bond substitution. Exemplary heteroaryl groups include furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridyl, and the like. Examples include aryl, cinnolyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazinyl, and the like. In general, heteroaryl groups are typically attached to the main structure through a carbon atom.

[0126] The term "heteroatom," as used herein, means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0127] The terms "heterocyclyl," "heterocycle," and "heterocyclic" refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, which contain at least one heteroatom, preferably 1 to 4 heteroatoms, and more preferably 1 or 2 heteroatoms. The terms "heterocyclyl" and "heterocyclic" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of which is heterocyclic; for example, the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

[0128] The individual rings of such polycyclic heterocycloalkyl groups can have different connectivities, eg, fused, bridged, spiro, etc., in addition to covalent bond substitution. Exemplary heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, azindinyl, azetidinyl, oxiranyl, methylenedioxyl, chromenyl, barbituryl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, Piperidin-2-onyl, piperidin-3-onyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl, imidazolidinyl, 2-imidazolidinyl, 1,4-dioxanyl, 8-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-di Examples include azabicyclo[2.2.2]octanyl, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[4.1.0]heptanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azaspiro[4.4]nonanyl, 7-oxa-1-aza-spiro[4.4]nonanyl, 7-azabicyclo[2.2.2]heptanyl, octahydro-1H-indolyl, and the like. In general, heterocycloalkyl groups are typically attached to the main structure through a carbon atom or a nitrogen atom.

[0129] The term "heterocyclylalkyl," as used herein, refers to an alkyl group substituted with a heterocycle group.

[0130] The term "hydrocarbyl," as used herein, refers to a group that has at least one carbon-hydrogen bond and a primarily carbon backbone, but which may optionally contain heteroatoms, without =0 or =S substituents, and is bonded through carbon atoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbyl for purposes of this application, while substituents such as acetyl (with =0 substituent on the bonded carbon) and ethoxy (bonded through an oxygen rather than a carbon) are not hydrocarbyl. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

[0131] The term "hydroxyalkyl," as used herein, refers to an alkyl group substituted with a hydroxy group.

[0132] When used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, the term "lower" is meant to include groups in which there are 10 or fewer, preferably 6 or fewer, non-hydrogen atoms in the substituent. "Lower alkyl," for example, refers to alkyl groups containing 10 or fewer, preferably 6 or fewer, carbon atoms. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, respectively, whether they appear alone or in combination with other substituents, for example, in recitations of hydroxyalkyl and aralkyl (where, for example, atoms in an aryl group are not included when counting the carbon atoms in an alkyl substituent).

[0133] The terms "polycyclyl," "polycycle," and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl) in which two or more atoms are common to two adjacent rings, e.g., the rings are "fused rings." Each of the rings of a polycycle can be substituted or unsubstituted. In certain embodiments, each ring of a polycycle contains 3 to 10 atoms, preferably 5 to 7 atoms, in the ring.

[0134] The term "silyl" refers to a silicon moiety having three hydrocarbyl moieties attached thereto.

[0135] The term "substituted" refers to a moiety having a substituent in place of a hydrogen on one or more carbon atoms of the backbone. It is understood that "substituted" or "substituted with" includes the implicit proviso that such substitution results in a stable compound, e.g., a stable compound that does not spontaneously undergo transformation by, for example, rearrangement, cyclization, elimination, and the like, subject to the permissible valences of the substituted atom and substituent. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituent of organic compounds described herein that satisfies the valence of the heteroatom. Substituents can include any substituent described herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. Those skilled in the art will understand that the substituents themselves can be substituted, where appropriate. Unless specifically stated as "unsubstituted," reference to a chemical moiety herein is understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0136] The term "sulfate" is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.

[0137] The term "sulfonamide" is art-recognized and can be represented by the general formula TIFF2025160375000307.tif16128, wherein R 9 and R 10 independently represent hydrogen or hydrocarbyl such as alkyl, or R 9 and R 10 together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0138] The term "sulfoxide" is art-recognized and refers to the group -S(O)-R 10 In the formula, R 10 represents a hydrocarbyl.

[0139] The term "sulfonate" is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.

[0140] The term “sulfone” is art-recognized and refers to the group —S(O)—R 10 In the formula, R 10 represents a hydrocarbyl.

[0141] The term "thioalkyl," as used herein, refers to an alkyl group substituted with a thiol group.

[0142] The term "thioester" as used herein refers to the group -C(O)SR 10 or -SC(O)R 10 In the formula, R 10 represents a hydrocarbyl.

[0143] The term "thioether" as used herein is equivalent to an ether, where an oxygen is replaced with a sulfur.

[0144] The term "urea" is art-recognized and has the general formula TIFF2025160375000308.tif15128, where R 9 and R10 independently represent hydrogen or hydrocarbyl such as alkyl, or R 10 and R together with the intervening atom(s) 9 Any occurrence of completes a heterocycle having 4 to 8 atoms in the ring structure.

[0145] The term "protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces, or prevents the reactivity of the functional group. Typically, a protecting group can be selectively removed when desired during the course of synthesis. Examples of protecting groups are found in Greene and Wuts, Protective Groups in Organic Chemistry, 3 rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("TES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl ("NVOC"), and the like. Representative hydroxyl protecting groups include, but are not limited to, those in which the hydroxyl group is acylated (esterified) or alkylated, such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers (e.g., ethylene glycol and propylene glycol derivatives), and allyl ethers.

[0146] The present invention also encompasses various isomers and mixtures thereof. Certain compounds of the present invention may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial configuration. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that serves as a chiral center. "Enantiomer" refers to one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms. "R" and "S" refer to the configuration of substituents around one or more chiral carbon atoms. If a chiral center is not defined as R or S, either a pure enantiomer or a mixture of both configurations exists.

[0147] "Racemate" or "racemic mixture" refers to a compound of equimolar amounts of two enantiomers, and such mixtures do not exhibit optical activity, i.e., they do not rotate the plane of polarized light. In certain embodiments, the compounds of the present invention may be racemic.

[0148] In certain embodiments, the compounds of the present invention can be enriched with one enantiomer.For example, the compounds of the present invention can have an enantiomeric excess of more than about 30%, an enantiomeric excess of more than about 40%, an enantiomeric excess of more than about 50%, an enantiomeric excess of more than about 60%, an enantiomeric excess of more than about 70%, an enantiomeric excess of more than about 80%, an enantiomeric excess of more than about 90%, or even an enantiomeric excess of more than about 95%.In certain embodiments, the compounds of the present invention can have two or more stereocenters.In certain such embodiments, the compounds of the present invention can be enriched with one or more diastereomers. For example, compounds of the present invention may have a diastereomeric excess of greater than about 30%, greater than about 40%, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, or even a diastereomeric excess of about 95% or greater.

[0149] In certain embodiments, therapeutic preparations can be enriched to provide primarily one enantiomer of a compound (e.g., of Formula (I)). An enantiomerically enriched mixture can contain, for example, at least about 60 mole percent of one enantiomer, or more preferably at least about 75, about 90, about 95, or even about 99 mole percent of one enantiomer. In certain embodiments, a compound enriched in one enantiomer is substantially free of the other enantiomer, where substantially free means that the substance in question accounts for, for example, 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 in the composition or compound mixture. For example, if a composition or compound mixture contains about 98 grams of a first enantiomer and about 2 grams of a second enantiomer, it would be said to contain about 98 mole percent of the first enantiomer and only about 2% of the second enantiomer.

[0150] In certain embodiments, therapeutic preparations can be enriched to provide predominantly one diastereomer of a compound (e.g., of Formula (I)). A diastereomerically enriched mixture can contain, for example, at least about 60 mole percent, or more preferably at least about 75, about 90, about 95, or even about 99 mole percent of one diastereomer.

[0151] The compounds of the present invention can be prepared as individual isomers either by isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include using an optically active acid to form a salt of the free base of each isomer of the isomeric 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 of the isomeric 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 isomer of the isomeric pair (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either the starting material or the final product using various well-known chromatographic methods. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least about 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight relative to other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% by weight optically pure. Percent optical purity by weight is the ratio of the weight of the enantiomer present divided by the total weight of the enantiomers present and the weight of that optical isomer.

[0152] In the pictorial representations of compounds given throughout this application, thick tapered lines TIFF2025160375000309.tif5128 indicates substituents above the plane of the ring to which the asymmetric carbon belongs, and dotted lines TIFF2025160375000310.tif5128 shows substituents below the plane of the ring to which the asymmetric carbon belongs.

[0153] As used herein, the compounds of the present invention may be in the form of one of the possible isomers, rotamers, atropisomers, tautomers, or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates, or mixtures thereof.

[0154] Isotopically labeled forms of the disclosed compounds have one or more atoms of the compound replaced with one or more atoms having an atomic mass or mass number different from that normally occurring in greater natural abundance. Examples of isotopes that are readily commercially available and can be incorporated into the disclosed compounds by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphate, 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 carrying out the procedures disclosed herein, substituting isotopically labeled reactants for non-isotopically labeled reactants.

[0155] The concentration of such a heavier isotope, specifically deuterium, can be defined by the isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a specified isotope. When hydrogen atoms in compounds of the invention are replaced with deuterium, such compounds have an isotopic enrichment factor, per designated deuterium, of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0156] The isotopically labeled compounds provided herein can be used in many beneficial ways. Compounds incorporating 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. Heavier isotopes, such as deuterium (2H), have therapeutic advantages due to their greater metabolic stability. Metabolism undergoes a first-order kinetic isotope effect, with heavier isotopes having lower ground states, resulting in reduced rate-limiting bond ruptures. Slowing metabolism may result in increased in vivo half-life, reduced dosage requirements, or improved therapeutic index.

[0157] For further discussion, see S.L. Harbeson and R.D. Tung, Deuterium in Drug Discovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417; Foster, A.B., "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends in Pharmacological Sciences, 5:524-527 (1984); and Foster, A.B., "Deuterium Isotope Effects in the Metabolism of Drugs and Xenobiotics: Implications for Drug Design," Advances in Drug Research, 14:1-40 (1985).

[0158] Metabolic stability can be affected by the processing of a compound in various organs of the body. For example, compounds with poor pharmacokinetic profiles are prone to oxidative metabolism. Currently available in vitro liver microsome assays provide valuable information on the course of this type of oxidative metabolism, which in turn aids in the rational design of deuterated compounds as disclosed herein. Improvements can be measured in several assays known in the art, such as in vivo half-life (t), the concentration at maximum therapeutic effect (C), the area under the dose-response curve (AUC), and bioavailability, as well as in terms of increased clearance, reduced dose, and reduced material costs.

[0159] Another effect of deuterated compounds can be the reduction or elimination of undesired toxic metabolites. For example, if a toxic metabolite is produced through oxidative carbon-hydrogen (CH) bond cleavage, the deuterated analog will have a slower reaction time, slowing the production of the undesired metabolite, even if the specific oxidation is not the rate-limiting step. See, e.g., 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.

[0160] The term "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., male or female of any age, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly adult)) and / or another primate (e.g., cynomolgus monkey, rhesus monkey), mammals, including commercially relevant mammals such as cows, pigs, horses, sheep, goats, cats, and / or dogs, and / or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and / or turkeys. A preferred subject is a human.

[0161] As used herein, a therapeutic agent that "prevents" a disorder or condition refers to a compound that, in a statistical sample, reduces or delays the occurrence of the disorder or condition in a treated sample relative to an untreated control sample, or reduces the severity of one or more symptoms of the disorder or condition relative to an untreated control sample.

[0162] The term "treating" means reducing, inhibiting, attenuating, curtailing, arresting, or stabilizing the onset or progression of a disease (e.g., a disease or disorder described herein), reducing the severity of the disease, or ameliorating the symptoms associated with the disease. Treatment includes treating the symptoms of a disease, disorder, or condition. Without being bound by any theory, in some embodiments, treatment involves enhancing defective CFTR activity. When administered before the clinical manifestation of an undesired condition (e.g., a disease or other undesired condition in a subject), treatment is prophylactic (i.e., protects the subject from developing the undesired condition), whereas when administered after the onset of symptoms of the undesired condition, treatment is therapeutic (i.e., intended to reduce, ameliorate, or stabilize an existing undesired condition or its side effects).

[0163] As used herein, the term "prodrug" refers to a pharmacological derivative of a parent drug molecule that requires either spontaneous or enzymatic biotransformation in an organism to release the active drug. For example, a prodrug is a variant or derivative of a compound of the present invention that has groups that are cleavable under certain metabolic conditions, resulting in a compound of the present invention upon cleavage. As a result, such prodrugs are pharmaceutically active in vivo when they undergo solvolysis under physiological conditions or enzymatic degradation. Prodrug compounds herein may be referred to as single, double, triple, etc., depending on the number of biotransformation steps required to release the active drug in an organism and the number of functional groups present in the precursor form. Prodrug forms often offer advantages of 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 generally known in the art include well-known acid derivatives, such as esters prepared by reacting the parent acid with a suitable alcohol, amides prepared by reacting the parent acid compound with an amine, and basic groups reacted to form acylated base derivatives. Of course, other prodrug derivatives can be combined with other features disclosed herein to enhance bioavailability.

[0164] Thus, those skilled in the art will understand that certain compounds of the present disclosure having free amino, amide, hydroxy, or carboxylic acid groups can be converted into prodrugs. Prodrugs include compounds having an amino acid residue or a polypeptide chain of two or more (e.g., 2, 3, or 4) amino acid residues covalently attached via peptide bonds to a free amino, hydroxy, or carboxylic acid group of a compound of the present disclosure. Amino acid residues include the 20 naturally occurring amino acids, commonly designated by their three-letter symbols, and also include 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3-methylhistidine, norvaline, β-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine, and methionine sulfone. Prodrugs also include compounds having a carbonate, carbamate, amide, or alkyl ester moiety covalently attached to any of the above substituents disclosed herein.

[0165] As used herein, "therapeutically effective amount" refers to an amount sufficient to achieve a desired therapeutic effect. For example, a therapeutically effective amount can refer to an amount sufficient to ameliorate at least one sign or symptom of cystic fibrosis.

[0166] A "response" to a treatment method can include, among other things, a decrease or amelioration 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 relief of the disease, etc.

[0167] As used herein, "CFTR" refers to the cystic fibrosis transmembrane conductance regulator. Defects in the function of the CFTR ion channel result from loss-of-function mutations in CFTR. Such mutations cause exocrine dysfunction, abnormal mucociliary clearance, and lead to 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, known as "ΔF508," is found in approximately 70% of CF patients worldwide. The ΔF508 mutation reduces the stability of the CFTR NBD1 domain and limits CFTR interdomain assembly. Because CF is an autosomal recessive disease, CF patients carrying the ΔF508 CFTR mutation must also carry a second defective copy of CFTR. Approximately 2,000 different CF-causing CFTR mutations have been identified in CF patients. A CF patient with a ΔF508 CFTR mutation can be homozygous for that mutation (ΔF508 / ΔF508). A CF patient can also be ΔF508 heterozygous if the second CFTR allele carried by such a patient contains a different CFTR loss-of-function mutation instead. Such 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.

[0168] As used herein, the term "CFTR modulator" refers to a compound that increases the activity of CFTR. In certain embodiments, a CFTR modulator is a CFTR corrector or a CFTR potentiator, or a dual-acting compound with corrector and potentiator activity. These dual-acting agents are useful when mutations result in the absence or reduced amount of synthetic CFTR protein.

[0169] As used herein, the term "CFTR corrector" refers to a compound that increases the amount of functional CFTR protein on the cell surface, thus enhancing ion transport through CFTR. CFTR correctors partially "rescue" misfolding of the CFTR protein, particularly misfolding resulting from mutations within CFTR, thereby allowing CFTR to mature and functionally express on the cell surface. CFTR correctors may alter the folding environment of a cell in a way that promotes CFTR folding, and may include compounds that directly interact with the CFTR protein to alter its folding, conformational maturation, or stability. Examples of correctors include, but are not limited to, VX-809, VX-661, VX-152, VX-440, VX-445, VX-659, VX-121, VX-983, compounds described in US2019 / 0248809A1, GLPG2222, GLPG2737, GLPG3221, GLPG2851, FDL169, FDL304, FDL2052160, FD2035659, and PTI-801.

[0170] As used herein, the term "CFTR potentiator" refers to a compound that increases the ion channel activity of the CFTR protein located on the cell surface and enhances ion transport. CFTR potentiators restore defective channel function resulting from CFTR mutations or otherwise increase the activity of CFTR on the cell surface. Examples of potentiators include, but are not limited to, ivacaftor (VX770), deuterated ivacaftor (CPT656, VX-561), PTI-808, QBW251, GLPG1837, GLPG2451, ABBV-3067, ABBV-974, ABBV-191, FDL176, and genistein.

[0171] As used herein, "CFTR disease or condition" refers to a disease or condition associated with a defect in CFTR activity, such as cystic fibrosis, congenital bilateral absence of the vas deferens (CBAVD), acute, recurrent, or chronic pancreatitis, disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis, smoking-related lung diseases such as chronic obstructive pulmonary disease (COPD), rhinosinusitis, congenital pneumonia, intestinal malabsorption, celiac disease, nasal polyposis, nontuberculous mycobacteriosis, pancreatic steatorrhea, intestinal atresia, dry eye disease, protein C deficiency, abetalipoproteinemia, lysosomal storage diseases, type 1 chylomyocarditis, mild lung disease, lipid processing deficiency, hereditary angioedema type 1, coagulation-fibrinolysis, hereditary hemochromatosis, CFTR-related metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, and Sjogren's syndrome.

[0172] How to use Disclosed herein is a method of treating a defect in CFTR activity in a cell, comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, the contacting of the cell is carried out in a subject in need thereof, thereby treating a disease or disorder mediated by a defect in CFTR activity.

[0173] Also disclosed herein is a method for treating a disease or disorder mediated by defective CFTR activity, comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is a mammal, preferably a human. In some embodiments, the disease is associated with the regulation of fluid volume across epithelial membranes, particularly obstructive airway diseases such as CF or COPD.

[0174] Such diseases and conditions include cystic fibrosis, asthma, smoking-induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild lung disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), congenital pneumonia, intestinal malabsorption, celiac disease, nasal polyposis, nontuberculous mycobacteriosis, pancreatic steatorrhea, and intestinal atresia. , liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiency, protein C deficiency, type 1 hereditary angioedema, lipid processing deficiency, familial hypercholesterolemia, type 1 chylomyocarditis, abetalipoproteinemia, lysosomal storage diseases, I-cell disease / pseudo-Hurler disease, mucopolysaccharidoses, Sandhoff / Tay-Sachs disease, Crigler-Najjar disease type II, polyendocrinopathy / hyperinsulinemia sulemia, diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG1 type, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie-Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, some polyglutamine neuropathies, Huntington's disease, spinocerebellar ataxia type I, spinal-bulbar muscular atrophy, dentatorubral-pallidoluysian syndromepallidoluysian, myotonic dystrophy, spongiform encephalopathy, hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry eye disease, Sjogren's syndrome, osteoporosis, osteopenia, bone healing and growth, bone repair, bone regeneration, decreased bone resorption, increased bone deposition, Gorham syndrome, chloride channelopathy, congenital myotonia, Bartter syndrome type III, Dent syndrome, hyperakinemia, epilepsy, hyperakinemia, lysosomal storage diseases, Angelman syndrome, primary ciliary dyskinesia (PCD), PCD with situs inversus, PCD without situs inversus, and ciliary aplasia.

[0175] Such diseases and conditions include, but are not limited to, cystic fibrosis, congenital bilateral absence of the vas deferens (CBAVD), acute, recurrent, or chronic pancreatitis, disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis, chronic obstructive pulmonary disease (COPD), chronic sinusitis, congenital pneumonia, intestinal malabsorption, celiac disease, nasal polyposis, nontuberculous mycobacteriosis, pancreatic steatorrhea, intestinal atresia, dry eye disease, protein C deficiency, abetalipoproteinemia, lysosomal storage diseases, type 1 chylomyocarditis, mild pulmonary disease, lipid processing deficiency, hereditary angioedema type 1, coagulation-fibrinolysis, hereditary hemochromatosis, CFTR-associated metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, and Sjogren's syndrome. In some embodiments, the disease is cystic fibrosis.

[0176] Provided herein are methods for treating cystic fibrosis, comprising administering to a subject in need thereof a compound disclosed herein or a pharmaceutically acceptable salt thereof. Also provided herein are methods for reducing the severity of cystic fibrosis, comprising administering to a subject in need thereof a compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is a human. In some embodiments, the subject is at risk of developing cystic fibrosis, and administration occurs prior to the onset of cystic fibrosis symptoms in the subject.

[0177] Provided herein are compounds disclosed herein for use in treating a disease or condition mediated by a defect in CFTR activity. Also provided herein is the use of a compound disclosed herein for the manufacture of a medicament for treating a disease or condition mediated by a defect in CFTR activity.

[0178] The compounds and methods described herein can be used to treat subjects with defective CFTR activity and CFTR mutations, such as ΔF508. The ΔF508 mutation disrupts normal CFTR folding, stability, trafficking, and function by reducing the stability of the NBD1 domain of CFTR, the ability of CFTR domain-domain assembly, or both. Due to its effect on the ICL4 interface, CFTR correctors with ICL4-directed mechanisms may be effective in subjects with the following mutations: ΔF508-CFTR (of which more than 70% of all CF patients have at least one copy) and mutations that cause ICL4 interface instability, such as G85E, H139R, H1054D, L1065P, L1077P, and R1066C, as well as other CFTR mutations that impair ICL4 interface stability.

[0179] Provided herein are kits for use in measuring the activity of CFTR or a fragment thereof in a biological sample in vitro or in vivo. The kit can include: (i) a compound disclosed herein or a pharmaceutical composition comprising a disclosed compound; and (ii) instructions for a) contacting the compound or composition with a biological sample and b) measuring the activity of the CFTR or fragment thereof. In some embodiments, the biological sample is a biopsy obtained from a mammal or an extract thereof, such as blood, saliva, urine, feces, semen, tears, other bodily fluids, or an extract thereof. In some embodiments, the mammal is a human.

[0180] Combination therapy As used herein, the term "combination therapy" refers to the administration to a subject (e.g., a human) of two or more CFTR modulators, or a CFTR modulator and an agent such as an antibiotic, an ENaC inhibitor, a GSNO (S-nitrosothiol s-nitroglutant thione) reductase inhibitor, and a CRISPR Cas correction therapy or system (e.g., as described in US2007 / 0022507).

[0181] In certain embodiments, methods for treating or preventing diseases or conditions mediated by defective CFTR activity include administering a compound disclosed herein in combination with one or more other therapeutic agent(s). In some embodiments, one other therapeutic agent is administered. In other embodiments, at least two other therapeutic agents are administered.

[0182] Additional therapeutic agents include, for example, ENaC inhibitors, mucolytic agents, bronchodilators, antibiotics, anti-infectives, anti-inflammatory agents, ion channel modulators, therapeutic agents used in gene therapy, agents that reduce airway surface liquid and / or reduce airway surface pH, CFTR correctors, and CFTR potentiators, or other agents that modulate CFTR activity.

[0183] In some embodiments, the at least one additional therapeutic agent is selected from one or more CFTR modulators, one or more CFTR correctors, and one or more CFTR potentiators.

[0184] Non-limiting examples of CFTR modulators, correctors, and potentiators include VX-770 (Ivacaftor), VX-809 (Lumacaftor, 3-(6-(1-(2,2-5 difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, VX-661 (Tezacaftor, 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indole-5-yl]benzoic acid, [5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid), VX-983, VX-152, VX-440, VX-445, VX-659, VX-371, VX-121, Orkambi, compounds described in US 2019 / 0248809 A1, Ataluren (PTC124) (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 WO 2011 / 113894, N30 Pharmaceuticals compounds (e.g., WO2014 / 186704), deuterated ivacaftor (e.g., CTP-656 or VX-561), GLPG2222, GLPG3221, GLPG2451, GLPG3067, GLPG2851, GLPG2737, GLPG1837 (N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,[3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide), GLPG2665 (Galapagos), ABBV-191 (Abbvie), ABBV-974, FDL169 (Flatley Discovery Lab), FDL176, FDL438, FDL304, FD2052160, FD1881042, FD2027304, FD2035659, FD2033129, FD1860293, CFFT-Pot01, CFFT-Pot-02, P-1037, glycerol, phenylbutyrate, and the like. Non-limiting examples of anti-inflammatory agents are N6022 (3-(5-(4-(1H-imidazol-1-yl)10phenyl)-1-(4-carbamoyl-2-methylphenyl)-'H-pyrrol-2-yl)propanoic acid), ibuprofen, Lenabasum (anabasum), Acebilustat (CTX-4430), LAU-7b, POL6014, docosahexaenoic acid, alpha-1 antitrypsin, and sildenafil. Additional therapeutic agents also include, but are not limited to, mucolytic agents, mucus rheology modifiers (such as hypertonic saline, mannitol, and oligosaccharide-based therapies), bronchodilators, anti-infectives (such as tazobactam, piperacillin, rifampin, meropenem, ceftazidime, aztreonam, tobramycin, fosfomycin, azithromycin, vancomycin, gallium, and colistin), anti-infectives, anti-inflammatory agents, CFTR modulators other than the compounds of the invention, and nutritional agents. Additional therapeutic agents can include treatment of cystic fibrosis comorbid conditions, such as exocrine pancreatic insufficiency, which can be treated with pancrelipase or lipotamase.

[0185] Examples of CFTR potentiators include, but are not limited to, ivacaftor (VX-770), CTP-656, NVS-QBW251, PTI-808, ABBV-3067, ABBV-974, ABBV-191, FDL176, FD1860293, GLPG2451, GLPG1837, and N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide. Examples of potentiators are also disclosed in the following publications: WO2005 / 120497, WO2008 / 147952, WO2009 / 076593, WO2010 / 048573, WO2006 / 002421, WO2008 / 147952, WO2011 / 072241, WO2011 / 113894, WO20 13 / 038373, WO2013 / 038378, WO2013 / 038381, WO2013 / 038386, WO2013 / 038390, WO2014 / 180562, WO2015 / 018823, and U.S. patent application Ser. Nos. 14 / 271,080, 14 / 451,619, and 15 / 164,317.

[0186] Non-limiting examples of correctors include lumacaftor (VX-809), 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl}cyclopropanecarboxamide (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 collectors are also disclosed in US2016 / 0095858A1, US2019 / 0248809A1, and US application Ser. Nos. 14 / 925,649 and 14 / 926,727.

[0187] In certain embodiments, the additional therapeutic agent is a CFTR amplifier. CFTR amplifiers enhance the effects of known CFTR modulators, such as potentiators and correctors. Examples of CFTR amplifiers include PTI130 and PTI-428. Examples of amplifiers are also disclosed in the following publications: WO2015 / 138909 and WO2015 / 138934.

[0188] In certain embodiments, the additional therapeutic agent is a drug that reduces the activity of epithelial sodium channel blockers (ENaC) directly by blocking the channel or indirectly by regulating proteases (e.g., serine proteases, channel-activating proteases) that increase ENaC activity. Examples of such drugs include camostat (trypsin-like protease inhibitor), QAU145, 552-02, ETD001, GS-9411, INO-4995, Aerolytic, amiloride, AZD5634, and VX-371. Additional drugs that reduce the activity of epithelial sodium channel blockers (ENaC) can be found, for example, in PCT Publication Nos. WO 2009 / 074575 and WO 2013 / 043720, and U.S. Patent No. 8,999,976.

[0189] In one embodiment, the ENaC inhibitor is VX-371. In one embodiment, the ENaC inhibitor is SPX-101 (S18).

[0190] In certain embodiments, the additional therapeutic agent is an agent that modulates the activity of the non-CFTR Cl- channel TMEM16A. Non-limiting examples of such agents include TMEM16A activators, denufosol, melittin, cinnamaldehyde, 3,4,5-trimethoxy-N-(2-methoxyethyl)-N-(4-phenyl-2-thiazolyl)benzamide, INO-4995, CLCA1, ETX001, ETD002, and phosphatidylinositol diC8-PIP2, and TMEM16A inhibitors, 10bm, arctigenin, dehydroandrographolide, Ani9, niclosamide, and benzbromarone.

[0191] In certain embodiments, combining a compound of Formula (I) with a second therapeutic agent may have a synergistic effect in the treatment of cancer and other diseases or disorders mediated by adenosine. In other embodiments, the combination may have an additive effect.

[0192] Pharmaceutical Compositions The compositions and methods of the present invention can be used to treat subjects in need of treatment. In certain 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 as a pharmaceutical composition, e.g., comprising 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 vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In preferred embodiments, when such pharmaceutical compositions are intended for human administration, particularly for invasive routes of administration (i.e., routes such as injection or implantation that avoid transport or diffusion through epithelial barriers), the aqueous solutions are pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to provide delayed release of the drug or to selectively target one or more cells, tissues, or organs. Pharmaceutical compositions can be in unit dosage form, such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilized forms for reconstitution, powders, solutions, syrups, suppositories, infusions, etc. The composition may also be present in a transdermal delivery system, for example, a skin patch.The composition may also be present in a solution suitable for topical administration, such as eye drops.

[0193] Pharmaceutically acceptable carriers can contain physiologically acceptable agents that, for example, stabilize, increase the solubility, or enhance the absorption of a compound, such as a compound of the present invention. 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 containing a physiologically acceptable agent depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying or self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) can also be a liposome or other polymer matrix, into which, for example, a compound of the present invention can be incorporated. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers that are relatively easy to prepare and administer.

[0194] As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic response, or other problem or complication, and that are within the scope of sound medical judgment and commensurate with a reasonable benefit / risk ratio.

[0195] As used herein, the phrase "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the subject. Examples of materials that can function as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) celluloses and their derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; and (9) peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil. (10) glycols such as propylene glycol, (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol, (12) esters such as ethyl oleate and ethyl laurate, (13) agar, (14) buffers such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) phosphate buffer solution, and (21) other non-toxic, compatible substances used in pharmaceutical formulations.

[0196] Pharmaceutical compositions (preparations) can be administered to a subject by any of a number of routes of administration, including, for example, orally (e.g., as drenches such as aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, or pastes for application to the tongue), absorption through the oral mucosa (e.g., sublingually), anally, rectally, or vaginally (e.g., as pessaries, creams, or foams), parenterally (e.g., as sterile solutions or suspensions, including intramuscularly, intravenously, subcutaneously, or intrathecally), nasally, intraperitoneally, subcutaneously, transdermally (e.g., as a patch applied to the skin), and topically (e.g., as a cream, ointment, or spray applied to the skin, or as eye drops). The compounds may also be formulated for inhalation. In certain embodiments, the compounds may simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable therefor can be found, for example, in U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970, and 4,172,896, as well as patents cited therein.

[0197] The formulations can be conveniently provided in unit dosage form and can be prepared by any method well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the subject being treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of 100 percent, this amount will range from about 1 percent to about 99 percent of the active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent.

[0198] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the present invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0199] Formulations of the present invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), lyophiles, powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion, or an elixir or syrup, or pastille (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or mouthwash, each containing a predetermined amount of a compound of the present invention as an active ingredient. The compounds of the present invention may also be administered as a bolus, electuary, or paste.

[0200] To prepare solid dosage forms for oral administration (such as capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules, etc.), 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 carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; and (4) disintegrating agents. Ingredients that may be used include, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (5) solution retardants, for example, paraffin, (6) absorption accelerators, for example, quaternary ammonium compounds, (7) wetting agents, for example, cetyl alcohol and glycerol monostearate, (8) absorbents, for example, kaolin and bentonite clay, (9) lubricants, for example, 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. For capsules (including sprinkle capsules and gelatin capsules), tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using lactose or milk sugar, high molecular weight polyethylene glycols, and similar excipients.

[0201] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0202] Tablets and other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills, and granules, can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They can also be formulated to provide sustained or controlled release of the active ingredient therein, for example, using various proportions of hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres to provide the desired release profile. They can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or other injectable sterile medium immediately before use. These compositions can also optionally contain opacifying agents and can be compositions that release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0203] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophilized formulations for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to the active ingredient, the liquid dosage form may contain, for example, an inert diluent commonly used in the art, such as water or other solvents, cyclodextrin and its derivatives, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0204] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0205] Suspensions may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0206] Formulations of pharmaceutical compositions for rectal, vaginal, or urethral administration can be provided as suppositories, which can 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, a suppository wax, or a salicylate, which are solid at room temperature but liquid at body temperature and will melt in the rectal or vaginal cavity to release the active compound(s).

[0207] Formulations of the pharmaceutical composition for oral administration may be presented as a mouthwash, oral spray, or oral ointment.

[0208] Alternatively or additionally, the compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device, which may be particularly useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

[0209] Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0210] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers, or propellants which may be required.

[0211] The ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0212] Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.

[0213] Transdermal patches have the additional advantage of providing controlled delivery of the compound of the present invention to the body.Such dosage forms can be prepared by dissolving or dispersing the active compound in a suitable medium.Absorption enhancers can also be used to increase the flux of the compound across the skin.The rate of such flux can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0214] Ophthalmic formulations, eye ointments, powders, solutions, and the like are also contemplated within the scope of the present disclosure. Exemplary ophthalmic formulations are described in U.S. Patent Publication Nos. 2005 / 0080056, 2005 / 0059744, 2005 / 0031697, and 2005 / 004074, and U.S. Patent No. 6,583,124, the contents of which are incorporated herein by reference. If desired, the liquid ophthalmic formulation has properties similar to those of tears, aqueous humor, or vitreous humor, or is compatible with such fluids. A preferred route of administration is topical administration (e.g., topical administration such as eye drops, or administration via an implant).

[0215] As used herein, the phrases "parenteral administration" and "parenterally administered" refer to modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0216] Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0217] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersion, and by the use of surfactants.

[0218] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include isotonic agents, such as sugars and sodium chloride, in the composition. In addition, prolonged absorption of the injectable dosage form can be brought about by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0219] In some cases, in order to prolong the effect of a drug, it is desirable to delay the absorption of the drug from subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.The absorption rate of the drug can then depend on its dissolution rate, which in turn depends on the crystal size and crystalline form.Alternatively, the delayed absorption of the drug form of parenterally administered dosage form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0220] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the drug-to-polymer ratio and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0221] For use in the methods of the invention, the active compound can be provided per se or as a pharmaceutical composition containing 0.1 to 99.5% (more preferably, 0.5 to 90%) of the active ingredient in combination with, for example, a pharmaceutically acceptable carrier.

[0222] The method of introduction may be provided by a rechargeable or biodegradable device. A variety of sustained-release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form implants for the sustained release of compounds at specific target sites.

[0223] The actual dosage level of the active ingredient in the pharmaceutical composition can be varied to obtain an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0224] The selected dosage level will depend on a variety of factors, including the activity of the particular compound or combination of compounds, or esters, salts, or amides thereof, used, the route of administration, the time of administration, the rate of excretion of the particular compound(s) used, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular compound(s) used, the age, sex, weight, condition, general health, and previous medical history of the patient being treated, and similar factors well known in the medical arts.

[0225] A physician or veterinarian of ordinary skill in the art can easily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can start by administering a pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. A "therapeutically effective amount" refers to the concentration of a compound sufficient to elicit 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 that affect the effective amount may include, but are not limited to, the severity of the subject's condition, the disorder being treated, the stability of the compound, and, if desired, other types of therapeutic agents administered together with the compound of the present invention. A larger total dose can be delivered by multiple administrations of the drug. 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 ed., 1814-1882, incorporated herein by reference).

[0226] Generally, a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0227] If desired, the effective daily dose of active compound can be administered as 1, 2, 3, 4, 5, 6 or more sub-doses that are administered separately at appropriate intervals throughout the day, optionally in unit dosage form.In certain embodiments of the present invention, active compound can be administered 2 or 3 times a day.In preferred embodiments, active compound is administered once a day.

[0228] In certain embodiments, dosing follows a 3+3 design. The traditional 3+3 design does not require dose-toxicity curve modeling beyond the classical assumption of increasing toxicity with dose for cytotoxic drugs. This rule-based design proceeds with cohorts of three patients, with the first cohort treated at a starting dose deemed safe based on extrapolation from animal toxicology data, and subsequent cohorts treated at pre-fixed escalating dose levels. In some embodiments, three doses of the compound of Formula (I) are administered orally in the range of about 100 mg to about 1000 mg, e.g., about 200 mg to about 800 mg, e.g., about 400 mg to about 700 mg, e.g., about 100 mg to about 400 mg, e.g., about 500 mg to about 1000 mg, and further e.g., about 500 mg to about 600 mg. Administration is three times daily when taken without food and twice daily when taken with food. In certain embodiments, three doses of the compound of Formula (I) range from about 400 mg to about 800 mg, e.g., from about 400 mg to about 700 mg, e.g., from about 500 mg to about 800 mg, or further, for example, from about 500 mg to about 600 mg twice daily. In certain preferred embodiments, doses greater than about 600 mg are administered twice daily.

[0229] If none of the three patients in a cohort experience dose-limiting toxicity, the other three patients are treated at the next higher dose level. However, if one of the first three patients experiences dose-limiting toxicity, three more patients are treated at the same dose level. Dose escalation continues until at least two patients in a cohort of three to six patients experience dose-limiting toxicity (i.e., approximately 33% or more of patients at that dose level have dose-limiting toxicity). The recommended dose for Phase II trials is traditionally defined as the dose level immediately below this toxic dose level.

[0230] In certain embodiments, the dosing schedule is about 40 mg / m 2 ~about 100mg / m 2 , for example, about 50 mg / m 2 ~about 80mg / m 2 , and further about 70 mg / m2 ~about 90mg / m 2 and so on, 3 weeks out of a 4 week cycle, by IV.

[0231] In certain embodiments, the compounds of the present invention can be administered alone or in combination with another type of therapeutic agent.As used herein, the term "conjoint administration" refers to any form of administration of two or more different therapeutic compounds, such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (for example, the two compounds are effective in the subject at the same time, and the synergistic effect of the two compounds may be included).For example, different therapeutic compounds can be administered simultaneously or sequentially, either in the same formulation or in separate formulations.In certain embodiments, different therapeutic compounds can be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or 1 week of each other.Therefore, subjects receiving such treatment can benefit from the combined effect of different therapeutic compounds.

[0232] In certain embodiments, the combined administration of a compound of the invention with one or more additional therapeutic agent(s) (e.g., one or more additional chemotherapeutic agent(s)) provides improved efficacy compared to the separate administration of either the compound of the invention (e.g., a compound of Formula I or Ia) or the one or more additional therapeutic agent(s). In certain such embodiments, the combined administration provides an additive effect, where additive effect refers to the sum of the effects of the separate administration of the compound of the invention with the one or more additional therapeutic agent(s).

[0233] The present invention includes the use of pharmaceutically acceptable salts of the compounds of the present invention in the compositions and methods of the present invention. Salts of the compounds of the present invention are formed between an acid and a basic group of the compound (such as an amino functional group), or a base and an acidic group of the compound (such as a carboxyl functional group). In another embodiment, the compound is a pharmaceutically acceptable acid addition salt.

[0234] A "pharmaceutically acceptable salt" means any non-toxic salt that is capable of providing, directly or indirectly, a compound of the present invention upon administration to a recipient. A "pharmaceutically acceptable counterion" is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.

[0235] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid, and phosphoric acid, and organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. Thus, such pharmaceutically acceptable salts include sulfate, pyrosulfate, hydrogen sulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dicarboxylate, hexyne-1,6-dicarboxylate, and the like. Included are carboxylates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include salts formed with mineral acids such as hydrochloric acid and hydrobromic acid, and particularly salts formed with organic acids such as fumaric acid and maleic acid.

[0236] In certain embodiments, contemplated salts of the present invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetra-alkylammonium salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts.

[0237] Pharmaceutically acceptable acid addition salts may also exist as various solvates, for example with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates may also be prepared. The source of such solvates may be from the solvent of crystallization, may be inherent in the solvent of preparation or crystallization, or may be adventitious to such solvent.

[0238] Wetting agents, emulsifying agents, and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the compositions.

[0239] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium disulfate, sodium metabisulfite, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and (3) metal chelators such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0240] While specific embodiments of the present disclosure will be described with reference to preparations and schemes, it should be understood that such embodiments are merely illustrative and illustrate only a few of the many possible specific embodiments that can represent applications of the principles of the present disclosure. Various changes and modifications will be apparent to those skilled in the art upon consideration of the benefit of this disclosure and are deemed to be within the spirit and scope of the present disclosure as further defined in the appended claims.

[0241] 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 belongs. Although other compounds or methods may be used in practice or testing, certain preferred methods are described in the context of the following preparations and schemes.

[0242] Several synthetic protocols were used to generate the compounds described herein. These synthetic protocols (see schemes below) have common intersections and can be alternatively used to synthesize the compounds described herein. [Example]

[0243] General Scheme Compounds of formula (I) and intermediates may be prepared by the general procedures shown in Schemes 1-9. Scheme 1. Scheme 1 illustrates the synthesis of intermediate A, an aryl methyl ketone. Any commercially available starting material that can be converted to an aryl methyl ketone is applicable in this case using conventional chemical reactions well known in the art. For example, acid 1 can be converted to Weinreb amide (3) by coupling the acid with methoxy(methyl)amine (2) (Step 1a). A methyl anion source, such as a Grignard reagent or methyllithium, can then be added to the Weinreb amide (Step 2a) to form the desired aryl methyl ketone, intermediate A. Alternatively, an aryl halide derivative (4) can be Stille coupled (Step 1b) to form aryl methyl ketone intermediate A. Alternatively, an aldehyde can be converted to alcohol (7) by reaction with a Grignard reagent or methyllithium (Step 1c), followed by oxidation (Step 2b).

[0244] Scheme 2. In Scheme 2, aryl methyl ketones (intermediate A) can be converted to aryl bromomethyl ketones (8) by treating intermediate A with a brominating agent such as pyridinium tribromide (Step 1d). Condensation of 8 with thiourea in a polar solvent such as ethanol at room temperature or elevated temperature provides arylaminothiazoles 9 (Step 2d). A halogen (X = bromine or iodine) substituent can be introduced at the 5-position of the arylaminothiazole by treating 9 with a suitable halogenating agent such as NBS or NIS (Step 3d) to provide intermediate B.

[0245] Scheme 3. TIFF2025160375000313.tif69128 Scheme 3 illustrates the preparation of arylaminothiazoles (intermediate C). Aryl methyl ketones (intermediate A) are coupled with aryl bromides (10) using a catalyst such as X-phos-Pd at elevated temperatures to give ketones 11 (Step 1e). Aryl bromides 10 can be obtained by suitable reactions, such as alkylation of substituted phenols with alkyl halides or alkyl triflates (see "Preparation of Intermediates" for illustrative examples). Condensation of 11 with thiourea (Step 2e) gives intermediate C.

[0246] Scheme 4. In Scheme 4, aryl bromide 10 is converted to an aryl boronic acid or pinacol boronic ester (intermediate D1 or D2) by conventional chemical reactions well known in the art (step 1f). Both D1 and D2 can be used interchangeably in the synthesis of intermediate C.

[0247] Scheme 5. TIFF2025160375000315.tif28128 Scheme 5 shows an alternative method for preparing intermediate C by coupling intermediate B with a boronic acid or pinacol boronic ester (D1 or D2) (step 1g).

[0248] Scheme 6. TIFF2025160375000316.tif23128 In Scheme 6, the amino group in intermediate C is converted to a bromine substituent in intermediate G by a CuBr2-catalyzed reaction at elevated temperature (Step 1h).

[0249] Scheme 7. TIFF2025160375000317.tif29140 Scheme 7 shows the substituent Cy 1This figure shows the preparation of intermediate G, in which the aryl group contains a nitrogen-linked group. In step 1i, the amino group in the thiazole (intermediate B) can be removed via a tert-butyl nitrite-mediated reaction to avoid complications in the next step, the halogen substitution reaction at the 5-position. After replacing the halogen at the 5-position with an amino group (step 2i), the halogen at the 2-position can be reintroduced by a simple bromination or iodination reaction (step 3i) to give intermediate G.

[0250] Scheme 8. Synthesis of compounds of formula (I), method 1. TIFF2025160375000318.tif22128 Scheme 8 illustrates method 1 for the synthesis of compounds of formula (I) by the direct sulfonamide-forming reaction of aminothiazole (intermediate C) with arylsulfonyl chlorides (Step 1j).

[0251] Scheme 9. Synthesis of compounds of formula (I), method 2. TIFF2025160375000319.tif22128 Scheme 9 illustrates Method 2 for the synthesis of compounds of Formula (I) via the Buchwald coupling reaction (Step 1k) of a bromide derivative (Intermediate G) with a sulfonamide (Intermediate R). For the synthesis of sulfonamides (Intermediate R) that are not commercially available, see the section entitled "Preparation of Intermediates."

[0252] Analysis procedure 1 H NMR spectra were performed at 400 MHz on a Gemini 400 or Varian Mercury 400 mass spectrometer equipped with an ASW 5 mm probe and were typically recorded at ambient temperature in deuterated solvents such as DO, DMSO-D, or CDCl unless otherwise noted. Chemical shift values ​​(δ) are given in parts per million (ppm) with reference to tetramethylsilane (TMS) as the internal standard.

[0253] High pressure liquid chromatography-mass spectrometry (LCMS) experiments to determine retention times (RT) and associated mass ions were performed using one of the following methods.

[0254] Mass spectra (MS) were recorded using a Micromass mass spectrometer. Typically, the method used was positive electrospray ionization, with a mass m / z scan from 100 to 1000. Liquid chromatography was performed on a Hewlett Packard 1100 Series Binary Pump & Degasser. The auxiliary detectors used were: a Hewlett Packard 1100 Series UV detector, wavelength = 220 nm, and a Sedere SEDEX 75 evaporative light scattering (ELS) detector, temperature = 46 °C, N2 pressure = 4 bar. LCT: Gradient (AcN + 0.05% TFA): (H2O + 0.05% TFA) = 5:95 (0 min) → 95:5 (2.5 min) → 95:5 (3 min). Column: YMC Jsphere 33 x 2 4 μM, 1 ml / min. MUX: Column: YMC Jsphere 33 x 2, 1 ml / min Gradient (AcN + 0.05% TFA): (HO + 0.05% TFA) = 5:95 (0 min) → 95:5 (3.4 min) → 95:5 (4.4 min). LCT2:YMC Jsphere 33×2 4μM, (AcN+0.05%TFA):(H2O+0.05%TFA)=5:95 (0 minutes) → 95:5 (3.4 minutes) → 95:5 (4.4 minutes). QU:YMC Jsphere 33 × 2 1 ml / min, (AcN + 0.08% formic acid):(H2O + 0.1% formic acid) = 5:95 (0 min) → 95:5 (2.5 min) → 95:5 (3.0 min).

[0255] Preparation of intermediates This section, "Preparation of Intermediates," presents the synthesis of common intermediates used in the preparation of the examples. It is not intended to list all intermediates. Rather, the procedures presented herein are for illustrative purposes only. No limitations or restrictions should be imposed on the methods used to synthesize the examples.

[0256] Intermediate A-1 1-(2-isopropylphenyl)ethan-1-one TIFF2025160375000320.tif17128

[0257] Step 1. TIFF2025160375000321.tif18128

[0258] To a solution of 2-isopropylbenzoic acid (1.39 g, 8.45 mmol) in DMF (13 mL) was added 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) at room temperature. The resulting mixture was stirred at the same temperature for 3 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 2). The extract was washed with water (100 mL x 2), dried over sodium sulfate, and evaporated. The crude product thus obtained was purified by silica gel chromatography (PE / EA = 5 / 1) to give 2-isopropyl-N-methoxy-N-methylbenzamide (1.50 g, 85.5%) as a colorless oil. LCMS: MS(ESI): m / z 208 [M+H] + .

[0259] Step 2. TIFF2025160375000322.tif20128

[0260] To a solution of 2-isopropyl-N-methoxy-N-methylbenzamide (1.75 g, 8.44 mmol) in THF (17 mL) was added MeMgBr (8.5 mL, 25.5 mmol, 3.0 M) under N at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The mixture was poured into water (50 mL) and extracted with ethyl acetate (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 give 1-(2-isopropylphenyl)ethan-1-one (1.25 g, 91.3%) as a colorless oil. LCMS: MS(ESI): m / z 163 [M+H]+ .

[0261] Intermediate A-2 1-(2-isopropoxy-6-methylphenyl)ethan-1-one TIFF2025160375000323.tif23128

[0262] Step 1. TIFF2025160375000324.tif23128

[0263] 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 showed that 2-hydroxy-6-methyl-benzoic acid remained, so additional 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 for an additional 4 hours at 50° C. After cooling to room temperature, water (250 mL) was added and extracted with ethyl acetate (80 mL×3). The combined organic layers were washed with brine (100 mL × 3), dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (8% ethyl acetate in petroleum ether) to give the product isopropyl 2-isopropoxy-6-methylbenzoate as a colorless oil (7.648 g, 99% yield). LCMS: Retention time 2.24 minutes. MS(ESI)m / z 237[M+H] + .

[0264] Step 2. TIFF2025160375000325.tif23128

[0265] 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, and the resulting mixture was stirred overnight at 100° C. Diluted with water (30 mL), the mixture was acidified to pH=2 with 6 N HCl at 0° C., then extracted with ethyl acetate (80 mL×3), washed with brine (80 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product 2-isopropoxy-6-methylbenzoic acid as a pale yellow oil (5.28 g). 1 H NMR (400 MHz, chloroform-d) δ 7.30 (t, J = 8.0 Hz, 1 H), 6.90 (d, J = 7.6 Hz, 1 H), 6.86 (d, J = 8.0 Hz, 1 H), 4.69 (m, 1 H), 2.54 (s, 3 H), 1.41 (d, J = 6.0 Hz, 6 H) ppm. LCMS: Retention time 1.84 minutes. MS(ESI)m / z 177[M-OH] + .

[0266] Step 3. TIFF2025160375000326.tif23128

[0267] Borane-methyl 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) at 0° C. under an argon atmosphere. The resulting mixture was stirred at 60° C. for 3 hours. 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 give the crude product (2-isopropoxy-6-methylphenyl)methanol as a yellow oil (4.21 g), which was used directly in the next step without further purification. LCMS: LC retention time 1.95 minutes. MS(ESI)m / z 163[M-OH] + .

[0268] Step 4. TIFF2025160375000327.tif23128

[0269] To a stirred solution of (2-isopropoxy-6-methylphenyl)methanol (4.21 g, 23.4 mmol) in dichloromethane (50 mL) was added activated manganese dioxide (40.7 g, 468 mmol). The resulting mixture was stirred at 50° C. for 3 hours. Additional activated manganese dioxide (40.7 g, 468 mmol) and dichloromethane (10 mL) were added. The resulting mixture was stirred at 50° C. for 18 hours. The manganese dioxide was filtered through Celite, washed with ethyl acetate, and the filtrate was evaporated under reduced pressure to give the crude product, 2-isopropoxy-6-methylbenzaldehyde, as a yellow oil (3.6 g). LCMS: LC retention time 2.15 minutes. MS(ESI)m / z 179[M+H] + .

[0270] Step 5. TIFF2025160375000328.tif23128

[0271] To a solution of 2-isopropoxy-6-methylbenzaldehyde (3.60 g, 20.2 mmol) in tetrahydrofuran (30.0 mL) was added methylmagnesium bromide (20.2 mL, 3.0 M solution in diethyl ether, 60.6 mmol) under an argon atmosphere at 0° C. The resulting mixture was stirred at room temperature for 3 hours. It was quenched with saturated aqueous ammonium chloride solution (30 mL), diluted with water (120 mL), extracted with ethyl acetate (60 mL × 3), and the combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, 1-(2-isopropoxy-6-methylphenyl)ethan-1-ol, as a pale yellow oil (3.82 g). LCMS: LC retention time 2.07 minutes. MS(ESI)m / z 177[M-OH]+ .

[0272] Step 6. TIFF2025160375000329.tif23128

[0273] Activated manganese dioxide (44 g, 506 mmol) was added to a solution of 1-(2-isopropoxy-6-methylphenyl)ethan-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 additional activated 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 Celite, washed with ethyl acetate, and the solvent was evaporated under reduced pressure to give the crude product, which was purified by silica gel chromatography (5% ethyl acetate in petroleum ether) to give 1-(2-isopropoxy-6-methylphenyl)ethan-1-one as a pale yellow oil (3.14 g, 62% yield over four steps). LCMS: LC retention time 2.12 minutes. MS(ESI)m / z 193[M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.17 (t, J = 8.0 Hz, 1 H), 6.73-6.77 (m, 2 H), 4.56 (m, 1 H), 2.49 (s, 3 H), 2.22 (s, 3 H), 1.32 (d, J = 6.0 Hz, 6 H) ppm.

[0274] Intermediate A-3 1-(2-Isopropoxy-4-(trifluoromethyl)phenyl)ethan-1-one TIFF2025160375000330.tif22128

[0275] Step 1. TIFF2025160375000331.tif17128

[0276] To a solution of 2-hydroxy-4-(trifluoromethyl)benzoic acid (2.50 g, 12.1 mmol) in THF (30 mL) was added N,O-dimethylhydroxylamine (1.18 g, 12.1 mmol), HATU (4.61 g, 12.1 mmol), and DIPEA (7.82 g, 60.6 mmol). The mixture was stirred at room temperature for 2 h. It was then diluted with EtOAc (50 mL) and HO (50 mL). The two layers were separated, and the aqueous solution was extracted with EtOAc (10 mL × 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by SGC (PE / EA = 5 / 1) to give the desired compound, 2-hydroxy-N-methoxy-N-methyl-4-(trifluoromethyl)benzamide, as a colorless oil (2.40 g, 79.4%). LC retention time 1.77 minutes. MS(ESI)m / z 250[M+H] + .

[0277] Step 2. TIFF2025160375000332.tif23128

[0278] To a solution of 2-hydroxy-N-methoxy-N-methyl-4-(trifluoromethyl)benzamide (3.80 g, 15.2 mmol) in THF (50 mL) were added 2-iodopropane (2.59 g, 15.2 mmol) and KCO (4.21 g, 30.5 mmol). The mixture was stirred at 40 °C overnight. It was then extracted twice with EA (50 mL) and HO (50 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel chromatography (PE / EA = 20 / 1) to give 2-isopropoxy-N-methoxy-N-methyl-4-(trifluoromethyl)benzamide (3.60 g, 81%) as a pale yellow oil. LC retention time 2.03 minutes. MS(ESI)m / z 292[M+H] + .

[0279] Step 3. TIFF2025160375000333.tif23128

[0280] To a solution of 2-isopropoxy-N-methoxy-N-methyl-4-(trifluoromethyl)benzamide (2.00 g, 6.87 mmol) in THF (20 mL) was added MeMgBr (3.42 mL, 10.3 mmol). The mixture was stirred at room temperature for 2 hours. It was then quenched with aqueous NH4Cl (50 mL) and extracted with EA (50 mL x 2). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel column chromatography (PE / EA = 20 / 1) to give the title intermediate (1.20 g, 71%) as a pale yellow oil. LCMS: LC retention time 2.22 minutes. MS(ESI)m / z 247[M+H] + .

[0281] Intermediate A-4 1-(2-cyclopropylphenyl)ethan-1-one TIFF2025160375000334.tif20128

[0282] Step 1. TIFF2025160375000335.tif20128

[0283] Under a nitrogen atmosphere, palladium acetate (113 mg, 0.5 mmol) was added to a solution of 1-(2-bromophenyl)ethan-1-one (2.00 g, 10.0 mmol), cyclopropylboronic acid (1.12 g, 13.0 mmol), KPO (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, stirred at the same temperature for 3 h, and then cooled to room temperature. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phase was washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (PE / EA=10 / 1) to give the title intermediate (1.40 g, yield 87.0%) as a yellow oil. LCMS: LC retention time 2.02 minutes. MS(ESI)m / z 161[M+H] + .

[0284] Intermediate A-5 1-(2-methyl-6-(trifluoromethyl)phenyl)ethan-1-one TIFF2025160375000336.tif18128

[0285] Step 1. TIFF2025160375000337.tif19128

[0286] A mixture of 2-bromo-1-methyl-3-(trifluoromethyl)benzene (2.00 g, 8.37 mmol), tributyl(1-ethoxyvinyl)stannane (4.30 g, 11.9 mmol), and Pd(PPh3)4 (194 mg, cat.) in toluene (50 mL) was stirred at 120 °C for 16 h under a N2 atmosphere. The mixture was concentrated, and the residue was purified by SGC (PE / EA = 10 / 1) to give the intermediate as a light oil. It was then treated with THF (40 mL) and 6 N aqueous HCl (80 mL), and the mixture was stirred at room temperature for 6 h. The mixture was extracted with EA (50 mL × 3). The organic layers were combined, washed with brine (50 mL x 2), dried over Na2SO4, and concentrated to give 1-(2-methyl-6-(trifluoromethyl)phenyl)ethan-1-one as a yellow oil (1.50 g, 88.7%).

[0287] Intermediate A-6 1-(2-(difluoromethyl)-6-methylphenyl)ethan-1-one TIFF2025160375000338.tif18128

[0288] Step 1. TIFF2025160375000339.tif19128

[0289] To a solution of methyl 2-bromo-3-methylbenzoate (7.50 g, 32.7 mmol) in THF (53.6 mL) was added LiAlH (1.87 g, 49.1 mmol) at 0 °C. The mixture was stirred at room temperature for 3 h. Then, HO / 15% NaOH / HO (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 in vacuo. The mixture was purified by reverse-phase column chromatography to give the title product (2-bromo-3-methylphenyl)methanol (6.00 g, 91.1%). LCMS (acid): LC retention time 2.01 minutes. MS(ESI)m / z 200[M+H] + .

[0290] Step 2. TIFF2025160375000340.tif19128

[0291] To a solution of (2-bromo-3-methyl-phenyl)methanol (6.00 g, 0.0298 mol) in CHCl (60.0 mL) was added Dess-Martin periodinane (12.7 g, 29.8 mol) at 0 °C. The mixture was stirred at room temperature for 3 h. It was then washed with ammonia 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 in vacuo. The residue was purified by reverse-phase column chromatography to give the title product, 2-bromo-3-methylbenzaldehyde (5.60 g, 94.2%). LCMS (acid): LC retention time 2.09 minutes. MS(ESI)m / z 199[M+H] + .

[0292] Step 3. TIFF2025160375000341.tif19128

[0293] To a solution of 2-bromo-3-methyl-benzaldehyde (5.60 g, 28.1 mmol) in CHCl (30.0 mL) was added DAST (6.79 g, 42.2 mmol) at 0° C. The mixture was stirred at room temperature for 3 hours. The DCM solution was then washed with ammonia 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 in vacuo. The residue was purified by SGC (PE) to give the title product 2-bromo-1-(difluoromethyl)-3-methylbenzene (4.00 g, 64.3%). LCMS (acid): LC retention time 2.09 minutes. MS(ESI)m / z 221[M+H] + .

[0294] Step 4. TIFF2025160375000342.tif22128

[0295] To a solution of 2-bromo-1-(difluoromethyl)-3-methyl-benzene (4.00 g, 18.1 mmol) in toluene (20.0 mL) were added Pd(PPh3)4 (1.05 g, 0.905 mmol) and tributyl(1-ethoxyvinyl)stannane (7.84 g, 21.7 mmol). The mixture was stirred at room temperature for 3 hours. Aqueous potassium fluoride solution was then added. The mixture was stirred at room temperature for 3 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. HCl in THF (12 N) was added to the mixture and stirred for 3 hours. The mixture was then diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The mixture was purified by SGC (PE) to give the title product 1-(2-(difluoromethyl)-6-methylphenyl)ethan-1-one (3.00 g). LCMS (acid): LC retention time 1.97 minutes. MS(ESI)m / z 184[M+H] + .

[0296] Intermediate A-7 1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)ethan-1-one TIFF2025160375000343.tif24128

[0297] Step 1. TIFF2025160375000344.tif22128

[0298] To a solution of 2-bromo-4-(trifluoromethyl)aniline (9.0 g, 37.5 mmol) in 1,4-dioxane (100 mL) and HO (50 mL) was added methylboronic acid (3.37 g, 56.2 mmol), Pd(dppf)Cl·DCM (613 mg, 0.750 mmol), and CsCO (18.3 g, 56.2 mmol). 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 in vacuo to give 2-methyl-4-(trifluoromethyl)aniline (5.20 g, 63.3%) as a yellow oil. LCMS: LC retention time 1.92 minutes. MS(ESI)m / z 176[M+H] + .

[0299] Step 2. TIFF2025160375000345.tif23128

[0300] To a solution of 2-methyl-4-(trifluoromethyl)aniline (5.20 g, 23.8 mmol) in CHCN (100 mL) was added NBS (6.27 g, 35.6 mmol). The mixture was stirred at room temperature for 16 hours. Water (100 mL) was added to the mixture, which was then extracted with ethyl acetate (100 mL × 2). The organic layer was washed with brine (100 mL), dried over sodium sulfate, and concentrated in vacuo to give 2-bromo-6-methyl-4-(trifluoromethyl)aniline (5.10 g, 71.8% yield) as a yellow oil. LCMS: LC retention time 2.19 minutes. MS(ESI)m / z 256[M+H] + .

[0301] Step 3. TIFF2025160375000346.tif23128

[0302] To a solution of 2-bromo-6-methyl-4-(trifluoromethyl)aniline (5.1 g, 20.1 mmol) in 1,4-dioxane (100 mL) and HO (50 mL) was added methylboronic acid (1.81 g, 30.1 mmol), Pd(dppf)Cl·DCM (328 mg, 0.402 mmol), and CsCO (9.82 g, 30.1 mmol). The mixture was stirred at 100 °C for 16 h. Water (200 mL) was added to the mixture, which was then extracted with ethyl acetate (200 mL × 2). The organic layer was washed with brine (200 mL), dried over sodium sulfate, and concentrated in vacuo to give 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. LCMS: LC retention time 2.01 minutes. MS(ESI)m / z 190[M+H] + .

[0303] Step 4. TIFF2025160375000347.tif24128

[0304] 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 to 0 °C. Aqueous sodium nitrite (3.94 g, 57.1 mmol) solution was added dropwise. The mixture was stirred at the current temperature for 20 minutes. Aqueous KI (6.32 g, 38.1 mmol) solution was added dropwise. The mixture was stirred at room temperature for 3 hours. Water (100 mL) was added to the mixture, and it was extracted 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 give 2-iodo-1,3-dimethyl-5-(trifluoromethyl)benzene (3.00 g, 52.5% yield) as a yellow oil.

[0305] Step 5. TIFF2025160375000348.tif25128

[0306] To a solution of 2-iodo-1,3-dimethyl-5-(trifluoromethyl)benzene (3.0 g, 10.0 mmol) in toluene (80 mL) was added tributyl(1-ethoxyvinyl)stannane (5.42 g, 15.0 mmol) and Pd(PPh3)4 (119 mg, 0.1 mmol). The mixture was stirred at 100 °C under Ar for 16 h. The reaction was then cooled to room temperature, and concentrated HCl (20.0 mL) was added. The mixture was stirred at room temperature for 6 h and extracted with Et2O (100 mL). The organic layer was washed with water (100 mL), brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE) to give the title compound (1.70 g, 77.9%) as a colorless oil. 1 H NMR (400 MHz, chloroform-d)): δ 7.29 (s, 2H), 2.49 (s, 3H), 2.30 (s, 6H) ppm.

[0307] Intermediate A-8 1-(2-chloro-6-(trifluoromethyl)phenyl)ethan-1-one TIFF2025160375000349.tif17128

[0308] Step 1. TIFF2025160375000350.tif17128

[0309] Borane-methyl 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) at 0°C under an argon atmosphere. The resulting mixture was stirred at 60°C for 27 hours. LCMS showed that reactants remained. Then, borane-methyl sulfide complex (33.5 mL, 66.9 mmol, 2.0 M) was added dropwise at 0°C. The resulting mixture was reacted at 60°C for 65 hours. 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 x 3). The combined organic layers were washed with brine (100 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the product (2-chloro-6-(trifluoromethyl)phenyl)methanol as a brown solid (6.23 g). LCMS: LC retention time 1.89 minutes. MS(ESI)m / z 193[M-17] + .

[0310] Step 2. TIFF2025160375000351.tif17128

[0311] Dess-Martin periodinane (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) at room temperature. The resulting reaction mixture was stirred at room temperature for 19 h. 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 Celite, washed with diethyl ether, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (6% ethyl acetate in petroleum ether) to give 2-chloro-6-(trifluoromethyl)benzaldehyde as a pale yellow oil (3.47 g, 75% yield, two steps). LCMS: LC retention time 1.95 min. MS (ESI) m / z not observed. 1H NMR (400 MHz, chloroform-d) δ 10.50 (s, 1 H), 7.72–7.66 (m, 2 H), 7.58 (t, J = 8.0 Hz, 1 H) ppm.

[0312] Step 3. TIFF2025160375000352.tif17128

[0313] MeMgBr (27.8 mL, 3.0 M solution in diethyl ether, 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 at room temperature overnight. It was quenched with saturated aqueous ammonium chloride solution (40 mL), diluted with water (30 mL), and 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 give the desired product, 1-(2-chloro-6-(trifluoromethyl)phenyl)ethan-1-ol, as a pale yellow oil (3.78 g). LCMS: LC retention time 2.08 minutes. MS(ESI)m / z 207[M-OH] + .

[0314] Step 4. TIFF2025160375000353.tif17128

[0315] Dess-Martin periodinane (14.2 g, 33.4 mmol) was added portionwise to a solution of 1-(2-chloro-6-(trifluoromethyl)phenyl)ethan-1-ol (3.78 g, crude, 16.7 mmol) in dichloromethane (40.0 mL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 3 h. 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 Celite and washed with diethyl ether. The filtrate was evaporated under reduced pressure. The crude product was purified by silica gel chromatography (10% ethyl acetate in petroleum ether) to give 1-(2-chloro-6-(trifluoromethyl)phenyl)ethan-1-one as a pale yellow oil (2.63 g, 71% yield, two steps). LCMS: LC retention time 2.15 minutes. MS(ESI)m / z 223[M+H] + .

[0316] Intermediate A-9 1-(2-isopropoxyphenyl)ethan-1-one TIFF2025160375000354.tif21128

[0317] Step 1. TIFF2025160375000355.tif21128

[0318] A mixture of 1-(2-hydroxyphenyl)ethan-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 at 80 °C for 16 h. The mixture was quenched with brine (300 mL), extracted with ethyl acetate (150 mL × 2), dried over anhydrous Na2SO4, then filtered and concentrated. The crude product was purified by silica gel chromatography (PE / EA = 10 / 1) to give the desired compound 1-(2-isopropoxyphenyl)ethan-1-one (4.41 g, 84.2%) as a pale yellow oil. 1H NMR (400 MHz, chloroform-d) δ 7.72 (dd, J = 7.9, 1.8 Hz, 1H), 7.42 (td, J = 8.1, 1.8 Hz, 1H), 6.95 (t, J = 7.6Hz, 2H), 4.69 (dt, J = 12.1, 6.1 Hz, 1H), 2.622 (s, 3H), 1.40 (d, J = 6.1 Hz, 1H) ppm.

[0319] Intermediate B-1 5-Iodo-4-(2-isopropylphenyl)thiazol-2-amine TIFF2025160375000356.tif24128

[0320] Step 1. TIFF2025160375000357.tif16128

[0321] To a solution of 1-(2-isopropylphenyl)ethan-1-one (835 mg, 5.15 mmol) in DCM (8.0 mL) was added pyridine hydrobromide perbromide (1.64 g, 5.15 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was poured into water (50 mL) and extracted with DCM (50 mL x 2). The extract was washed with water (40 mL x 2), dried over sodium sulfate, and evaporated. The resulting crude product was purified by silica gel chromatography (PE / EA = 10 / 1) to give 2-bromo-1-(2-isopropylphenyl)ethan-1-one (1167 mg, 93.9%) as a colorless oil. LCMS: MS(ESI): m / z 243 [M+H] + .

[0322] Step 2. TIFF2025160375000358.tif18128

[0323] To a solution of 2-bromo-1-(2-isopropylphenyl)ethan-1-one (1.17 g, 4.84 mmol) in ethanol (12 mL) was added thiourea (741 mg, 9.74 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was basified to pH = 12 with aqueous NaOH (2.0 M) and extracted with ethyl acetate (10 mL × 4). The combined organic phase was washed with aqueous NaSO (20 mL × 2), HO (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (PE / EA = 5 / 1) to give 4-(2-isopropylphenyl)thiazol-2-amine (1.00 g, 94.7%) as a pale yellow solid. LCMS: Retention time 2.24 minutes. MS(ESI):m / z 219[M+H] + .

[0324] Step 3. TIFF2025160375000359.tif24128

[0325] To a solution of 4-(2-isopropylphenyl)thiazol-2-amine (1250 mg, 5.73 mmol) in DCM (20 mL) was added NIS (1.48 mg, 6.61 mmol) and AIBN (150 mg, 0.914 mmol) at room temperature. The reaction mixture was then stirred at the same temperature for 3 h. The mixture was extracted with EA (200 mL × 2), washed with brine (200 mL), and dried over anhydrous NaSO. The filtrate was concentrated and purified by silica gel chromatography (PE / EA = 5 / 1) to give 5-iodo-4-(2-isopropylphenyl)thiazol-2-amine (1286 mg, 65.2%) as a yellow solid. LCMS:MS(ESI) m / z 345[M+H] +

[0326] Intermediate B-2a 5-Bromo-4-(2,6-dimethylphenyl)thiazol-2-amine TIFF2025160375000360.tif19128

[0327] Intermediate B-2b 4-(2,6-dimethylphenyl)-5-iodothiazol-2-amine TIFF2025160375000361.tif19128

[0328] Step 1. TIFF2025160375000362.tif17128

[0329] 1-(2,6-dimethylphenyl)ethan-1-one (5.00 g, 33.78 mmol) was dissolved in acetonitrile (60 mL). To this solution was added pyridinium tribromide (10.81 g, 33.78 mmol). The mixture was stirred at room temperature overnight 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 in vacuo to give 2-bromo-1-(2,6-dimethylphenyl)ethan-1-one (7.29 g, 82.1%) as a yellow oil. LCMS: LC retention time 2.06 minutes. MS(ESI)m / z 229[M+H] + .

[0330] Step 2. TIFF2025160375000363.tif19128

[0331] To a solution of 2-bromo-1-(2,6-dimethylphenyl)ethan-1-one (7.29 g, 32.11 mmol) in ethanol (75 mL) was added thiourea (2.44 g, 32.11 mmol), and the reaction mixture was refluxed for 2 h. After removing the solvent, the resulting white precipitate was suspended and washed with water / saturated aqueous NaHCO3 (30 / 70, 250 mL) for 1 h. The solution was extracted with ethyl acetate (200 mL × 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to give the crude product, which was purified by silica gel chromatography (PE / EA = 1 / 1) to give 4-(2,6-dimethylphenyl)thiazol-2-amine (5.30 g, 80.8%) as a yellow solid. LCMS: LC retention time 1.45 minutes. MS(ESI)m / z 205[M+H] + .

[0332] Step 3a. TIFF2025160375000364.tif19128

[0333] To a solution of 4-(2,6-dimethylphenyl)thiazol-2-amine (1.0 g, 4.90 mmol) in anhydrous tetrahydrofuran (20 mL) was added NBS (872.5 mg, 4.90 mmol). 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 NaSO, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (PE / EA = 3 / 1) to give 5-bromo-4-(2,6-dimethylphenyl)thiazol-2-amine (0.964 g, 69.5%) as a pale yellow solid. LCMS: LC retention time 1.92 minutes. MS(ESI)m / z 285[M+H] + .

[0334] Step 3b. TIFF2025160375000365.tif19128

[0335] To a solution of 4-(2,6-dimethylphenyl)thiazol-2-amine (500 mg, 2.45 mmol) in tetrahydrofuran (5.0 mL), N-iodosuccinimide (551 mg, 2.45 mmol) was added, and the resulting mixture was reacted at room temperature for 3 hours. The reaction was quenched by adding water (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated under vacuum (temperature controlled at about 40 °C), and purified by silica gel column chromatography (PE / EA = 5 / 1) to give the title compound 4-(2,6-dimethylphenyl)-5-iodothiazol-2-amine (600 mg, 74%) as a brown solid. LCMS: LC retention time 1.85 minutes. MS(ESI)m / z 331[M+H] + .

[0336] Intermediate B-3 4-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-5-iodothiazol-2-amine TIFF2025160375000366.tif20128

[0337] Step 1. TIFF2025160375000367.tif25128

[0338] To a solution of 1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)ethan-1-one (Intermediate A-7) (1.7 g, 6.29 mmol) in acetonitrile (60 mL) was added pyridinium tribromide (2.01 g, 6.29 mmol). The mixture was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was extracted with dichloromethane (50 mL × 2) and washed with water (100 mL). The organic layers were combined and concentrated in vacuo to give crude 2-bromo-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)ethan-1-one (1.90 g).

[0339] Step 2. TIFF2025160375000368.tif24128

[0340] To a solution of 2-bromo-1-(2,6-dimethyl-4-(trifluoromethyl)phenyl)ethan-1-one (1.90 g, 4.51 mmol) in ethanol (50.0 mL) was added thiourea (377 mg, 4.96 mmol), and the mixture was refluxed for 4 hours. After the solvent was removed under vacuum, the residue was stirred with saturated aqueous sodium bicarbonate solution (40 mL) for 20 minutes. The mixture was then extracted with ethyl acetate (50 mL × 2). The combined organic solution was 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 give the title compound, 4-(2,6-dimethyl-4-(trifluoromethyl)phenyl)thiazol-2-amine (1.10 g, 89.6% yield) as a colorless solid. LCMS: LC retention time 1.68 minutes. MS(ESI)m / z 273[M+H] + .

[0341] Step 3. TIFF2025160375000369.tif21128

[0342] To a solution of 4-(2,6-dimethyl-4-(trifluoromethyl)phenyl)thiazol-2-amine (1.30 g, 4.77 mmol) in CHCN (60 mL) was added NIS (1.07 g, 4.77 mmol). The mixture was stirred at room temperature for 16 h. Then, the solvent was removed on a rotavapor. Water (100 mL) was added to the residue and extracted with EA (100 mL). The organic layer was washed with brine (100 mL), dried over NaSO, filtered, and purified by silica gel column chromatography (PE / EA=3:1) to give 4-(2,6-dimethyl-4-(trifluoromethyl)phenyl)-5-iodothiazol-2-amine (1.30 g, 61.5%) as a yellow solid. LCMS: LC retention time 2.15 minutes. MS(ESI)m / z 399[M+H] + .

[0343] Intermediate B-4 5-Iodo-4-(2-methyl-6-(trifluoromethyl)phenyl)thiazol-2-amine TIFF2025160375000370.tif21128

[0344] Step 1. TIFF2025160375000371.tif23128

[0345] To a mixture of 1-[2-methyl-6-(trifluoromethyl)phenyl]ethanone (Intermediate A5) (1.50 g, 7.42 mmol) in CHCN (40 mL) was added pyridinium tribromide (2.37 g, 7.42 mmol) slowly at 0 °C. The resulting mixture was stirred at room temperature for 12 h, and the mixture was concentrated. The residue was diluted with brine (70 mL), extracted with EA (50 mL × 3), dried over NaSO, and concentrated to give 2-bromo-1-[2-methyl-6-(trifluoromethyl)phenyl]ethanone as a brown solid (1.80 g, 86.3%). LCMS: LC retention time 2.109 minutes. MS(ESI)m / z 281[M+H] + .

[0346] Step 2. TIFF2025160375000372.tif23128

[0347] A solution of 2-bromo-1-[2-methyl-6-(trifluoromethyl)phenyl]ethanone (1.8 g, 6.4 mmol), thiourea (487 mg, 6.4 mmol) in ethanol (30 mL) was stirred for 16 hours at 80° C. The mixture was concentrated, and the residue was purified by SGC (PE / EA=2 / 1) to give 4-[2-methyl-6-(trifluoromethyl)phenyl]thiazol-2-amine as a yellow solid (700 mg, 42.3%). LCMS: LC retention time 1.85 minutes. MS(ESI)m / z 259[M+H] + .

[0348] Step 3. TIFF2025160375000373.tif21128

[0349] To a solution of 4-[2-methyl-6-(trifluoromethyl)phenyl]thiazol-2-amine (700 mg, 2.71 mmol) in THF (20 mL) was added NIS (732 mg, 3.25 mmol) at room temperature. After the addition, the mixture was stirred for 12 hours. The mixture was dried by blowing N. The residue was diluted with brine (60 mL) and extracted with EA (40 mL × 3). The organic layers were combined, washed with brine (40 mL × 3), dried over NaSO, and concentrated to give 5-iodo-4-(2-methyl-6-(trifluoromethyl)phenyl)thiazol-2-amine as a brown solid (960 mg, 92.2%). LCMS: LC retention time 1.686 minutes. MS(ESI)m / z 385[M+H] + .

[0350] Intermediate B-5 5-Bromo-4-(2-(difluoromethyl)-6-methylphenyl)thiazol-2-amine TIFF2025160375000374.tif25128

[0351] Step 1. TIFF2025160375000375.tif22128

[0352] To a solution of 1-[2-(difluoromethyl)-6-methyl-phenyl]ethanone (Intermediate A-6) (3.00 g, 0.0163 mol) in CHCl (30.0 mL) was added pyridinium tribromide (3.19 g, 0.0179 mol). The mixture was stirred at room temperature for 1 hour. 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 in vacuo to give the title compound 2-bromo-1-(2-(difluoromethyl)-6-methylphenyl)ethan-1-one (3.70 g). LCMS (acid): LC retention time 2.03 minutes. MS(ESI) m / z 262[M+H]+ .

[0353] Step 2. TIFF2025160375000376.tif21128

[0354] To a solution of 2-bromo-1-(2-(difluoromethyl)-6-methylphenyl)ethan-1-one (3.70 g, 14.1 mmol) in EtOH (30.0 mL) was added thiourea (1.07 g, 14.1 mmol). The mixture was stirred at room temperature for 1 hour. 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 in vacuo. The crude product was purified by SGC (PE / EA = 3 / 1) to give the title product 4-(2-(difluoromethyl)-6-methylphenyl)thiazol-2-amine (2.70 g). LCMS (acid): LC retention time 1.60 minutes. MS(ESI)m / z 241[M+H] + .

[0355] Step 3. TIFF2025160375000377.tif22128

[0356] To a solution of 4-[2-(difluoromethyl)-6-methyl-phenyl]thiazol-2-amine (2.70 g, 0.0112 mol) in THF (30.0 mL) was added NBS (2.00 g, 11.2 mmol). The mixture was stirred at room temperature for 1 hour. 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 in vacuo. The crude product was purified by SGC (PE / EA = 3 / 1) to give the title product 5-bromo-4-(2-(difluoromethyl)-6-methylphenyl)thiazol-2-amine (2.20 g, 61.3%). LCMS (acid): LC retention time 2.04 minutes. MS(ESI)m / z 320[M+H] + .

[0357] Intermediate B-6 5-Iodo-4-(2-isopropoxy-6-methylphenyl)thiazol-2-amine TIFF2025160375000378.tif25128

[0358] Step 1. TIFF2025160375000379.tif24128

[0359] To a solution of 1-(2-isopropoxy-6-methylphenyl)ethan-1-one (3.14 mg, 16.3 mmol) in acetonitrile (30 mL) was added pyridinium tribromide (5.21 g, 16.3 mmol) at room temperature. The resulting mixture was stirred at room temperature for 17 hours. LCMS showed that 1-(2-isopropoxy-6-methylphenyl)ethanone remained, and additional pyridinium tribromide (1.56 g, 4.89 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for an additional 3 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (30 mL), diluted with water (50 mL), and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product 2-bromo-1-(2-isopropoxy-6-methylphenyl)ethan-1-one as a yellow oil (4.882 g). LCMS: LC retention time 2.20 minutes. MS(ESI)m / z 273[M+H] + .

[0360] Step 2. TIFF2025160375000380.tif26128

[0361] To a solution of 2-bromo-1-(2-isopropoxy-6-methylphenyl)ethan-1-one (4.88 g, crude, 16.4 mmol) in ethanol (25 mL) was added thiourea (1.87 g, 24.6 mmol). The resulting mixture was stirred at 80° C. for 3 hours. The solvent was removed under reduced pressure and diluted with water (30 mL) and saturated aqueous sodium bicarbonate solution (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, and the residue was purified by silica gel chromatography (35% ethyl acetate in petroleum ether) to give 4-(2-isopropoxy-6-methylphenyl)thiazol-2-amine as a white solid (3.21 g, 80% yield over two steps). LCMS: LC retention time 2.05 minutes. MS(ESI)m / z 387[M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.16 (t, J = 8.0 Hz, 1 H), 6.84 (d, J = 7.6 Hz, 1 H), 6.80 (d, J = 8.4 Hz, 1 H), 6.40 (s, 1 H), 4.96 (s, 2 H), 4.32 (m, 1 H), 2.21 (s, 3 H), 1.19 (d, J = 6.0 Hz, 6 H) ppm.

[0362] Step 3. TIFF2025160375000381.tif26128

[0363] To a solution of 4-(2-isopropoxy-6-methylphenyl)thiazol-2-amine (3.21 g, 12.9 mmol) in tetrahydrofuran (30 mL) was added 1-iodopyrrolidine-2,5-dione (2.9 g, 12.9 mmol) at 0° C. The resulting mixture was stirred at room temperature for 1.5 hours, and additional 1-iodopyrrolidine-2,5-dione (0.871 g, 3.87 mmol) was added at room temperature. The resulting reaction mixture was stirred at room temperature for an additional 40 minutes. The reaction was quenched with saturated aqueous sodium bicarbonate (30 mL), diluted with water (40 mL), extracted with ethyl acetate (3×30 mL), and the combined organic layers were washed with saturated aqueous sodium bicarbonate (60 mL), and brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the product, 5-iodo-4-(2-isopropoxy-6-methylphenyl)thiazol-2-amine, as a brown solid (5.54 g). LCMS: LC retention time 1.79 minutes. MS(ESI)m / z 375[M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.22 (t, J = 8.0 Hz, 1 H), 6.85 (d, J = 7.6 Hz, 1 H), 6.79 (d, J = 8.4 Hz, 1 H), 5.36 (br, 2 H), 4.38 (m, 1 H), 2.09 (s, 3 H), 1.22 (d, J = 5.2 Hz, 6 H) ppm.

[0364] Intermediate B-7 4-(2-chloro-6-(trifluoromethyl)phenyl)-5-iodothiazol-2-amine TIFF2025160375000382.tif21128

[0365] Step 1. TIFF2025160375000383.tif17128

[0366] To a solution of 1-(2-chloro-6-(trifluoromethyl)phenyl)ethan-1-one (2.625 g, 11.8 mmol) in acetonitrile (20.0 mL) was added pyridinium tribromide (4.53 g, 14.2 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The solvent was removed. Saturated aqueous sodium bicarbonate solution (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 give the product, 2-bromo-1-(2-chloro-6-(trifluoromethyl)phenyl)ethan-1-one, as a yellow oil (3.32 g). LCMS: LC retention time 2.17 minutes. MS(ESI)m / z 301[M+H] + .

[0367] Step 2. TIFF2025160375000384.tif21128

[0368] To a solution of 2-bromo-1-(2-chloro-6-(trifluoromethyl)phenyl)ethan-1-one (3.32 g, 11.0 mmol) in ethanol (24 mL) was added thiourea (1.26 g, 16.5 mmol). The reaction was stirred at 80° C. for 70 hours. The solvent was removed under reduced pressure and diluted with water (70 mL) and saturated aqueous sodium bicarbonate solution (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 in petroleum ether) to give 4-(2-chloro-6-(trifluoromethyl)phenyl)thiazol-2-amine as a brown solid (2.17 g, 67% yield over two steps). LCMS: LC retention time 1.81 minutes. MS(ESI)m / z 279[M+H] + . 1H NMR (400 MHz, chloroform-d) δ 7.65-7.63 (m, 2 H), 7.42 (m, 1 H), 6.49 (s, 1 H), 5.06 (s, 2 H) ppm.

[0369] Step 3. TIFF2025160375000385.tif20128

[0370] To a solution of 4-(2-chloro-6-(trifluoromethyl)phenyl)thiazol-2-amine (2.18 g, 7.81 mmol) in tetrahydrofuran (20 mL) was added 1-iodopyrrolidine-2,5-dione (2.11 g, 9.37 mmol) at 0° C. The resulting mixture was stirred at room temperature for 1 hour. 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 give a brown solid, which was suspended in petroleum ether (30 mL) and dichloromethane (0.5 mL) and stirred at room temperature for 30 minutes. After filtration, the product 4-(2-chloro-6-(trifluoromethyl)phenyl)-5-iodothiazol-2-amine was obtained as a brown solid (3.14 g). LCMS: LC retention time = 2.04 minutes. MS(ESI)m / z 405[M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.68 (m, 2 H), 7.48 (t, J = 8.0 Hz, 1 H), 5.22 (br, s, 2 H) ppm.

[0371] Intermediate B-8 5-Bromo-4-(2-isopropoxyphenyl)thiazol-2-amine TIFF2025160375000386.tif26128

[0372] Step 1. TIFF2025160375000387.tif22128

[0373] To a solution of 1-(2-isopropoxyphenyl)ethan-1-one (1.78 g, 10 mmol) in acetonitrile (50 mL) was added pyridinium tribromide (3.20 g, 10 mmol). The mixture was stirred at room temperature overnight until the solution turned pale yellow or colorless. The mixture was extracted with dichloromethane (100 mL x 3). The DCM solution was washed with water (80 mL). The organic layers were combined and concentrated in vacuo to give 2-bromo-1-(2-isopropoxyphenyl)ethan-1-one (2.41 g, 93.8%) as a yellow oil. LCMS: LC retention time 2.10 minutes. MS(ESI)m / z 257[M+H] + .

[0374] Step 2. TIFF2025160375000388.tif25128

[0375] To a solution of 2-bromo-1-(2-isopropoxyphenyl)ethan-1-one (2.41 g, 9.38 mmol) in ethanol (50 mL) was added thiourea (742 mg, 9.75 mmol), and the reaction mixture was refluxed for 2 hours. After removing the solvent, the resulting white precipitate was suspended and washed with saturated aqueous NaHCO3 (100 mL) for 1 hour. The solution was extracted with ethyl acetate (80 mL x 3). The organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated to give the desired compound, 4-(2-isopropoxyphenyl)thiazol-2-amine (2.20 g, 100% yield), as a yellow oil. LCMS: LC retention time 1.56 minutes. MS(ESI)m / z 235[M+H] + .

[0376] Step 3. TIFF2025160375000389.tif26128

[0377] To a solution of 4-(2-isopropoxyphenyl)thiazol-2-amine (2.20 g, 9.4 mmol) in anhydrous tetrahydrofuran (50 mL) was added NBS (1.67 g, 9.4 mmol). After stirring at room temperature overnight, 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 NaSO, and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (PE / EA = 3 / 1) to give the desired compound 5-bromo-4-(2-isopropoxyphenyl)thiazol-2-amine (1.70 g, 58%) as a reddish-brown oil. LCMS: LC retention time 1.85 minutes. MS(ESI)m / z 315[M+H] + .

[0378] Intermediate B-9 5-Iodo-4-(2-(trifluoromethyl)phenyl)thiazol-2-amine TIFF2025160375000390.tif20128 Intermediate B-9 was prepared in essentially the same manner as intermediate B-7.

[0379] Intermediate B-10 4-(2,2-dimethylcyclopentyl)thiazol-2-amine TIFF2025160375000391.tif22128

[0380] Step 1. TIFF2025160375000392.tif17128

[0381] To a stirred suspension of NaH (5.12 g, 134 mmol of a 60% mineral oil dispersion) in anhydrous toluene (180 mL), 2-methylcyclohexan-1-one (10.00 g, 89.2 mol) was added dropwise at 100 °C for 2 h. To this, CHCl (19.00 g, 134 mol) was added dropwise over 2 h at 60 °C. The mixture was stirred at 60 °C for an additional 2 h. After cooling, a mixture of NaOMe (10.60 g, 196 mmol) and HCOMe (11.2 g, 152 mmol) was added to the mixture at 5 °C. The reaction mixture was stirred at room temperature for 12 h and then poured into ice water (100 mL). The aqueous layer was acidified with 10% aqueous HCl and extracted with ether. The combined organic phase was washed with brine, dried over MgSO4 and concentrated to give (E)-6-(hydroxymethylene)-2,2-dimethylcyclohexan-1-one (9.00 g, 65%) as a brown oil. LCMS: LC retention time 2.09 minutes. MS(ESI)m / z 155[M+H] + .

[0382] Step 2. TIFF2025160375000393.tif17128

[0383] To a solution of (E)-6-(hydroxymethylene)-2,2-dimethylcyclohexan-1-one (7.50 g, 48.6 mmol) in 13 mL of t-BuOH, 30% HO (6.06 g, 53.5 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. The resulting solution was heated at 100 °C for 4 hours. The reaction mixture was cooled to room temperature. 80 mL of water was added to the solution, which was then extracted with ether. The organics were washed with 2 N NaOH solution (200 mL × 5). The extract was acidified with 4 N HCl, then extracted with EtO (150 mL × 2), dried over NaSO, filtered, and concentrated to give 2,2-dimethylcyclopentane-1-carboxylic acid (5.5 g, 79%) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 2.09-1.49 (m, 7H), 1.21 (s, 3H), 0.96 (s, 3H) ppm.

[0384] Step 3. TIFF2025160375000394.tif20128

[0385] A reaction mixture of 2,2-dimethylcyclopentane-1-carboxylic acid (2.50 g, 17.6 mmol) in SOCl2 (10 mL) was heated at 50 °C for 2 hours. The reaction mixture was then concentrated. The resulting residue was dissolved in CH3CN (10 mL). To this solution, 2 M diazomethyl(trimethyl)silane (22 mL, 44 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, cooled to 0 °C, and 40% HBr in AcOH (10.50 g, 52.7 mmol) was added dropwise. The mixture was stirred at 0 °C for 20 minutes. The mixture was filtered, and the filtrate was concentrated. The resulting residue was dissolved in EtOH (12 mL). To this solution, thiourea (1.34 g, 17.6 mmol) was added. The reaction was heated at 70 °C for 1 hour. The reaction mixture was concentrated, 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 give 4-(2,2-dimethylcyclopentyl)thiazol-2-amine (750 mg, 21%) as a brown oil. LCMS: LC retention time 1.32 minutes. MS(ESI)m / z 197[M+H] + .

[0386] Intermediate C-1 5-(3-(3,3-dimethylbutoxy)phenyl)-4-(2-isopropylphenyl)thiazol-2-amine TIFF2025160375000395.tif29128

[0387] Step 1. TIFF2025160375000396.tif11128

[0388] To a solution of 3-bromophenol (5.00 g, 28.9 mmol) in 1,4-dioxane (80 mL) were added 1-bromo-3,3-dimethylbutane (6.20 g, 37.6 mmol) and CsCO (14.1 g, 43.4 mmol). 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 combined organic layers were washed with brine (20 mL) and dried over anhydrous NaSO. The combined organic layers were concentrated in vacuo. The crude product thus obtained was purified by silica gel chromatography (100% PE) to give 1-bromo-3-(3,3-dimethylbutoxy)benzene (7.40 g, 99.6%) as a yellow oil. LCMS: LC retention time 2.73 minutes. MS(ESI)m / z 280[M+Na] +

[0389] Step 2. TIFF2025160375000397.tif22129

[0390] To a solution of 1-bromo-3-(3,3-dimethylbutoxy)benzene (1.80 g, 7.0 mmol) in toluene (20 mL) was added 1-(2-isopropylphenyl)ethanone (1.14 g, 7 mmol), followed by t-BuOK (1.57 g, 14 mmol) and X-phos-Pd (55.2 mg, 0.07 mmol). The resulting mixture was stirred at 65 °C under an Ar atmosphere for 4 h. The reaction mixture was cooled to room temperature and quenched with NH Cl (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 Na SO . The combined organic layers were concentrated in vacuo. The crude product was purified by silica gel chromatography (PE / EA=4%) to give 2-[3-(3,3-dimethylbutoxy)phenyl]-1-(2-isopropylphenyl)ethanone (1.80 g, 76.0%) as a yellow oil. LCMS: LC retention time 2.6 minutes. MS(ESI)m / z 339[M+H] + .

[0391] Step 3. TIFF2025160375000398.tif29128

[0392] To a solution of 2-[3-(3,3-dimethylbutoxy)phenyl]-1-(2-isopropylphenyl)ethanone (1.80 g, 5.32 mmol) in DMF (20 mL) was added thiourea (486 mg, 6.38 mmol), followed by KHCO (638 mg, 6.38 mmol) and BrCCl (2.11 g, 10.6 mmol). The resulting mixture was stirred at 80 °C under an Ar atmosphere for 2 h. The reaction mixture was cooled, quenched with an aqueous solution of NH Cl (30 mL), and extracted with EA (10 mL × 3). The organic layers were combined, washed with brine (20 mL), and dried over anhydrous Na SO . The organic layer was concentrated in vacuo. The crude product was purified by silica gel chromatography (PE / EA=40%) to give 5-(3-(3,3-dimethylbutoxy)phenyl)-4-(2-isopropylphenyl)thiazol-2-amine (800 mg, 38.1%) as a brown oil. LCMS: LC retention time 2.6 minutes. MS(ESI)m / z 395[M+H] + .

[0393] Intermediate C-2 5-(3-(2,2-difluoro-3,3-dimethylbutoxy)-4-fluorophenyl)-4-(2-isopropylphenyl)thiazol-2-amine TIFF2025160375000399.tif27128

[0394] Step 1. TIFF2025160375000400.tif17128

[0395] To a solution of 5-bromo-2-fluorophenol (5.00 g, 26.2 mmol) in N,N-dimethylformamide (60 mL) was added 2-tert-butyloxirane (3.93 g, 39.3 mmol) and cesium carbonate (17.08 g, 52.4 mmol) at room temperature. The resulting mixture was stirred at 80 °C overnight. 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 in petroleum ether) to give 1-(5-bromo-2-fluorophenoxy)-3,3-dimethylbutan-2-ol as a colorless oil (4.068 g, 53% yield). LCMS: LC retention time 2.19 minutes. MS(ESI)m / z 275[M-OH] + . 1 H NMR (400 MHz, 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 = 8.8Hz, 1H), 3.73-3.71 (m, 1H), 2.47 (s, 1H), 1.01 (s, 9H) ppm.

[0396] Step 2. TIFF2025160375000401.tif17128

[0397] To a solution of 1-(5-bromo-2-fluorophenoxy)-3,3-dimethylbutan-2-ol (4.07 g, 14 mmol) in dichloromethane (60 mL) was added (1,1-diacetoxy-3-oxo-1λ5,2-benziodoxol-1-yl)acetate (8.89 g, 21 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure. Diethyl ether (60 mL) was added to the residue, and the resulting mixture was stirred at room temperature for 3 hours, filtered through Celite, and washed with diethyl ether. The filtrate was concentrated, and the residue was purified by silica gel chromatography (5% ethyl acetate in petroleum ether) to give 1-(5-bromo-2-fluorophenoxy)-3,3-dimethylbutan-2-one as a yellow oil (3.50 g, 87% yield). LCMS: LC retention time 2.28 minutes. MS(ESI)m / z 291[M+H] + . 1 H NMR (400 MHz, chloroform-d)): δ 7.07-7.03 (m, 1H), 6.99-6.94 (m, 2H), 4.94 (s, 2H), 1.25 (s, 9H) ppm.

[0398] Step 3. TIFF2025160375000402.tif17128

[0399] To a solution of 1-(5-bromo-2-fluorophenoxy)-3,3-dimethylbutan-2-one (3.5 g, 12.1 mmol) in anhydrous dichloromethane (40 mL) was added N-ethyl-N-(trifluoro-λ4-sulfanyl)ethanamine (9.76 g, 60.5 mmol) under an argon atmosphere at 0 °C. The resulting mixture was stirred at room temperature for 40 h. The reaction was quenched with saturated aqueous sodium bicarbonate solution. After CO evolution ceased, the aqueous solution 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 in petroleum ether) to give the crude product, 4-bromo-2-(2,2-difluoro-3,3-dimethylbutoxy)-1-fluorobenzene, as a yellow oil (2.83 g, 75% yield). LCMS: LC retention time 2.36 min. MS (ESI) m / z not observed.

[0400] Step 4. TIFF2025160375000403.tif26139

[0401] 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) was added 1-(2-isopropylphenyl)ethanone (500 mg, 3.09 mmol) and potassium tert-butoxide (830 mg, 6.2 mmol), followed by XPhos precatalyst (25 mg, 0.0309 mmol). The reaction was stirred in a sealed tube under a nitrogen atmosphere at 60° C. for 6 hours. After cooling to room temperature, the mixture was filtered through Celite. The filtrate was concentrated. The residue was purified by silica gel chromatography (10% ethyl acetate in petroleum ether) to give the desired product 2-(3-(2,2-difluoro-3,3-dimethylbutoxy)-4-fluorophenyl)-1-(2-isopropylphenyl)ethan-1-one as a pale yellow oil (977 mg, 81% yield). LCMS: LC retention time 2.41 minutes. MS(ESI)m / z 393[M+H] + .

[0402] Step 5. TIFF2025160375000404.tif27128

[0403] To a solution of 2-(3-(2,2-difluoro-3,3-dimethylbutoxy)-4-fluorophenyl)-1-(2-isopropylphenyl)ethan-1-one (977 mg, 2.49 mmol) in DMF (8.0 mL) was added thiourea (227 mg, 2.99 mmol), potassium bicarbonate (324 mg, 3.24 mmol), and bromotrichloromethane (0.49 mL, 4.98 mmol). The reaction was stirred at 70° C. for 4 hours. After cooling to room temperature, the reaction was diluted with water (80 mL) and saturated aqueous sodium bicarbonate solution (80 mL). The aqueous solution 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 give the product 5-(3-(2,2-difluoro-3,3-dimethylbutoxy)-4-fluorophenyl)-4-(2-isopropylphenyl)thiazol-2-amine as a white solid (195 mg, 18% yield). LCMS: LC retention time 2.16 minutes. MS(ESI)m / z 449[M+H] + .

[0404] Intermediate C-3 5-(3-(2,2-difluoro-3,3-dimethylbutoxy)phenyl)-4-(2-isopropylphenyl)thiazol-2-amine TIFF2025160375000405.tif28128

[0405] Step 1. TIFF2025160375000406.tif16128

[0406] To a cooled (0 °C) and stirred solution of 1-(3-bromophenoxy)-3,3-dimethylbutan-2-one (4.36 g, 1.61 mmol) in DCM (50 mL) was added DAST (5.18 g, 3.22 mmol). The mixture was warmed to room temperature and stirred overnight. LCMS indicated that the starting material had been consumed. Saturated NaHCO (50 mL) was added to the mixture, which was extracted with DCM (120 mL), washed with water (100 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA = 20 / 1) to give the mixture 1-bromo-3-(2,2-difluoro-3,3-dimethylbutoxy)benzene, containing approximately 50% (1.22 g, 25.9%) of the desired compound as a colorless oil. LCMS: LC retention time 2.39 minutes. MS(ESI)m / z 294[M+H] + .

[0407] Step 2. TIFF2025160375000407.tif21128

[0408] To a solution of 1-bromo-3-(2,2-difluoro-3,3-dimethylbutoxy)benzene (1.22 g, 4.16 mmol) in toluene (15 mL) was added 1-(2-isopropylphenyl)ethan-1-one (743 mg, 4.58 mmol) and t-BuOK (932 mg, 8.32 mmol), followed by X-phos-Pd (30.8 mg, 0.04 mmol). The reaction was stirred at 60 °C under Ar for 5 h. After cooling to room temperature, saturated aqueous 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 washes were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (PE / EA=20 / 1) to give the desired compound 2-(3-(2,2-difluoro-3,3-dimethylbutoxy)phenyl)-1-(2-isopropylphenyl)ethan-1-one (1.23 g, 78.9%) as a pale yellow oil. LCMS: LC retention time 2.46 minutes. MS(ESI)m / z 397[M+Na] + .

[0409] Step 3. TIFF2025160375000408.tif28128

[0410] To a solution of 2-(3-(2,2-difluoro-3,3-dimethylbutoxy)phenyl)-1-(2-isopropylphenyl)ethan-1-one (1.23 g, 3.28 mmol) in DMF (40 mL) was added thiourea (300 mg, 3.94 mmol), KHCO (394 mg, 3.94 mmol), and BrCCl (1.30 g, 6.57 mmol). 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 NaSO, and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give the desired compound 5-(3-(2,2-difluoro-3,3-dimethylbutoxy)phenyl)-4-(2-isopropylphenyl)thiazol-2-amine (320 mg, yield 22.6%) as a white solid. LCMS: LC retention time 2.08 minutes. MS(ESI)m / z 431[M+H] + .

[0411] Intermediate C-4 5-(3-(3,3-dimethylbutoxy)phenyl)-4-(2-(trifluoromethyl)phenyl)thiazol-2-amine TIFF2025160375000409.tif24128

[0412] Step 1. TIFF2025160375000410.tif26128

[0413] To a stirred solution of 1-bromo-3,3-dimethylbutane (3.64 g, 22.06 mmol) in DMF (10 mL) was added 3-bromophenol (3.43 g, 19.83 mmol) and CsCO (12.93 g, 39.69 mmol). The resulting mixture was stirred at room temperature for 20 h. The reaction 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 NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE = 1 / 10) to afford 1-bromo-3-(3,3-dimethylbutoxy)benzene (4.61 g, 90.4%) as a colorless oil. LCMS: LC retention time 2.64 minutes. MS(ESI)m / z 282[M+Na] + . 1 H NMR (400 MHz, chloroform-d): 7.15 (t, J = 8.4 Hz, 1H), 7.10-7.07 (m, 2H), 6.86-6.83 (m, 1H), 4.02 (t, J = 7.6 Hz, 2H), 1.74 (t, J = 7.6 Hz, 2H), 1.01 (s, 9H) ppm.

[0414] Step 2. TIFF2025160375000411.tif35128

[0415] XPhos precatalyst (22 mg, 0.029 mmol) and CHOK (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 a Teflon septum and degassed / backfilled with argon. 1-(2-(trifluoromethyl)phenyl)ethan-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 via syringe. The reaction was heated to 60 °C for 5 h. After cooling to room temperature, saturated aqueous NH4Cl (4.0 mL) was added to the reaction mixture, and the resulting mixture was shaken vigorously. The mixture was then poured into a separatory funnel and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by silica gel chromatography (PE / EA=10 / 1) using a Biotage instrument to give 2-(3-(3,3-dimethylbutoxy)phenyl)-1-(2-(trifluoromethyl)phenyl)ethan-1-one (820 mg, 76.6%) as a pale yellow oil. LCMS: LC retention time 2.34 minutes. MS(ESI)m / z 387[M+Na] + .

[0416] Step 3. TIFF2025160375000412.tif33128

[0417] To a solution of 2-(3-(3,3-dimethylbutoxy)phenyl)-1-(2-(trifluoromethyl)phenyl)ethan-1-one (820 mg, 2.25 mmol) in DMF (5 mL) was added KHCO (339 mg, 3.39 mmol), thiourea (259 mg, 3.4 mmol), and CBrCl (852 mg, 4.3 mmol). 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 in vacuo. The residue was purified by silica gel chromatography (EA / PE = 1 / 1) to give 5-(3-(3,3-dimethylbutoxy)phenyl)-4-(2-(trifluoromethyl)phenyl)thiazol-2-amine (130 mg, 13.7%) as a pale yellow solid. LCMS: LC retention time 2.22 minutes. MS(ESI)m / z 421[M+H] + .

[0418] Intermediate C-5 4-(2,6-dimethylphenyl)-5-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)phenyl)thiazol-2-amine TIFF2025160375000413.tif25128 Intermediate C-5 was prepared by essentially the same protocol as intermediate C-3.

[0419] Intermediate C-6a 5-(3-(3,3-dimethylbutoxy)-5-fluorophenyl)-4-(2,6-dimethylphenyl)thiazol-2-amine TIFF2025160375000414.tif31128 Intermediate C-6a was prepared by essentially the same protocol as intermediate C-3.

[0420] Intermediate C-6b 5-(3-(3,3-dimethylbutoxy)phenyl)-4-(2,6-dimethylphenyl)thiazol-2-amine TIFF2025160375000415.tif25128 Intermediate C-6b was prepared by essentially the same protocol as intermediate C-3.

[0421] Intermediate C-7 5-(3-(3,3-dimethylbutoxy)-5-fluorophenyl)-4-(2-isopropylphenyl)thiazol-2-amine TIFF2025160375000416.tif24128

[0422] Step 1. TIFF2025160375000417.tif22128

[0423] 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) was added Na2CO3 (106 mg, 4.87 mmol) and 5-iodo-4-(2-isopropylphenyl)thiazol-2-amine (Intermediate B-1) (555 mg, 1.61 mmol). N2 was bubbled through the mixture for 5 minutes. Pd(Ph3P)4 (188 mg, 0.163 mmol) was then charged. The mixture was stirred at 80 °C for 12 hours and 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 give 5-(3-(3,3-dimethylbutoxy)-5-fluorophenyl)-4-(2-isopropylphenyl)thiazol-2-amine (500 mg, 75.3%) as a yellow solid. LCMS: MS(ESI): m / z 413 [M+H] + .

[0424] Intermediate C-8 5-(3-(3,3-dimethylbutoxy)-5-fluorophenyl)-4-(2-methyl-6-(trifluoromethyl)phenyl)thiazol-2-amine TIFF2025160375000418.tif26128

[0425] Step 1. TIFF2025160375000419.tif27128

[0426] 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(PPh) (579 mg, cat.), and NaCO (795 mg, 7.5 mmol) in toluene (20 mL), ethanol (10 mL), and water (5 mL) was stirred at 80 °C under a N atmosphere for 12 h. The mixture was concentrated, and the residue was purified by SGC (PE / EA = 2 / 1) to give the title intermediate as a yellow solid (400 mg, 36%). LCMS: LC retention time 2.234 minutes. MS(ESI)m / z 453[M+H] + .

[0427] Intermediate C-9 5-(3-(3,3-dimethylbutoxy)phenyl)-4-(2-methyl-6-(trifluoromethyl)phenyl)thiazol-2-amine TIFF2025160375000420.tif26128 Intermediate C-9 was prepared in the same manner as intermediate C-8.

[0428] Intermediate C-10 4-(2,6-dimethylphenyl)-5-(3-fluoro-5-(neopentyloxy)phenyl)thiazol-2-amine TIFF2025160375000421.tif31128

[0429] Step 1. TIFF2025160375000422.tif29128

[0430] To a stirred solution of (3-fluoro-5-(neopentyloxy)phenyl)boronic acid (Intermediate D-6) (800 mg, 2.42 mmol) in toluene / ethanol / HO (30 / 15 / 7.5 mL) was added 4-(2,6-dimethylphenyl)-5-iodothiazol-2-amine (Intermediate B-2b) (602 mg, 2.67 mmol), Pd(PhP) (280 mg, 0.24 mmol), and NaCO (770 mg, 7.27 mmol). 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 in vacuo. The residue was purified by silica gel chromatography (PE / EA=1 / 1) to give the product 4-(2,6-dimethylphenyl)-5-(3-fluoro-5-(neopentyloxy)phenyl)thiazol-2-amine (510 mg, 55%) as a brown oil. LC retention time 2.27 minutes. MS(ESI)m / z 385[M+H] + .

[0431] Intermediate C-11 5-(3-(3,3-dimethylbutoxy)-5-fluorophenyl)-4-(2,6-dimethylphenyl)thiazol-2-amine TIFF2025160375000423.tif25128

[0432] Step 1. TIFF2025160375000424.tif31133

[0433] To a solution of 5-bromo-4-(2,6-dimethylphenyl)thiazol-2-amine (Intermediate B-2a) (964 mg, 3.41 mmol) in toluene / ethanol / HO (52.5 mL, v / v / v = 4 / 2 / 1) was added (3-(3,3-dimethylbutoxy)-5-fluorophenyl)boronic acid (Intermediate D-1) (981 mg, 4.09 mmol), Pd(PhP) (393 mg, 0.34 mmol), and NaCO (1.08 g, 10.22 mmol). The resulting mixture was stirred at 80 °C under an argon atmosphere for 16 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo. 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 NaSO, and filtered. The filtrate was concentrated to dryness under reduced pressure to give the crude product, which was purified by silica gel chromatography (PE / EA = 3 / 1) to give 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. LCMS: LC retention time 2.49 minutes. MS(ESI)m / z 400[M+H] + .

[0434] Intermediate C-12 5-(3-(2,2-difluoro-3,3-dimethylbutoxy)phenyl)-4-(2-isopropoxy-6-methylphenyl)thiazol-2-amine TIFF2025160375000425.tif27128This intermediate was prepared in the same manner as intermediate C-11.

[0435] Intermediate D-1 (3-(3,3-dimethylbutoxy)-5-fluorophenyl)boronic acid TIFF2025160375000426.tif21128

[0436] Step 1. TIFF2025160375000427.tif21128

[0437] To a solution of 3-bromo-5-fluorophenol (4.80 g, 25.1 mmol) in NMP (22 mL) was added CsCO (16.4 g, 50.3 mmol) and 3,3-dimethylbutyl 4-methylbenzenesulfonate (7.73 g, 30.2 mmol). The mixture was stirred at 138 °C overnight. Volatiles were removed under reduced pressure. The residue was purified by SGC (PE = 100%) to give 1-bromo-3-(3,3-dimethylbutoxy)-5-fluorobenzene as a colorless oil (6.55 g, 93.5%). LCMS: LC retention time 2.18 min. No molecular ion observed.

[0438] Step 2. TIFF2025160375000428.tif24128

[0439] To a cooled (-78 °C) and stirred solution of 1-bromo-3-(3,3-dimethylbutoxy)-5-fluorobenzene (6.55 g, 23.8 mmol) in anhydrous THF (65 mL) was added n-BuLi (2.5 M in hexanes, 26.2 mmol) dropwise. The reaction mixture was stirred for 30 minutes. Triisopropyl borate (6.72 g, 35.7 mmol) was added dropwise while maintaining the reaction temperature at -78 °C. The reaction was allowed to warm to room temperature and stirred at room temperature for 2 hours. Water and 2 N HCl (50 mL) were added to the reaction mixture and stirred for an additional 2 hours. After completion of the reaction, 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 give (3-(3,3-dimethylbutoxy)-5-fluorophenyl)boronic acid (5.30 g). LCMS: LC retention time 2.12 minutes. MS(ESI)m / z 241[M+H] + .

[0440] Intermediate D-2 [3-(3,3-dimethylbutoxy)phenyl]boronic acid TIFF2025160375000429.tif20128

[0441] Step 1. TIFF2025160375000430.tif20128

[0442] 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 at 100 °C for 12 h. The mixture was filtered, diluted with brine (400 mL), and then extracted 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 Combiflash (eluted with PE / EA = 20 / 1) to give 1-bromo-3-(3,3-dimethylbutoxy)benzene (6.90 g, 66.3%) as a light oil. LCMS: LC retention time 2.47 minutes. MS(ESI)m / z 257[M+H] + .

[0443] Step 2. TIFF2025160375000431.tif21128

[0444] 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). n-Butyllithium solution (5.13 mL, 2.5 M in hexane) was added dropwise under argon, ensuring that the temperature did not rise above −60°C. After stirring at −70°C for 1.5 hours, trimethyl borate (3.64 g, 35 mmol) was also added dropwise, ensuring that the temperature did not rise above −60°C. After stirring in the cold for 1 hour, the mixture was allowed to warm to 25°C over the course of 2 hours. To the reaction solution, 500 mL of hydrochloric acid (6 N) was added. The mixture was stirred at 25°C for 15 hours. 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 (on silica gel, PE / EA=5 / 1) to give the title compound, [3-(3,3-dimethylbutoxy)phenyl]boronic acid (1.67 g, 64.5%) as a white solid. LCMS: LC retention time 1.99 minutes. MS(ESI)m / z 223[M+H] + .

[0445] Intermediate D-3 2-(2-Fluoro-5-(neopentyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane TIFF2025160375000432.tif34128

[0446] Step 1. TIFF2025160375000433.tif32128

[0447] To a solution of 3-bromo-4-fluorophenol (2.00 g, 10.47 mmol), neopentyl 4-methylbenzenesulfonate (3.00 g, 12.56 mmol) in NMP (10 mL) was added K2CO3 (2.90 g, 20.94 mmol). The reaction was stirred at 150 °C overnight. After cooling to room temperature, the reaction 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 in vacuo. The residue was purified by silica gel chromatography (EA / PE = 1 / 50) to give 2-bromo-1-fluoro-4-(neopentyloxy)benzene (2.40 g, 88%) as a colorless oil. LCMS:MS(ESI) m / z 261[M+H] + .

[0448] Step 2. TIFF2025160375000434.tif37128

[0449] To a stirred solution of 2-bromo-1-fluoro-4-(neopentyloxy)benzene (1.0 g, 3.83 mmol) in 1,4-dioxane (10 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.46 g, 5.75 mmol), KOAc (1.13 g, 11.49 mmol), and Pd(dppf)Cl (280 mg, 0.38 mmol). The solution was stirred at 80 °C for 3 h. Water (50 mL) was added to the reaction mixture, which was then extracted with EA (50 mL). The organic solution was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE) to give 2-(2-fluoro-5-(neopentyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (960 mg, crude) as a colorless oil. LCMS:MS(ESI) m / z 309[M+H] + .

[0450] The following intermediates were similarly synthesized using the procedures detailed above:

[0451] Intermediate D-4 4,4,5,5-Tetramethyl-2-(3-(neopentyloxy)phenyl)-1,3,2-dioxaborolane TIFF2025160375000435.tif21128

[0452] Intermediate D-5 2-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane TIFF2025160375000436.tif20128

[0453] Intermediate D-6 (3-Fluoro-5-(neopentyloxy)phenyl)boronic acid TIFF2025160375000437.tif20128

[0454] Intermediate D-7 2-(4-chloro-3-(neopentyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane TIFF2025160375000438.tif27128

[0455] Intermediate D-8 (4-Fluoro-3-(3,3,3-trifluoro-2,2-dimethylpropoxy)phenyl)boronic acid TIFF2025160375000439.tif17128

[0456] Intermediate D-9 2-(3-((4-(tert-butyl)cyclohexyl)oxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane TIFF2025160375000440.tif22128

[0457] Intermediate D-10 1-Bromo-3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)benzene TIFF2025160375000441.tif16128

[0458] Step 1. TIFF2025160375000442.tif13128

[0459] To a stirred solution of 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (6.0 g, 38.96 mmol) in anhydrous tetrahydrofuran (35 mL) was added borane-methyl sulfide complex (29.2 mL, 2.0 M solution in THF, 58.4 mmol) at room temperature under an argon atmosphere. The resulting reaction mixture was stirred at 40° C. for 18 hours. 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 solution was washed with saturated aqueous sodium bicarbonate solution (100 mL) and brine (100 mL). The organic solution was then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give (1-(trifluoromethyl)cyclopropyl)methanol as a pale yellow oil (5.11 g). LCMS: MS(ESI) m / z not observed. 1 H NMR (400 MHz, chloroform-d) δ 3.73 (s, 2H), 1.05-1.02 (m, 2H), 0.78 (m, 2H) ppm.

[0460] Step 2. TIFF2025160375000443.tif13128

[0461] To a stirred solution of (1-(trifluoromethyl)cyclopropyl)methanol (5.11 g, 38.96 mmol) in anhydrous dichloromethane (80 mL) was added triethylamine (16.3 mL, 116.9 mmol) under an argon atmosphere at 0 °C, 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 at room temperature for 15 h. The reaction mixture was diluted with dichloromethane (80 mL), and the organic layer was washed with 2 M HCl (90 mL), saturated aqueous sodium bicarbonate (80 mL), and brine (80 mL). The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated to give (1-(trifluoromethyl)cyclopropyl)methyl 4-methylbenzenesulfonate as a pale yellow oil (7.30 g, 64% over two steps). LCMS: LC retention time 2.08 minutes. MS(ESI)m / z 295[M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.79 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 4.10 (s, 2H), 2.46 (s, 3H), 1.12 (m, 2H), 0.84 (m, 2H) ppm.

[0462] Step 3. TIFF2025160375000444.tif13128

[0463] A mixture of (1-(trifluoromethyl)cyclopropyl)methyl 4-methylbenzenesulfonate (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 at 55° C. for 18 hours. 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 give 2-(1-(trifluoromethyl)cyclopropyl)acetonitrile as a yellow oil (1.31 g). LCMS: LC retention time 2.08 min. MS (ESI) m / z not observed. 1 H NMR (400 MHz, chloroform-d) δ 2.81 (s, 2H), 1.18 (m, 2H), 0.94 (m, 2H) ppm.

[0464] Step 4. TIFF2025160375000445.tif15128

[0465] 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 at 80° C. for 18 hours. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (20 mL). The pH was adjusted to pH 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 in vacuo to give 2-(1-(trifluoromethyl)cyclopropyl)acetic acid as a brown oil (1.31 g). LCMS: LC retention time 2.50 min. MS (ESI) m / z not observed. 1H NMR (400 MHz, chloroform-d) δ 2.60 (s, 2H), 1.12 (m, 2H), 0.86 (m, 2H) ppm.

[0466] Step 5. TIFF2025160375000446.tif15128

[0467] To a solution of 2-(1-(trifluoromethyl)cyclopropyl)acetic acid (1.31 g, 7.79 mmol) in anhydrous tetrahydrofuran (15 mL) was added borane-methyl sulfide complex (7.8 mL, 2.0 M solution in THF, 15.6 mmol) under an argon atmosphere at 0° C. The resulting reaction mixture was stirred at 40° C. for 18 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (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 saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-ol as a pale yellow oil (1.21 g). LCMS: LC retention time 2.56 min. MS (ESI) m / z not observed. 1 H NMR (400 MHz, chloroform-d) δ 3.79 (t, J = 7.2 Hz, 2H), 1.84 (t, J = 7.2 Hz, 2H), 0.98 (m, 2H), 0.67 (m, 2H) ppm.

[0468] Step 6. TIFF2025160375000447.tif13128

[0469] To a stirred solution of 2-(1-(trifluoromethyl)cyclopropyl)ethan-1-ol (0.91 g, crude, 5.9 mmol) in anhydrous dichloromethane (12 mL) was added triethylamine (1.79 g, 17.7 mmol) under an argon atmosphere at 0° C., 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 hours. The reaction mixture was diluted with dichloromethane (50 mL), and the organic layer was washed with 2 M HCl (40 mL), saturated aqueous sodium bicarbonate (50 mL), and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give 2-(1-(trifluoromethyl)cyclopropyl)ethyl 4-methylbenzenesulfonate as a yellow oil (1.26 g). LCMS: LC retention time 2.14 minutes. MS(ESI)m / z 331[M+Na] + 1 H NMR (400 MHz, chloroform-d) δ 7.79 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 4.16 (t, J = 7.2 Hz, 2H), 2.46 (s, 3H), 1.94 (t, J = 7.2 Hz, 2H), 0.97 (m, 2H), 0.65 (m, 2H) ppm.

[0470] Step 7 TIFF2025160375000448.tif16128

[0471] To a solution of 2-(1-(trifluoromethyl)cyclopropyl)ethyl 4-methylbenzenesulfonate (1.26 g, crude, 4.07 mmol) in DMF (15 mL) was added 3-bromophenol (916 mg, 5.3 mmol) and cesium carbonate (3.98 g, 12.2 mmol). The reaction was stirred at 120 °C overnight. The reaction was diluted with water (120 mL). The aqueous solution was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with water (50 mL × 2) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether) to give 1-bromo-3-(2-(1-(trifluoromethyl)cyclopropyl)ethoxy)benzene as a yellow oil (757 mg, 36% yield over 5 steps). LCMS: LC retention time 2.40 minutes. MS(ESI)m / z 309[M+H] + . 1 H NMR (400 MHz, 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.

[0472] Intermediate D-11a 2-[3-(3,3-dimethylcyclopentoxy)-5-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane TIFF2025160375000449.tif25128

[0473] Step 1. TIFF2025160375000450.tif25128

[0474] To a solution of 3-bromo-5-fluorophenol (836 mg, 4.38 mmol) in THF (50 mL) was added 3,3-dimethylcyclopentanol (500 mg, 4.38 mmol) and triphenylphosphine (1.72 g, 6.57 mmol), followed by diisopropyl azodicarboxylate (1.29 mL, 6.57 mmol) under argon at 0 °C. The resulting mixture was reacted at room temperature overnight. The solvent was removed under vacuum. The residue was purified by FCC (PE = 100%) to give the desired compound, 1-bromo-3-(3,3-dimethylcyclopentoxy)-5-fluorobenzene (890 mg, 71%), as a colorless oil. LCMS: LC retention time 2.67 minutes. MS(ESI)m / z 287[M+H] + .

[0475] Step 2. TIFF2025160375000451.tif26128

[0476] To a solution of 1-bromo-3-(3,3-dimethylcyclopentoxy)-5-fluoro-benzene (480 mg, 1.67 mmol), bis(pinacolato)diboron (509 g, 2.01 mmol) in DMSO (10 mL) was added Pd(dppf)Cl (62 mg, cat.) and potassium acetate (491 mg, 5.01 mmol). The reaction 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 NaSO, and filtered. The filtrate was concentrated in vacuo. The residue was purified by FCC (PE / EA=10 / 1) to give the desired compound 2-[3-(3,3-dimethylcyclopentoxy)-5-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (730 mg, 71%) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ 7.12 - 7.01 (m, 2H), 6.66 (dt, J = 10.9, 2.4 Hz, 1H), 4.82 (tt, J = 6.9, 3.6 Hz, 1H), 2.25 - 2.10 (m, 1H), 1.90 (dd, J = 13.8, 6.9 Hz, 2H), 1.69 (dt, J = 10.1, 6.7 Hz, 2H), 1.53 - 1.41 (m, 1H), 1.35 (s, 12H), 1.14 (s, 3H), 1.05 (s, 3H) ppm.

[0477] Intermediate D-11b 2-(3-((3,3-dimethylcyclopentyl)oxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane TIFF2025160375000452.tif20128 Intermediate D-11b was prepared by essentially the same protocol as intermediate D-11a.

[0478] Intermediate D-12 (3-(3,3-dimethylcyclopentyl)phenyl)boronic acid TIFF2025160375000453.tif21128

[0479] Step 1. TIFF2025160375000454.tif14128

[0480] A solution of diisopropylamine (5.2 g, 51.4 mmol) in anhydrous THF (40 mL) was cooled to 0 °C under Ar, n-BuLi (2.5 M in hexane, 18.8 mL, 47.1 mmol) was added, and the solution was stirred at 0 °C for 15 min and 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 PhNTf (16.80 g, 47.1 mmol) in anhydrous THF (80 mL) was added, and the mixture was warmed to 0 °C and stirred overnight. The mixture was poured into saturated aqueous NH Cl and extracted with EtO. The combined organic layers were washed with water and brine, dried and concentrated to give a mixture of 3,3-dimethylcyclopent-1-en-1-yl trifluoromethanesulfonate and 4,4-dimethylcyclopent-1-en-1-yl trifluoromethanesulfonate (8.00 g, 76.6%) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ 5.56-5.49 (m, 1H), 2.66-2.62 (m, 1H), 2.42-2.40 (m, 1H), 2.23-2.21 (m, 1H), 1.85 (t, J = 8.1 Hz, 1H), 1.15 (s, 3H), 1.14 (s, 3H) ppm.

[0481] Step 2. TIFF2025160375000455.tif21128

[0482] To a solution of 3,3-dimethylcyclopent-1-en-1-yl trifluoromethanesulfonate in toluene / EtOH / water (60 mL / 30 mL / 15 mL) was added 4,4-dimethylcyclopent-1-en-1-yl trifluoromethanesulfonate (2.00 g, 8.18 mmol), (3-nitrophenyl)boronic acid (1.71 g, 10.2 mmol), tetrakis(triphenylphosphine)palladium (236 mg, 0.205 mmol), and sodium carbonate (2.60 g, 24.6 mmol). The mixture was stirred at 90° C. for 16 hours. The mixture was then concentrated. The residue was taken up 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 in vacuo. The residue was purified by silica gel column chromatography (PE) to give 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 a yellow oil. 1 HNMR (400 MHz, chloroform-d) δ 8.23-8.20 (m, 1H), 8.06-8.03 (m, 1H), 7.72-7.69 (m, 1H), 7.48 (t, J = 8.0 Hz, 1H), 6.24-6.14 (m, 1H), 2.80-2.76 (m, 1H), 2.57-2.55 (m, 1H), 2.40-2.39 (m, 1H), 1.89 (t, J = 7.2 Hz, 1H), 1.19 (s, 3H), 1.16 (s, 3H) ppm.

[0483] Step 3. TIFF2025160375000456.tif22128

[0484] To a solution of 1-(3,3-dimethylcyclopent-1-en-1-yl)-3-nitrobenzene and 1-(4,4-dimethylcyclopent-1-en-1-yl)-3-nitrobenzene (1.30 g, 6.00 mmol) in MeOH (50 mL) was added 10 wt% Pd / C (130 mg) at room temperature under an Ar atmosphere. The flask was purged with hydrogen and stirred under a hydrogen atmosphere (1 atm) for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated to give 3-(3,3-dimethylcyclopentyl)aniline (700 mg, 62%) as a yellow oil. LCMS: LC retention time 1.953 minutes. MS(ESI)m / z 190[M+H] + . 1 HNMR (400 MHz, chloroform-d) δ 7.09 (t, J = 7.6 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 6.59 (s, 1H), 6.52-6.49 (m, 1H), 3.59 (br, 2H), 3.14-3.09 (m, 1H), 2.10-2.06 (m, 1H), 1.85-1.47 (m, 5H), 1.16 (s, 3H), 1.14 (s, 3H) ppm.

[0485] Step 4. TIFF2025160375000457.tif22128

[0486] To a solution of 3-(3,3-dimethylcyclopentyl)aniline (700 mg, 3.33 mmol) in anhydrous MeCN (20 mL) was added CuBr (445 mg, 2.00 mmol) and tert-butyl nitrite (343 mg, 3.33 mmol) at room temperature. The resulting mixture was stirred at reflux for 15 minutes. An aliquot checked by LCMS analysis showed the reaction was complete. The reaction was quenched by the addition of water (80 mL). The aqueous solution 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 give the crude product, which was purified by silica gel column chromatography (PE / EA = 50 / 1) to give the desired compound 1-bromo-3-(3,3-dimethylcyclopentyl)benzene (478 mg, 53.9%) as a yellow oil. 1 HNMR (400 MHz, chloroform-d)): δ 7.41-7.13 (m, 4H), 3.57-3.12 (m, 1H), 2.17-1.50 (m, 6H), 1.12 (s, 3H), 1.10 (s, 3H) ppm.

[0487] Step 5. TIFF2025160375000458.tif23128

[0488] To a cooled and stirred solution of 1-bromo-3-(3,3-dimethylcyclopentyl)benzene (470 mg, 1.67 mmol) in anhydrous tetrahydrofuran (20 mL) was added n-butyllithium (1.34 mL, 3.34 mmol, 2.5 M solution in hexane) dropwise at −78° C. After the addition, the reaction mixture was stirred at −78° C. for 0.5 hours. Trimethyl borate (347 mg, 3.34 mmol) was then added dropwise at −78° C., and the resulting mixture was stirred at −78° C. for 1 hour. The reaction mixture was then gradually warmed to room temperature over 2 hours. To this solution was added hydrochloric acid (6.0 N, 5 mL) at 0° C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (50 mL). The aqueous solution 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 give the product (3-(3,3-dimethylcyclopentyl)phenyl)boronic acid (400 mg, crude) as a yellow solid. 1 HNMR (400 MHz, chloroform-d)): δ 7.68-7.23 (m, 4H), 3.20-3.15 (m, 1H), 2.07-1.30 (m, 6H), 1.16 (s, 3H), 1.14 (s, 3H) ppm.

[0489] Intermediate D-13 4,4,5,5-tetramethyl-2-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)phenyl)-1,3,2-dioxaborolane TIFF2025160375000459.tif18128

[0490] Step 1. TIFF2025160375000460.tif13128

[0491] To a cooled, stirred solution of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (10.0 g, 64.1 mmol) in EtO (150 mL) was added LiAlH (4.87 g, 128 mmol) at 0 °C. The mixture was stirred at room temperature overnight. Upon completion of the reaction, the reaction was quenched with HO (5 mL), NaOH (15%, 5 mL), and HO (15 mL). The mixture was filtered through a Celite pad. The filtrate was concentrated to give 3,3,3-trifluoro-2,2-dimethylpropan-1-ol (8.40 g, 92.3%) as a yellow oil.

[0492] Step 2. TIFF2025160375000461.tif13128

[0493] To a solution of 3,3,3-trifluoro-2,2-dimethylpropan-1-ol (8.4 g, 59.1 mmol) in EtO (100 mL) was added NaOH (4.73 g, 118 mmol), followed by 4-methylbenzenesulfonyl chloride (12.4 g, 65.0 mmol). The resulting mixture was stirred at room temperature overnight. The two layers were separated, and the organic layer was washed with water (120 mL × 3) and NaHCO (50 mL). The organic solution was concentrated under vacuum and purified by silica gel column chromatography using PE:EA (5:1) as the eluent to give 3,3,3-trifluoro-2,2-dimethylpropyl-4-methylbenzenesulfonate (12.6 g, 71.9% yield) as a yellow oil. LCMS (acidic): LC retention time 2.130 minutes. MS(ESI)m / z 297[M+H] + .

[0494] Step 3. TIFF2025160375000462.tif15128

[0495] To a solution of 3,3,3-trifluoro-2,2-dimethylpropyl 4-methylbenzenesulfonate (6.00 g, 20.2 mmol) in DMSO (60 mL) was added 3-bromophenol (3.50 g, 20.2 mmol) and CsCO (19.8 g, 60.7 mmol). The mixture was heated at 130 °C overnight with stirring. Upon completion of the reaction, the mixture was cooled to room temperature and diluted with EA (100 mL). The organic solution was washed with HO (100 mL × 3). The organic solution was concentrated under vacuum and purified by silica gel column chromatography using PE as the eluent to give 1-bromo-3-(3,3,3-trifluoro-2,2-dimethylpropoxy)benzene (4.20 g, 69.8%) as a yellow oil. LCMS (acidic): LC retention time 2.337 min. MS (ESI) m / z not observed.

[0496] Step 4. TIFF2025160375000463.tif20128

[0497] 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) was added bis(pinacolato)diboron (5.13 g, 20.2 mmol), CHCOOK (3.30 g, 33.7 mmol), and Pd(dppf)Cl (985 mg, 1.35 mmol). The reaction was heated at 80 °C overnight under argon. The reaction mixture was concentrated and purified by SGC (PE:EA = 10:1) to give 4,4,5,5-tetramethyl-2-(3-(3,3,3-trifluoro-2,2-dimethylpropoxy)phenyl)-1,3,2-dioxaborolane (2.93 g, 63.2% yield) as a yellow oil. LCMS (acidic): LC retention time 2.539 minutes. MS(ESI)m / z 345[M+H] + .

[0498] Intermediate D-14 2-(3-(2,2-difluoro-3,3-dimethylbutoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane TIFF2025160375000464.tif20128

[0499] Step 1. TIFF2025160375000465.tif16128

[0500] To a solution of 3-bromophenol (1.9 g, 11.0 mmol) in DMF (20 mL) was added 2-(tert-butyl)oxirane (1.65 g, 16.5 mmol) and cesium carbonate (7.16 g, 22.0 mmol) at room temperature. The resulting mixture was stirred at 80 °C overnight. The mixture was cooled to room temperature, diluted with water (150 mL), and extracted with ethyl acetate (40 mL × 3). The organic 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 in petroleum ether) to give 1-(3-bromophenoxy)-3,3-dimethylbutan-2-ol as a colorless oil (2.46 g, 82% yield). LCMS: LC retention time 2.24 minutes. MS(ESI)m / z 275[M+H] + . 1 HNMR (400 MHz, chloroform-d) δ 7.17-7.06 (m, 3 H), 6.87-6.84 (m, 1 H), 4.10-4.07 (m, 1 H), 3.85 (t, J = 9.2 Hz, 1 H), 3.69-3.66 (m, 1 H), 2.36 (d, J = 3.2 Hz, 1 H), 1.01 (s, 9 H) ppm.

[0501] Step 2. TIFF2025160375000466.tif16128

[0502] To a solution of 1-(3-bromophenoxy)-3,3-dimethylbutan-2-ol (2.46 g, 9.01 mmol) in dichloromethane (30 mL) was added (1,1-diacetoxy-3-oxo-1λ5,2-benziodoxol-1-yl)acetate (5.73 g, 13.5 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (10% ethyl acetate in petroleum ether) to give 1-(3-bromophenoxy)-3,3-dimethylbutan-2-one as a colorless oil (2.18 g, 89% yield). LCMS: LC retention time 2.18 minutes. MS(ESI)m / z 273[M+H] + . 1 HNMR (400 MHz, chloroform-d) δ 7.16-7.10 (m, 2 H), 7.02 (s, 1 H), 6.81 (d, J = 7.2 Hz, 1 H), 4.85 (s, 2 H), 1.25 (s, 9 H) ppm.

[0503] Step 3. TIFF2025160375000467.tif16128

[0504] To a solution of 1-(3-bromophenoxy)-3,3-dimethylbutan-2-one (2.18 g, 8.04 mmol) in anhydrous dichloromethane (20 mL) was added N-ethyl-N-(trifluoro-λ4-sulfanyl)ethanamine (5.18 g, 32.2 mmol) dropwise at 0 °C under an argon atmosphere. The resulting mixture was stirred at room temperature for 65 h. The reaction was quenched with saturated aqueous sodium bicarbonate solution. After CO evolution ceased, the aqueous 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 give 1-bromo-3-(2,2-difluoro-3,3-dimethylbutoxy)benzene as a colorless oil (1.56 g, 66% yield). LCMS: LC retention time 2.35 min. MS(ESI) m / z not observed. 1 HNMR (400 MHz, chloroform-d) δ 7.18-7.10 (m, 3 H), 6.88 (m, 1 H), 4.23 (t, J = 13.2 Hz, 2 H), 1.14 (s, 9 H) ppm.

[0505] Step 4. TIFF2025160375000468.tif20128

[0506] To a solution of 1-bromo-3-(2,2-difluoro-3,3-dimethylbutoxy)benzene (1.56 g, 5.32 mmol) in anhydrous 1,4-dioxane (20.0 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.03 g, 7.99 mmol), potassium acetate (1.56 g, 15.96 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (389 mg, 0.532 mmol). The reaction was stirred overnight at 90 °C under an argon atmosphere. The solid was filtered off, diluted with water (120 mL), and extracted with ethyl acetate (50 mL x 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 (3% ethyl acetate in petroleum ether) to give 2-(3-(2,2-difluoro-3,3-dimethylbutoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a colorless oil (1.34 g, 74% yield). LCMS: LC retention time 2.42 minutes. MS(ESI)m / z 340[M+H] + .

[0507] Intermediate D-15 2-(4-(difluoromethoxy)-3-(3,3-dimethylbutoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane TIFF2025160375000469.tif28128

[0508] Step 1. TIFF2025160375000470.tif16128

[0509] To a solution of 4-bromo-2-fluorobenzaldehyde (8.0 g, 39.4 mmol) in dichloromethane (60 mL) was added 2-methylpropan-2-amine (14.4 g, 197 mmol) and magnesium sulfate (33.2 g, 276 mmol). The resulting mixture was stirred at room temperature for 43 hours. The solution was filtered and concentrated to give (E)-1-(4-bromo-2-fluorophenyl)-N-(tert-butyl)methanimine as a yellow oil (10.2 g). LCMS: LC retention time 2.04 minutes. MS(ESI)m / z 258[M+H] + .

[0510] Step 2. TIFF2025160375000471.tif16128

[0511] To a suspension of sodium hydride (60 wt% in mineral oil, 4.74 g, 119 mmol) in DMF (40 mL) was added dropwise a solution of 3,3-dimethylbutan-1-ol (4.84 g, 47.4 mmol) in DMF (30 mL) at 0° C. under an argon atmosphere. The resulting mixture was stirred at room temperature for 30 minutes, and then a solution of (E)-1-(4-bromo-2-fluorophenyl)-N-(tert-butyl)methanimine (10.2 g, 39.5 mmol) in DMF (30 mL) was added dropwise at 0° C. The resulting reaction mixture was stirred at room temperature overnight. 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), brine (150 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid, which was treated with tetrahydrofuran (50 mL), water (50 mL), and acetic acid (12 mL). After 18 hours, the solution was made basic with saturated aqueous sodium carbonate 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 in petroleum ether) to give 4-bromo-2-(3,3-dimethylbutoxy)benzaldehyde as a white solid (9.54 g, 85% yield over two steps). LCMS: LC retention time 2.56 minutes. MS(ESI)m / z 287[M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 10.4 (s, 1 H), 7.70-7.68 (m, 1 H), 7.17-7.15 (m, 2 H), 4.13 (t, J = 7.2 Hz, 2 H), 1.80 (t, J = 7.2 Hz, 2 H), 1.02 (s, 9 H) ppm.

[0512] Step 3. TIFF2025160375000472.tif12128

[0513] To a solution of 4-bromo-2-(3,3-dimethylbutoxy)benzaldehyde (6.9 g, 24.2 mmol) in dichloromethane (70 mL) was added 3-chlorobenzenecarboperoxoic acid (85 wt%, 7.37 g, 36.3 mmol). After stirring for 15 hours, saturated aqueous sodium sulfite solution was added at 0°C, and the solution was stirred until the aqueous solution was KL paper negative. The mixture was then extracted with dichloromethane (100 mL x 2). The combined organic layers were washed with 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 hours. The reaction mixture was acidified with 1 M potassium bisulfate solution (pH ∼4) and then extracted with dichloromethane (100 mL x 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 in petroleum ether) to give 4-bromo-2-(3,3-dimethylbutoxy)phenol as a yellow oil (5.77 g, 87% yield). LCMS: LC retention time 2.34 min. MS (ESI) m / z not observed. 1 H NMR (400 MHz, chloroform-d) δ 6.98-6.96 (m, 2 H), 6.79 (d, J = 8.8 Hz, 1 H), 5.57 (s, 1 H), 4.07 (t, J = 7.2 Hz, 2 H), 1.75 (t, J = 7.2 Hz, 2 H), 1.00 (s, 9 H) ppm.

[0514] Step 4. TIFF2025160375000473.tif25128

[0515] To a solution of 4-bromo-2-(3,3-dimethylbutoxy)phenol (1.25 g, 4.58 mmol) in MeCN (27 mL) was added a solution of KOH (5.0 g, 89.1 mmol) in HO (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 cold bath was removed. The mixture was stirred for 5 h. The reaction was diluted with EtOAc, and the layers were separated. The aqueous layer was extracted with EtOAc, and the combined organics were washed with 1 M NaOH, HO, and brine, then dried over NaSO and concentrated in vacuo. The residue was purified by preparative TLC (100% PE) to give 4-bromo-1-(difluoromethoxy)-2-(3,3-dimethylbutoxy)benzene (1.30 g, 87.9%) as a colorless oil. 1 H NMR (400 MHz, 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. 19 F NMR (400 MHz, chloroform-d)): δ −81.709 ppm.

[0516] Step 5. TIFF2025160375000474.tif26128

[0517] To a solution of 4-bromo-1-(difluoromethoxy)-2-(3,3-dimethylbutoxy)benzene (800 mg, 2.48 mmol) in 25 mL of dioxane was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.26 g, 4.95 mmol), KOAc (729 mg, 7.43 mmol), and Pd(dppf)Cl (90.5 mg, 0.124 mmol). The reaction was heated at 90° C. under Ar for 5 h. The reaction mixture was cooled to room temperature and then filtered. The filtrate was concentrated to give 2-(4-(difluoromethoxy)-3-(3,3-dimethylbutoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (917 mg, 100% yield) as a brown oil. LCMS: LC retention time 1.955 minutes. MS(ESI)m / z 371.2[M+H] + .

[0518] Intermediate D-16 4,4,5,5-tetramethyl-2-(6-neopentyl-3,6-dihydro-2H-pyran-4-yl)-1,3,2-dioxaborolane TIFF2025160375000475.tif19128

[0519] Step 1. TIFF2025160375000476.tif26128

[0520] To a stirred solution of 3,3-dimethylbutanal (1.0 g, 9.98 mmol) in dry dichloromethane (50.0 mL), triflic acid (1.8 g, 12.0 mmol) was added dropwise, followed by but-3-yn-1-ol (1.05 g, 15.0 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was treated with saturated sodium bicarbonate solution (100 mL). It was then extracted with DCM (80 mL × 2). The organic layer was washed with brine and dried over anhydrous NaSO. The organic compound was then concentrated to dryness. The mixture was purified by FCC (PE:EA = 10:1) to give 6-neopentyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (1.70 g, 56.3%) as a yellow oil.

[0521] Step 2. TIFF2025160375000477.tif29128

[0522] A reaction mixture of 6-neopentyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (1.7 g, 5.62 mmol), bis(pinacolato)diboron (2.14 g, 8.44 mmol), CHCOOK (1.10 g, 11.2 mmol), and Pd(dppf)Cl (411 mg, 0.562 mmol) in 1,4-dioxane (60 mL) was heated under Ar at 80° C. overnight. The reaction mixture was concentrated to give 4,4,5,5-tetramethyl-2-(6-neopentyl-3,6-dihydro-2H-pyran-4-yl)-1,3,2-dioxaborolane. LCMS: LC retention time 2.50 minutes. MS(ESI)m / z 281[M+H] + .

[0523] Intermediate D-17 (6-(3,3-dimethylbutoxy)pyridin-2-yl)boronic acid TIFF2025160375000478.tif26128

[0524] Step 1. TIFF2025160375000479.tif26128

[0525] To a stirred solution of 3,3-dimethylbutan-1-ol (500 mg, 4.89 mmol) in dry THF (10 mL) was added NaH (293.58 mg, 7.34 mmol, 60%) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h. To the reaction mixture was added 2,6-dibromopyridine (1.16 g, 4.89 mmol). The mixture was then stirred at room temperature for 12 h. The reaction 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 give the crude product, which was purified by silica gel chromatography (petroleum ether) to give 2-bromo-6-(3,3-dimethylbutoxy)pyridine (1.8 g, 71%, 2 batches) as a colorless oil. LCMS:MS(ESI) m / z 260[M+H] +

[0526] Step 2. TIFF2025160375000480.tif26128

[0527] To a stirred solution of 2-bromo-6-(3,3-dimethylbutoxy)pyridine (0.5 g, 1.93 mmol) in THF (6 mL) was added n-butyllithium (1.42 mL, 2.9 mmol) at −78° C. under a N atmosphere. The reaction was stirred at this temperature for 1 h, and then triisopropyl borate (436.3 mg, 2.32 mmol) was added. The mixture was warmed to room temperature and stirred at this temperature for 13 h. TLC (PE / EA=8 / 1) showed that the starting material was consumed. To the mixture was added MeOH (3 mL), the pH was adjusted to 3 with HCl (2 M), evaporated to remove organic solvents, the pH was adjusted to 7 with NaHCO3, and 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 give (6-(3,3-dimethylbutoxy)pyridin-2-yl)boronic acid (0.20 g, 46.29%) as a yellow solid. 1H NMR (400 MHz, methanol-d) δ 8.19 (t, J = 7.8 Hz, 1H), 7.46 (d, J = 7.4 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 4.46 (t, J = 7.2 Hz, 2H), 1.97 - 1.81 (m, 2H), 1.06 (s, 9H) ppm.

[0528] Intermediate D-18 2-(3-(1,1-difluoro-4,4-dimethylpentyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane TIFF2025160375000481.tif26128

[0529] Step 1. TIFF2025160375000482.tif12128

[0530] Magnesium turnings (2.10 g, 86.42 mmol) were initially charged in 60 mL of EtO. One spatula tip of iodine was added, and a solution of 1-bromo-3,3-dimethylbutane (17.500 g, 106 mmol) in 10 mL of EtO was slowly added. The reaction mixture was stirred under reflux for 2 hours. After cooling to room temperature, the reaction solution (3,3-dimethylbutyl)magnesium bromide was used directly in the next step.

[0531] Step 2. TIFF2025160375000483.tif34128

[0532] To a solution of 3-bromobenzaldehyde (5.42 g, 29.3 mmol) in EtO (30 mL) was added (3,3-dimethylbutyl)magnesium bromide (70 mL, 86.42 mmol) at room temperature under N. The resulting mixture was stirred at room temperature for 2 hours. The mixture was poured into 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 1-(3-bromophenyl)-4,4-dimethylpentan-1-ol was used directly in the next step. LCMS: LC retention time 2.34 minutes. MS(ESI)m / z 272[M+H + .

[0533] Step 3. TIFF2025160375000484.tif21128

[0534] To a stirred solution of 1-(3-bromophenyl)-4,4-dimethylpentan-1-ol (7.95 g, 29.3 mmol) in dry DCM (150 mL) was added PCC (17.60 g, 81.7 mmol) under nitrogen at 0° C. for 2 h. The resulting mixture was stirred at room temperature for 12 h. The mixture was filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography (PE / EA=98 / 2) to give 1-(3-bromophenyl)-4,4-dimethylpentan-1-one (6.95 g, 88.1% for three steps) as a pale yellow oil. LCMS: LC retention time 2.33 minutes. MS(ESI)m / z 271[M+H] + .

[0535] Step 4. TIFF2025160375000485.tif16128

[0536] To a stirred solution of 1-(3-bromophenyl)-4,4-dimethylpentan-1-one (1.74 g, 6.84 mmol) in DCM (20 mL) was added DAST (4.50 g, 27.9 mmol) at room temperature under nitrogen. The reaction mixture was stirred at 86 °C for 14 h. The mixture was poured into ice water. The aqueous layer was adjusted to pH 8. The aqueous solution was then extracted with EA. The organic layer was dried over NaSO, filtered, and concentrated. The crude residue was purified by flash chromatography (PE) to give 1-bromo-3-(1,1-difluoro-4,4-dimethylpentyl)benzene (1.59 g, 79.9%) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ 7.64 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 2.11-2.03 (m, 2H), 1.35-1.30 (m, 2H), 0.90 (s, 9H) ppm.

[0537] Step 5. TIFF2025160375000486.tif31128

[0538] 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-dioxaborolane) (255 mg, 1.0 mmol), tricyclohexylphosphane (27 mg, 0.096 mmol), and Pd(dba) (84 mg, 0.092 mmol) in 1,4-dioxane (10 mL) was stirred at 85 °C for 20 h under N protection. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated to give 2-(3-(1,1-difluoro-4,4-dimethylpentyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (235 mg, 100%) as a colorless oil. LCMS: LC retention time 2.19 minutes. MS(ESI)m / z 256.8[M+H] + .

[0539] Intermediate D-19 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(trifluoromethyl)isoxazole TIFF2025160375000487.tif20128

[0540] Step 1. TIFF2025160375000488.tif16128

[0541] Sodium (347 mg, 15.1 mmol) was dissolved in ethanol (10 mL) under inert conditions. To this solution, a solution of ethyl 2,2,2-trifluoroacetate (2.86 g, 20.1 mmol) in ethanol (10 mL) was added, followed by a solution of 1-(3-bromophenyl)ethanone (2.00 g, 10.0 mmol) in ethanol (10 mL). The reaction mixture was refluxed at 85° C. overnight. After completion of the reaction, the reaction was quenched with aqueous HCl (1N) solution (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 the crude product, which was purified by silica gel chromatography (15% ethyl acetate / petroleum ether) to give 1-(3-bromophenyl)-4,4,4-trifluoro-butane-1,3-dione (4.12 g) as a red oil. LCMS: LC retention time 1.18 minutes. MS(ESI)m / z 297[M+H] + .

[0542] Step 2. TIFF2025160375000489.tif17128

[0543] To a solution of hydroxylamine hydrochloride (236 mg, 3.39 mmol) in aqueous NaOH (142 mg, 3.56 mmol), 1-(3-bromophenyl)-4,4,4-trifluorobutane-1,3-dione (1 g, 3.39 mmol) was added over 1 h at 20–30°C. 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 NaSO, and filtered. The filtrate was concentrated under reduced pressure to give 3-(3-bromophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-5-ol (810 mg). LCMS: LC retention time 2.02 minutes. MS(ESI)m / z 311[M+H] + .

[0544] Step 3. TIFF2025160375000490.tif17128

[0545] 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 at 80° C. overnight. After completion of the reaction, the reaction was quenched with aqueous NaHCO (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 NaSO and filtered. The solution was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (11% ethyl acetate / petroleum ether) to give the product (190 mg). LCMS: LC retention time 1.54 min. MS (ESI) m / z not observed.

[0546] Step 4. TIFF2025160375000491.tif20134

[0547] 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-dioxaborolan-2-yl)-1,3,2-dioxaborolane (174 mg, 0.685 mmol), Pd(dppf)Cl (25.1 mg, 0.034 mmol), and potassium acetate (134 mg, 1.37 mmol) in 1,4-dioxane (10 mL) was heated at 80 °C overnight under a nitrogen atmosphere. After completion of the reaction, the mixture was filtered. The filtrate was extracted with ethyl a...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof: During the ceremony, R １ is hydrogen or C １－６ is alkyl, X is C １－６ alkyl, 5- to 6-membered aryl, 4- to 10-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which occurs 0 to 3 times. ２ is replaced by Cy １ But C ３－９ cycloalkyl, 5- to 6-membered aryl, 4- to 10-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which occurs 0 to 3 times. ３ is replaced by Cy ２ But C ３－９ cycloalkyl, 5- to 6-membered aryl, 4- to 10-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which occurs 1 to 3 times. ４ is replaced by Each R ２ are independently hydroxyl, halo, -NH ２ , Nitro, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ haloalkoxy, 4- to 10-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－９ Cycloalkyl, C ３－９ Cycloalkoxy, —C(O)NH ２ , -N(R ａ ) (R ５ ), -N(R ａ ) C(O)-R ５ , -N(R ａ ) SO ２ -R ５ , -SO ２ -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 and C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C ３－９ Each of cycloalkyl or 4- to 10-membered heterocycloalkyl occurs 0 to 3 times in R ５ is further replaced by Each R ３ But independently, Halo, C １－８ Alkyl, C １－８ Alkenyl, C １－８ Alkoxy, C １－８ Haloalkyl, C １－８ Haloalkoxy, 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- to 6-membered aryl, aralkyl, aralkoxy, 5- to 6-membered heteroaryl, 4- to 10-membered heterocycloalkyl, —C(O)—R ７ , -C(O)N(R ａ ) (R ７ ) or -N(R ａ ) (R ８ ) and C ３－９ Cycloalkyl, C ３－９ Cycloalkoxy, C １－８ Haloalkoxy, C １－８ Alkoxy, 4- to 10-membered heterocycloalkyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl, cycloalkenyl, C １－４ Alkyl-C ３－９ Cycloalkyl or C １－４ Alkoxy-C ３－９ Each cycloalkyl may be selected from 0 to 3 occurrences of R ７ is further substituted with Each R ４ But independently, Halo, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Haloalkyl, C １－６ Haloalkoxy, C ３－６ Cycloalkyl, N(R ａ ) ２ or 4- to 10-membered heterocycloalkyl, each 4- to 10-membered heterocycloalkyl being selected from 0 to 3 R ｂ may be further substituted with Each R ５ But independently, C １－６ Alkyl, C １－６ Haloalkyl, C ３－９ Cycloalkyl, hydroxyl, —SO ２ -R ６ , -CO ２ H, —NH ２ , -CO ２ -C １－４ alkyl or 4- to 10-membered heterocycloalkyl; １－６ Alkyl, C ３－９ Each of cycloalkyl or 4- to 10-membered heterocycloalkyl occurs 0 to 3 times in R ６ is further replaced by Each R ６ are independently hydroxyl, —NH ２ , Haro, C １－４ Alkyl, C １－４ Haloalkyl, —CO ２ H or -CO ２ -(C １－４ alkyl), Each R ７ But independently, Halo, C １－５ Alkyl, C １－５ Alkoxy, C １－５ Haloalkyl, C １－５ Haloalkoxy, C １－５ Haloalkenyl, C ３－７ Cycloalkyl, hydroxyl, 5- to 6-membered aryl, aralkyl, aralkoxy, —C(O)—O—C １－４ Alkyl, —C(O)N(R ａ ) (C １－４ alkyl), 5- to 6-membered heteroaryl or 4- to 10-membered heterocycloalkyl; ３－７ cycloalkyl, 5- to 6-membered aryl, or 4- to 10-membered heterocycloalkyl occur 0 to 3 times each in R ８ is further replaced by Each R ８ But independently, Halo, 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 are independently H or C １－６ is alkyl, Each R ｂ But C １－４ is alkyl, where: a) Cy １ is phenyl and three occurrences of R ３ When R ３ is not methoxy, b) X and Cy ２ are each phenyl, R ２ and R ４ are not methyl, c) R ３ and R ４ is not simultaneously tert-butyl and methoxy, d) Cy １ and Cy ２ is monosubstituted phenyl, X is not thienyl, and e) Cy １ and Cy ２ When R is monosubstituted phenyl, ２ is not OH, but R ３ is not Cl, but R ４ is not OMe.

2. R １ The compound of claim 1 , wherein is H.

3. R １ But C １－６ 10. The compound of claim 1, which is alkyl (e.g., methyl or ethyl).

4. R with 0 to 3 Xs ２ The compound of any one of claims 1 to 3, wherein the aryl is substituted with aryl (for example, phenyl).

5. R where X appears 0 times ２ 5. The compound of claim 4, wherein the phenyl is substituted with

6. R with one occurrence of X ２ 5. The compound of claim 4, wherein the phenyl is substituted with

7. R ２ R appears 0 to 3 times ５ 7. The compound of claim 6, wherein the heteroaryl is substituted with , for example, 1-pyrazolyl or 5-pyrazolyl.

8. R ２ But -N(R ａ ) (R ５ 7. The compound of claim 6, wherein

9. R ａ is H or C １－６ alkyl (e.g., methyl), and R ５ But C １－６ 9. The compound of claim 8, which is alkyl (e.g., methyl).

10. R ａ is H and R ５ appears 0 or 1 time ６ C substituted with １－６ haloalkyl (e.g., trifluoromethyl or 1,1,1-trifluoroisopropyl), heterocycloalkyl (e.g., 3-tetrahydrofuranyl), and C ３－９ 9. The compound of claim 8, wherein the aryl group is selected from cycloalkyl (e.g., cyclobutyl or cyclopentyl).

11. R ６ But -CO ２ H, —C(O) ２ -C １－４ Alkyl (e.g., —CO ２ Me or -CO ２ Et), hydroxyl, and C １－４ 11. The compound of claim 10, wherein the alkyl is selected from alkyl (e.g., methyl).

12. R ２ But -N(R ａ ) C(O)-R ５ 7. The compound of claim 6, wherein:

13. R ａ is H, R ５ But C １－６ Alkyl (e.g., methyl, ethyl, or isopropyl) and C ３－９ cycloalkyl (e.g., cyclopropyl), each of which occurs 0 to 3 times. ６ is replaced by The compound of claim 12.

14. R ６ But -NH ２ , hydroxyl, halo (e.g., fluoro), and C １－４ 14. The compound of claim 13, selected from haloalkyl (e.g., trifluoromethyl).

15. R ２ R appears 0 to 3 times ５ 7. The compound of claim 6, wherein the heterocycloalkyl is substituted with N-pyrrolidinyl (eg, N-pyrrolidinyl).

16. Each R ５ R appears 0 to 3 times ６ C substituted with １－６ 16. The compound of claim 15, wherein the alkyl is selected from alkyl (e.g., methyl).

17. R ２ is -C(O)-N(R ａ ) (R ５ 7. The compound of claim 6, wherein

18. R ａ is H and R ５ R appears 0 to 3 times ６ C substituted with １－６ 18. The compound of claim 17, which is alkyl (e.g., methyl or ethyl).

19. R ２ But -N(R ａ )S(O)(NH)-R ５ 7. The compound of claim 6, wherein:

20. R ａ is H and R ５ R appears 0 to 3 times ６ C substituted with １－６ 20. The compound of claim 19, which is alkyl (e.g., methyl).

21. X is, 7. The compound of claim 6, wherein:

22. R with two Xs ２ 5. The compound of claim 4, wherein the phenyl is substituted with

23. Each R ２ 23. The compound of claim 22, wherein is halo (e.g., fluoro or chloro).

24. One R ２ But -NH ２ and one R ２ 23. The compound of claim 22, wherein is halo (e.g., fluoro).

25. On the other hand, R ２ But C １－６ alkyl (e.g., methyl), and the other R ２ But C １－６ 23. The compound of claim 22, which is haloalkyl (e.g., difluoromethyl).

26. On the other hand, R ２ is halo (e.g., fluoro), and the other R ２ But -N(R ａ ) (R ５ ) (e.g., -NHMe).

27. R ａ is H and R ５ R appears 0 to 3 times ６ C substituted with ３－９ 27. The compound of claim 26, which is cycloalkyl (e.g., cyclopentyl).

28. R ａ is H and R ５ R appears 0 to 3 times ６ 27. The compound of claim 26, wherein the heterocycloalkyl is substituted with , for example, 3-pyrrolidinyl.

29. R ６ But C １－６ 29. The compound of claim 27 or 28, which is alkyl (e.g., methyl).

30. X is, 23. The compound of claim 22, wherein:

31. R with three Xs ２ 5. The compound of claim 4, wherein the phenyl is substituted with

32. Two R's ２ is halo (e.g., fluoro), and the remaining R ２ But -NH ２ 32. The compound of claim 31 , wherein:

33. X is, 33. The compound of claim 32, wherein:

34. R with 0 to 3 Xs ２ The compound according to any one of claims 1 to 3, wherein the heteroaryl is a 5- to 6-membered heteroaryl substituted with

35. R with 0 to 3 Xs ２ 35. The compound of claim 34, wherein the substituted group is selected from pyridinyl, pyrazolyl, isoxazolyl, pyrazolyl, indolyl, thiazolyl, thiophenyl, or furanyl.

36. X is, -NH ２ , halo (e.g., fluoro or chloro), and 0 to 3 occurrences of R ５ C substituted with １－６ Alkoxy (e.g., methoxy or isopropoxy) One R selected from ２ 35. The compound of claim 34, which is 2-pyridinyl substituted with:

37. R ５ appears once or twice ６ C substituted with ３－９ 37. The compound of claim 36, which is cycloalkyl (e.g., cyclopropyl or cyclobutyl).

38. R ６ But C １－４ 38. The compound of claim 37, wherein the alkyl group is selected from haloalkyl (e.g., trifluoromethyl) and halo (e.g., fluoro).

39. R ２ But -N(R ａ ) SO ２ -R ５ 35. The compound of claim 34, wherein:

40. R ａ is H and R ５ R appears 0 to 3 times ６ C substituted with １－６ 40. The compound of claim 39, which is alkyl (e.g., methyl).

41. R ２ But -N(R ａ ) C(O)-R ５ or -N(R ａ ) (R ５ 35. The compound of claim 34, wherein

42. R ａ is H and R ５ R appears 0 to 3 times ６ C substituted with １－６ 42. The compound of claim 41, which is alkyl (e.g., methyl or isopropyl or neopentyl).

43. R ａ But C １－６ alkyl (e.g., methyl or ethyl), and R ５ R appears 0 to 3 times ６ C substituted with １－６ 42. The compound of claim 41, which is alkyl (e.g., methyl or isopropyl).

44. R ａ is H and R ５ R appears 0 to 3 times ６ C substituted with ３－９ 42. The compound of claim 41, which is cycloalkyl (e.g., cyclopropyl or cyclopentyl).

45. R ａ is H and R ５ R appears 0 to 3 times ６ C substituted with １－６ 42. The compound of claim 41, which is haloalkyl (e.g., 1,1,1-trifluoroisopropyl).

46. R ａ But C １－６ alkyl (e.g., methyl), and R ５ R appears 0 to 3 times ６ C substituted with １－６ 42. The compound of claim 41, which is haloalkyl (e.g., 2,2,2-trifluoroethyl).

47. R ６ But -CO ２ H or -CO ２ -C １－４ Alkyl (e.g., —CO ２ Me or -CO ２ Et).

48. R ２ R appears 0 to 3 times ５ C substituted with ３－９ cycloalkoxy (e.g., cyclopropoxy), C １－６ haloalkoxy (e.g., trifluoromethyl, 2,2-difluoroethyl, 1,1,1-trifluoroisopropyl, 1,1,1-trifluoro-tert-butyl, or 1,3-difluoroisopropyl), and C ３－９ 35. The compound of claim 34, wherein the cycloalkyl is selected from cycloalkyl (e.g., cyclopentyl or cyclohexyl).

49. R ２ R appears 0 to 3 times ５ 35. The compound of claim 34, wherein the heterocycloalkyl is heterocycloalkyl substituted with (e.g., azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl).

50. R ５ halo (e.g., fluoro), 0 to 3 occurrences of R ６ C substituted with １－６ alkyl (e.g., methyl), R ６ But -CO ２ H, and —CO ２ -C １－４ Alkyl (e.g., —CO ２ 50. The compound of claim 49, wherein the compound is selected from the group consisting of:

51. X is, 35. The compound of claim 34, wherein:

52. R with two Xs ２ 35. The compound of claim 34, which is 2-pyridinyl substituted with:

53. R ２ But -NH ２ 53. The compound of claim 52, wherein the aryl group is selected from , hydroxyl, and halo (e.g., fluoro).

54. X is, 54. The compound of claim 53, wherein:

55. R with 0 to 3 Xs ２ 35. The compound of claim 34, which is 3-pyrazolyl or 4-isoxazolyl substituted with

56. X is, 56. The compound of claim 55, wherein:

57. R with 0 to 3 Xs ２ 35. The compound of claim 34, which is 3-pyridinyl substituted with:

58. R ２ But -NH ２ , -N(R ａ ) SO ２ -R ５ , C １－６ 58. The compound of claim 57, wherein the alkyl is selected from alkoxy (eg, methoxy), and heterocycloalkyl (eg, N-oxetanyl).

59. R ａ is H and R ５ R appears 0 to 3 times ６ C substituted with １－６ 59. The compound of claim 58, which is alkyl (e.g., methyl).

60. X is, 59. The compound of claim 58, wherein:

61. R with 0 to 3 Xs ２ 35. The compound of claim 34, which is 5-thiazolyl substituted with:

62. R ２ But -NH ２ , halo (e.g., chloro), and —N(R ａ ) (R ５ 62. The compound of claim 61, wherein the compound is selected from:

63. R ａ is H and R ５ appears 0 or 1 time ６ C substituted with １－６ 63. The compound of claim 62, which is alkyl (e.g., ethyl).

64. but, 63. The compound of claim 62, wherein:

65. R with 0 to 3 Xs ２ 35. The compound of claim 34, which is 4-pyrazolyl substituted with:

66. R ２ 63. The compound of claim 62, wherein is selected from haloalkyl (eg, difluoromethyl), and heterocycloalkyl (eg, 3-tetrahydrofuranyl).

67. X is, 67. The compound of claim 66, wherein:

68. X is C １－６ Alkyl (e.g., methyl) and C １－６ two occurrences of R selected from haloalkyl (e.g., 1,1,1-trifluoroisopropyl); ２ 35. The compound of claim 34, which is 4-pyrazolyl substituted with:

69. X is, 69. The compound of claim 68, wherein:

70. R with 0 to 3 Xs ２ 35. The compound of claim 34, which is 6-indolyl, 3-thiazolyl, 4-thiazolyl, 3-thiophenyl, 4-pyridinyl substituted with:

71. R ２ But -NH ２ , nitro, hydroxyl, -N(R ａ ) (R ５ ), -N(R ａ ) C(O)-R ５ , and 0 to 3 occurrences of R ５ 71. The compound of claim 70, wherein the heterocycloalkyl is selected from heterocycloalkyl substituted with N-(N-pyrrolidinyl).

72. R ａ is H or C １－６ alkyl (e.g., methyl), and R ５ R appears 0 to 3 times ６ C substituted with １－６ 72. The compound of claim 71, which is alkyl (e.g., methyl).

73. X is, 72. The compound of claim 71, wherein:

74. Cy ２ However, 1 to 3 R appears ４ 74. The compound of any one of claims 1 to 73, wherein the compound is aryl substituted with

75. R ４ But C １－６ alkyl (e.g., methyl or isopropyl), C １－６ haloalkyl (e.g., trifluoromethyl, difluoromethyl, 2-fluoroisopropyl, or fluoromethyl), C １－６ alkoxy (e.g., methoxy, isopropoxy, or 3,3-dimethylbutoxy), C １－６ haloalkoxy (e.g., trifluoromethoxy) and C ３－６ 75. The compound of claim 74, wherein the cycloalkyl is selected from cycloalkyl (e.g., cyclopropyl).

76. Cy ２ but, 76. The compound of claim 75, wherein:

77. Cy ２ But, two or three occurrences of R ４ 76. The compound of claim 75, wherein the compound is phenyl substituted with

78. R ４ is halo (e.g., fluoro or chloro), C １－６ haloalkyl (e.g., trifluoromethyl or difluoromethyl), C １－６ Alkyl (e.g., methyl), C １－６ Alkoxy (e.g., isopropoxy), C １－６ haloalkoxy (e.g., trifluoromethoxy, 1,1,1-trifluoroisopropoxy, or difluoromethoxy) and —N(R ａ ) ２ (For example, -N(CH ３ ) ２ 78. The compound of claim 77, wherein the compound is selected from:

79. Cy ２ but, 76. The compound of claim 75, wherein:

80. Cy ２ However, 1 to 3 R appears ４ 75. The compound of any one of claims 1 to 74, which is a 5- to 6-membered heteroaryl (eg, 3-pyridinyl) substituted with

81. R ４ R appears 0 to 3 times ｂ 82. The compound of claim 81, wherein the heterocycloalkyl is a 4- to 10-membered heterocycloalkyl (e.g., N-pyrrolidinyl) substituted with:

82. Cy ２ but, 82. The compound of claim 81, wherein:

83. Cy ２ But C １－６ Alkyl (e.g., isopropyl) and C １－６ 1 to 3 occurrences of R selected from haloalkyl (e.g., trifluoroalkyl) ４ 82. The compound of claim 81, which is 3-pyrazolyl substituted with:

84. Cy ２ but, 84. The compound of claim 83, wherein:

85. Cy ２ but, 75. The compound according to any one of claims 1 to 74,

86. Cy １ R appears 0 to 3 times ３ 86. The compound of any one of claims 1 to 85, wherein the aryl is substituted with aryl (for example, phenyl).

87. R ３ But C １－８ Alkyl (e.g., o-isopropyl), C １－８ haloalkyl (e.g., m-trifluoromethyl, m-1,1-difluoro-3,3-dimethylbutyl, or m-1,1-difluoro-4,4-dimethylpentyl), and C １－８ 87. The compound of claim 86, wherein the alkoxy is selected from 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.

88. Cy １ but, 88. The compound of claim 87, wherein:

89. R ３ is selected from 5- to 6-membered heteroaryl (e.g., 5-thiazolyl) and 4- to 10-membered heterocycloalkyl (e.g., 2-azetidinyl or N-morpholinyl); ７ C is substituted with １－８ 88. The compound of claim 87, which is alkoxy (e.g., methoxy or ethoxy).

90. R ７ But C １－４ Alkyl (e.g., isopropyl), C(O)(C １－４ alkyl) (e.g., C(O)-t-butyl) and C(O)N(R ａ ) (C １－４ one R selected from C(O)—NH-t-butyl) ８ 90. The compound of claim 89, further substituted with:

91. Cy １ but, 88. The compound of claim 87, wherein:

92. R ３ But C １－８ 88. The compound of claim 87, which is haloalkoxy (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) or cycloalkyl (e.g., cyclopentyl).

93. Cy １ but, 88. The compound of claim 87, wherein:

94. R ３ But C １－４ haloalkoxy (e.g., trifluoromethoxy), C １－４ haloalkyl (e.g., 1,1-difluoroethyl or 2,2-difluoropropyl) and C １－４ one occurrence of R selected from alkyl (e.g., methyl) ７ 88. The compound of claim 87, wherein the cyclopentyl group is m-cyclopentyl or p-cyclopentyl substituted with

95. Cy １ but, 96. The compound of claim 95, wherein:

96. R ３ But C １－４ 0 to 3 occurrences of R selected from alkyl (e.g., methyl) ７ C further substituted with ３－９ 88. The compound of claim 87, which is cycloalkoxy (e.g., cyclopentoxy).

97. Cy １ but, 98. The compound of claim 97, wherein:

98. R ３ R appears 0 to 3 times ７ C substituted with １－４ Alkyl-C ３－９ cycloalkyl (e.g., cyclopentylmethyl) or C １－４ Alkoxy-C ３－９ 88. The compound of claim 87, which is cycloalkyl (e.g., cyclohexylmethoxy, cyclopropylmethoxy, or 2-cyclopropylethoxy).

99. R ７ is halo (e.g., fluoro), hydroxyl, C １－４ Alkyl (e.g., methyl) and C １－４ 99. The compound of claim 98, wherein the alkyl is selected from haloalkyl (e.g., trifluoromethyl).

100. Cy １ but, 100. The compound of claim 99, wherein:

101. R ３ R appears 0 to 3 times ７ or -C(O)-R ７ 88. The compound of claim 87, wherein the heteroaryl is substituted with (for example, 3-isoxazolyl).

102. R ７ R appears 0 to 3 times ８ C substituted with １－４ 102. The compound of claim 101, which is haloalkyl (eg, trifluoromethyl) or heterocycloalkyl (eg, N-pyrrolidinyl).

103. R ８ But C １－４ 103. The compound of claim 102, which is haloalkoxy (e.g., trifluoromethoxy) or halo (e.g., fluoro).

104. Cy １ but, 103. The compound of claim 102, wherein:

105. Cy １ But there are two R ３ 88. The compound of claim 87, wherein the compound is phenyl substituted with:

106. Each R ３ are independently halo (e.g., fluoro or chloro), C １－８ alkyl (e.g., methyl, ethyl, isobutyl, or neopentyl), C １－８ haloalkyl (e.g., difluoromethyl), C ３－９ cycloalkyl (e.g., cyclohexyl), C １－８ alkoxy (e.g., methoxy, ethoxy, propoxy, 3,3-dimethylbutoxy, 2,3-dimethylbutoxy, neopentyloxy, (3-methylbutanyl-2-yl)oxy, 2,3,3-trimethylbutoxy, (4,4-dimethylpentan-2-yl)oxy, isopentyloxy, 2,3,3-trimethylbutoxy or 2,3-dimethylbutoxy), C ３－９ Alkoxy (e.g., cyclopentoxy or cyclohexyloxy), C １－８ haloalkoxy (e.g., trifluoromethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy, 2,2-difluoro-3,3-dimethylbutoxy, 3,3,3-trifluoro-2-methylpropoxy, (1,1,1-trifluoropropan-2-yl)oxy, or 4,4,4-trifluoro-3-methylbutoxy), C １－４ Alkoxy-C ３－９ -cycloalkyl (methoxycyclobutyl or methoxycyclohexyl), C ３－９ Cycloalkenyl (e.g., cyclohexenyl), aryl (e.g., phenyl), heterocycloalkyl (e.g., pyrrolidinyl), —C(O)R ７ , and —C(O)N(R ａ ) (R ７ 106. The compound of claim 105, wherein the compound is selected from:

107. R ３ is hydroxyl, —C(O)—O—C １－４ Alkyl (e.g., —CO ２ Me), C １－４ Alkyl (e.g., methyl, isopropyl, t-butyl, neopentyl), C １－８ alkenyl (e.g., 2-methylprop-1-en-1-yl), C １－４ Alkoxy (e.g., methoxy), aralkoxy (e.g., benzoxy), C １－４ at least one R selected from haloalkoxy (e.g., trifluoromethoxy), and heterocycloalkyl (e.g., morpholinyl); ７ 107. The compound of claim 106, further substituted with:

108. Cy １ but, 107. The compound of claim 106, wherein:

109. Cy １ But there are three R ３ 88. The compound of claim 87, wherein the compound is phenyl substituted with:

110. Each R ３ are independently halo (e.g., fluoro), C １－８ Alkoxy (e.g., neopentyloxy or 3,3-dimethylbutoxy), and C ３－９ 110. The compound of claim 109, selected from cycloalkoxy (e.g., cyclopentoxy).

111. R ３ But C １－５ At least one R selected from alkyl (e.g., methyl) ７ 111. The compound of claim 110, further substituted with:

112. Cy １ but, 111. The compound of claim 110, wherein:

113. Cy １ R appears 0 to 3 times ３ 87. The compound of any one of claims 1 to 86, which is heterocycloalkyl substituted with:

114. 114. The compound of claim 113, wherein said heterocycloalkyl is selected from N-azetidinyl, N-pyrrolidinyl, N-morpholinyl, N-piperidinyl, N-piperidine-2-only, N-pyrrolidine-2-only, 3-tetrahydropyranyl, 3-(3,6-dihydro-2H-pyranyl), 2N-6-oxa-9-azaspiro[4.5]decanyl, 2N-6-oxa-2,9-diazaspiro[4.5]decanyl, 9-(oxa-9-azaspiro[4.5]decanyl), and 2-(3-oxa-1-azaspiro[4.4]non-1-enyl).

115. R ３ But C １－８ alkyl (e.g., methyl, neopentyl, 4,4-dimethylpentyl, 3-methylbutyl, or 3,3-dimethylbutyl), C １－８ Alkoxy (e.g., 3,3-dimethylbutoxy, neopentyloxy, or tert-butoxy), C １－８ haloalkoxy (e.g., trifluoromethoxy), and —C(O)—R ７ 115. The compound of claim 114, selected from:

116. Cy １ but, 115. The compound of claim 114, wherein:

117. Cy １ R appears 0 to 3 times ３ 87. The compound of any one of claims 1 to 86, which is heteroaryl substituted with:

118. 118. The compound of claim 117, wherein said heteroaryl is selected from 4-thiazolyl, 2-pyridinyl, 4-pyridinyl, 1-pyrazolyl, 3-pyrazolyl, 2-thiophenyl, 4-pyrazolyl, and 2-(1,3,4-thiadiazolyl).

119. R ３ halo (e.g., fluoro, chloro), C １－８ Alkyl (e.g., 3,3-dimethylbutyl), C １－８ haloalkyl (e.g., trifluoromethyl, 1,1-difluoroethyl, 4,4,4-trifluoro-3,3-dimethylbutyl or 5,5,5-trifluoro-4,4-dimethylpentan-2-yl), C １－８ Alkoxy (e.g., 3,3-dimethylbutoxy, neopentyloxy, or 4,4-dimethylpentyloxy), C １－８ haloalkoxy (e.g., 2,2,2-trifluoroethoxy, 3,3,3-trifluoro-2,2-dimethylpropoxy and 2,2-difluoro-3,3-dimethylbutoxy), C ３－９ Cycloalkyl (e.g., cyclohexyl), heterocycloalkyl (e.g., N-pyrrolidinyl), C １－４ Alkyl-C ３－９ Cycloalkyl, C １－４ Alkoxy-C ３－９ cycloalkyl, and -C(O)R ７ 119. The compound of claim 118, selected from:

120. R ３ is halo (e.g., fluoro), hydroxyl, C １－５ haloalkyl (e.g., 1,1-difluoroethyl), C １－５ haloalkoxy (e.g., trifluoromethoxy), and C ３－７ At least one R selected from cycloalkyl (e.g., cyclopentyl) ７ 120. The compound of claim 119, substituted by:

121. Cy １ but, 119. The compound of claim 118, wherein:

122. Cy １ R appears 0 to 3 times ３ 87. The compound of any one of claims 1 to 86, wherein the compound is cycloalkyl substituted with

123. The cycloalkyl is cyclohexyl or cyclopentyl, and R ３ But C １－８ 123. The compound of claim 122, which is alkoxy (e.g., 3,3-dimethylbutoxy).

124. Cy １ but, 124. The compound of claim 123, wherein:

125. R １ is hydrogen, X is a 5- to 6-membered aryl or a 5- to 6-membered heteroaryl, each of which occurs 0 to 3 times. ２ is replaced by Cy １ is a 5- to 6-membered aryl, a 4- to 10-membered heterocycloalkyl, or a 5- to 6-membered heteroaryl, each of which occurs 0 to 3 times. ３ is replaced by Cy ２ is a 5- to 6-membered aryl, and this occurs 1 to 3 times in R ４ is replaced by Each R ２ are independently halo, -NH ２ , C １－６ Alkyl, C １－８ haloalkoxy, 5- to 6-membered heteroaryl, —N(R ａ ) (R ５ ), -N(R ａ ) C(O)-R ５ , -SO-R ５ or -SO ２ -R ５ and Each R ３ But independently, Halo, C １－８ Alkyl, C １－８ Alkoxy, C １－８ Haloalkoxy, C ３－９ Cycloalkyl, C ３－９ cycloalkoxy, or 4- to 10-membered heterocycloalkyl, C ３－９ Cycloalkyl, C ３－９ Cycloalkoxy, C １－８ Haloalkoxy, C １－８ Alkoxy and 4- to 10-membered heterocycloalkyl each occur 0 to 3 times in R ７ is further substituted with Each R ４ But independently, Halo, C １－６ Alkyl, C １－６ Alkoxy, or C １－６ is haloalkyl, Each R ５ But independently, C １－６ Alkyl, C １－６ Haloalkyl, C ３－９ cycloalkyl, hydroxyl, or —CO ２ H and C １－６ Alkyl or C ３－９ Each cycloalkyl may occur 0 to 3 times. ６ is further replaced by Each R ６ are independently halo, hydroxyl, C １－６ Alkyl, —CO ２ H or -CO ２ -(C １－４ alkyl), Each R ７ But independently, Halo, C １－５ Alkyl, C １－５ Haloalkoxy, C ３－７ cycloalkyl, and hydroxyl; Each R ａ are independently H or C １－６ is alkyl, The compound of claim 1.

126. A compound selected from any of the compounds shown in Table 1.

127. A compound selected from any of the compounds shown in Table 2.

128. 128. The compound of any one of claims 1 to 127, which is a CFTR corrector.

129. A pharmaceutical composition comprising a compound according to any one of claims 1 to 128 and a pharmaceutically acceptable carrier or excipient.

130. 130. The pharmaceutical composition of claim 129, further comprising one or more CFTR therapeutic agents.

131. 129. A method of treating a deficiency in CFTR activity in a cell, comprising contacting said cell with a compound of any one of claims 1-128.

132. 132. The method of claim 131, wherein the contacting of the cell is performed in a subject in need thereof, thereby treating a CFTR-mediated condition and / or disease.

133. The disease or condition is selected from the group consisting of cystic fibrosis, asthma, smoking-induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild lung disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), congenital pneumonia, intestinal malabsorption, celiac disease, nasal polyposis, nontuberculous mycobacteriosis, pancreatic steatorrhea, intestinal atresia, liver disease, hereditary pulmonary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiency, protein C deficiency, type 1 hereditary angioedema, lipid processing deficiency, familial hypercholesterolemia, type 1 chylomya, abetalipoproteinemia, lysosomal storage disease, I-cell disease / pseudo-Hurler disease, mucopolysaccharidoses, Sandhoff / Tay-Sachs disease, Crigler's disease, and - Najjar disease type II, polyendocrinopathy / hyperinsulinemia, diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG1 type, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neurophyseal DI, nephrogenic DI, Charcot-Marie-Tooth syndrome, Pelizaeus-Merzbacher disease, neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, some polyglutamine neuropathies, Huntington's disease, spinocerebellar ataxia type I, spinal-bulbar muscular atrophy, dentatorubral-pallidoluysian dysplasia pallidoluysian), myotonic dystrophy, spongiform encephalopathy, hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry eye disease, Sjogren's syndrome, osteoporosis, osteopenia, bone healing and growth, bone repair, bone regeneration, decreased bone resorption, increased bone deposition, Gorham syndrome, chloride channelopathy, congenital myotonia, Bartter syndrome type III, Dent disease, hyperconvulsive disorder, epilepsy, hyperconvulsive disorder, lysosomal storage disease, Angelman syndrome, primary ciliary dyskinesia (PCD), PCD with situs inversus, PCD without situs inversus, and ciliary aplasia.

134. 134. The method of claim 132 or 133, wherein the disease or condition is selected from cystic fibrosis, congenital bilateral absence of the vas deferens (CBAVD), acute, recurrent, or chronic pancreatitis, disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis, congenital pneumonia, intestinal malabsorption, celiac disease, nasal polyposis, nontuberculous mycobacteriosis, pancreatic steatorrhea, intestinal atresia, chronic obstructive pulmonary disease (COPD), chronic sinusitis, dry eye disease, protein C deficiency, abetalipoproteinemia, lysosomal storage diseases, type 1 chylomyocarditis, mild pulmonary disease, lipid processing deficiency, hereditary angioedema type 1, coagulation-fibrinolysis, hereditary hemochromatosis, CFTR-associated metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, and Sjogren's syndrome.

135. 135. The method of any one of claims 133 to 134, wherein the disease or condition is cystic fibrosis.

136. 10. A method for treating cystic fibrosis or a symptom thereof in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1.

137. 137. The method of claim 136, wherein the subject is a human.

138. 138. The method of claim 136 or 137, wherein the subject is at risk of developing cystic fibrosis, and the administering step is performed prior to the onset of symptoms of cystic fibrosis in the subject.

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