Dihydroceramide desaturase inhibitors for treating diseases

Abstract

To provide new dihydroceramide desaturase (Des) inhibitor compounds and compositions, and their application as pharmaceuticals for the treatment of disease.SOLUTION: For example, the following compound is illustrated.SELECTED DRAWING: None

Description

Technical Field

[0001] This application claims the benefit of priority of U.S. Provisional Patent Application No. 62 / 616,253, filed on Jan. 11, 2018, the disclosure of which is incorporated herein by reference in its entirety as if set forth herein in full.

[0002] This disclosure relates to novel dihydroceramide desaturase (Des) inhibitor compounds and compositions, and their use as pharmaceuticals for the treatment of diseases. Methods of inhibiting dihydroceramide desaturase 1 (Des1) and / or Des2 activity in human or animal subjects are also provided for the treatment of metabolic, cardiovascular, fibrotic, renal, autoimmune / chronic inflammatory diseases, as well as cystic fibrosis, various cancers, lipid storage disorders, neurodegenerative disorders, and ischemia / reperfusion injury.

[0003] Statement Regarding Federally Sponsored Research or Development This invention was made with government support under grant number 2 R44 DK116450-02 awarded by the National Institutes of Health. The government has certain rights in this invention.

Background Art

[0004] Dihydroceramide desaturase catalyzes the formation of ceramide by introducing a 4,5-trans double bond into the sphingoid base backbone of dihydroceramide. Studies using cultured cells and isolated muscle have revealed that endogenous ceramide and glucosylceramide antagonize insulin-stimulated glucose uptake and anabolism, and thus may mimic the effects of exogenous sphingolipid analogs. Further, studies in obese rodent models have shown that genetic or pharmacological inhibition of ceramide or glucosylceramide biosynthesis is insulin-sensitizing. Thus, overproduction of ceramide is now recognized as an important nutrient metabolite that accumulates in obesity, alters cellular metabolism, promotes apoptosis, and thus causes many of the characteristic events associated with metabolic disease.

[0005] There are at least two isoforms of human dihydroceramide desaturase protein, Des1 and Des2. Des1 was first identified and is more broadly expressed, and thus most of the studies published so far have been on this isoform. Published data suggest that inhibitors of ceramide synthesis, i.e., inhibitors of dihydroceramide desaturase (e.g., Des1), may prove effective as therapeutic agents for treating insulin resistance and metabolic diseases. Furthermore, published data also suggest that inhibitors of dihydroceramide desaturase (e.g., Des1) may prove effective as therapeutic agents for treating various cancers, cystic fibrosis, fibrotic diseases, cardiovascular diseases, autoimmune / chronic inflammatory diseases, and ischemia-reperfusion injury.

[0006] Certain novel compounds and pharmaceutical compositions have been discovered that inhibit dihydroceramide desaturase, along with methods of use including methods for synthesizing the compounds and methods for treating a patient's metabolic disorder by administering the compounds. Detailed description Disclosure of the Invention

[0007] Embodiment 1 provided herein is a compound having the structure of formula (I) or a salt thereof. [Chemical formula] In the formula, L is selected from -C(=O)-, -S(=O)2-, -NR3S(=O)2-, -NR3C(=O)-, and -OC(=O)-, W is selected from -NH- and -O-, R 1 is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any of which may be optionally substituted with one, two, or three R 5 groups, R2 is selected from aryl and heteroaryl and may be optionally substituted with one, two or three R 4 groups; R 3 is H or is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any of which may be optionally substituted with one, two or three R 5 groups, or R 3 is joined to R 1 and the intervening N to form heterocycloalkyl, which may be optionally substituted with one, two or three R 5 groups; R 4 wherein at least one of R is hydroxy and the others may be one or more other optional substituents; 5 each R 6 is independently selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (aryl)alkyl, (heteroaryl)alkyl, (aryl)aryl, (heteroaryl)aryl, (aryl)heteroaryl, and (heteroaryl)heteroaryl and may be optionally substituted with one, two or three R each R 6 is independently selected from alkoxy, alkyl, amino, carboxy, cyano, halo, haloalkoxy, haloalkyl, and hydroxy.

[0008] The specific compounds disclosed herein have useful Des1 inhibitory activity and can be used for the treatment or prevention of diseases or conditions in which Des1 exerts its activity. Thus, in a broad aspect, certain embodiments provide a pharmaceutical composition comprising one or more of the compounds disclosed herein, together with a pharmaceutically acceptable carrier, and methods of making and using the compounds and the composition. Certain embodiments provide a method for inhibiting Des1. Other embodiments provide a method for treating a patient in need of treatment for a Des1-mediated disorder, the method comprising administering to the patient a therapeutically effective amount of a compound or composition according to the invention. Also provided is the use of a specific compound disclosed herein for use in the manufacture of a medicament for the treatment of a disease or condition ameliorated by inhibition of Des1.

[0009] In certain embodiments, L is -C(=O)-.

[0010] In certain embodiments, L is selected from -S(=O)2-, -NR3S(=O)2-.

[0011] In certain embodiments, L is -S(=O)2-.

[0012] In certain embodiments, L is -NR3S(=O)2-.

[0013] In certain embodiments, L is selected from -NR3C(=O)- and -OC(=O)-.

[0014] In certain embodiments, L is -NR3C(=O)-.

[0015] In certain embodiments, L is -OC(=O)-.

[0016] In certain embodiments, W is -NH-.

[0017] In certain embodiments, W is -O-.

[0018] In certain embodiments, R 2 is selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl and is optionally substituted with one or two R 4 groups.

[0019] In certain embodiments, R 2 is selected from phenyl, pyridinyl, pyridazinyl, and pyrazinyl and is substituted with one or two R 4 groups.

[0020] In certain embodiments, R 2 is selected from phenyl and pyridin-2-yl and is substituted with one or two R 4 groups.

[0021] In certain embodiments, R 2 is selected from phenyl and pyridin-2-yl and is optionally substituted with one or two R 4 groups.

[0022] In certain embodiments, R 3 is bonded to R 1 and the intervening N to form a heterocycloalkyl, which is optionally substituted with one, two, or three R 5 groups.

[0023] In certain embodiments, R 3 is bonded to R 1 and the intervening N to form a 6-membered heterocycloalkyl, which is optionally substituted with one or two R 5 groups.

[0024] In certain embodiments, R 3 is bonded to R 1 and the intervening N to form a piperidine or piperazine ring substituted with an R 5 group.

[0025] In certain embodiments, R 3 is bonded to R 1and combines with the intervening N to form a 7-membered heterocycloalkyl, which is optionally substituted with 1 or 2 R 5 groups.

[0026] In certain embodiments, R 3 is, 1 and combines with the intervening N to form an azepane or diazepane ring substituted with an R 5 group.

[0027] In certain embodiments, R 5 is selected from alkyl and heteroalkyl and is optionally substituted with 1 or 2 R 6 groups.

[0028] In certain embodiments, R 5 is selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl and is optionally substituted with 1 or 2 R 6 groups.

[0029] In certain embodiments, R 5 is selected from phenyl and pyridinyl and is optionally substituted with 1 or 2 R 6 groups.

[0030] In certain embodiments, R 5 is phenyl optionally substituted with 1 or 2 R 6 groups.

[0031] In certain embodiments, R 5 is pyridinyl optionally substituted with 1 or 2 R 6 groups.

[0032] In certain embodiments, R 5 is selected from (aryl)alkyl and (heteroaryl)alkyl, any of which is optionally substituted with 1 or 2 R 6 groups.

[0033] In certain embodiments, R 5is selected from (aryl)methyl and (heteroaryl)methyl, any of which is optionally substituted with one or two R 6 groups.

[0034] In certain embodiments, R 5 is (phenyl)methyl and is optionally substituted with one or two R 6 groups.

[0035] In certain embodiments, R 5 is selected from 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4-(trifluoromethyl)phenyl, 4-(trifluoromethyl)pyridin-2-yl, 5-(trifluoromethyl)pyridin-2-yl, 5-fluoropyridin-2-yl, and 3,5-difluoropyridin-2-yl.

[0036] In certain embodiments, R 5 is selected from 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, and 4-(trifluoromethyl)phenyl.

[0037] In certain embodiments, R 5 is selected from 4-(trifluoromethyl)pyridin-2-yl, 5-(trifluoromethyl)pyridin-2-yl, 5-fluoropyridin-2-yl, and 3,5-difluoropyridin-2-yl.

[0038] In certain embodiments, R 5 is selected from 4-fluorophenyl, 4-(trifluoromethyl)phenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 5-fluoropyridin-2-yl, and 5-(trifluoro)pyridin-2-yl.

[0039] In certain embodiments, each R 6 is independently selected from halo, haloalkyl, and cyano.

[0040] In certain embodiments, each R6 is independently selected from halo and haloalkyl.

[0041] In certain embodiments, each R 6 is independently selected from fluoro, chloro, and trifluoromethyl.

[0042] In certain embodiments, each R 6 is independently selected from fluoro and chloro.

[0043] In certain embodiments, each R 6 is independently selected from fluoro and trifluoromethyl.

[0044] The present disclosure provides further embodiments:

[0045] Embodiment 2: In the formula, each R 4 is independently selected from alkyl, alkoxy, cyano, halo, and hydroxy, and at least one R 4 is hydroxy, the compound according to Embodiment 1.

[0046] Embodiment 3: In the formula, each R 4 is independently selected from cyano, halo, and hydroxy, and at least one R 4 is hydroxy, the compound according to Embodiment 2.

[0047] Embodiment 4: In the formula, each R 4 is hydroxy, the compound according to Embodiment 3.

[0048] Embodiment 5: In the formula, R 2 is selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, and is optionally substituted with one, two, or three R 4 groups, the compound according to any one of Embodiments 1 to 4.

[0049] Embodiment 6: In the formula, R 2 is selected from phenyl, pyridin-2-yl, pyridazin-3-yl, pyrimidin-2-yl, and pyrazin-2-yl, and one, two, or three R 4 groups, and the compound according to Embodiment 5, which is optionally substituted.

[0050] Embodiment 7: In the formula, R 2 is selected from phenyl, pyridin-2-yl, pyridazin-3-yl, and pyrimidin-2-yl, and one, two, or three R 4 groups, and the compound according to Embodiment 5, which is optionally substituted.

[0051] Embodiment 8: In the formula, R 2 is selected from phenyl and pyridin-2-yl, and one, two, or three R 4 groups, and the compound according to Embodiment 7, which is optionally substituted.

[0052] Embodiment 9: In the formula, R 2 is pyridin-2-yl, and one, two, or three R 4 groups, and the compound according to Embodiment 8, which is substituted.

[0053] Embodiment 10: In the formula, R 2 is substituted with one, two, or three R 4 groups, and at least one R 4 is hydroxy, and the compound according to any one of Embodiments 1 to 9.

[0054] Embodiment 11: In the formula, R 2 is substituted with one or two R 4 groups, and at least one R 4 is hydroxy, and the compound according to Embodiment 10.

[0055] Embodiment 12: In the formula, R 2 is substituted with one hydroxy group, and the compound according to Embodiment 11.

[0056] Embodiment 13: In the formula, R 2 is a para-position R 4 group substituted from the bonding point of W, and the compound according to any one of Embodiments 10 to 12.

[0057] Embodiment 14: In the formula, R 2 is substituted with a hydroxy group at the para-position from the bonding point of W, and the compound according to Embodiment 13.

[0058] Embodiment 15: In the formula, R 2 is 4-hydroxyphenyl, and the compound according to Embodiment 1.

[0059] Embodiment 16: In the formula, R 2 is 5-hydroxypyridin-2-yl, and the compound according to Embodiment 1.

[0060] Embodiment 17: In the formula, R 2 is 5-hydroxypyrimidin-2-yl, and the compound according to Embodiment 1.

[0061] Embodiment 18: In the formula, R 2 is 5-hydroxypyrazin-2-yl, and the compound according to Embodiment 1.

[0062] Embodiment 19: In the formula, R 2 is 6-hydroxypyridazin-3-yl, and the compound according to Embodiment 1.

[0063] Embodiment 20: In the formula, W is -NH-, and the compound according to any one of Embodiments 1 to 19.

[0064] Embodiment 21: In the formula, W is -O-, and the compound according to any one of Embodiments 1 to 19.

[0065] Embodiment 22: In the formula, L is selected from -C(=O)-, -S(=O)2-, and -OC(=O)-, and the compound according to any one of Embodiments 20 and 21.

[0066] Embodiment 23: The compound according to Embodiment 22, wherein L is -C(=O)-.

[0067] Embodiment 24: The compound according to Embodiment 22, wherein L is -S(=O)2-.

[0068] Embodiment 25: The compound according to Embodiment 22, wherein L is -OC(=O)-.

[0069] Embodiment 26: The compound according to any one of Embodiments 20 and 21, wherein L is selected from -NR 3 S(=O)2- and -NR 3 C(=O)-.

[0070] Embodiment 27: The compound according to Embodiment 26, wherein L is -NR 3 S(=O)2-.

[0071] Embodiment 28: The compound according to Embodiment 26, wherein L is -NR 3 C(=O)-.

[0072] Embodiment 29: The compound according to any one of Embodiments 1 to 19, wherein L-W is -NR 3 C(=O)NH-.

[0073] Embodiment 30: The compound according to any one of Embodiments 1 to 19, wherein L-W is -NR 3 C(=O)O-.

[0074] Embodiment 31: The compound according to any one of Embodiments 1 to 19, wherein L-W is -NR 3 S(=O)2NH-.

[0075] Embodiment 32: The compound according to any one of Embodiments 1 to 19, wherein L-W is -OC(=O)NH-.

[0076] Embodiment 33: A compound according to any one of Embodiments 1 to 19, wherein L-W is -S(=O)2NH-.

[0077] Also, in the present specification, having structural formula II,

Chemical formula

[0078] In a specific embodiment of the compound of formula II, X is N.

[0079] In a specific embodiment of the compound of formula II, X is CH.

[0080] In a specific embodiment of the compound of formula II, n is 1.

[0081] In a specific embodiment of the compound of formula II, n is 2.

[0082] Also, in the present specification, having structural formula III,

Chemical formula

[0083] Embodiment 36: A compound according to any one of Embodiments 34 and 35, wherein N is 1.

[0084] Embodiment 37: A compound according to any one of Embodiments 34 and 35, wherein N is 2.

[0085] Embodiment 38: A compound according to any one of Embodiments 34 to 37, wherein Y is CH.

[0086] Embodiment 39: A compound according to any one of Embodiments 34 to 37, wherein Y is N.

[0087] Also, herein, having structural formula IV,

Chemical formula

[0088] Also, herein, having structural formula V,

Chemical formula

[0089] Embodiment 42: A compound according to any one of Embodiments 34 to 41, wherein X is CH.

[0090] Embodiment 43: A compound according to any one of Embodiments 34 to 41, wherein X is N.

[0091] Embodiment 44: In the formula, R 3 is H, and the compound according to any one of Embodiments 26 to 31 and 41.

[0092] Embodiment 45: In the formula, R 3 is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with one, two, or three R 5 groups, and the compound according to any one of Embodiments 26 to 31 and 41.

[0093] Embodiment 46: In the formula, R 3 is bonded to R 1 and the intervening N to form heterocycloalkyl, which is optionally substituted with one, two, or three R 5 groups, and the compound according to any one of Embodiments 26 to 31 and 41.

[0094] Embodiment 47: In the formula, R 3 is bonded to R 1 and the intervening N to form 6-membered heterocycloalkyl, which is optionally substituted with one, two, or three R 5 groups, and the compound according to Embodiment 46.

[0095] Embodiment 48: In the formula, R 3 is bonded to R 1 and the intervening N to form a piperidine or piperazine ring, which is optionally substituted with one, two, or three R 5The compound according to embodiment 47, optionally substituted with a radical.

[0096] Embodiment 49: In the formula, R 3 is combined with R 1 and the intervening N to form a 7-membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 R 5 radicals, the compound according to embodiment 46.

[0097] Embodiment 50: In the formula, R 3 is combined with R 1 and the intervening N to form an azepane or diazepane ring, which is optionally substituted with 1, 2, or 3 R 5 radicals, the compound according to embodiment 49.

[0098] Embodiment 51: In the formula, the heterocycloalkyl formed by the bond of R 3 , R 1 , and the intervening N is optionally substituted with 1 or 2 R 5 radicals, the compound according to any one of embodiments 46 to 50.

[0099] Embodiment 52: In the formula, the heterocycloalkyl formed by the bond of R 3 , R 1 , and the intervening N is substituted with 1 or 2 R 5 radicals, the compound according to embodiment 51.

[0100] Embodiment 53: In the formula, the heterocycloalkyl formed by the bond of R 3 , R 1 , and the intervening N is optionally substituted with 1 R 5 radical, the compound according to embodiment 51.

[0101] Embodiment 54: R 3 , R 1 , and the heterocycloalkyl formed by the bond of the intervening N is substituted with 1 R 5 radical, the compound according to embodiment 53.

[0102] Embodiment 55: In the formula, R 3 , R 1 , and the heterocycloalkyl formed by the bond of the intervening N is unsubstituted, the compound according to Embodiment 53.

[0103] Embodiment 56: In the formula, R 1 is selected from C 1-16 alkyl, C 3-7 cycloalkyl, 3- to 7-membered monocyclic heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, any of which is optionally substituted with one, two, or three R 5 groups, the compound according to any one of Embodiments 1 to 45.

[0104] Embodiment 57: In the formula, R 1 is selected from cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuryl, tetrahydropyranyl, oxepanyl, pyrrolidinyl, piperidinyl, and azepanyl, any of which is optionally substituted with one, two, or three R 5 groups, the compound according to Embodiment 56.

[0105] Embodiment 58: In the formula, R 1 is selected from cyclopentyl, cyclohexyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, and piperidinyl, any of which is optionally substituted with one, two, or three R 5 groups, the compound according to Embodiment 57.

[0106] Embodiment 59: In the formula, R 1 is selected from phenyl, naphthalenyl, quinolinyl, isoquinolinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrimidinyl, and pyrazinyl, any of which is optionally substituted with one, two, or three R 5 groups, the compound according to Embodiment 56.

[0107] Embodiment 60: In the formula, R 1is selected from phenyl and pyridine, any of which is optionally substituted with 1, 2, or 3 R 5 groups, the compound according to embodiment 59.

[0108] Embodiment 61: In the formula, R 1 is C 1-12 alkyl, and is optionally substituted with 1, 2, or 3 R 5 groups, the compound according to embodiment 56.

[0109] Embodiment 62: In the formula, R 1 is C 1-10 alkyl, and is optionally substituted with 1, 2, or 3 R 5 groups, the compound according to embodiment 61.

[0110] Embodiment 63: In the formula, R 1 is C 1-8 alkyl, and is optionally substituted with 1, 2, or 3 R 5 groups, the compound according to embodiment 62.

[0111] Embodiment 64: In the formula, R 1 is C 4-8 alkyl, and is optionally substituted with 1, 2, or 3 R 5 groups, the compound according to embodiment 63.

[0112] Embodiment 65: In the formula, R 1 is C 6-8 alkyl, and is optionally substituted with 1, 2, or 3 R 5 groups, the compound according to embodiment 64.

[0113] Embodiment 66: In the formula, R 1 is optionally substituted with 1 or 2 R 5 groups, the compound according to any one of embodiments 1 to 45 and 56 to 65.

[0114] Embodiment 67: In the formula, R 1 is substituted with 1 or 2 R 5 groups, the compound according to embodiment 66.

[0115] Embodiment 68: In the formula, R 1 is a compound according to Embodiment 66, optionally substituted with a 1R 5 group.

[0116] Embodiment 69: In the formula, R 1 is a compound according to Embodiment 68, substituted with one R 5 group.

[0117] Embodiment 70: In the formula, R 1 is a compound according to Embodiment 66, which is unsubstituted.

[0118] Embodiment 71: In the formula, R 1 is (CH2) m CH3, and m is an integer between 3 and 15, inclusive, and is a compound according to Embodiment 56.

[0119] Embodiment 72: In the formula, m is less than 14, and is a compound according to Embodiment 71.

[0120] Embodiment 73: In the formula, m is less than 12, and is a compound according to Embodiment 72.

[0121] Embodiment 74: In the formula, m is less than 10, and is a compound according to Embodiment 73.

[0122] Embodiment 75: In the formula, m is less than 8, and is a compound according to Embodiment 74.

[0123] Embodiment 76: In the formula, m is less than 6, and is a compound according to Embodiment 75.

[0124] Embodiment 77: In the formula, m is greater than 4, and is a compound according to any one of Embodiments 71 to 76.

[0125] Embodiment 78: In the formula, m is greater than 6, and is a compound according to any one of Embodiments 71 to 75.

[0126] Embodiment 79: A compound according to any one of Embodiments 71 to 74, wherein m is greater than 8.

[0127] Embodiment 80: A compound according to any one of Embodiments 71 to 73, wherein m is greater than 10.

[0128] Embodiment 81: A compound according to Embodiment 56, wherein R 1 is

Chemical formula

[0129] Embodiment 82: A compound according to Embodiment 56, wherein R 1 is

Chemical formula

[0130] Embodiment 83: A compound according to any one of Embodiments 81 and 82, wherein L is -C(=O).

[0131] Embodiment 84: A compound according to Embodiment 83, wherein W is -NH-.

[0132] Embodiment 85: A compound according to any one of Embodiments 1 to 54, 56 to 69, and 81 to 84, wherein R 5 is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (aryl)methyl, and (heteroaryl)methyl, and is optionally substituted with one, two, or three R 6 groups.

[0133] Embodiment 86: A compound according to Embodiment 85, wherein R 5 is selected from phenyl, naphthyl, monocyclic heteroaryl, and bicyclic heteroaryl, and is optionally substituted with one or two R 6 groups.

[0134] Embodiment 87: In the formula, R 5 is selected from quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, pyrrolopyridinyl, and imidazopyridinyl, and is optionally substituted with one or two R 6 groups, and the compound according to Embodiment 86.

[0135] Embodiment 88: In the formula, R 5 is indazolyl, and is optionally substituted with one or two R 6 groups, and the compound according to Embodiment 87.

[0136] Embodiment 89: In the formula, R 5 is selected from indazol-4-yl and indazol-6-yl, and is optionally substituted with one or two R 6 groups, and the compound according to Embodiment 88.

[0137] Embodiment 90: In the formula, R 5 is selected from pyrrolyl, imidazolyl, and pyrazolyl, and is optionally substituted with one or two R 6 groups, and the compound according to Embodiment 86.

[0138] Embodiment 91: In the formula, R 5 is selected from indolyl and indazolyl, and is optionally substituted with one or two R 6 groups, and the compound according to Embodiment 86.

[0139] Embodiment 92: In the formula, R 5 is selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, and is optionally substituted with one or two R 6 groups, and the compound according to Embodiment 86.

[0140] Embodiment 93: In the formula, R 5 is selected from phenyl, pyridinyl, and pyrimidinyl, and is optionally substituted with one or two R 6 groups, and the compound according to Embodiment 86.

[0141] Embodiment 94: In the formula, R 5 is selected from phenyl, pyridin-2-yl, and pyrimidin-2-yl, and one or two R 6 groups, and the compound according to Embodiment 86.

[0142] Embodiment 95: In the formula, R 5 is selected from (aryl)alkyl, (heteroaryl)alkyl, and one or two R 6 groups, and the compound according to Embodiment 85.

[0143] Embodiment 96: In the formula, R 5 is selected from (aryl)methyl, (heteroaryl)methyl, and one or two R 6 groups, and the compound according to Embodiment 95.

[0144] Embodiment 97: In the formula, R 5 is (phenyl)methyl, and one or two R 6 groups, and the compound according to Embodiment 96.

[0145] Embodiment 98: In the formula, each R 5 is optionally substituted with one or two R 6 groups, and the compound according to any one of Embodiments 1 to 54, 56 to 69, 81 to 84, and 85 to 97.

[0146] Embodiment 99: In the formula, each R 5 is substituted with one or two R 6 groups, and the compound according to Embodiment 98.

[0147] Embodiment 100: In the formula, each R 5 is optionally substituted with one R 6 group, and the compound according to Embodiment 98.

[0148] Embodiment 101: In the formula, each R 5 is substituted with one R 6 group, and the compound according to Embodiment 100.

[0149] Embodiment 102: In the formula, each R 5 is unsubstituted, and the compound according to Embodiment 100.

[0150] Embodiment 103: In the formula, each R 6 is independently selected from alkoxy, alkyl, amino, cyano, halo, haloalkoxy, haloalkyl, and hydroxy, and the compound according to any one of Embodiments 1 to 54, 56 to 69, 81 to 84, and 85 to 101.

[0151] Embodiment 104: In the formula, each R 6 is independently selected from cyano, halo, hydroxy, and haloalkyl, and the compound according to Embodiment 103.

[0152] Embodiment 105: In the formula, each R 6 is independently selected from halo and haloalkyl, and the compound according to Embodiment 104.

[0153] Embodiment 106: In the formula, each R 6 is independently selected from fluoro, chloro, and trifluoromethyl, and the compound according to Embodiment 105.

[0154] Embodiment 107: In the formula, each R 6 is independently selected from halo and trifluoromethyl, and the compound according to Embodiment 106.

[0155] Embodiment 108: In the formula, each R 6 is independently selected from fluoro, chloro, methoxy, methyl, cyano, trifluoromethyl, and trifluoromethoxy, and the compound according to Embodiment 103.

[0156] Also, the following embodiments are provided: Embodiment C-2: In the formula, L is selected from -S(=O)2-, -NR3S(=O)2-, -NR3C(=O)-, and -OC(=O)-, and the compound according to Embodiment 1.

[0157] Embodiment C-3: In the formula, each R 4 is independently selected from cyano, halo, and hydroxy, the compound of Embodiment C-2.

[0158] Embodiment C-4: In the formula, R 2 is selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, and the compound of Embodiment C-3 substituted with one or two R 4 groups.

[0159] Embodiment C-5: In the formula, R 2 is substituted with an R 4 group para to the point of attachment of W, the compound of Embodiment C-4.

[0160] Embodiment C-6: In the formula, R 2 is

Chemical formula

[0161] Embodiment C-7: In the formula, L is -NR3C(=O)-, the compound of Embodiment C-6.

[0162] Embodiment C-8: In the formula, L is -OC(=O)-, the compound of Embodiment C-7.

[0163] Embodiment C-10: In the formula, X is N, the compound of Embodiment 34.

[0164] Embodiment C-11: In the formula, R 5 is selected from aryl and heteroaryl and is optionally substituted with one or two R 6 groups, the compound of Embodiment C-10.

[0165] Embodiment C-12: In the formula, each R 6The compound of embodiment C-11, wherein each is independently selected from alkyl, halo, haloalkyl, and hydroxy.

[0166] Embodiment C-13: wherein R 5 is selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, and the compound of embodiment C-12, optionally substituted with one or two R 6 groups.

[0167] Embodiment C-14: wherein each R 6 is independently selected from halo and trifluoromethyl, and the compound of embodiment C-13.

[0168] Embodiment C-15: wherein n is 1, and the compound of embodiment C-14.

[0169] Embodiment C-16: wherein W is NH, and the compound of embodiment C-15.

[0170] Embodiment C-17: wherein Y is N, and the compound of embodiment C-16.

[0171] Embodiment C-18: wherein R 5 is selected from phenyl and pyridin-2-yl, and the compound of embodiment C-17, optionally substituted with one or two R 6 groups.

[0172] Embodiment C-19: wherein each R 6 is independently selected from fluoro and trifluoromethyl, and the compound of embodiment C-18.

[0173] Embodiment C-20: wherein R 5 is selected from 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4-(trifluoromethyl)phenyl, 4-(trifluoromethyl)pyridin-2-yl, 5-(trifluoromethyl)pyridin-2-yl, 5-fluoropyridin-2-yl, and 3,5-difluoropyridin-2-yl, and the compound of embodiment C-19.

[0174] Embodiment C-21: In the formula, R 5 is 2,4-difluorophenyl, the compound of Embodiment C-20.

[0175] Embodiment C-23: In the formula, X is N, the compound of Embodiment 35.

[0176] Embodiment C-24: In the formula, Y is N, the compound of Embodiment C-23.

[0177] Embodiment C-25: In the formula, each R 6 is independently selected from halo and trifluoromethyl, the compound of Embodiment C-24.

[0178] Embodiment C-26: In the formula, R 5 is selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, and is optionally substituted with one or two R 6 groups, the compound of Embodiment C-25.

[0179] Embodiment C-27: In the formula, R 5 is selected from phenyl and pyridin-2-yl, and is optionally substituted with one or two R 6 groups, the compound of Embodiment C-26.

[0180] Embodiment C-28: In the formula, each R 6 is independently selected from fluoro and chloro, the compound of Embodiment C-27.

[0181] Embodiment C-29: In the formula, R 5 is selected from 4-fluorophenyl, 4-chlorophenyl, 4-(trifluoromethyl)phenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 5-fluoropyridin-2-yl, and 5-(trifluoro)pyridin-2-yl, the compound of Embodiment C-28.

[0182] Embodiment C-30: [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] The compound of Embodiment 1 selected from

[0183] Also provided are embodiments in which any of the above embodiments can be combined with any one or more of these embodiments, and the combinations are not mutually exclusive.

[0184] As used herein, two embodiments are "mutually exclusive" if one is defined as being different from the other. For example, an embodiment in which two groups combine to form a cycloalkyl is mutually exclusive with an embodiment in which one group is ethyl and the other group is hydrogen. Similarly, an embodiment in which one group is CH2 is mutually exclusive with an embodiment in which the same group is NH.

[0185] Compounds selected from the examples disclosed herein are also provided.

[0186] The present invention also relates to a method of inhibiting at least one Des1 function, comprising the step of contacting a compound described herein with Des1. Changes in cell phenotype, cell proliferation, Des1 activity, biochemical output produced by active Des1, Des1 expression, or binding to a natural binding partner of Des1 can be monitored. Such methods can be in the form of disease treatment modalities, biological assays, cell assays, biochemical assays, and the like.

[0187] Also provided herein is a method of treating a Des1-mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a salt thereof disclosed herein.

[0188] Also provided herein are compounds disclosed herein for use as a medicament.

[0189] Also provided herein are compounds disclosed herein for use as a medicament for treating a Des1-mediated disease.

[0190] Also provided is the use of a compound disclosed herein as a medicament.

[0191] Also provided is the use of a compound disclosed herein as a medicament for treating a Des1-mediated disease.

[0192] Also provided are compounds disclosed herein for use in the manufacture of a medicament for treating a Des1-mediated disease.

[0193] Also provided is the use of a compound disclosed herein for treating a Des1-mediated disease.

[0194] Also provided herein is a method of inhibiting Des1, comprising contacting Des1 with a compound or a salt thereof disclosed herein.

[0195] In certain embodiments, the Des1-mediated disease is a metabolic disorder selected from metabolic syndrome, diabetes, dyslipidemia, hypertriglyceridemia, hypercholesterolemia, fatty liver disease, alcoholic liver disease, non-alcoholic steatohepatitis, obesity, and insulin resistance.

[0196] In some embodiments, the Des1-mediated disease is a lipid storage disorder selected from Farber disease, Niemann-Pick disease, Fabry disease, Krabbe disease, Gaucher disease, Tay-Sachs disease, and metachromatic leukodystrophy.

[0197] In certain embodiments, the Des1-mediated disease is an autoimmune disease.

[0198] In certain embodiments, the Des1-mediated disease is a chronic inflammatory disease.

[0199] In certain embodiments, the Des1-mediated disease is a cardiovascular disease.

[0200] In certain embodiments, the Des1-mediated disease is fibrosis or a related disease.

[0201] In certain embodiments, the Des1-mediated fibrosis is selected from pulmonary fibrosis, cystic fibrosis, liver fibrosis, cirrhosis, atrial fibrosis, endomyocardial fibrosis, articular fibrosis, myelofibrosis, glial scar, Peyronie's disease, progressive massive fibrosis, pneumoconiosis, retroperitoneal fibrosis, scleroderma, systemic sclerosis, abdominal adhesions, and adhesive synovitis.

[0202] In certain embodiments, the Des1-mediated fibrosis is cystic fibrosis.

[0203] In certain embodiments, the Des1-mediated disease is cancer.

[0204] In certain embodiments, Des1-mediated cancers are selected from leukemia, lymphoma, ovarian cancer, breast cancer, endometrial cancer, colon cancer (colorectal cancer), rectal cancer, bladder cancer, lung cancer (non-small cell lung cancer, lung adenocarcinoma, squamous cell lung cancer), bronchial cancer, bone cancer, prostate cancer, pancreatic cancer, gastric cancer, hepatocellular cancer, gallbladder cancer, bile duct cancer, esophageal cancer, renal cell cancer, thyroid cancer, head and neck squamous cell cancer (head and neck cancer), testicular cancer, endocrine gland cancer, adrenal gland cancer, pituitary gland cancer, skin cancer, soft tissue cancer, blood vessel cancer, brain cancer, nerve cancer, eye cancer, meninges cancer, oropharyngeal cancer, hypopharyngeal cancer, cervical cancer, and uterine cancer, glioblastoma, medulloblastoma, astrocytoma, glioma, meningioma, gastrinoma, neuroblastoma, melanoma, myelodysplastic syndrome, and sarcoma.

[0205] Also provided is the use of a compound disclosed herein for treating ischemia / reperfusion injury.

[0206] Also provided is the use of a compound disclosed herein for treating ischemia / reperfusion injury that occurs in organ transplantation, acute kidney injury, cardiopulmonary bypass, pulmonary hypertension, sickle cell disease, myocardial infarction, stroke, surgical resection and reconstruction surgery, reattachment of appendages or other body parts, skin grafting, or trauma.

[0207] Also provided is a method of modulating Des1-mediated function in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein.

[0208] Also provided is a pharmaceutical composition comprising a compound disclosed herein together with a pharmaceutically acceptable carrier.

[0209] In certain embodiments, the pharmaceutical composition is formulated for oral administration.

[0210] In certain embodiments, the oral pharmaceutical composition is selected from tablets and capsules.

[0211] Abbreviations and Definitions As used herein, the following terms have the indicated meanings.

[0212] When introducing elements of the present disclosure or preferred embodiments (s) thereof, the articles "a", "an", "the", and "said" are intended to mean that one or more of the elements are present. The terms "comprising", "including", and "having" are intended to be inclusive and mean that additional elements other than the recited elements may exist.

[0213] The term "and / or" when used in a list of two or more items means that any one of the listed items can be used by itself or in combination with any one or more of the listed items. For example, the expression "A and / or B" is intended to mean either or both of A and B, i.e., only A, only B, or a combination of A and B. The expression "A, B, and / or C" is intended to mean only A, only B, only C, a combination of A and B, a combination of A and C, a combination of B and C, or a combination of A, B, and C.

[0214] When a range of values is disclosed and the notation "n1... to n2" or "between n1... and n2" is used, where n1 and n2 are numbers, this notation is intended to include the numbers themselves and the range between them, unless otherwise specified. This range can be integral or continuous between and including the end values. By way of example, the range "2 to 6 carbon atoms" is intended to include 2, 3, 4, 5, and 6 carbon atoms since carbon is in integer units. By way of example, compare the range "1 to 3 μM (micromolar)", which is intended to include 1 μM, 3 μM, and everything in between, to any number of significant values (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0215] As used herein, the term "about" is intended to modify a numerical value such that it indicates a variable within the range of error. When no specific error, such as a standard deviation relative to an average value given in a graph or data table, is listed, the term "about" is understood to mean a range that includes the recited value and ranges that are included by rounding up or down that numerical value, taking into account significant figures.

[0216] As used herein, the term "acyl" refers, alone or in combination, to a carbonyl bonded to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety where the atom bonded to the carbonyl is carbon. An "acetyl" group refers to a -C(O)CH3 group. An "alkylcarbonyl" or "alkanoyl" group refers to an alkyl group bonded to the parent molecular moiety through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl, and aroyl.

[0217] As used herein, the term "alkenyl" refers, alone or in combination, to a straight or branched chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, the alkenyl will contain from 2 to 6 carbon atoms. The term "alkenylene" refers to a carbon-carbon double bond system bonded at two or more positions such as ethenylene [(-CH=CH-), (-C::C-)]. Examples of suitable alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl, and the like. Unless otherwise specified, the term "alkenyl" may include "alkenylene" groups.

[0218] As used herein, the term "alkoxy," alone or in combination, refers to an alkyl ether group, and the term alkyl is as defined below. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

[0219] As used herein, the term "alkyl," alone or in combination, refers to a straight or branched chain alkyl radical containing from 1 to 20 carbon atoms. In certain embodiments, alkyl will contain from 1 to 10 carbon atoms. In further embodiments, alkyl will contain from 1 to 6 carbon atoms. The alkyl group may be optionally substituted as defined herein. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl, nonyl, and the like. As used herein, the term "alkylene," alone or in combination, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon bonded at two or more positions such as methylene (-CH2-). Unless otherwise specified, the term "alkyl" may include an "alkylene" group.

[0220] The term "straight chain alkyl" refers to an alkyl radical containing from 1 to 20 carbon atoms in an unbranched, straight chain arrangement. Examples of straight chain alkyl radicals include n-octyl (-CH2CH2CH2CH2CH2CH2CH2CH2-), n-butyl (-CH2CH2CH2CH2-), and ethyl (-CH2CH2-).

[0221] As used herein, the term "alkylamino," alone or in combination, refers to an alkyl group bonded to a parent molecule moiety through an amino group. Suitable alkylamino groups are mono- or dialkylated and can form groups such as, for example, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino, and the like.

[0222] As used herein, the term "alkylidene," alone or in combination, refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.

[0223] As used herein, the term "alkylthio," alone or in combination, refers to an alkylthioether (R-S-) radical, where the term alkyl is as defined above and sulfur may be mono- or dioxygenated. Examples of suitable alkylthioether radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

[0224] As used herein, the term "alkynyl," alone or in combination, refers to a straight or branched chain hydrocarbon radical having one or more triple bonds and containing 2 to 20 carbon atoms. In certain embodiments, alkynyl contains 2 to 6 carbon atoms. In further embodiments, alkynyl contains 2 to 4 carbon atoms. The term "alkynylene" refers to a carbon-carbon triple bond bonded at two positions such as ethynylene (-C:::C-, -C≡C-). Examples of alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like. Unless otherwise specified, the term "alkynyl" may include an "alkynylene" group.

[0225] As used herein, the terms "amide" and "carbamoyl", alone or in combination, refer to the amino groups described below that are attached to the parent molecular moiety via a carbonyl group or vice versa. As used herein, the term "C-amide", alone or in combination, refers to a -C(O)N(RR') group, where R and R' are as defined herein or as defined by the "R" groups listed in the specified details. As used herein, the term "N-amide", alone or in combination, refers to an RC(O)N(R')- group, where R and R' are as defined herein or as defined by the "R" groups listed in the specified details. As used herein, the term "acylamino", alone or in combination, encompasses an acyl group attached to the parent moiety via an amino group. An example of an "acylamino" group is acetylamino (CH3C(O)NH-).

[0226] As used herein, the term "amino", alone or in combination, refers to -NRR', where R and R' are independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may be optionally substituted on its own. Further, R and R' may be joined to form a heterocycloalkyl, any of which may be optionally substituted.

[0227] As used herein, the term "aryl", alone or in combination, means a carbocyclic aromatic system containing one, two, or three rings, such polycyclic ring systems being fused together. The term "aryl" encompasses aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl.

[0228] As used herein, the terms "arylalkenyl" or "aralkenyl", alone or in combination, refer to an aryl group attached to the parent molecular moiety via an alkenyl group.

[0229] As used herein, the term "arylalkoxy" or "aralkoxy", alone or in combination, refers to an aryl group bonded to the parent molecular moiety through an alkoxy group.

[0230] As used herein, the term "arylalkyl" or "aralkyl", alone or in combination, refers to an aryl group bonded to the parent molecular moiety through an alkyl group.

[0231] As used herein, the term "arylalkynyl" or "aralkynyl", alone or in combination, refers to an aryl group bonded to the parent molecular moiety through an alkynyl group.

[0232] As used herein, the term "arylalkanoyl" or "aralkanoyl" or "aroyl", alone or in combination, refers to an acyl radical derived from an aryl-substituted alkane carboxylic acid such as benzoyl, naphthoyl, phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, etc.

[0233] As used herein, the term aryloxy, alone or in combination, refers to an aryl group bonded to the parent molecular moiety through oxy.

[0234] As used herein, the terms "benzo" and "benz", alone or in combination, refer to the divalent radical C6H4= derived from benzene. Examples include benzothiophene and benzimidazole.

[0235] As used herein, the term "carbamate", alone or in combination, refers to an ester of carbamic acid (-NHCOO-) that can be bonded to the parent molecular moiety from either the nitrogen or the acid terminus and can be optionally substituted as defined herein.

[0236] As used herein, the term "O-carbamyl" alone or in combination refers to the group -OC(O)NRR' having R and R' as defined herein.

[0237] As used herein, the term "N-carbamyl" alone or in combination refers to the group ROC(O)NR'- having R and R' as defined herein.

[0238] As used herein, the term "carbonyl" alone includes formyl [-C(O)H] and in combination is the group -C(O)-.

[0239] As used herein, the terms "carboxyl" or "carboxy" refer to -C(O)OH or the corresponding "carboxylate" anion such as in a carboxylate salt. The "O-carboxy" group refers to the group RC(O)O-, where R is as defined herein. The "C-carboxy" group refers to the group -C(O)OR, where R is as defined herein.

[0240] As used herein, the term "cyano" alone or in combination refers to -CN.

[0241] As used herein, the term "cycloalkyl", or alternatively "carbocyclic", alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic, or tricyclic alkyl group, each cyclic moiety containing from 3 to 12 carbon atoms in the ring members and optionally being an optionally substituted benzo-fused ring system as defined herein. In certain embodiments, cycloalkyl will contain from 5 to 7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl, and the like. As used herein, "bicyclic" and "tricyclic" are intended to include both fused ring systems, e.g., decahydronaphthalene, octahydronaphthalene, as well as polycyclic (polycentric) saturated or partially unsaturated types. Isomers of the latter type are generally exemplified by bicyclo[1,1,1]pentane, camphor, adamantane, and bicyclo[3,2,1]octane.

[0242] As used herein, the term "ester", alone or in combination, refers to a carboxy group that bridges two moieties bonded through a carbon atom.

[0243] As used herein, the term "ether", alone or in combination, refers to an oxy group that bridges two moieties bonded through a carbon atom.

[0244] As used herein, the term "halo" or "halogen", alone or in combination, refers to fluorine, chlorine, bromine, or iodine.

[0245] As used herein, the term "haloalkoxy", alone or in combination, refers to a haloalkyl group bonded to the parent molecular moiety through an oxygen atom.

[0246] As used herein, the term "haloalkyl" alone or in combination refers to an alkyl radical having the meaning defined above, wherein one or more hydrogens are replaced by halogen. Specifically, mono-haloalkyl, di-haloalkyl, and poly-haloalkyl radicals are included. A mono-haloalkyl radical can have, for example, an iodine, bromo, chloro, or fluoro atom within the radical. Di-halo and poly-haloalkyl radicals can have two or more of the same halo atoms, or a combination of different halo radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "Haloalkylene" refers to a haloalkyl group bonded at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF2-), chloromethylene (-CHCl-), etc.

[0247] As used herein, the term "heteroalkyl" alone or in combination refers to a stable straight-chain, branched-chain, or combination thereof, including fully saturated or 1 to 3 degrees of unsaturation, consisting of a specified number of carbon atoms and 1 to 3 heteroatoms selected from N, O, and S, wherein the N and S atoms can be optionally oxidized and the N heteroatom can be optionally quaternized. The heteroatom(s) can be located at any internal position of the heteroalkyl group. Up to two heteroatoms can be consecutive, for example, -CH2-NH-OCH3.

[0248] As used herein, the term "heteroaryl", alone or in combination, refers to an unsaturated heterocyclic ring of 3 to 15 members, or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic, and contains at least one atom selected from N, O, and S. In certain embodiments, heteroaryl will contain 1 to 4 heteroatoms as ring members. In further embodiments, heteroaryl will contain 1 to 2 heteroatoms as ring members. In certain embodiments, heteroaryl will contain 5 to 7 atoms. The term also encompasses fused polycyclic groups in which a heterocyclic ring is fused to an aryl ring, a heteroaryl ring is fused to another heteroaryl ring, a heteroaryl ring is fused to a heterocycloalkyl ring, or a heteroaryl ring is fused to a cycloalkyl ring. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazopyrrolidinyl, tetrahydroisoquinolinyl, thienopyridinyl, phenopyridinyl, pyrropyridinyl, pyrrolidinyl, and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidryl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[0249] As used herein, the term "heterocycloalkyl" and interchangeably "heterocycle" each refer, alone or in combination, to a saturated, partially unsaturated, or fully unsaturated (but non-aromatic) monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, where each heteroatom can independently be selected from nitrogen, oxygen, and sulfur. In certain embodiments, heterocycloalkyl will contain from 1 to 4 heteroatoms as ring members. In further embodiments, heterocycloalkyl will contain from 1 to 2 heteroatoms as ring members. In certain embodiments, heterocycloalkyl will contain from 3 to 8 ring members in each ring. In further embodiments, heterocycloalkyl will contain from 3 to 7 ring members in each ring. In even further embodiments, heterocycloalkyl will contain from 5 to 6 ring members in each ring. "Heterocycloalkyl" and "heterocycle" are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, as well as carbocyclic fused and benzo-fused ring systems, and further, both terms include systems where the heterocycle as defined herein is fused to an aryl group or additional heterocyclic group. Examples of heterocyclic groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. The heterocyclic group can be optionally substituted, unless otherwise prohibited.

[0250] As used herein, the term "hydrazinyl" refers, alone or in combination, to two amino groups linked by a single bond, i.e., -N-N-.

[0251] As used herein, the term "hydroxy" refers, alone or in combination, to -OH.

[0252] As used herein, the term "hydroxyalkyl", alone or in combination, refers to a hydroxy group bonded to a parent molecular moiety via an alkyl group.

[0253] As used herein, the term "imino", alone or in combination, refers to =N-.

[0254] As used herein, the term "iminohydroxy", alone or in combination, refers to =N(OH) and =N-O-.

[0255] The phrase "in the main chain" refers to the longest continuous or adjacent chain of carbon atoms starting from the point of attachment of a group to any one of the compounds of the formulas disclosed herein.

[0256] The term "isocyanate" refers to the -NCO group.

[0257] The term "isothiocyanato" refers to the -NCS group.

[0258] The phrase "straight chain of atoms" refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen, and sulfur.

[0259] As used herein, the term "lower", alone or in combination, means containing from 1 to 6 carbon atoms (i.e., C1-C6 alkyl) unless otherwise specifically defined.

[0260] As used herein, the term "lower aryl", alone or in combination, means phenyl or naphthyl, either of which may be optionally substituted as provided.

[0261] As used herein, the term "lower heteroaryl", alone or in combination, means 1) a monocyclic heteroaryl containing 5 or 6 ring members, wherein 1 to 4 of the ring members can be heteroatoms selected from N, O, and S, or 2) a bicyclic heteroaryl, wherein each of the fused rings contains 5 or 6 ring members containing 1 to 4 heteroatoms selected from N, O, and S between them.

[0262] As used herein, the term "lower cycloalkyl", alone or in combination, means a monocyclic cycloalkyl having 3 to 6 ring members (i.e., C3-C6 cycloalkyl). Lower cycloalkyl can be unsaturated. Examples of lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0263] As used herein, the term "lower heterocycloalkyl", alone or in combination, means a monocyclic heterocycloalkyl having 3 to 6 ring members, 1 to 4 of which can be heteroatoms selected from N, O, and S (i.e., C3-C6 heterocycloalkyl). Examples of lower heterocycloalkyl include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyl can be unsaturated.

[0264] As used herein, the term "lower amino", alone or in combination, refers to -NRR', where R and R' are independently selected from the group consisting of hydrogen, alkyl, and lower heteroalkyl, any of which can be optionally substituted. Further, R and R' of the lower amino group can be joined to form a 5- or 6-membered heterocycloalkyl, any of which can be optionally substituted.

[0265] As used herein, the term "mercaptilyl", alone or in combination, refers to an RS group, where R is as defined herein.

[0266] As used herein, the term "nitro" refers to -NO2, either alone or in combination.

[0267] As used herein, the term "oxy" or "oxa" refers to -O-, either alone or in combination.

[0268] As used herein, the term "oxo" refers to =O, either alone or in combination.

[0269] The term "perhaloalkoxy" refers to an alkoxy group in which all hydrogen atoms are replaced by halogen atoms.

[0270] As used herein, the term "perhaloalkyl" refers to an alkyl group in which all hydrogen atoms are replaced by halogen atoms, either alone or in combination.

[0271] As used herein, the terms "sulfonate", "sulfonic acid", and "sulfonic" refer to the -SO3H group and its anions when sulfonic acid is used for salt formation, either alone or in combination.

[0272] As used herein, the term "sulfanyl" refers to -S-, either alone or in combination.

[0273] As used herein, the term "sulfinyl" refers to -S(O)-, either alone or in combination.

[0274] As used herein, the term "sulfonyl" refers to -S(O)2-, either alone or in combination.

[0275] The term "N-sulfonamide" refers to an RS(=O)2NR'- group having R and R' as defined herein.

[0276] The term "S-sulfonamide" refers to an -S(=O)2NRR' group having R and R' as defined herein.

[0277] As used herein, the terms "thia" and "thio", alone or in combination, refer to an -S- group or an ether in which oxygen is replaced by sulfur. Oxidation derivatives of the thio group, namely, sulfinyl and sulfonyl, are included in the definitions of thia and thio.

[0278] As used herein, the term "thiol" refers to an -SH group, alone or in combination.

[0279] As used herein, the term "thiocarbonyl", when alone, includes thioformyl -C(S)H, and when in combination, is a -C(S)- group.

[0280] The term "N-thiocarbamyl" refers to an ROC(S)NR'- group having R and R' as defined herein.

[0281] The term "O-thiocarbamyl" refers to an -OC(S)NRR' group having R and R' as defined herein.

[0282] The term "thiocyanato" refers to a -CNS group.

[0283] The term "trihalomethanesulfonamide" refers to an X3CS(O)2NR- group in which X is halogen and having R as defined herein.

[0284] The term "trihalomethanesulfonyl" refers to an X3CS(O)2- group, where X is halogen.

[0285] The term "trihalomethoxy" refers to an X3CO- group, where X is halogen.

[0286] As used herein, the term "trisubstituted silyl" refers to a silicone group substituted with three free valences by groups listed herein under the definition of substituted amino, either alone or in combination. Examples include trimethylsilyl, tert-butyldimethylsilyl, triphenylsilyl, and the like.

[0287] Any definition herein can be used in combination with any other definition to describe a complex structural group. By convention, the subsequent elements of any such definition are the elements that attach to the parent moiety. For example, the complex group alkylamide represents an alkyl group attached to the parent molecule via an amide group, and the term alkoxyalkyl represents an alkoxy group attached to the parent molecule via an alkyl group.

[0288] When a group is defined as "null", it means that the group is absent.

[0289] The term "optionally substituted" means that the precursor group can be substituted or unsubstituted. When substituted, the substituents of an "optionally substituted" group can independently include, alone or in combination, one or more substituents selected from the following groups or a particular specified set of groups, but are not limited thereto: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkynyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxyalkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkyl carboxylate ester, lower carboxamide, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amide, nitro, thiol, lower alkylthio, lower haloalkylthio, lower haloalkylthio, lower haloalkylthio, aryl, thio, sulfonate, sulfonic acid, trisubstituted silyl, N3, SH, SCH3, C(O)CH3, CO2CH3, CO2H, pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Where structurally possible, two substituents can be joined together to form a 5-, 6-, or 7-membered fused carbon or heterocyclic ring consisting of 0 to 3 heteroatoms, such as methylenedioxy or ethylenedioxy. An optionally substituted group can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully substituted and monosubstituted (e.g., -CH2CF3). When a substituent is described without limitation as to substitution, both substituted and unsubstituted forms are included. When a substituent is limited as "substituted", the substituted form is specifically intended. Further, different sets of optional substituents for a particular moiety can be defined as needed, in which case any substitution is as defined, and often follows immediately after the phrase "optionally substituted".

[0290] The term R or the term R’ is presented by itself and without numerical designation, unless otherwise defined, and refers to a moiety selected from hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, and heterocycloalkyl, any of which may be optionally substituted. It should be understood that such R and R’ groups are optionally substituted as defined herein. Whether or not the R group has a numerical designation, R, R’, and all R n groups including R (wherein n = (1, 2, 3,...n), all substituents, and all terms are to be understood as being independent of one another with respect to selection from the groups. Any variability, substituent, or term (e.g., aryl, heterocycle, R, etc.) that appears more than once in a formula or general structure has its definition at each occurrence independent of its definition at other occurrences. One of ordinary skill in the art will further recognize that a particular group may be bonded to the parent molecule or occupy a position in the chain of elements from either terminus as described. For example, an asymmetric group such as -C(O)N(R)- can be bonded to the parent moiety at either carbon or nitrogen.

[0291] Asymmetric centers are present in the compounds disclosed herein. These centers are designated by the symbols "R" or "S" depending on the arrangement of the substituents around the chiral carbon atoms. It is to be understood that the present disclosure encompasses all stereochemical isomeric forms, including diastereomers, enantiomers, and epimeric forms, as well as d and l isomers, and mixtures thereof. The individual stereoisomers of the compounds can be prepared synthetically from commercially available starting materials containing chiral centers, or by separation such as the preparation of mixtures of enantiomeric products followed by conversion to mixtures of diastereomers, followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other suitable method known in the art. Specific stereochemical starting compounds are either commercially available or can be made and resolved by techniques known in the art. Further, the compounds disclosed herein may exist as geometric isomers. The present disclosure includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, and suitable mixtures thereof. Further, the compounds may exist as tautomers, and all tautomers are provided by the present disclosure. Compounds containing a hydroxypyridine group may contain pyridone tautomers to varying degrees. Both the hydroxypyridine and pyridone tautomeric forms are provided by the present disclosure. Further, the compounds disclosed herein can exist in unsolvated and solvated forms using pharmaceutically acceptable solvents such as water, ethanol. In general, solvated forms are considered equivalent to unsolvated forms.

[0292] The term "bond" refers to a covalent bond between two atoms, or between two moieties, when the atoms linked by the bond are considered part of a larger substructure. The bond can be single, double, or triple, unless otherwise specified. A dashed line between two atoms in a molecular drawing indicates that additional bonds may or may not be present at that position.

[0293] As used herein, the term "disease" is generally synonymous with the terms "disorder", "syndrome", and "condition", and is intended to be used interchangeably with these terms (as well as medical conditions), all reflecting an abnormal condition of a human or animal body, or a part thereof, that impairs normal function, typically manifested by distinguishing signs and symptoms, and resulting in a reduced life span or quality of life for a human or animal.

[0294] The term "combination therapy" means the administration of two or more therapeutic agents for treating a treatment condition or disorder described in the present disclosure. Such administration includes co-administering these therapeutic agents substantially simultaneously, such as within a single capsule having a fixed ratio of active ingredients, or within a plurality of separate capsules for each active ingredient. In addition, such administration also includes using each type of therapeutic agent sequentially. In either case, the treatment regimen will provide the beneficial effects of the drug combination in treating the conditions or disorders described herein.

[0295] The term "Des" means dihydroceramide desaturase and includes Des1 and Des2 isoforms. It should be understood that when modulation of Des1 by a compound is referred to, the compound may also modulate other isoforms unless specifically stated to be selective for Des1.

[0296] The term "Des inhibitor" (including Des1 inhibitor) is used herein and refers to a compound that exhibits an IC 50 for Des activity of about 100 μM or less, more typically about 50 μM or less, as measured in, for example, the Des1 cell assay generally described below. IC 50 is the concentration of an inhibitor that reduces the activity of an enzyme (e.g., Des) by half. Certain compounds disclosed herein have been found to exhibit inhibition against Des. In certain embodiments, the compound exhibits an IC 50 for Des of about 10 μM or less, and in further embodiments, the compound exhibits an IC for Des of about 5 μM or less.50 is shown, and in yet further embodiments, the compound has an IC with respect to Des of about 1 μM or less 50 is shown, and in yet further embodiments, the compound has an IC with respect to Des of about 200 nM or less 50 is shown, and in yet further embodiments, the compound has an IC with respect to Des of about 100 nM or less 50 is shown, and in yet further embodiments, the compound has an IC with respect to Des of about 50 nM or less 50 is shown, and in yet further embodiments, the compound has an IC with respect to Des of about 25 nM or less 50 is shown, and in yet further embodiments, the compound has an IC with respect to Des of about 10 nM or less 50 will be shown.

[0297] The term "fibrosis" describes the development of fibrous connective tissue as a repair response to injury or damage. When referred to as a disease to be treated herein, fibrosis means the pathological formation / deposition of excessive fibrous connective tissue in an organ or tissue that interferes with normal organ or body function.

[0298] The phrase "therapeutically effective" is intended to limit the amount of an active ingredient used in the treatment of a disease or disorder or the effect on a clinical endpoint.

[0299] The term "therapeutically acceptable" refers to a compound (or salt, prodrug, tautomer, zwitterionic form, etc.) that is suitable for use in contact with the tissues of a patient without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio, and effective for their intended use.

[0300] As used herein, "treating," "treatment," etc. mean ameliorating, improving, or eliminating one or more of the cause, progression, severity, or symptoms thereof, or otherwise beneficially modifying the disease of interest in the subject. References to "treating" or "treatment" of a patient are intended to include prevention. Treatment can also be essentially prophylactic, i.e., can include prevention of disease in a subject exposed to or at risk of the disease. Prevention of a disease can involve complete protection from the disease, as in the case of preventing infection by a pathogen, or can involve prevention of progression of a disease, such as from pre-diabetes to diabetes. For example, prevention of a disease does not mean complete elimination of any and all effects associated with the disease, but rather can mean preventing the symptoms of the disease from reaching a clinically significant or detectable level. Prevention of a disease can also mean prevention of progression to a later stage of the disease.

[0301] In the present disclosure, the term "radiation" means ionizing radiation, including particles or photons that have sufficient energy or can generate sufficient energy through nuclear interactions to produce ionization (acquisition or loss of electrons). Exemplary and preferred ionizing radiation is X-rays. Means for delivering X-rays to a target tissue or cell are well known in the art. The amount of ionizing radiation required in a given cell generally depends on the nature of that cell. Means for determining an effective amount of radiation are well known in the art. As used herein, the term "effective dose" means a dose of ionizing radiation that results in an increase in cell damage or death.

[0302] The term "radiation therapy" refers to the use of electromagnetic or particulate radiation in the treatment of tumors and includes the use of ionizing and non-ionizing radiation.

[0303] The term "patient" is generally synonymous with the term "subject" and includes all mammals including humans. Examples of patients include humans, domestic animals such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

[0304] The term "prodrug" refers to a compound that is more activated in vivo. Certain compounds disclosed herein may also exist as prodrugs. A prodrug of a compound described herein is a structurally modified form of the compound that readily undergoes a chemical change under physiological conditions to provide the compound. In addition, a prodrug can be converted to the compound by chemical or biochemical means in an ex vivo environment. For example, a prodrug can be slowly converted to the compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because they may in some cases be easier to administer than the compound or the parent drug. They may be, for example, bioavailable by oral administration, while the parent drug is not. Prodrugs can have improved solubility in a pharmaceutical composition compared to the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. By way of non-limiting example, one example of a prodrug is a compound that is administered as an ester but is then metabolically hydrolyzed to the carboxylic acid that is the active substance. Further examples include peptidyl derivatives of the compound.

[0305] The compounds disclosed herein can exist as therapeutically acceptable salts. The present disclosure includes the compounds listed above in the form of salts including acid addition salts. Suitable salts include salts formed with both organic and inorganic acids. Such acid addition salts will generally be pharmaceutically acceptable. However, salts of pharmaceutically unacceptable acids can be useful in the preparation and purification of the compound in question. Basic addition salts may also be formed and are pharmaceutically acceptable.

[0306] As used herein, the term "therapeutically acceptable salt" refers to salts or zwitterionic forms of the compounds disclosed herein that are water- or oil-soluble or dispersible and therapeutically acceptable, as defined herein. Salts can be prepared separately during the final isolation and purification of the compound or by reacting the appropriate compound in the free base form with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisinate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthalenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, paratoluenesulfonate (p-tosylate), and undecanoate. Also, the bases in the compounds disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides, dimethyl, diethyl, dibutyl, and diamyl sulfates, decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides, benzyl bromide, and phenethyl bromide. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, citric acid. Salts can also be formed by coordinating the compound with alkali metal or alkaline earth ions. Accordingly, the present disclosure contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, among others.

[0307] Basic addition salts can be prepared during the final isolation and purification of the compound by reacting a carboxy group with a suitable base such as a metal cation hydroxide, carbonate, or bicarbonate, or by reacting with ammonia or an organic primary, secondary, or tertiary amine. Cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and non-toxic quaternary amine cations such as N,N'-dibenzylethylenediamine. Other representative organic amines useful in the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0308] Salts of the compound can be made by reacting the appropriate compound in free base form with a suitable acid.

[0309] Pharmaceutical composition While it may be possible to administer the compounds of the present disclosure as raw chemical substances, it is also possible to present them as pharmaceutical formulations. Accordingly, provided herein are pharmaceutical formulations comprising one or more of the specific compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, one or more pharmaceutically acceptable carriers, and optionally one or more other therapeutic ingredients. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to its recipient. Suitable formulations depend on the chosen route of administration. Any of the well-known techniques, carriers, and excipients may be suitable and may be used as understood in the art. The pharmaceutical compositions disclosed herein may be manufactured by any method known in the art, for example, by conventional mixing, dissolving, granulating, tablet coating, pulverizing, emulsifying, encapsulating, entrapping, or compression processes.

[0310] Formulations suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intra-articular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal, and topical (including dermal, buccal, sublingual, and intraocular) administration are included, although the most suitable route may depend, for example, on the condition and disorder of the recipient. The formulations may be conveniently presented in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art. Typically, these methods involve associating the compounds of the present disclosure, or pharmaceutically acceptable salts, esters, amides, prodrugs, or solvates thereof (“active ingredient”), with a carrier which constitutes one or more accessory ingredients. Generally, the formulations are prepared by uniformly and intimately associating the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

[0311] Formulations of the compounds disclosed herein may be presented as discrete units such as capsules, tablets, cachets, packets, or ampoules, each containing a predetermined quantity of the active ingredient.

[0312] The compounds described in this specification can be administered as follows.

[0313] Oral administration The compounds of the present disclosure may be administered orally, including swallowing, and thus the compounds may enter the gastrointestinal tract or be absorbed directly from the mouth into the bloodstream, including sublingual or buccal administration.

[0314] Compositions suitable for oral administration include solid formulations such as tablets, pills, cachets, lozenges, and hard or soft capsules, which may contain liquids, gels, powders, or granules.

[0315] In tablet or capsule dosage forms, the amount of drug present can be from about 0.05% to about 95% by weight of the dosage form, more typically from about 2% to about 50% by weight.

[0316] In addition, tablets or capsules may contain a disintegrant in an amount from about 0.5% to about 35% by weight of the dosage form, more typically from about 2% to about 25% by weight. Examples of disintegrants include methylcellulose, sodium or calcium carboxymethylcellulose, croscarmellose sodium, polyvinylpyrrolidone, hydroxypropylcellulose, starch, and the like.

[0317] Binders suitable for use in tablets include gelatin, polyethylene glycol, sugars, gums, starch, hydroxypropylcellulose, and the like. Diluents suitable for use in tablets include mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, and starch.

[0318] Surfactants and fluidizing agents suitable for use in tablets or capsules may be present in an amount from about 0.1% to about 3% by weight and include polysorbate 80, sodium dodecyl sulfate, talc, and silicon dioxide.

[0319] Lubricants suitable for use in tablets or capsules may be present in an amount of about 0.1% to about 5% by weight and include calcium stearate, zinc stearate, or magnesium stearate, sodium stearyl fumarate, and the like.

[0320] Tablets can be prepared by compression or molding, optionally using one or more auxiliary components. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as powder or granules, in a suitable machine and optionally mixing with a binder, an inert diluent, or a lubricant, surfactant, or dispersant. Molded tablets can be prepared by molding a mixture of a powdered compound moistened with a liquid diluent in a suitable machine. Dyes or pigments can be added to the tablets for identification or to characterize different combinations of the active compound dosage.

[0321] Liquid formulations can include emulsions, solutions, syrups, elixirs, and suspensions and can be used in soft or hard capsules. Such formulations can include a pharmaceutically acceptable carrier, such as water, ethanol, polyethylene glycol, cellulose, or oil. The formulations can also include one or more emulsifying and / or suspending agents.

[0322] Compositions for oral administration can be formulated, optionally with an enteric coating, as immediate release or modified release, including delayed release or sustained release.

[0323] In another embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0324] Pharmaceutical formulations that can be used orally include tablets, gelatin push-fit capsules, and sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets can be prepared by compression or molding, optionally using one or more auxiliary components. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form such as powder or granules with a suitable machine and optionally mixing with a binder, an inert diluent, or a lubricant, surfactant, or dispersant. Molded tablets can be prepared by molding a mixture of a powdered compound moistened with an inert liquid diluent with a suitable machine. Tablets can optionally be coated or scored and formulated to provide sustained or controlled release of the active ingredient. All formulations for oral administration should be in a dosage suitable for such administration. Push-fit capsules can contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Additionally, a stabilizer can be added. The sugar-coated tablet core is provided with a suitable coating. For this purpose, a concentrated sugar solution that can optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture can be used. Dyes or pigments can be added to the tablets or the sugar-coated tablet coating for identification or to characterize different combinations of the active compound dosage.

[0325] Parenteral administration The compounds of the present disclosure can be administered directly into the bloodstream, muscle, or viscera by injection, for example, by bolus injection or continuous infusion. Suitable means for parenteral administration include intravenous, intramuscular, intra-subcutaneous arterial, intraperitoneal, intrathecal, intracranial, etc. Suitable devices for parenteral administration include syringes (including needles and needleless syringes) and infusion methods. The formulations can be presented in unit dose or multi-dose containers, for example, sealed ampoules and vials.

[0326] Most parenteral formulations are aqueous solutions containing salts, buffers, suspending agents, stabilizers, and / or dispersing agents, antioxidants, bacteriostatic agents, preservatives, and solutes that render the formulation isotonic with the blood of the intended recipient, and excipients including carbohydrates.

[0327] Parenteral formulations can also be prepared in dehydrated form (e.g., by lyophilization) or as sterile non-aqueous solutions. These formulations can be used with suitable vehicles such as sterile water. Solubility enhancers can also be used in the preparation of parenteral solutions. Compositions for parenteral administration can be formulated as immediate release or modified release, including delayed release or sustained release. The compounds can also be formulated as depot preparations. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymers or hydrophobic materials (e.g., as emulsions in acceptable oils) or ion exchange resins, or as poorly soluble derivatives, for example, as poorly soluble salts.

[0328] The compound can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Injectable formulations can be presented in unit dosage form, for example, in ampoules or multi-dose containers, with added preservatives as appropriate. The composition can take the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and can contain formulation agents such as suspending agents, stabilizers and / or dispersing agents. The formulation can be provided in unit dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in powder form or in a lyophilized (freeze-dried) state, requiring only the addition of a sterile liquid carrier, for example, physiological saline or pyrogen-free water, immediately prior to use. Immediate injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the aforementioned types.

[0329] Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound that can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that can contain suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, for example, sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compound and enable the preparation of highly concentrated solutions.

[0330] In addition to the aforementioned formulations, the compound can be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or intramuscular injection. Thus, for example, the compound can be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in a tolerated oil) or an ion exchange resin, or as a poorly soluble derivative, for example, as a poorly soluble salt.

[0331] Topical administration The compounds of the present disclosure can be administered locally (e.g., to the skin, mucosa, ear, nose, or eye) or transdermally. Formulations for topical administration can include, but are not limited to, lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, etc. Pharmaceutically acceptable carriers for topical administration formulations can include water, alcohol, mineral oil, glycerin, polyethylene glycol, etc. Topical administration can also be performed, for example, by electroporation, iontophoresis, phonophoresis, etc.

[0332] Typically, the active ingredient for topical administration can comprise from 0.001% to 10% w / w (weight) of the formulation. In certain embodiments, the active ingredient can comprise up to 10% w / w, less than 5% w / w, from 2% w / w to 5% w / w, or from 0.1% to 1% w / w of the formulation.

[0333] Compositions for topical administration can be formulated as immediate release or modified release, including delayed release or sustained release.

[0334] Certain compounds disclosed herein can be administered locally, i.e., by non-systemic administration. This includes applying the compounds disclosed herein to the outside of the epidermis or oral cavity, as well as dropping such compounds into the ear, eye, and nose such that the compounds do not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0335] Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation, such as gels, topical medications, lotions, creams, ointments, or pastes, and drops suitable for administration to the eyes, ears, or nose. The active ingredient for topical administration can, for example, comprise from 0.001% to 10% w / w (weight) of the formulation. In certain embodiments, the active ingredient can comprise up to 10% w / w. In other embodiments, it can comprise less than 5% w / w. In certain embodiments, the active ingredient can comprise from 2% w / w to 5% w / w. In other embodiments, it can comprise from 0.1% to 1% w / w of the formulation.

[0336] Rectal, oral, sublingual administration Suppositories for rectal administration of the compounds of the present disclosure can be prepared by mixing the active agent with a suitable non-irritating excipient such as cocoa butter, synthetic mono-, di-, or triglycerides, fatty acids, or polyethylene glycol, which are solid at room temperature but liquid at rectal temperature and thus dissolve within the rectum to release the drug.

[0337] For oral or sublingual administration, the composition can take the form of tablets, lozenges, pastilles, or gels formulated by conventional methods. Such compositions can contain the active ingredient on a flavor base such as sucrose and acacia or tragacanth.

[0338] The compound can be included in rectal compositions such as suppositories or retention enemas with conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0339] Administration by inhalation For administration by inhalation, the compounds can conveniently be delivered from a nebulizer, atomizer pressurized pack, or other convenient means for delivering an aerosol spray. The pressurized pack can contain a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds according to the present disclosure can be in the form of a dry powder composition, for example, a powder mixture of the compound and a suitable powder base such as lactose or starch. The powder composition can be provided in unit dosage form, for example, in capsules, cartridges, gelatin, or blister packs from which the powder can be administered using an inhaler or insufflator.

[0340] Other carrier materials and modes of administration known in the pharmaceutical art can also be used. The pharmaceutical compositions of the present invention can be prepared by any of the pharmaceutically well-known techniques, such as effective formulations and administration procedures. Preferred unit dosage formulations contain the active ingredient in an effective amount as listed hereinafter in this specification, or an appropriate fraction thereof.

[0341] It should be understood that, in addition to the components specifically mentioned above, the formulations described above can contain other conventional agents in the art, taking into account the type of formulation in question. For example, those suitable for oral administration can contain flavoring agents.

[0342] The compounds can be administered orally or by injection at a dosage of 0.1 to 500 mg / kg per day. The dosage range for adult humans is generally 5 mg to 2 g per day. Tablets or other presentation forms provided in discrete units can conveniently contain units that contain one or more compounds effective at such dosages or multiples thereof, for example, 5 mg to 500 mg, usually about 10 mg to 200 mg.

[0343] The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the host to be treated and the particular mode of administration.

[0344] The compounds can be administered in various modes, for example, orally, topically, or by injection. The exact amount of the compound to be administered to a patient is the responsibility of the attending physician. The specific dosage level for any particular patient will depend on a variety of factors including the activity of the specific compound being used, age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, combination of drugs, the exact disorder being treated, and the severity of the condition or disorder being treated. In addition, the route of administration may vary depending on the condition and its severity. The above considerations regarding effective formulations and administration procedures are well known in the art and are described in standard textbooks.

[0345] Method of treatment The present disclosure provides compounds and pharmaceutical compositions that inhibit Des activity and are thus useful for the treatment or prevention of disorders associated with Des. The compounds and pharmaceutical compositions of the present disclosure are useful for the treatment or prevention of various disorders associated with Des1 because they inhibit Des.

[0346] Metabolic disorder In some embodiments, the compounds and pharmaceutical compositions of the present disclosure are useful for the treatment or prevention of metabolic disorders.

[0347] In some embodiments, the metabolic disorder is selected from metabolic syndrome, diabetes, dyslipidemia, hypertriglyceridemia, hypercholesterolemia, fatty liver disease, non-alcoholic steatohepatitis, obesity, and insulin resistance.

[0348] In some embodiments, the compounds and pharmaceutical compositions of the present disclosure are useful for the treatment or prevention of lipid storage disorders. In some embodiments, the lipid storage disorder is selected from Farber disease, Niemann-Pick disease, Fabry disease, Krabbe disease, Gaucher disease, Tay-Sachs disease, and metachromatic leukodystrophy.

[0349] In some embodiments, the compounds and pharmaceutical compositions may be effective against conditions selected from dyslipidemia, type II diabetes, atherosclerosis, obesity, cardiovascular disease, and liver disease.

[0350] In some embodiments, the compounds and pharmaceutical compositions may be effective against liver diseases selected from NASH and NAFLD.

[0351] In some embodiments, the compounds and pharmaceutical compositions may be effective against insulin resistance.

[0352] In some embodiments, the compounds and pharmaceutical compositions may be effective against hyperglycemia.

[0353] Cardiovascular disorder In some embodiments, the compounds and pharmaceutical compositions of the present disclosure may be useful for the treatment or prevention of atherosclerosis, including coronary artery disease and peripheral vascular disease, hypertension and cardiomyopathy.

[0354] In some embodiments, the compounds and pharmaceutical compositions may be useful in the treatment of atherosclerosis.

[0355] Cystic fibrosis In some embodiments, the compounds and pharmaceutical compositions of the present disclosure may be useful for the treatment or prevention of cystic fibrosis. Various studies have shown that sphingolipids, particularly ceramides, accumulate in the lungs of humans with cystic fibrosis, as well as in corresponding mouse models of cystic fibrosis, including mice with gene disruption of the cystic fibrosis transmembrane conductance regulator. This accumulation has been shown to cause inflammation, increased susceptibility to bacterial infection (Grassme et al. 2013 Ceramide in cystic fibrosis. Handb. Exp. Pharmacol. 216, 265 - 274), and pulmonary fibrosis (Ziobro et al. 2013 Ceramide mediates lung fibrosis in cystic fibrosis. Biochem. Biophys. Res. Commun. 434, 705 - 709).

[0356] In some embodiments, the compounds and pharmaceutical compositions of the present disclosure are useful for the treatment or prevention of autoimmune diseases or inflammatory disorders, including acute and chronic inflammatory diseases.

[0357] Inflammatory conditions include, but are not limited to, arthritis, including subtypes and related conditions such as rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, acute rheumatoid arthritis, enteropathic arthritis, neuropathic arthritis, psoriatic arthritis, and pyogenic arthritis; osteoporosis; tendinitis; bursitis; and other related bone and joint disorders; gastroesophageal reflux disease; diarrhea; inflammatory bowel disease; Crohn's disease; gastritis; irritable bowel syndrome; ulcerative colitis; gastrointestinal diseases such as acute and chronic inflammation of the pancreas; lung inflammation associated with viral infection and cystic fibrosis; psoriasis; eczema; burns; sunburn; skin conditions such as dermatitis (such as contact dermatitis, atopic dermatitis, and allergic dermatitis); and urticaria. In addition, the compounds of the present invention are useful for organ transplant patients, either alone or in combination with conventional immunosuppressive agents. Autoimmune diseases are often also classified as inflammatory diseases.

[0358] Autoimmune diseases include Crohn's disease, ulcerative colitis, dermatitis, dermatomyositis, type 1 diabetes, Goodpasture syndrome, Graves' disease, Guillain-Barré syndrome (GBS), autoimmune encephalomyelitis (AE), Hashimoto's disease, idiopathic thrombocytopenic purpura, lupus erythematosus, mixed connective tissue disease, multiple sclerosis (MS), myasthenia gravis, narcolepsy, pemphigus vulgaris, pernicious anemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, rheumatoid arthritis (RA), Sjögren's syndrome, scleroderma, temporal arteritis (also known as "giant cell arteritis"), vasculitis, and Wegener's granulomatosis.

[0359] In some embodiments, the autoimmune disease or chronic inflammatory disease is selected from arthritis, multiple sclerosis, psoriasis, Crohn's disease, inflammatory bowel disease, lupus, Graves' disease and Hashimoto's thyroiditis, ankylosing spondylitis, and cystic fibrosis.

[0360] In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure may have disease-modifying anti-rheumatic drug (DMARD) activity. In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure may be used for the treatment of rheumatoid arthritis. In certain further embodiments, the treatment of rheumatoid arthritis with the compounds and pharmaceutical compositions of the present disclosure includes co-administration with another agent selected from analgesics (including conventional NSAIDs and COX2-selective inhibitors), steroids, methotrexate, gold salts, hydroxychloroquine, PAD4 inhibitors, sulfasalazine, leflunomide, anti-TNFα, Janus kinase inhibitors, abatacept, rituximab, and anakinra.

[0361] In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure may have synergistic activity against multiple sclerosis when co-administered with a therapeutic agent selected from fingolimod, sphingosine-1-phosphate receptor modulators, teriflunomide, dimethyl fumarate, PAD4 inhibitors, anti-CD20 mAb, anti-CD52 mAb, natalizumab, glatiramer acetate, and interferon-β.

[0362] In some embodiments, the autoimmune disease inflammatory disease is autoimmune arthritis.

[0363] In some embodiments, the autoimmune disease inflammatory disease is rheumatoid arthritis.

[0364] In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure may have synergistic activity against arthritis when administered in combination with a therapeutic agent selected from analgesics (including conventional NSAIDs and COX2 selective inhibitors), steroids, methotrexate, gold salts, hydroxychloroquine, PAD4 inhibitors, sulfasalazine, leflunomide, anti-TNFα, Janus kinase inhibitors, abatacept, rituximab, and anakinra.

[0365] In some embodiments, the compounds and pharmaceutical compositions of the present disclosure may be useful for the treatment or prevention of cardiovascular diseases. In some embodiments, the cardiovascular disease is selected from atherosclerosis, hypertension, and cardiomyopathy.

[0366] In some embodiments, the compounds and pharmaceutical compositions of the present disclosure may be useful for the treatment or prevention of ischemia / reperfusion injury. In some embodiments, the ischemia / reperfusion injury occurs in organ transplantation, acute kidney injury, cardiopulmonary bypass, pulmonary hypertension, sickle cell disease, myocardial infarction, stroke, surgical resection and reconstruction surgery, reattachment of appendages or other body parts, skin transplantation, or trauma.

[0367] For example, proliferative diseases such as cancer In some embodiments, the compounds and pharmaceutical compositions of the present disclosure may be useful for the treatment or prevention of cancer.

[0368] In some embodiments, the cancer is selected from leukemia, lymphoma, ovarian cancer, breast cancer, endometrial cancer, colon cancer (colorectal cancer), rectal cancer, bladder cancer, lung cancer (non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma), bronchial cancer, bone cancer, prostate cancer, pancreatic cancer, gastric cancer, hepatocellular cancer, gallbladder cancer, bile duct cancer, esophageal cancer, renal cell cancer, thyroid cancer, head and neck squamous cell cancer (head and neck cancer), testicular cancer, cancer of endocrine glands, cancer of adrenal glands, cancer of pituitary gland, skin cancer, soft tissue cancer, blood vessel cancer, brain cancer, nerve cancer, eye cancer, meninges cancer, oropharyngeal cancer, hypopharyngeal cancer, cervical cancer, and uterine cancer, glioblastoma, medulloblastoma, astrocytoma, glioma, meningioma, gastrinoma, neuroblastoma, melanoma, myelodysplastic syndrome, and sarcoma.

[0369] In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure are effective against tumor growth, angiogenesis, and chemoresistance and can potentially promote tumor killing either directly by cytotoxicity (including induction of apoptosis) or indirectly by enhancing the tumor killing ability of the immune system.

[0370] In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure may have synergistic activity against cancer when co-administered with immune checkpoint inhibitors.

[0371] In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure may have synergistic activity against cancer when co-administered with monoclonal antibodies targeting a target selected from PD1, PD-L1, CTLA-4, CD47, and OX40.

[0372] In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure may have synergistic activity against cancer when co-administered with small molecules targeting a target selected from indoleamine-2,3-dioxygenase 1 and arginase-1.

[0373] In some embodiments, the compounds and pharmaceutical compositions of the present disclosure may be useful for the treatment or prevention of fibrosis and related diseases. Fibrosis is a pathological condition involving excessive extracellular matrix production in connective tissue. As a result, tissue dysfunction and organ failure may be included.

[0374] In some embodiments, fibrosis affects a site selected from the lungs, kidneys, liver, heart, skin, and connective tissue.

[0375] In some embodiments, fibrosis can be in the lungs, such as pulmonary fibrosis or cystic fibrosis, the liver, such as cirrhosis, the heart, such as atrial fibrillation, endomyocardial fibrosis resulting from myocardial infarction, the brain, such as glial scarring, kidney fibrosis resulting from diabetic nephropathy, gallbladder fibrosis, the skin or dermal fibrosis, such as scleroderma, hypertrophic scars and keloids, myelofibrosis resulting from myelofibrosis, intestinal fibrosis such as Crohn's disease, or some other wound, in which case it may be referred to as a scar. Fibrosis can also be selected from arthrofibrosis, Dupuytren's contracture, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, progressive massive fibrosis, a complication of anthracosis in coal workers, retroperitoneal fibrosis, scleroderma, systemic sclerosis, and adhesive synovitis, as well as abdominal adhesions following abdominal surgery.

[0376] In some embodiments, the compounds and pharmaceutical compositions of the present disclosure can be used to prevent, treat, or improve a heart attack.

[0377] In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure can be used for the treatment of various types of congestive heart failure. In certain further embodiments, the congestive heart failure is secondary to ischemia. In certain further embodiments, the congestive heart failure is associated with a disorder selected from diabetes, obesity, and lipotoxicity. In certain further embodiments, the treatment of congestive heart failure with the compounds and pharmaceutical compositions of the present disclosure includes co-administration of another agent selected from angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), β-adrenergic receptor blockers (including carvedilol), diuretics (including furosemide), aldosterone antagonists (including eplerenone), inotropes (including milrinone), guanylate cyclase inhibitors, and digoxin.

[0378] In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure can be used for the treatment of kidney diseases. In certain further embodiments, the kidney disease is selected from diabetic kidney disease and nephrosis. In certain further embodiments, the treatment of kidney disease with the compounds and pharmaceutical compositions of the present disclosure includes co-administration of standard therapeutic agents. In certain further embodiments, the standard therapeutic agents are selected from ACE inhibitors, angiotensin receptor blockers (ARBs), cholesterol-lowering agents (including statins and / or PCSK9 inhibitors), and agents that manage calcium phosphate levels for bone health (including sevelamer).

[0379] In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure can be used for the treatment of sarcopenia. In certain further embodiments, the etiology of sarcopenia is selected from aging, chronic kidney disease, malignancy, and chemotherapy. In certain further embodiments, the treatment of sarcopenia with the compounds and pharmaceutical compositions of the present disclosure includes co-administration of another agent selected from testosterone, selective androgen receptor modulators, ghrelin agonists, myostatin antibodies, activin IIR antagonists, ACE inhibitors, beta antagonists, and fast skeletal muscle troponin activators.

[0380] In some embodiments, the compounds and pharmaceutical compositions of the present disclosure can be used to prevent, treat, or ameliorate neurodegenerative diseases. Elevated ceramide levels are often found in connection with various neurodegenerative diseases.

[0381] In some embodiments, the neurodegenerative disease is selected from Alzheimer's disease, vascular dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Lewy body disease, spinal muscular atrophy, Friedreich's ataxia, and spinocerebellar ataxia.

[0382] In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure can be used to treat Alzheimer's disease. In certain further embodiments, the compounds and pharmaceutical compositions of the present disclosure can have disease-modifying activity. In certain further embodiments, the compounds and pharmaceutical compositions of the present disclosure can provide symptom relief. In certain further embodiments, the treatment of Alzheimer's disease with the compounds and pharmaceutical compositions of the present disclosure includes co-administration of another agent selected from cholinesterase inhibitors and memantine.

[0383] In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure can have synergistic activity against neurodegenerative diseases when co-administered with a therapeutic agent selected from cholinesterase inhibitors and memantine.

[0384] In certain embodiments, the compounds and pharmaceutical compositions of the present disclosure can have synergistic activity against ALS when co-administered with a second therapeutic agent for ALS. In certain embodiments, the second therapeutic agent for ALS is selected from riluzole and edaravone.

[0385] Combination and combination therapies The compounds of the present invention can be used, alone or in combination with other pharmaceutically active compounds, to treat conditions such as those described above. The compound(s) of the present invention and other pharmaceutically active compound(s) can be administered simultaneously (either in the same dosage form or in separate dosage forms) or sequentially. Thus, in one embodiment, the present invention includes a method of treating a condition in a subject by administering a therapeutically effective amount of one or more compounds of the present invention and one or more additional pharmaceutically active compounds.

[0386] In another embodiment, there is provided a pharmaceutical composition comprising one or more compounds of the present invention, one or more additional pharmaceutically active compounds, and a pharmaceutically acceptable carrier.

[0387] In another embodiment, the one or more additional pharmaceutically active compounds are metformin, an inhibitor of HMG-CoA reductase, an inhibitor of sodium / glucose cotransporter, fibrate, omega-3 fatty acid, glucagon-like peptide-1 analog, and an agonist of glucagon-like peptide-1 receptor (e.g., PF-06882961), an FXR agonist (e.g., obeticholic acid, INT-767, GS-9674, tropifexor, MET409, EDP-305), an LXR ligand, a PPAR agonist (e.g., elafibranor), vitamin E, an FGF19 analog (e.g., NGM-282), an FGF21 analog (e.g., BMS-986036), an agonist of fibroblast growth factor receptor 1c-beta-croto (e.g., NGM-313), an inhibitor of acetyl-CoA carboxylase (e.g., GS-0976, PF-05221304, MK4074), an inhibitor of stearoyl-CoA desaturase-1, a CCR2 / CCR5 antagonist (e.g., cenicriviroc), an inhibitor of ketohexokinase (e.g., PF-06835919), an inhibitor of diacylglycerol O-acyltransferase 2 (e.g., PF-06865571), an inhibitor of ASK1 (e.g., selonsertib, SRT-015), an agonist of thyroid hormone receptor-β (e.g., MGL-3196, MGL-3745, VK2809), an inhibitor of dipeptidyl peptidase-4 (e.g., evogliptin), an inhibitor of stearoyl-CoA desaturase-1 (e.g., alamchol), an inhibitor of AOC3 (e.g., BI 1467335), an inhibitor of caspase (e.g., emricasan), an inhibitor of galectin-3 (e.g., GR-MD-02), an inhibitor of ileal bile acid sodium transporter (e.g., volixibat), an agonist of P2Y13 receptor (e.g., CER209), DUR-928, DS102, and butyric acid, and are selected from the group consisting of antimetabolic agents.

[0388] As additional non-limiting examples of possible combination therapies, use of the compounds disclosed herein and at least one other agent selected from the group consisting of: a) anti-diabetic agents such as insulin, insulin derivatives and mimetics, sulfonylureas, such as insulin secretagogues like glypidide, glibride, and amaryl, insulin secretory sulfonylurea receptor ligands, such as meglitinides like nateglinide and repaglinide, insulin sensitizers such as protein tyrosine phosphatase-1B (PTP-1B) inhibitors like PTP-112, GSK3 (glycogen synthase kinase-3) inhibitors such as SB-517955, SB-4195052, SB-216763, NN-57-05441, and NN-57-05445, RXR ligands such as GW-0791 and AGN-194204, sodium-dependent glucose cotransport inhibitors such as empagliflozin, canagliflozin, dapagliflozin, T-1095, glycogen phosphorylase A inhibitors such as BAY R3401, biguanides such as metformin, alpha-glucosidase inhibitors such as acarbose, GLP-1 (glucagon-like peptide-1) such as exendin-4 and mimetics of GLP-1, GLP-1 analogs, januvia, galvus, ongliza, DPP728, LAF237 (Example 1 of vildagliptin - WO 00 / 34241), MK-0431, saxagliptin, DPPIV (dipeptidyl peptidase IV) inhibitors such as GSK23A, AGE breakers, thiazolidinedione derivatives (glitazones) such as pioglitazone or rosiglitazone, and non-glitazone type PPAR delta agonists such as GI-262570, b) 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, such as lipid-lowering agents like lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, verostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin and rivastatin, squalene synthase inhibitors, FXR (farnesoid X receptor) and LXR (liver X receptor) ligands, PCSK9 antagonists such as alirocumab and evolocumab,Cholesterol absorption inhibitors, such as ezetimibe, bile resins, such as cholestyramine, colesevelam, fibrates, nicotinic acid, and aspirin, c) anti-obesity agents or appetite regulators such as phentermine, leptin, bromocriptine, dexfenfluramine, amphetamine, fenfluramine, dexfenfluramine, sibutramine, orlistat, dexfenfluramine, mazindol, phentermine, phentermine, diethylpropion, fluoxetine, bupropion, topiramate, benzylethylpropitamine, diethylpropion, phenylpropanolamine or ecopipam, ephedrine, pseudoephedrine, or cannabinoid antagonists, d) antihypertensive agents, such as loop diuretics such as ethacrynic acid, furosemide, and torsemide, thiazide derivatives, diuretics such as chlorothiazide, hydrochlorothiazide, amiloride, angiotensin-converting enzyme (ACE) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, inhibitors of the Na-K-ATPase membrane pump such as digoxin, neutral endopeptidase (NEP) inhibitors, such as thiorphan, terteo-thiorphan, SQ29072, ECE inhibitors, such as SLV306, omapatrilat, sampatrilat, and fasidotril, ACE / NEP inhibitors such as candesartan, eprosartan, irbesartan, losartan, telmisartan, valsartan, particularly valsartan, angiotensin n antagonists, renin inhibitors such as aliskiren, terlakiren, ditelakiren, RO 66-1132, RO-66-1168, orthoadrenergic receptor blockers such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, carvedilol, nadolol, propranolol, sotalol, timolol, cardiotonic agents such as digoxin, dobutamine, milrinone, calcium channel blockers such as amlodipine, bepridil, diltiazem, felodipine, nicardipine, nimodipine, nifedipine, nisoldipine, and verapamil, aldosterone receptor antagonists, as well as aldosterone synthase inhibitors, e) HDL-increasing compounds,f) Cholesterol absorption modifiers such as ezetimibe and KT6-971, [

[0148] ], g) Apo-A1 analogs and mimetics, h) Thrombin inhibitors such as ximelagatran, Aldosterone inhibitors such as anastrozole, fadrozole, and eplerenone, Inhibitors of platelet aggregation such as aspirin, and Clopidogrel bisulfate.,

[0389] In another embodiment, the one or more additional pharmaceutically active compounds include anti-cancer agents including chemotherapeutic agents, alkyl sulfonates such as thiotepa and cyclophosphamide, busulfan, improsulfan, piposulfan, aziridines such as benzodepa, carbocone, meturedopa, and uredopa, ethyleneimines and methylmelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolmelamine, chlorambucil, chloronaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine hydrochloride, melphalan, nobemycin, phenesterine, prednimustine, trofosfamide, nitrogen mustards such as uracil mustard, nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, antibiotics such as aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, caminomycin, cardinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, keramycin, rodorubicin, streptozocin, zorubicin, antimetabolites such as methotrexate and 5-fluorouracil (5-FU), folic acid analogs such as denopterin, methotrexate, pteropterin, trimethoprim, purine analogs such as fludarabine, 6-mercaptopurine, thiampurine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, didoxyridine, doxifluridine, enocitabine, floxuridine, 5-FU, androgens such as calusterone, drospirolone propionate, epitioestanol, mepitiostane, testolactone, anti-adrenals such as aminoglutethimide, mitotane, trilostane, folic acid supplements such as folinic acid, aceglatone, aldophosphamide glycoside;Selected from the group consisting of aminolevulinic acid, amsacrine; bestrabucil, bisantrene, edatraxate, desosamine, demeclocycline, diazicon, efrotomycin, elliptinium acetate, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidamine, mitoguazone, mitoxantrone, mopidamol, nitracrine, pentostatin, phenamet, pirarubicin, podophyllinic acid, 2-ethylhydrazide, procarbazine, razoxane, sizofiran, spirogermanium, tenuazonic acid, triazicon, 2,2’,2”-trichloroethylamine, urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, cytosine arabinoside (Ara-C), cyclophosphamide, thiotepa, taxoids such as paclitaxel and docetaxel, chlorambucil, gemcitabine, 6-thioguanine, mercaptopurine, methotrexate, platinum and platinum coordination complexes such as cisplatin and carboplatin, vinblastine, etoposide (VP-16), ifosfamide, mitomycin C, mitoxantrone, vincristine, vinorelbine, navelbine, novantrone, teniposide, daunomycin, aminopterin, zeloda, ibandronate, CPT11, topoisomerase inhibitors, difluoromethylornithine (DMFO), retinoic acid, esperamicin, capecitabine, and any pharmaceutically acceptable salts, acids, or derivatives of the foregoing.;

[0390] Chemotherapeutic agents also include anti-estrogens, selective estrogen receptor modulators and selective estrogen receptor degraders (including, for example, tamoxifen, raloxifene, aromatase inhibitory 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, keoxifene, onapristone, toremifene, and fulvestrant), as well as anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin, and anti-hormonal agents that act to modulate or inhibit the hormonal action on tumors, such as pharmaceutically acceptable salts, acids, or derivatives of any of the above. In certain embodiments, the combination therapy includes administration of a hormone or a related hormonal agent.

[0391] Chemotherapeutic agents also include signal transduction inhibitors (STIs). The term "signal transduction inhibitor" refers to an agent that selectively inhibits one or more steps in a signal transduction pathway. Signal transduction inhibitors (STIs) of the present invention include (i) bcr / abl kinase inhibitors (e.g., GLEEVEC), (ii) epidermal growth factor (EGF) receptor inhibitors including kinase inhibitors and antibodies, (iii) her-2 / neu receptor inhibitors (e.g., HERCEPTIN), (iv) inhibitors of the Akt family kinase or Akt pathway (e.g., rapamycin), (v) cell cycle kinase inhibitors (e.g., flavopiridol and palbociclib), (vi) phosphatidylinositol kinase inhibitors, (vii) selective estrogen receptor modulators (e.g., tamoxifen), (viii) selective estrogen receptor degraders (e.g., fulvestrant), (ix) selective androgen receptor modulators (e.g., enzalutamide, apalutamide), (x) angiogenesis inhibitors (e.g., bevacizumab, SUTENT).

[0392] The chemotherapeutic agent also includes various immunomodulatory agents, including checkpoint inhibitors (e.g., anti-PD1, anti-PDL1, anti-CTLA4 antibodies), as well as anti-GITR, anti-OX40, and anti-CD47 antibodies, IDO1 inhibitors, arginase-1 inhibitors, glucocorticoid receptor inhibitors, regulatory T cell inhibitors, and other immunomodulatory agents including myeloid-derived suppressor cell inhibitors.

[0393] In another embodiment, the one or more additional pharmaceutically active compounds are selected from the group consisting of disease-modifying antirheumatic drugs (DMARDs) including steroids, methotrexate, sulfasalazine, gold salts, as well as inhibitors of anti-TNF, anti-IL1, anti-IL6, and NLRP3 inflammasome, and Janus kinase inhibitors.

[0394] In another embodiment, the one or more additional pharmaceutically active compounds are selected from the group consisting of multiple sclerosis drugs including interferon-beta1a, interferon-beta1b, glatiramer acetate, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, anti-alpha4 integrin monoclonal antibody, anti-CD52 monoclonal antibody, anti-CD25 monoclonal antibody, and anti-CD20 monoclonal antibody.

[0395] In another embodiment, the one or more additional pharmaceutically active compounds are selected from the group consisting of enzyme replacement therapies. Enzyme replacement therapies may include, for example, recombinant human acid ceramidase.

[0396] In another embodiment, the one or more additional pharmaceutically active compounds are selected from the group consisting of pancreatic enzyme supplements, multivitamins, mucolytics, antibiotics, bronchodilators, anti-inflammatory agents, insulin, bisphosphonates, antifibrotic agents (e.g., pirfenidone, nintedanib), N-acetylcysteine, ivacaftor, and lumacaftor / ivacaftor.

[0397] In another embodiment, the one or more additional pharmaceutically active compounds are selected from the group consisting of donepezil, galantamine, rivastigmine, memantine, riluzole, levodopa / carbidopa, pramipexole, ropinirole, rotigotine, selegiline, apomorphine, selegiline, rasagiline, entacapone, tolcapone, benztropine, trihexyphenidyl, amantadine, tetrabenazine, haloperidol, risperidone, quetiapine, levetiracetam, clonazepam, edaravone.

[0398] The Des inhibitor compounds and compositions described herein may also optionally be used in combination with other therapeutic agents selected for their therapeutic value against the condition being treated. Generally, in embodiments where the compounds described herein and combination therapies are used, the other agents need not be administered in the same pharmaceutical composition and may optionally be administered by different routes due to their different physical and chemical characteristics. Initial dosing is generally carried out according to established protocols, and then the dosage, mode of administration, and time of administration are subsequently modified based on the effects observed. In certain cases, it may be appropriate to administer the Des1 inhibitor compounds described herein in combination with another therapeutic agent. By way of example only, the therapeutic efficacy of a Des1 inhibitor is enhanced by the administration of another therapeutic agent (including therapeutic regimens) that also has a therapeutic benefit. Regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient can be either simply additive of the two therapeutic agents or the patient may experience a potentiated (i.e., synergistic) benefit. Alternatively, if the compounds disclosed herein have side effects, it may be appropriate to administer an agent to reduce the side effects, or the therapeutic efficacy of the compounds described herein may be enhanced by the administration of an adjuvant.

[0399] The therapeutically effective dosage changes when the drug is used in combination therapy. Methods for experimentally determining the therapeutically effective dosages of the agent and other agents for use in a combination therapy regimen are well-documented methodologies. Combination therapy further includes cyclical therapy that starts and stops at various times to assist in the clinical management of the patient. In any case, multiple therapeutic agents (one of which is a Des inhibitor disclosed herein) can be administered in any sequential or simultaneous order. When simultaneous, the multiple therapeutic agents can optionally be provided in a single, unified form or in multiple forms (by way of example only, either as a single pill or as two separate pills).

[0400] In some embodiments, one of the therapeutic agents is given in multiple doses or both are given as multiple doses. When not simultaneous, the timing between multiple doses can optionally vary from greater than 0 weeks to less than 12 weeks.

[0401] In addition, the combination methods, compositions, and formulations are not limited to the use of only two agents and the use of multiple therapeutic combinations is also envisioned. It is understood that the dosing regimen for treating, preventing, or ameliorating a condition(s) for which relief is sought can optionally be varied according to various factors. These factors include the disorder the subject is suffering from as well as the subject's age, weight, gender, diet, and medical condition. Accordingly, in some embodiments, the dosing regimen actually used can vary widely and thus deviate from the dosing regimens described herein.

[0402] The pharmaceutical agents that make up the combination therapy disclosed herein are optionally in a combined dosage form or separate dosage forms intended for substantially simultaneous administration. The agents that make up the combination therapy are optionally administered sequentially, and any of the agents are administered by a regimen that requires two-step administration. The two-step administration regimen optionally requires continuous administration of the active agent or spaced administration of separate active agents. The time between multiple administration steps ranges from minutes to hours, depending on the characteristics of each agent, such as the effectiveness, solubility, bioavailability, plasma half-life, and kinetic profile of the agent.

[0403] In another embodiment, the Des inhibitor is optionally used in combination with a procedure that provides additional benefit to the patient. The Des inhibitor and any additional therapy are optionally administered before, during, or after the occurrence of the disease or condition, and the timing of administration of the composition containing the Des inhibitor varies in some embodiments. Thus, for example, the Des inhibitor is used as a prophylactic agent and is continuously administered to a subject having a tendency to develop a condition or disease to prevent the occurrence of the disease or condition. The Des inhibitor and composition are optionally administered to the subject as soon as possible during or after the onset of symptoms. Although embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, modifications, and substitutions will occur to those skilled in the art without departing from the invention. It should be understood that in some embodiments of the invention, various alternatives to the embodiments described herein are used in practicing the invention.

[0404] Compound Synthesis The compounds of the present disclosure can be prepared using methods exemplified by the general synthetic schemes and experimental procedures detailed below. The general synthetic schemes and experimental procedures are presented for illustrative purposes and are not intended to be limiting. The starting materials used to prepare the compounds of the present disclosure are either commercially available or can be prepared using conventional methods known in the art.

[0405] List of Abbreviations Ac2O = acetic anhydride; AcCl = acetyl chloride; AcOH = acetic acid; AIBN = azobisisobutyronitrile; aq. = aqueous; Bu3SnH = tributyltin hydride; CD3OD = deuterated methanol; CDCl3 = deuterated chloroform; CDI = 1,1'-carbonyldiimidazole; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM = dichloromethane; DEAD = diethyl azodicarboxylate; DIBAL-H = diisobutylaluminum hydride; DIEA = DIPEA = N,N-diisopropylethylamine; DMAP = 4-dimethylaminopyridine; DMF = N,N-dimethylformamide; DMSO-d6 = deuterated dimethyl sulfoxide; DMSO = dimethyl sulfoxide; DPPA = diphenylphosphoryl azide; EDC.HCl = EDCI.HCl = 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; Et2O = Diethyl ether; EtOAc = Ethyl acetate; EtOH = Ethanol; h = hour; HATU = 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanamine; HMDS = Hexamethyldisilazane; HOBT = 1-Hydroxybenzotriazole; i-PrOH = Isopropanol; LAH = Lithium aluminum hydride; LiHMDS = Lithium bis(trimethylsilyl)amide; MeCN = Acetonitrile; MeOH = Methanol; MP carbonate resin = Macroporous triethylammonium methylpolystyrene carbonate resin; MsCl = Methanesulfonyl chloride; MTBE = Methyl tertiary butyl ether; MW = Microwave irradiation; n-BuLi = n-Butyllithium; NaHMDS = Sodium bis(trimethylsilyl)amide; NaOMe = Sodium methoxide; NaOtBu = Sodium t-butoxide; NBS = N-Bromosuccinimide; NCS = N-Chlorosuccinimide; NMP = N-Methyl-2-pyrrolidone; Pd(Ph3)4 = Tetrakis(triphenylphosphine)palladium(0); Pd2(dba)3 = Tris(dibenzylideneacetone)dipalladium(0); PdCl2(PPh3)2 = Bis(triphenylphosphine)palladium(II) dichloride; PG = Protecting group; Preparative HPLC = Preparative high performance liquid chromatography; PyBop = (Benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate; Pyr = Pyridine; RT = Room temperature; RuPhos = 2-Dicyclohexylphosphino-2’,6’-diisopropoxybiphenyl; sat. = Saturated; ss = Saturated solution; t-BuOH = tert-Butanol; T3P = Propylphosphonic anhydride; TBS = TBDMS = tert-Butyldimethylsilyl; TBSCl = TBDMSCl = tert-Butyldimethylchlorosilane; TEA = Et3N = Triethylamine; TFA = Trifluoroacetic acid; TFAA = Trifluoroacetic anhydride; THF = Tetrahydrofuran; Tol = Toluene; TsCl = Tosyl chloride; XPhos = 2-Dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl.

[0406] General synthetic methods for preparing compounds The following scheme can generally be used to practice the present invention.

Chemical formula

[0407] Example 1 can be synthesized using the following general synthetic procedure described in Scheme I. Amine 101 is converted to acid chloride 102 using triphosgene in the presence of a base, as described herein and elsewhere abbreviated as (COCl2)3. The acid chloride is then reacted with arylamine 103 in the presence of a base to obtain urea 103. As used herein and elsewhere, the formula H2N-Ar-OTBS of 103 represents an aryl compound substituted with both an NH2 group and an OTBS group. Formula 103 includes, for example, 4-[(tert-butyldimethylsilyl)oxy]aniline and 5-[(tert-butyldimethylsilyl)oxy]pyridin-2-amine. In the final step, the TBS group is removed with either an acid or a fluoride to obtain 105.

Chemical formula

[0408] Examples 2-39 can be synthesized using the following general synthetic procedure described in Scheme II. In the first step, amine 201 is reacted directly with 4-fluorophenyl carbamate having formula 202 in the presence of a base to obtain urea 203. As used herein and elsewhere, the formula of carbamate 202 includes an arylamino moiety substituted with an OTBS group. Formula 202 includes, for example, 4-fluorophenyl N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]carbamate and 4-fluorophenyl N-[4-[(tert-butyldimethylsilyl)oxy]phenyl]carbamate. In the second step, the TBS group is removed with either an acid or a fluoride to obtain 204.

Chemical formula

[0409] Example 40 can be synthesized using the following general synthetic procedure described in Scheme III. In the first step, alkyl isocyanate 301 is reacted with arylamine 103 as defined in Scheme I to obtain urea 302. The TBS group is removed by treatment with any acid of fluoride ions in the second step to obtain 303.

Chemical formula

[0410] Examples 41 - 42 can be synthesized using the following general synthetic procedure described in Scheme IV. In the first step, acid chloride 401 is reacted with arylamine 103 as defined in Scheme I to obtain carbamate 402. The TBS group is removed by treatment with any acid of fluoride ions in the second step to obtain 403.

Chemical formula

[0411] Examples 43 - 44 can be synthesized using the following general synthetic procedure described in Scheme V. Alcohol 501 is reacted with arylamine 103 as defined in Scheme I in the presence of triphosgene and a base to obtain carbamate 502. In the final step, the TBS group is removed with either an acid or fluoride to obtain 503.

Chemical formula

[0412] Examples 45 - 52 can be synthesized using the following general synthetic procedure described in Scheme VI. The synthesis starts from an amine / carbamate 601 where the "L" moiety is a linking group. In some embodiments, 601 is 1 - Boc - piperazine. In some embodiments, 601 is 1 - Cbz - piperazine. In some embodiments, 601 is 3-(BocNH)-piperidine. In some embodiments, 601 is 4-(BocNH)-piperidine.

[0413] Next, the amine / carbamate 601 is reacted with an arene 602 to obtain an arylamine - substituted product 603. In certain embodiments, the arene 602 is substituted with an electron - withdrawing group that facilitates a direct S N Ar reaction. In certain embodiments, the substitution reaction is assisted by the presence of a metal catalyst.

[0414] In the final step, either an acid for R 601 =t - Bu (Boc protection) or hydrolysis for R 601 =Bn (CBz protection) is used to remove the carbamate protecting group of 603. Other amine protecting groups known in the art may be used. Then, the amine 604 is converted to the product 605 using either Scheme I, II, or III, or any other method that may be available.

Chemical Structure

[0415] Examples 53 - 60 can be synthesized using the following general synthetic procedure described in Scheme VIII. The synthesis starts from an amino alcohol 701 where the "L" moiety is a linking group. In some embodiments, 701 is 4 - hydroxypiperidine.

[0416] Next, the amino alcohol 701 is reacted with an arene 702 to obtain an arylamine - substituted product 703. In certain embodiments, the arene 702 is substituted with an electron - withdrawing group that facilitates a direct S NIt is substituted with an electron-withdrawing group that promotes the Ar reaction. In certain embodiments, the substitution reaction is assisted by the presence of a metal catalyst. Alcohol 703 is then converted to carbamate product 704 using either Scheme IV or V, or other methods that may be available.

Chem.

[0417] Examples 61 - 70 can be synthesized using the following general synthetic procedure described in Scheme VIII. In the first step, sulfonyl chloride 801 is reacted with arylamine 103 as defined in Scheme I to obtain sulfonamide 802. The TBS group is removed in the second step by treatment with an acid of any fluoride ion to obtain 803.

Chem.

[0418] Example 71 can be synthesized using the following general synthetic procedure described in Scheme IX. In the first step, amine 901 is reacted with sulfuryl chloride to obtain acid chloride 902. In the next step, acid chloride 902 is reacted with arylamine 103 as defined to obtain sulfonamide 903. The TBS group is removed in the second step by treatment with an acid of any fluoride ion to obtain 904.

Chem.

[0419] Examples 72 to 75 can be synthesized using the following general synthetic procedure described in Scheme X. In the first step, the arylamine 103 defined in Scheme I is converted to oxazolidinone 1001 when treated with 2-bromoethanol and chlorosulfonyl isocyanate. In the next step, amine 1002 is reacted with 1001 to form sulfonylurea 1003. In the final step, the TBS group is removed by treatment with either an acid of fluoride ion in the second step to obtain 1004.

Chemical formula

[0420] Examples 77 to 87 can be synthesized using the following general synthetic procedure described in Scheme XI. In the first step, the carbamate-protected cyclic amine 1101 (n = 1, 2) is reacted with a suitable aryl halide to form the coupled product 1102. In the next step, the carbamate protecting group is removed to obtain the secondary amine 1103, which can then be treated in the steps of Scheme I or Scheme II to obtain 1104.

Chemical formula

[0421] Example 88 can be synthesized using the following general synthetic procedure described in Scheme I. The aryl or heteroaryl alcohol 1201 is converted to chloroformate 1202 using (COCl2)3 in the presence of a base. Herein and elsewhere, the formula HO-Ar-OTBS of 1201 represents an aryl compound substituted with both an OH group and an OTBS group. The formula 1201 includes, for example, 4-[(tert-butyldimethylsilyl)oxy]phenol and 5-[(tert-butyldimethylsilyl)oxy]pyridin-2-ol. The chloroformate is then reacted with amine 1203 in the presence of a base to obtain carbamate 1204. In the final step, the TBS group is removed with either an acid or fluoride to obtain 1205. [Chemical]

[0422] Example 89 can be synthesized using the following general synthetic procedure described in Scheme I. Carboxylic acid 1301 is coupled with arylamine 103 using a carbodiimide reagent such as EDCI (shown). In the second step, the TBS group is removed with either an acid or a fluoride to give 1303.

[0423] The present invention is further illustrated by the following examples.

[0424] Chromatography procedure Instrument "A": 2# SHIMADZU.

[0425] Instrument "B": 2# - Analytical HPLC - SHIMADZU.

[0426] Column "A": XBridge OBD C18 preparative column, 30 x 150 mm x 5 μm.

[0427] Column "B": XBridge OBD C18 preparative column, 19 x 250 mm x 5 μm.

[0428] Column "C": XSelect CSH C18 OBD preparative column, 19 x 250 mm, 5 μm.

[0429] Column "D": Xselect CSH C18 OBD column 30 x 150 mm 5 μm.

[0430] Column "E": SunFire C18 OBD preparative column, 19 mm x 250 mm, 5 μm.

[0431] Intermediate Intermediate "A" 4 - Fluorophenyl N - [5 - [(tert - butyldimethylsilyl)oxy]pyridin - 2 - yl]carbamate [Chem.] A solution of 5-[(tert-butyldimethylsilyl)oxy]pyridin-2-amine (3.7 g, 16.49 mmol, 1.00 equiv), 4-fluorophenyl chloroformate (4.3 g, 24.63 mmol, 1.50 equiv), and Et3N (5 g, 49.41 mmol, 3.00 equiv) in CH2Cl2 (40 mL) was stirred at room temperature for 2 h and then extracted with 3 × 80 mL of EtOAc. The combined organic layers were concentrated under vacuum and purified by silica gel chromatography using EtOAc / hexane (1:10) to afford 1.8 g (30%) of the title compound as a white solid.

[0432] LC-MS: (ES, m / z): 363 1 H NMR (300 MHz, DMSO-d6) δ 10.58 (s, 1H), 7.93 (dd, J = 3.0, 0.7 Hz, 1H), 7.69 (dd, J = 8.9, 0.7 Hz, 1H), 7.35 (dd, J = 9.0, 3.0 Hz, 1H), 7.25 (d, J = 6.6 Hz, 4H), 0.95 (s, 9H), 0.19 (s, 6H).

[0433] Intermediate "B" 4-Fluorophenyl N-[4-[(tert-butyldimethylsilyl)oxy]phenyl]carbamate [Chem.] Step 1. Synthesis of 4-[(tert-butyldimethylsilyl)oxy]aniline [Chem.] To a solution of 4-aminophenol (5 g, 45.82 mmol) in DMF (50 mL), imidazole (6.24 g) was added portionwise, followed by dropwise addition of TBSCl (8.26 g) with stirring at 0 °C for 5 minutes. The resulting solution was stirred at room temperature for 2 hours, then quenched by adding 100 mL of H2O and extracted with 2 × 150 mL of EtOAc. The combined organic layers were concentrated under vacuum and purified by silica gel chromatography using EtOAc / hexane (1:5) to give 4 g (39%) of the title compound as an off-white oil.

[0434] LC-MS: (ES, m / z): 224 1 H NMR (400 MHz, DMSO-d6) δ 6.57~6.48 (m, 2 H), 6.49~6.40 (m, 2H), 4.60 (s, 2H), 0.92 (s, 9H), 0.11 (s, 6H).

[0435] Step 2. Synthesis of 4-fluorophenyl N-[4-[(tert-butyldimethylsilyl)oxy]phenyl]carbamate

Chemical formula

[0436] LC-MS: (ES, m / z): 362 11H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 7.36 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 6.5 Hz, 4H), 6.88 - 6.77 (m, 2H), 0.94 (s, 9H), 0.17 (s, 6H).

[0437] Scheme I Example 1 N-(5-Hydroxypyridin-2-yl)-4-phenylpiperidine-1-carboxamide [Chemical formula] Step 1: Synthesis of 4-Phenylpiperidine-1-carbonyl Chloride [Chemical formula] A solution of 4-phenylpiperidine (1 g, 6.20 mmol, 1.00 equivalent), Et3N (1.3 g, 12.85 mmol, 2.00 equivalents), and triphosgene (1.9 g, 1.00 equivalent) in CH2Cl2 (10 mL) was stirred at room temperature for 6 hours and then extracted with 30 mL of EtOAc. The combined organic layers were concentrated under vacuum to give 800 mg (58%) of the title compound as a solid.

[0438] LC-MS: (ES, m / z): 224 Step 2: Synthesis of N-[5-[(tert-Butyldimethylsilyl)oxy]pyridin-2-yl]-4-phenylpiperidine-1-carboxamide [Chemical formula] A solution of the product from the previous step (500 mg, 2.24 mmol, 1.00 equivalent) and 5-[(tert-butyldimethylsilyl)oxy]pyridin-2-amine (502 mg, 2.24 mmol, 1.00 equivalent) in pyridine (5 mL) was stirred at 30 °C for 16 hours and then extracted with 20 mL of EtOAc. The combined organic layers were concentrated under vacuum and purified by preparative TLC (EtOAc / hexane 1:2) to give 200 mg (22%) of the title compound as a solid.

[0439] LC-MS: (ES, m / z): 412 Step 3: Synthesis of N-(5-Hydroxypyridin-2-yl)-4-phenylpiperidine-1-carboxamide

Chem.

[0440] LC-MS: (ES, m / z): 298 1 1H NMR (300 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.13 (s, 1H), 7.78 (d, J = 2.9 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.36 - 7.08 (m, 6H), 4.34 - 4.22 (m, 2H), 2.92 - 2.63 (m, 3H), 1.82 - 1.70 (m, 2H), 1.53 (qd, J = 12.5, 4.0 Hz, 2H).

[0441] Scheme II Example 2 N-[5-[Hydroxy]pyridin-2-yl]-4-(4-fluorophenyl)piperidine-1-carboxamide

Chem.

Chem.

[0442] LC-MS: (ES, m / z): 430 Step 3: Synthesis of N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]-4-(4-fluorophenyl)piperidine-1-carboxamide

Chemical formula

[0443] LC-MS: (ES, m / z): 316 1 1H NMR (300 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.78 (s, 1H), 7.78 (d, J = 2.9 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.28 (dd, J = 8.5, 5.6 Hz, 2H), 7.18 - 7.04 (m, 3H), 4.27 (d, J = 13.1 Hz, 2H), 2.91 - 2.64 (m, 3H), 1.81 - 1.64 (m, 2H), 1.51 (qd, J = 12.6, 4.0 Hz, 2H).

[0444] Example 3 N-(5-Hydroxypyridin-2-yl)-4-phenylpiperazine-1-carboxamide

Chem.

Chem.

[0445] Step 2: Synthesis of N-(5-Hydroxypyridin-2-yl)-4-phenylpiperazine-1-carboxamide

Chem.

[0446] LC-MS: (ES, m / z): 299 11H NMR (300 MHz, DMSO-d6) δ 9.49~9.39 (m, 1H), 8.90 (s, 1H), 7.79 (d, J = 2.9 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.28~7.08 (m, 3H), 6.96 (d, J = 8.1 Hz, 2H), 6.80 (t, J = 7.3 Hz, 1H), 3.59 (t, J = 5.0 Hz, 4H), 3.12 (t, J = 5.0 Hz, 4H).

[0447] Example 4 4-(4-Chlorophenyl)-N-(5-hydroxypyridin-2-yl)piperidine-1-carboxamide

Chemical Structure

Chemical Structure

[0448] Step 2: Synthesis of 4-(4-chlorophenyl)-N-(5-hydroxypyridin-2-yl)piperidine-1-carboxamide

Chemical Structure

[0449] LC-MS: (ES, m / z): 332 1 1H NMR (300 MHz, DMSO-d6) δ 9.48~9.27 (m, 1H), 8.78 (s, 1H), 7.78 (d, J = 2.9 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.39~7.22 (m, 4H), 7.13 (dd, J = 9.0, 3.0 Hz, 1H), 4.27 (d, J = 13.2 Hz, 2H), 2.91~2.64 (m, 2H), 1.80~1.68 (m, 2H), 1.51 (qd, J = 12.7, 3.9 Hz, 2H).

[0450] Example 5 4-(4-Fluorophenyl)-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide

Chemical formula

Chemical formula

[0451] Step 2: Synthesis of 4-(4-fluorophenyl)-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide

Chemical Structure

[0452] LC-MS: (ES, m / z): 328 1 1H NMR (300 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.91 (s, 1H), 7.79 (d, J = 2.9 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.19 - 6.92 (m, 5H), 3.58 (t, J = 4.9 Hz, 4H), 3.06 (t, J = 5.0 Hz, 4H).

[0453] Example 6 N-(5-Hydroxypyridin-2-yl)-4-(4-methoxyphenyl)piperidine-1-carboxamide [Chemical formula] Step 1: Synthesis of N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]-4-(4-methoxyphenyl)piperidine-1-carboxamide [Chemical formula] A solution of intermediate "A" (200 mg, 0.55 mmol, 1.00 equivalent), 4-(4-methoxyphenyl)piperidine (320 mg, 1.67 mmol, 3.00 equivalents), and Et3N (170 mg, 1.68 mmol, 3.00 equivalents) in CH2Cl2 (3 mL) was stirred at room temperature for 2 hours. The resulting solution was extracted with 2 × 15 mL of EtOAc, and the combined organic layers were concentrated under vacuum and purified by silica gel chromatography using EtOAc / hexane (1:2) to obtain 250 mg (103%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 442

[0454] Step 2: Synthesis of N-(5-hydroxypyridin-2-yl)-4-(4-methoxyphenyl)piperidine-1-carboxamide [Chemical formula] A solution of the product from the previous step (230 mg, 0.52 mmol, 1.00 equivalent) in 2N aqueous HCl (1 mL) and THF (2 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum. The crude product (240 mg) was purified by preparative-HPLC under the conditions of instrument "A"; column "A"; mobile phase, 10 mM aqueous NH4HCO3, and ACN (up to 50.0% in 7 minutes with 20.0% ACN); detector, uv254 / 220 nm to obtain 92.8 mg (55%) of the title compound as an off-white solid.

[0455] LC-MS: (ES, m / z): 328 11H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.76 (s, 1H), 7.78 (d, J = 2.9 Hz, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.13 (td, J = 6.8, 3.3 Hz, 3H), 6.90 - 6.79 (m, 2H), 4.32 - 4.20 (m, 2H), 3.71 (s, 3H), 2.82 (td, J = 12.9, 2.5 Hz, 2H), 2.50 (q, J = 1.9 Hz, 1H), 1.79 - 1.67 (m, 2H), 1.49 (qd, J = 12.6, 3.9 Hz, 2H).

[0456] Example 7 N-[5-Hydroxy]pyridin-2-yl]-4-(3-chlorophenyl)piperidine-1-carboxamide

Chemical formula

Chemical formula

[0457] Step 2: Synthesis of N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]-4-(3-chlorophenyl)piperidine-1-carboxamide

Chemical formula

[0458] LC-MS: (ES, m / z): 332 1 1H NMR (300 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.78 (s, 1H), 7.78 (d, J = 2.9 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.36 - 7.29 (m, 2H), 7.25 (dt, J = 7.5, 1.6 Hz, 2H), 7.13 (dd, J = 8.9, 3.0 Hz, 1H), 4.27 (d, J = 13.2 Hz, 2H), 2.79 (ddd, J = 21.3, 12.5, 9.5 Hz, 3H), 1.82 - 1.69 (m, 2H), 1.53 (qd, J = 12.7, 4.0 Hz, 2H).

[0459] Example 8 4-Benzyl-N-(5-hydroxypyridin-2-yl)piperidine-1-carboxamide

Chemical formula

Chemical formula

[0460] Step 2: Synthesis of 4-benzyl-N-(5-hydroxypyridin-2-yl)piperidine-1-carboxamide

Chemical Structure

[0461] LC-MS: (ES, m / z): 312 1 1H NMR (300 MHz, methanol-d4) δ 7.80 (dd, J = 3.0, 0.7 Hz, 1H), 7.50 (dd, J = 8.9, 0.8 Hz, 1H), 7.34 - 7.11 (m, 6H), 4.13 (dq, J = 13.7, 2.2 Hz, 2H), 2.85 (td, J = 13.3, 2.6 Hz, 2H), 2.58 (d, J = 7.1 Hz, 2H), 1.92 - 1.65 (m, 3H), 1.23 (qd, J = 12.6, 4.2 Hz, 2H).

[0462] Example 9 N-(5-Hydroxypyridin-2-yl)-4-(propan-2-yl)piperidine-1-carboxamide

Chem.

Chem.

[0463] Step 2: Synthesis of N-(5-Hydroxypyridin-2-yl)-4-(propan-2-yl)piperidine-1-carboxamide

Chem.

[0464] LC-MS: (ES, m / z): 264 11H NMR (300 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.70 (s, 1H), 7.82 - 7.74 (m, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.13 (d, J = 8.9, 3.0 Hz, 1H), 4.19 (d, J = 13.4, 3.5 Hz, 2H), 2.67 (td, J = 12.4, 2.3 Hz, 2H), 1.68 - 1.56 (m, 2H), 1.43 (d, J = 13.2, 6.7 Hz, 1H), 1.31 - 0.97 (m, 3H), 0.87 (d, J = 6.7 Hz, 6H).

[0465] Example 10 N-(5-Hydroxypyridin-2-yl)piperidine-1-carboxamide

Chem.

Chem.

[0466] Step 3: Synthesis of N-(5-Hydroxypyridin-2-yl)piperidine-1-carboxamide

Chem.

[0467] LC-MS: (ES, m / z): 222 1 1H-NMR (300 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.67 (s, 1H), 7.77 (d, J = 2.9 Hz, 1H), 7.57 (d, J = 8.9 Hz, 1H), 7.12 (d, J = 8.9, 3.0 Hz, 1H), 3.45~3.37 (m, 4H), 1.51 (m, 6H).

[0468] Example 11 N-(5-Hydroxypyridin-2-yl)azepane-1-carboxamide

Chemical formula

Chemical formula

[0469] Step 2: Synthesis of N-(5-Hydroxypyridin-2-yl)azepane-1-carboxamide [Chemical formula] A solution of the product (180 mg, 0.51 mmol, 1.00 equivalent) from the previous step in 2N HCl aqueous solution (2 mL) and THF (4 mL) was stirred at room temperature for 2 hours and then extracted with EtOAc. The combined organic layers were purified by preparative-HPLC under the conditions of instrument "B"; column "C"; mobile phase, water (0.1% FA) and ACN (12.0% ACN with a maximum of 31.0% in 7 minutes), and 66.2 mg (55%) of the title compound was obtained as an off-white solid.

[0470] LC-MS: (ES, m / z): 236 1 1H NMR (300 MHz, DMSO-d6) δ 10.85 (s, 1H), 10.23 (s, 1H), 7.94~7.76 (m, 3H), 3.55 (t, J = 6.1 Hz, 4H), 1.71 (d, J = 9.4, 4.7 Hz, 4H), 1.53 (t, J = 4.9 Hz, 4H).

[0471] Example 12 4-(2-Fluorophenyl)-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide [Chemical formula] Step 1: Synthesis of N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]-4-(2-fluorophenyl)piperazine-1-carboxamide [Chemical formula] A solution of intermediate "A" (200 mg, 0.55 mmol), 1-(2-fluorophenyl)-piperazine (298 mg, 1.65 mmol), and Et3N (170 mg, 1.68 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for 16 h. The resulting solution was extracted with 2 x 20 mL of CH2Cl2, and the combined organic layers were concentrated under vacuum and purified by silica gel column chromatography using EtOAc / hexane (1:2) to afford 230 mg (97%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 431

[0472] Step 2: Synthesis of 4-(2-fluorophenyl)-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide

Chemical formula

[0473] LC-MS: (ES, m / z): 317 1 1H NMR (300 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.90 (s, 1H), 7.79 (d, J = 2.9 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.18 - 7.00 (m, 5H), 3.70 - 3.52 (m, 4H), 3.05 - 2.93 (m, 4H).

[0474] Example 13 4-(2,4-difluorophenyl)-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide

Chemical formula

Chem.

[0475] Step 2: Synthesis of 4-(2,4-difluorophenyl)-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide

Chem.

[0476] LC-MS: (ES, m / z): 335 11H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.90 (s, 1H), 7.79 (d, J = 2.9 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.28 - 6.92 (m, 4H), 3.64 - 3.54 (m, 4H), 2.93 (t, J = 4.9 Hz, 4H).

[0477] Example 14 N-(5-Hydroxypyridin-2-yl)-4-[4-(trifluoromethyl)phenyl]piperazine-1-carboxamide

Chemical Structure

Chemical Structure

[0478] Step 2: Synthesis of N-(5-Hydroxypyridin-2-yl)-4-[4-(trifluoromethyl)phenyl]piperazine-1-carboxamide

Chemical Structure

[0479] LC-MS: (ES, m / z): 367 1 1H NMR (300 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.94 (s, 1H), 7.80 (d, J = 3.0 Hz, 1H), 7.55 (dd, J = 28.2, 8.7 Hz, 3H), 7.25 - 6.94 (m, 3H), 3.60 (dd, J = 6.6, 3.7 Hz, 4H), 3.30 (dd, J = 6.5, 3.8 Hz, 4H).

[0480] Example 15 N-(5-Hydroxypyridin-2-yl)-4-(4-methoxyphenyl)piperazine-1-carboxamide

Chemical formula

Chemical formula

[0481] Step 2: Synthesis of N-(5-hydroxypyridin-2-yl)-4-(4-methoxyphenyl)piperazine-1-carboxamide [Chemical formula] A solution of the product from the previous step (230 mg, 0.52 mmol) in 2N aqueous HCl (4 mL) and THF (2 mL) was stirred at room temperature for 2 h and then concentrated under vacuum. The crude product (230 mg) was purified by preparative-HPLC using apparatus "B"; column "B"; mobile phase, 10 mM aqueous NH4HCO3, and ACN (5.0% ACN up to 70.0% in 7 min) to give 84.2 mg (49%) of the title compound as an off-white solid.

[0482] LC-MS: (ES, m / z): 329 1 1H NMR (300 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.89 (s, 1H), 7.79 (dd, J = 2.9, 0.7 Hz, 1H), 7.59 (dd, J = 9.0, 0.7 Hz, 1H), 7.13 (dd, J = 9.0, 2.9 Hz, 1H), 6.99~6.88 (m, 2H), 6.88~6.78 (m, 2H), 3.68 (s, 3H), 3.58 (t, J = 5.0 Hz, 4H), 2.98 (dd, J = 6.0, 3.7 Hz, 4H).

[0483] Example 16 N-(5-Hydroxypyridin-2-yl)-4-(pyrimidin-2-yl)piperazine-1-carboxamide

Chem.

Chem.

[0484] Step 2: Synthesis of N-(5-Hydroxypyridin-2-yl)-4-(pyrimidin-2-yl)piperazine-1-carboxamide

Chem.

[0485] LC-MS: (ES, m / z): 415 11H NMR (300 MHz, methanol-d4) δ 8.36 (d, J = 4.7 Hz, 2H), 7.83 (d, J = 3.0 Hz, 1H), 7.52 (d, J = 8.9 Hz, 1H), 7.21 (dd, J = 8.9, 3.0 Hz, 1H), 6.64 (t, J = 4.8 Hz, 1H), 3.94 - 3.83 (m, 4H), 3.68 - 3.58 (m, 4H).

[0486] Example 17 N-(5-Hydroxypyridin-2-yl)-4-(pyridin-2-yl)piperazine-1-carboxamide

Chemical Structure

Chemical Structure

[0487] Step 2: Synthesis of N-(5-Hydroxypyridin-2-yl)-4-(pyridin-2-yl)piperazine-1-carboxamide

Chemical Structure

[0488] LC-MS: (ES, m / z): 300 1 1H NMR (300 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.89 (s, 1H), 8.12 (ddd, J = 4.9, 2.0, 0.8 Hz, 1H), 7.79 (d, J = 2.9 Hz, 1H), 7.64 - 7.48 (m, 2H), 7.13 (dd, J = 8.9, 3.0 Hz, 1H), 6.85 (d, J = 8.6 Hz, 1H), 6.70 - 6.60 (m, 1H), 3.52 (m, 8H).

[0489] Example 18 N-(5-Hydroxypyridin-2-yl)-4-[5-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide

Chemical formula

Chemical formula

[0490] Step 2: Synthesis of N-(5-hydroxypyridin-2-yl)-4-[5-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide

Chemical Structure

[0491] LC-MS: (ES, m / z): 368 1 H NMR (300 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.92 (s, 1H), 8.42 (d, J = 2.3 Hz, 1H), 7.80 (dd, J = 7.6, 2.7 Hz, 2H), 7.60 (d, J = 8.9 Hz, 1H), 7.14 (dd, J = 8.9, 3.0 Hz, 1H), 6.98 (d, J = 9.1 Hz, 1H), 3.71~3.51 (m, 8H).

[0492] Example 19 3-(5-Hydroxypyridin-2-yl)-1-[(1r,4r)-4-phenylcyclohexyl]urea [Chemical formula] Step 1: Synthesis of N-benzyl-4-phenylcyclohexan-1-amine [Chemical formula] A solution of 4-phenylcyclohexan-1-one (8.1 g, 46.49 mmol, 1.00 equivalent), benzylamine (5 g, 46.66 mmol, 1.00 equivalent), and NaBH(OAc)3 (19.8 g, 93.42 mmol, 2.00 equivalents) in CH2Cl2 (100 g) was stirred at room temperature for 16 hours and then extracted with 2 × 300 mL of EtOAc. The combined organic layers were concentrated under vacuum and purified by silica gel chromatography using EtOAc / hexane (1:2) to obtain 4 g (32%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 266

[0493] Step 2: Synthesis of 4-phenylcyclohexan-1-amine [Chemical formula] A solution of the product from the previous step (500 mg, 1.88 mmol, 1.00 equivalent) and AcOH (1 mg) in MeOH (10 mg) was stirred on Pd / C (100 mg) at 30 °C for 16 hours. The solid was removed by filtration, and the filtrate was concentrated under vacuum to obtain 300 mg (91%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 176.

[0494] Step 3: Synthesis of 3-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]-1-[(1r,4r)-4-phenylcyclohexyl]urea [Chemical formula] A solution of the product (300 mg, 1.71 mmol) from the previous step, intermediate "A" (186 mg, 0.51 mmol), and Et3N (173 mg, 1.71 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for 16 h and then extracted with 50 mL of EtOAc. The combined organic layers were concentrated under vacuum and purified by silica gel chromatography using EtOAc / hexane (1:1) to give 220 mg (30%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 426.

[0495] Step 4: Synthesis of 3-(5-hydroxypyridin-2-yl)-1-[(1r,4r)-4-phenylcyclohexyl]urea

Chemical formula

[0496] LC-MS: (ES, m / z): 312 1 1H NMR (300 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.74 (s, 1H), 7.74 (t, J = 5.7 Hz, 2H), 7.27 (p, J = 7.2, 6.1 Hz, 7H), 7.23 - 7.09 (m, 1H), 3.57 (br, 1H), 2.51 (s, 1H), 2.02 (m, 2H), 1.83 (m, 2H), 1.56 (br q, J = 12.6 Hz, 2H), 1.32 (br q, J = 12.8 Hz, 2H).

[0497] Example 20 3-(5-hydroxypyridin-2-yl)-1-(oxan-4-yl)urea

Chemical formula

Chem.

[0498] Step 2. Synthesis of 3-(5-hydroxypyridin-2-yl)-1-(oxan-4-yl)urea

Chem.

[0499] LC-MS: (ES, m / z): 238 11H NMR (300 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.75 (s, 1H), 7.85 (d, J = 7.3 Hz, 1H), 7.72 (d, J = 2.9 Hz, 1H), 7.25 (d, J = 8.9 Hz, 1H), 7.13 (dd, J = 8.9, 2.9 Hz, 1H), 3.88 - 3.78 (m, 2H), 3.78 - 3.68 (m, 1H), 3.46 - 3.31 (m, 2H), 1.87 - 1.73 (m, 2H), 1.38 (m, 2H).

[0500] Example 21 1-Cyclohexyl-3-(5-hydroxypyridin-2-yl)urea

Chemical formula

Chemical formula

[0501] Step 2. Synthesis of 1-cyclohexyl-3-(5-hydroxypyridin-2-yl)urea

Chemical formula

[0502] LC-MS: (ES, m / z): 236 1 1H NMR (300 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.72 (s, 1H), 7.85~7.75 (m, 1H), 7.70 (d, J = 2.9 Hz, 1H), 7.23 (d, J = 8.9 Hz, 1H), 7.12 (dd, J = 8.9, 2.9 Hz, 1H), 3.52 (tp, J = 10.0, 3.7 Hz, 1H), 1.86~1.73 (m, 2H), 1.65 (m, 2H), 1.52 (dd, J = 11.9, 5.8 Hz, 1H), 1.25 (m, 5H).

[0503] Example 22 4-(5-Chloropyridin-2-yl)-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide

Chemical formula

Chemical formula

[0504] Step 2. Synthesis of 4-(5-chloropyridin-2-yl)-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide

Chemical Structure

[0505] LC-MS: (ES, m / z): 334 1 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.89 (s, 1H), 8.12 (d, J = 2.7 Hz, 1H), 7.79 (d, J = 2.9 Hz, 1H), 7.68 - 7.53 (m, 2H), 7.14 (dd, J = 8.9, 3.0 Hz, 1H), 6.90 (d, J = 9.1 Hz, 1H), 3.63 - 3.46 (m, 8H).

[0506] Example 23 4-(2,4-dichlorophenyl)-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide [Chemistry] Step 1. Synthesis of Tert-butyl 4-(2,4-dichlorophenyl)piperazine-1-carboxylate [Chemistry] A solution of Tert-butyl piperazine-1-carboxylate (2 g, 17.54 mmol), 1-bromo-3,5-dichlorobenzene (4 g, 17.71 mol), NaOtBu (2.5 g), BINAP (108 mg, 0.17 mmol), Pd2(dba)3 (160 mg, 0.17 mmol, 0.01 equiv) in toluene (20 mL) was stirred at 80 °C for 16 h under N2, then quenched by adding 50 mL of H2O and extracted with 2 x 60 mL of EtOAc. The combined organic layers were concentrated under vacuum and purified by silica gel chromatography using EtOAc / hexane (1 / 2) to give 3.3 mg (57%) of the title compound as an off-white solid.

[0507] LC-MS: (ES, m / z): 331 1 H NMR (400 MHz, DMSO-d6) δ 7.56 (d, J = 2.5 Hz, 1H), 7.37 (dd, J = 8.7, 2.5 Hz, 1H), 7.17 (d, J = 8.7 Hz, 1H), 3.47 (t, J = 4.9 Hz, 4H), 2.90 (t, J = 5.0 Hz, 4H), 1.42 (s, 9H).

[0508] Step 2. Synthesis of 1-(2,4-dichlorophenyl)piperazine [Chemistry] To a solution of the product from the previous step (1 g, 3.02 mmol) in 1,4-dioxane (6 mL) was added 4M HCl / dioxane (3 mL). The resulting solution was stirred at room temperature for 6 h and then concentrated in vacuo to give 200 mg (29%) of the title compound as a pale yellow solid.

[0509] LC-MS: (ES, m / z): 231 1 1H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J = 2.5 Hz, 1H), 7.35 (dd, J = 8.7, 2.5 Hz, 1H), 7.13 (d, J = 8.7 Hz, 1H), 2.85 (hept, J = 3.3 Hz, 8H).

[0510] Step 3. Synthesis of N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]-4-(2,4-dichlorophenyl)piperazine-1-carboxamide

Chem.

[0511] Step 4. Synthesis of 4-(2,4-dichlorophenyl)-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide

Chem.

[0512] LC-MS: (ES, m / z): 367 1 1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.89 (s, 1H), 7.80 (d, J = 3.0 Hz, 1H), 7.71~7.53 (m, 2H), 7.37 (dd, J = 8.6, 2.5 Hz, 1H), 7.28~7.09 (m, 2H), 3.60 (m, 4H), 2.95 (m, 4H).

[0513] Example 24 4-(5-Fluoropyridin-2-yl)-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide

Chemical formula

Chemical formula

[0514] Step 2. Synthesis of 4-(5-fluoropyridin-2-yl)-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide

Chemical Structure

[0515] LC-MS: (ES, m / z): 318 1 1H NMR (400 MHz, DMSO-d6) δ 9.36 (br, 1H), 8.90 (s, 1H), 8.11 (d, J = 3.1 Hz, 1H), 7.79 (d, J = 2.9 Hz, 1H), 7.69 - 7.46 (m, 2H), 7.14 (dd, J = 8.9, 3.0 Hz, 1H), 6.92 (dd, J = 9.3, 3.5 Hz, 1H), 3.51 (m, 8H).

[0516] Example 25 4-(3,4-difluorophenyl)-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide [Chemistry] Step 1. Synthesis of Tert-butyl 4-(3,4-difluorophenyl)piperazine-1-carboxylate [Chemistry] A solution of Tert-butyl piperazine-1-carboxylate (2 g, 17.54 mmol), 1,2-difluoro-4-iodobenzene (4.2 g, 17.50 mmol), NaOtBu (2.5 g), BINAP (108 mg, 0.17 mmol, 0.01 equiv), and Pd2(dba)3 (160 mg, 0.17 mmol) in toluene (20 mL) at room temperature was stirred at 80 °C under N2 for 16 h. The reaction was then quenched by adding 40 mL of H2O and extracted with 2 x 50 mL of EtOAc. The combined organic layers were concentrated under vacuum and purified by silica gel chromatography using EtOAc / hexane (1 / 2) to give 3.2 mg (61%) of the title compound as an off-white solid.

[0517] LC-MS: (ES, m / z): 299 1 H NMR (400 MHz, DMSO-d6) δ 7.25 (dt, J = 10.6, 9.3 Hz, 1H), 7.00 (ddd, J = 14.2, 7.1, 3.0 Hz, 1H), 6.74 (dtd, J = 9.1, 3.3, 1.4 Hz, 1H), 3.43 (t, J = 5.2 Hz, 4H), 3.07 (dd, J = 6.3, 4.2 Hz, 4H), 1.42 (s, 9H).

[0518] Step 2. Synthesis of 1-(3,4-difluorophenyl)piperazine [Chemistry] To a solution of the product (1 g, 3.35 mmol) from the previous step in 1,4-dioxane (6 mL) was added 4 M HCl / dioxane (3 mL) dropwise with stirring. The resulting solution was stirred at room temperature for 4 h. The pH was adjusted to 7 with 2 N NaHCO3. The resulting solution was extracted with 2 × 20 mL of EtOAc, and the combined organic layers were concentrated under vacuum to give 640 mg (96%) of the title compound as an off-white solid.

[0519] LC-MS: (ES, m / z): 199 1 1H NMR (400 MHz, DMSO-d6) δ 7.22 (dt, J = 10.6, 9.3 Hz, 1H), 6.94 (ddd, J = 14.5, 7.1, 3.0 Hz, 1H), 6.69 (dtd, J = 8.5, 3.3, 1.5 Hz, 1H), 3.06~2.93 (m, 4H), 2.87~2.72 (m, 4H).

[0520] Step 3. Synthesis of N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]-4-(3,4-difluorophenyl)piperazine-1-carboxamide

Chemical Structure

[0521] Step 4. Synthesis of 4-(3,4-difluorophenyl)-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide [Chem.] To a solution of the product (180 mg, 0.40 mmol) from the previous step in THF (2 mL), 2N aqueous HCl solution (1 mL) was added dropwise with stirring at room temperature. The resulting solution was stirred at room temperature for 1 hour and then concentrated under vacuum. The crude product (180 mg) was purified by preparative-HPLC under the conditions of apparatus "A"; column "A"; mobile phase, 10 mM aqueous NH4HCO3 solution, and ACN (25.0% ACN with a maximum of 57.0% in 8 minutes), and 68.7 mg (51%) of the title compound was obtained as an off-white solid.

[0522] LC-MS: (ES, m / z): 335 1 1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.92 (s, 1H), 7.79 (d, J = 2.9 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.25 (q, J = 9.7 Hz, 1H), 7.15 (d, J = 3.1 Hz, 1H), 7.02 (ddd, J = 14.2, 7.1, 3.0 Hz, 1H), 6.76 (dd, J = 8.9, 4.1 Hz, 1H), 3.58 (m, 4H), 3.12 (m, 4H).

[0523] Example 26 4-(3,5-Difluorophenyl)-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide [Chem.] Step 1. Synthesis of tert-butyl 4-(3,5-difluorophenyl)piperazine-1-carboxylate [Chem.] A solution of Tert-butyl piperazine-1-carboxylate (2 g, 17.54 mmol), 1,3-difluoro-5-iodobenzene (4.2 g, 17.50 mmol), NaOtBu (2.5 g), BINAP (108 mg, 0.17 mmol), and Pd2(dba)3 (160 mg, 0.17 mmol) in toluene (20 mL) was stirred at 80 °C for 16 h and then quenched by adding 40 mL of H2O. The resulting solution was extracted with 2 × 40 mL of EtOAc, the combined organic layers were concentrated under vacuum, and purified by silica gel chromatography using EtOAc / hexane (1 / 2) to give 3.1 g (59%) of the title compound as an off-white solid.

[0524] LC-MS: (ES, m / z): 299 1 H NMR (400 MHz, DMSO-d6) δ 6.69~6.57 (m, 2H), 6.49 (tt, J = 9.3, 2.2 Hz, 1H), 3.42 (t, J = 5.3 Hz, 4H), 3.26~3.13 (m, 4H), 1.42 (s, 9H).

[0525] Step 2. Synthesis of 1-(3,5-difluorophenyl)piperazine

Chemical formula

[0526] LC-MS: (ES, m / z): 199 1 H NMR (400 MHz, DMSO-d6) δ 6.65~6.51 (m, 2H), 6.44 (tt, J = 9.2, 2.2 Hz, 1H), 3.13~3.06 (m, 4H), 2.86~2.73 (m, 4H).

[0527] Step 3. Synthesis of N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]-4-(3,5-difluorophenyl)piperazine-1-carboxamide

Chem.

[0528] Step 4. Synthesis of 4-(3,5-difluorophenyl)-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide

Chem.

[0529] LC-MS: (ES, m / z): 335 11H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.93 (s, 1H), 7.79 (d, J = 2.9 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.14 (dd, J = 8.9, 3.0 Hz, 1H), 6.80 - 6.56 (m, 2H), 6.49 (tt, J = 9.2, 2.2 Hz, 1H), 3.57 (m, 4H), 3.24 (m, 4H).

[0530] Example 27 4-(4-Cyanophenyl)-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide

Chemical formula

Chemical formula

[0531] LC-MS: (ES, m / z): 438 Step 2. Synthesis of 4-(4-cyanophenyl)-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide

Chemical formula

[0532] LC-MS: (ES, m / z): 324 1 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.91 (s, 1H), 7.79 (d, J = 3.0 Hz, 1H), 7.59 (d, J = 8.8 Hz, 3H), 7.14 (dd, J = 9.0, 3.0 Hz, 1H), 7.12 - 7.00 (m, 2H), 3.59 (m, 4H), 3.38 (m, 4H).

[0533] Example 28 4-(2,4-Difluorophenyl)-N-(4-hydroxyphenyl)piperazine-1-carboxamide

Chemical formula

Chemical formula

[0534] LC-MS: (ES, m / z): 448 Step 2.4 - Synthesis of (2,4-difluorophenyl)-N-(4-hydroxyphenyl)piperazine-1-carboxamide

Chem.

[0535] LC-MS: (ES, m / z): 334 1 1H NMR (300 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.31 (s, 1H), 7.29 - 6.93 (m, 5H), 6.67 - 6.58 (m, 2H), 3.54 (m, 4H), 2.93 (m, 4H).

[0536] Example 29 4-(4-Fluorophenyl)-N-(4-hydroxyphenyl)piperazine-1-carboxamide

Chem.

Chem.

[0537] LC-MS: (ES, m / z): 430 Step 2. Synthesis of 4-(4-fluorophenyl)-N-(4-hydroxyphenyl)piperazine-1-carboxamide

Chem.

[0538] LC-MS: (ES, m / z): 316 1 1H NMR (300 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.32 (s, 1H), 7.23~7.13 (m, 2H), 7.11~6.92 (m, 4H), 6.68~6.57 (m, 2H), 3.53 (m, 4H), 3.06 (m, 4H).

[0539] Example 30 N-(4-Hydroxyphenyl)-4-[4-(trifluoromethyl)phenyl]piperazine-1-carboxamide

Chem.

Chem.

Chem.

[0540] Example 31 N-(4-Hydroxyphenyl)-4-[5-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide

Chemical formula

Chemical formula

[0541] LC-MS: (ES, m / z): 481 Step 2. Synthesis of N-(4-Hydroxyphenyl)-4-[5-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide

Chemical formula

[0542] LC-MS: (ES, m / z): 367 1 1H NMR (300 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.45 - 8.38 (m, 1H), 8.33 (s, 1H), 7.80 (dd, J = 9.2, 2.6 Hz, 1H), 7.23 - 7.12 (m, 2H), 6.97 (d, J = 9.1 Hz, 1H), 6.69 - 6.58 (m, 2H), 3.66 (m, 4H), 3.52 (m, 4H).

[0543] Example 32 3-(5-Hydroxypyridin-2-yl)-1-(1-phenylpiperidin-4-yl)urea

Chemical formula

Chemical formula

[0544] LC-MS (ES, m / z): 427.5 Step 2.3 - Synthesis of (5-Hydroxypyridin-2-yl)-1-(1-phenylpiperidin-4-yl)urea

Chem.

[0545] LC-MS: (ES, m / z): 313.2 1 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.78 (s, 1H), 7.91 (s, 1H), 7.71 (d, J = 3.0 Hz, 1H), 7.29 - 7.10 (m, 4H), 6.95 (d, J = 8.2 Hz, 2H), 6.75 (t, J = 7.3 Hz, 1H), 3.76 - 3.66 (m, 1H), 3.59 - 3.49 (m, 2H), 2.94 - 2.82 (m, 2H), 1.98 - 1.88 (m, 2H), 1.57 - 1.43 (m, 2H).

[0546] Example 33 N-(5-Hydroxypyridin-2-yl)-4-[4-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide

Chem.

Chem.

[0547] Step 2. Synthesis of N-(5-hydroxypyridin-2-yl)-4-[4-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide

Chemical formula

[0548] LC-MS: (ES, m / z): 368 1 1H NMR (300 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.92 (s, 1H), 8.32 (d, J = 5.2 Hz, 1H), 7.78 (d, J = 2.9 Hz, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.18~7.07 (m, 2H), 6.88 (dd, J = 5.2, 1.3 Hz, 1H), 3.66~3.49 (m, 8H).

[0549] Example 34 4-(5-Cyanopyridin-2-yl)-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide

Chemical formula

Chemical formula

[0550] Step 2. Synthesis of 4-(5-cyanopyridin-2-yl)-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide

Chemical formula

[0551] LC-MS: (ES, m / z): 325 1 1H NMR (300 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.92 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 7.85 (dd, J = 9.1, 2.4 Hz, 1H), 7.77 (d, J = 2.9 Hz, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.12 (dd, J = 8.9, 3.0 Hz, 1H), 6.94 (d, J = 9.1 Hz, 1H), 3.68 (m, 4H), 3.54 (m, 4H).

[0552] Example 35 4-(6-Fluoropyridin-2-yl)-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide [Chemical formula] Step 1. Synthesis of N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]-4-(6-fluoropyridin-2-yl)piperazine-1-carboxamide [Chemical formula] A solution of 4-fluorophenyl N-5-[(tert-butyldimethylsilyl)oxy]pyridin-2-ylcarbamate (100 mg, 0.28 mmol), Et3N (84 mg, 0.83 mmol), and 1-(6-fluoropyridin-2-yl)piperazine (58 mg, 0.32 mmol) in CH2Cl2 (5 mL). The resulting solution was stirred at room temperature for 16 h and then quenched by the addition of 20 mL of H2O and extracted with 2 × 20 mL of EtOAc. The combined organic layers were concentrated under vacuum to give 110 mg (80%) as an off-white solid. LC-MS: (ES, m / z): 432

[0553] Step 2. Synthesis of 4-(6-fluoropyridin-2-yl)-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide

Chemical Structure

[0554] LC-MS (ES, m / z): 318 1 1H NMR (300 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.91 (s, 1H), 7.78 (d, J = 2.9 Hz, 1H), 7.66 (ddd, J = 7.5, 8.3, 8.3 Hz, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.12 (dd, J = 8.9, 2.9 Hz, 1H), 6.70 (dd, J = 8.3, 2.7 Hz, 1H), 6.27 (m, 1H), 3.51 (m, 8H).

[0555] Example 36 N-(5-Hydroxypyridin-2-yl)-4-[6-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide

Chem.

Chem.

[0556] Step 2. Synthesis of N-(5-hydroxypyridin-2-yl)-4-[6-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide

Chem.

[0557] LC-MS: (ES, m / z): 368 1 1H NMR (300 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.92 (s, 1H), 7.82~7.68 (m, 2H), 7.59 (d, J = 8.9 Hz, 1H), 7.13 (m, 2H), 7.04 (d, J = 7.5 Hz, 1H), 3.56 (m, 8H).

[0558] Example 37 4-Benzyl-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide

Chemical formula

Chemical formula

[0559] LC-MS (ES, m / z): 427.1 Step 2. Synthesis of 4-Benzyl-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide

Chem.

[0560] LC-MS (ES, m / z): 313.0 1 ¹H NMR (300 MHz, methanol-d₄) δ 8.25 (s, 1H), 7.81 (d, J = 2.9 Hz, 1H), 7.49 (d, J = 8.9 Hz, 1H), 7.44 - 7.27 (m, 5H), 7.20 (dd, J = 8.9, 2.8 Hz, 1H), 3.78 (s, 2H), 3.60 (m, 4H), 2.71 (m, 4H).

[0561] Example 38 4-[(4-Fluorophenyl)methyl]-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide

Chem.

Chem.

[0562] Step 2. Synthesis of 4-[(4-fluorophenyl)methyl]-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide

Chemical Structure

[0563] LC-MS (ES, m / z): 331.0 1 1H NMR (300 MHz, methanol-d4) δ 8.20 (s, 1H), 7.81 (d, J = 2.9 Hz, 1H), 7.49 (d, J = 8.9 Hz, 1H), 7.46 - 7.33 (m, 2H), 7.20 (dd, J = 8.9, 2.9 Hz, 1H), 7.10 (t, J = 8.7 Hz, 2H), 3.75 (s, 2H), 3.60 (m, 4H), 2.69 (m, 4H).

[0564] Example 39 1-[((5-Hydroxypyridin-2-yl)amino)carbonyl]-4-(pyridin-3-yl)piperazine [Chemistry] This compound can be prepared using other disclosed methods.

[0565] Step 1. Synthesis of N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]-4-(pyridin-3-yl)piperazine-1-carboxamide [Chemistry] A solution of 4-fluorophenyl N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]carbamate (200 mg, 0.55 mmol), Et3N (170 mg, 1.68 mmol), and 1-(pyridin-3-yl)piperazine (270 mg, 1.65 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for 16 h and then extracted with 2 × 30 mL of EtOAc. The combined organic layers were concentrated under vacuum and purified by silica gel column chromatography using EtOAc / hexane (1:2) to afford 140 mg (61%) of the title compound as an off-white solid. LC-MS: (ES, m / z): 414.

[0566] Step 2. Synthesis of 1-[((5-hydroxypyridin-2-yl)amino)carbonyl]-4-(pyridin-3-yl)piperazine [Chemistry] A solution of the product from the previous step (140 mg, 0.34 mmol) in 1N aqueous HCl (1 mL) and THF (2 mL) was stirred at room temperature for 2 h and then concentrated under vacuum. The crude product (140 mg) was purified by preparative-HPLC under the conditions of instrument "A"; column "B"; mobile phase, water (10 mM NH4HCO3), and ACN (5.0% ACN with a maximum of 40.0% in 7 min); detector, uv254 / 220 nm to afford 49.7 mg (49%) of the title compound as an off-white solid.

[0567] LC-MS: (ES, m / z): 300. 1 1H NMR (300 MHz, DMSO-d6) δ 9.75 - 9.17 (m, 1H), 8.94 (s, 1H), 8.32 (d, J = 2.9 Hz, 1H), 8.01 (dd, J = 4.6, 1.3 Hz, 1H), 7.79 (d, J = 2.9 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.42 - 7.31 (m, 1H), 7.22 (dd, J = 8.5, 4.5 Hz, 1H), 7.13 (dd, J = 8.9, 3.0 Hz, 1H), 3.84 - 3.46 (m, 4H), 3.19 (m, 4H).

[0568] Example 40 1-Hexyl-3-(5-hydroxypyridin-2-yl)urea

Chemical Structure

Chemical Structure

[0569] LC-MS: (ES, m / z): 352 Step 2: Synthesis of 3-Hexyl-1-(5-hydroxypyridin-2-yl)urea

Chemical Structure

[0570] LC-MS: (ES, m / z): 238 1 1H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.79 (s, 1H), 7.88 (s, 1H), 7.72 (d, J = 2.9 Hz, 1H), 7.22 (d, J = 8.9 Hz, 1H), 7.14 (dd, J = 8.9, 2.9 Hz, 1H), 3.13 (q, J = 6.5 Hz, 2H), 1.53~1.38 (m, 2H), 1.29 (dt, J = 9.4, 3.5 Hz, 6H), 0.94~0.79 (m, 3H).

[0571] Example 41 Hexyl N-(5-hydroxypyridin-2-yl)carbamate

Chemical Structure

Chemical Structure

[0572] Step 2: Synthesis of hexyl N-(5-hydroxypyridin-2-yl)carbamate

Chemical formula

[0573] LC-MS: (ES, m / z): 239 1 1H NMR (300 MHz, DMSO-d6) δ 9.72 (s, 1H), 9.53 (s, 1H), 7.82 (d, J = 2.9 Hz, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.19 (d, J = 8.9, 3.0 Hz, 1H), 4.06 (t, J = 6.6 Hz, 2H), 1.59 (q, J = 6.8 Hz, 2H), 1.44~1.20 (m, 6H), 0.96~0.82 (m, 3H).

[0574] Example 42 Cyclohexyl N-(5-hydroxypyridin-2-yl)carbamate

Chemical formula

Chemical formula

[0575] Step 2: Synthesis of cyclohexyl N-(5-hydroxypyridin-2-yl)carbamate

Chemical formula

[0576] LC-MS: (ES, m / z): 237 11H NMR (300 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.60 (s, 1H), 7.81 (d, J = 2.9 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.21 (d, J = 8.9, 3.0 Hz, 1H), 4.62 (m, 1H), 1.78 (m, 4H), 1.58 - 1.13 (m, 6H).

[0577] Scheme V Example 43 (1r,4r)-4-Phenylcyclohexyl N-(5-hydroxypyridin-2-yl)carbamate

Chemical Structure

Chemical Structure

[0578] Step 2: Synthesis of (1r,4r)-4-Phenylcyclohexan-1-ol

Chemical Structure

[0579] LC-MS-: (ES, m / z): 159 Step 3: Synthesis of (1r,4r)-4-phenylcyclohexyl N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]carbamate

Chem.

[0580] LC-MS: (ES, m / z): 427 Step 4: Synthesis of (1r,4r)-4-phenylcyclohexyl N-(5-hydroxypyridin-2-yl)carbamate

Chem.

[0581] LC-MS: (ES, m / z): 313 11H NMR (300 MHz, DMSO-d6) δ 7.79 (d, J = 2.9 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.34 - 7.11 (m, 6H), 4.67 (m, 1H), 2.56 (dt, J = 11.6, 3.6 Hz, 1H), 2.08 (dd, J = 9.8, 5.1 Hz, 2H), 1.84 (d, J = 11.5 Hz, 2H), 1.70 - 1.36 (m, 4H).

[0582] Example 44 1-Phenylpiperidin-4-yl N-(5-hydroxypyridin-2-yl)carbamate

Chemical Structure

Chemical Structure

[0583] LC-MS: (ES, m / z): 428 Step 2: Synthesis of 1-Phenylpiperidin-4-yl N-(5-hydroxypyridin-2-yl)carbamate

Chemical Structure

[0584] LC-MS: (ES, m / z): 314 1 1H NMR (300 MHz, DMSO-d6) δ 9.71 (s, 1H), 9.55 (s, 1H), 7.80 (d, J = 2.9 Hz, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.27 - 7.12 (m, 3H), 7.01 - 6.89 (m, 2H), 6.75 (tt, J = 7.2, 1.1 Hz, 1H), 4.81 (m, 1H), 3.51 (m, 2H), 3.02 (m, 2H), 1.97 m, 2H), 1.68 (m, 2H).

[0585] Scheme VI Example 45 N-(5-Hydroxypyridin-2-yl)-4-(5-methoxypyridin-2-yl)piperazine-1-carboxamide [Chemical formula] Step 1. Synthesis of tert-butyl 4-(5-methoxypyridin-2-yl)piperazine-1-carboxylate [Chemical formula] A solution of Tert-butyl piperazine-1-carboxylate (2 g, 10.74 mmol), 2-bromo-5-methoxypyridine (2 g, 10.64 mmol), Pd2(dba)3 (98 mg, 0.11 mmol), BINAP (67 mg, 0.11 mmol), and NaOtBu (1.5 g, 15.62 mmol) in toluene (20 mL) was stirred at 80 °C for 16 h, then quenched by adding H2O and extracted with EtOAc. The combined organic layers were concentrated in vacuo and purified by silica gel chromatography using EtOAc / petroleum ether (1:3) to give 2 g (63%) of the title compound as a white solid.

[0586] LC-MS: (ES, m / z): 294.3 1 1H NMR (300 MHz, DMSO-d6) δ 7.87 (dd, J = 3.1, 0.6 Hz, 1H), 7.26 (dd, J = 9.1, 3.1 Hz, 1H), 6.82 (dd, J = 9.2, 0.7 Hz, 1H), 3.71 (s, 3H), 3.44 - 3.27 (m, 8H), 1.40 (s, 9H).

[0587] Step 2. Synthesis of 1-(5-methoxypyridin-2-yl)piperazine

Chemical formula

[0588] Step 3. Synthesis of N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]-4-(5-methoxypyridin-2-yl)piperazine-1-carboxamide

Chemical formula

[0589] LC-MS: (ES, m / z): 444.5 Step 4. Synthesis of N-(5-hydroxypyridin-2-yl)-4-(5-methoxypyridin-2-yl)piperazine-1-carboxamide

Chemical formula

[0590] LC-MS: (ES, m / z): 330.0 1 1H NMR (300 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.88 (s, 1H), 7.88 (d, J = 3.1 Hz, 1H), 7.77 (d, J = 2.9 Hz, 1H), 7.57 (d, J = 8.9 Hz, 1H), 7.26 (dd, J = 9.1, 3.1 Hz, 1H), 7.12 (dd, J = 9.0, 3.0 Hz, 1H), 6.85 (d, J = 9.1 Hz, 1H), 3.71 (s, 3H), 3.53 (m, 4H), 3.40 - 3.31 (m, 4H).

[0591] Example 46 N-(5-Hydroxypyridin-2-yl)-4-[5-(trifluoromethoxy)pyridin-2-yl]piperazine-1-carboxamide

Chem.

Chem.

[0592] Step 2. Synthesis of 1-[5-(Trifluoromethoxy)pyridin-2-yl]piperazine

Chem.

[0593] LC-MS: (ES, m / z): 248 Step 3. Synthesis of N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]-4-[5-(trifluoromethoxy)pyridin-2-yl]piperazine-1-carboxamide

Chem.

[0594] LC-MS: (ES, m / z): 498 Step 4. Synthesis of N-(5-hydroxypyridin-2-yl)-4-[5-(trifluoromethoxy)pyridin-2-yl]piperazine-1-carboxamide

Chem.

[0595] LC-MS: (ES, m / z): 384 11H NMR (300 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.91 (s, 1H), 8.15 (m, 1H), 7.78 (m, 1H), 7.65 - 7.53 (m, 2H), 7.12 (dd, J = 8.9, 3.0 Hz, 1H), 6.95 (d, J = 9.3 Hz, 1H), 3.53 (br s, 8H).

[0596] Example 47 1-[1-(4-Fluorophenyl)piperidin-3-yl]-3-(5-hydroxypyridin-2-yl)urea

Chem.

Chem.

[0597] LC-MS (ES, m / z): 295.20 Step 2. Synthesis of 1-(4-Fluorophenyl)piperidin-3-amine

Chem.

[0598] Step 3. Synthesis of 3-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]-1-[1-(4-fluorophenyl)piperidin-3-yl]urea

Chemical formula

[0599] Step 4. Synthesis of 1-[1-(4-fluorophenyl)piperidin-3-yl]-3-(5-hydroxypyridin-2-yl)urea

Chemical formula

[0600] LC-MS (ES, m / z): 331.0 1 1H NMR (300 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.84 (s, 1H), 8.03 (s, 1H), 7.69 (d, J = 2.9 Hz, 1H), 7.28 (d, J = 8.9 Hz, 1H), 7.14 (dd, J = 8.9, 2.9 Hz, 1H), 7.09~7.00 (m, 2H), 7.00~6.91 (m, 2H), 3.90~3.73 (m, 1H), 3.40 (dd, J = 11.9, 3.5 Hz, 1H), 3.21 (d, J = 12.6 Hz, 1H), 2.95 (t, J = 9.6 Hz, 1H), 2.80 (dd, J = 11.7, 7.7 Hz, 1H), 1.78 (s, 2H), 1.70~1.56 (m, 1H), 1.48 (d, J = 8.6 Hz, 1H).

[0601] Example 48 1-[1-(4-Chlorophenyl)piperidin-3-yl]-3-(5-hydroxypyridin-2-yl)urea

Chemical formula

Chemical formula

[0602] Step 2. Synthesis of 1-(4-chlorophenyl)piperidin-3-amine

Chemical formula

[0603] Step 3. Synthesis of 3-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]-1-[1-(4-chlorophenyl)piperidin-3-yl]urea

Chemical formula

[0604] Step 4. Synthesis of 1-[1-(4-chlorophenyl)piperidin-3-yl]-3-(5-hydroxypyridin-2-yl)urea

Chemical formula

[0605] LC-MS (ES, m / z): 347.0 1 1H NMR (300 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.84 (s, 1H), 8.00 (s, 1H), 7.68 (d, J = 2.9 Hz, 1H), 7.40 - 7.08 (m, 4H), 7.04 - 6.87 (m, 2H), 3.78 (d, J = 9.4 Hz, 1H), 3.50 (dd, J = 11.9, 3.5 Hz, 1H), 3.30 (s, 1H), 3.00 (t, J = 9.3 Hz, 1H), 2.85 (dd, J = 12.1, 7.9 Hz, 1H), 1.82 (d, J = 12.3 Hz, 2H), 1.69 - 1.42 (m, 2H).

[0606] Example 49 1-[1-(5-Fluoropyridin-2-yl)piperidin-4-yl]-3-(5-hydroxypyridin-2-yl)urea

Chem.

Chem.

[0607] Step 2. Synthesis of 1-(5-fluoropyridin-2-yl)piperidin-4-amine

Chem.

[0608] Step 3.3 - Synthesis of [5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]-1-[1-(5-fluoropyridin-2-yl)piperidin-4-yl]urea

Chem.

[0609] Step 4.1 - Synthesis of [1-(5-fluoropyridin-2-yl)piperidin-4-yl]-3-(5-hydroxypyridin-2-yl)urea

Chem.

[0610] LC-MS (ES, m / z): 332 11H NMR (300 MHz, methanol-d4) δ 8.00 (s, 1H), 7.77 (s, 1H), 7.41 (d, J = 9.0 Hz, 1H), 7.22 (d, J = 8.9 Hz, 1H), 7.02 (d, J = 9.0 Hz, 1H), 6.87 (dd, J = 9.6, 3.5 Hz, 1H), 3.98 (m, 3H), 3.43 - 3.03 (m, 2H), 2.11 - 2.00 (m, 2H), 1.59 (m, 2H).

[0611] Example 50 4-(6-Fluoropyridin-3-yl)-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide

Chemical formula

Chemical formula

[0612] Step 2. Synthesis of 1-(6-fluoropyridin-3-yl)piperazine

Chemical formula

[0613] Step 3. Synthesis of N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]-4-(6-fluoropyridin-3-yl)piperazine-1-carboxamide

Chemical Structure

[0614] Step 4. Synthesis of 4-(6-fluoropyridin-3-yl)-N-(5-hydroxypyridin-2-yl)piperazine-1-carboxamide

Chemical Structure

[0615] LC-MS (ES, m / z): 318.0 1 1H NMR (300 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.93 (s, 1H), 7.84 (t, J = 2.5 Hz, 1H), 7.78 (d, J = 3.0 Hz, 1H), 7.68 - 7.52 (m, 2H), 7.14 (dd, J = 8.9, 3.0 Hz, 1H), 7.02 (dd, J = 8.9, 3.5 Hz, 1H), 3.59 (m, 4H), 3.13 m, 4H).

[0616] Example 51 1-[1-(4-Fluorophenyl)piperidin-4-yl]-3-(5-hydroxypyridin-2-yl)urea

Chemical formula

Chemical formula

[0617] Step 2. Synthesis of 1-(4-fluorophenyl)piperidin-4-amine

Chemical Structure

[0618] LC-MS: (ES, m / z): 195 1 1H NMR (400 MHz, DMSO-d6) δ 7.10~6.97 (m, 2H), 6.97~6.90 (m, 2H), 3.55~3.44 (m, 2H), 2.65 (td, J = 11.9, 2.7 Hz, 3H), 1.76 (d, J = 12.7 Hz, 2H), 1.39~1.22 (m, 2H).

[0619] Step 3. Synthesis of 3-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]-1-[1-(4-fluorophenyl)piperidin-4-yl]urea [Chemistry] To a 40 mL vial containing the product from the previous step (150 mg, 0.41 mmol), Et3N (126 g) was added portionwise, followed by a solution of 1-(4-fluorophenyl)piperidin-4-amine (80 mg, 0.41 mmol) in CH2Cl2 (5 mL). The resulting solution was stirred at room temperature for 16 h and then quenched by adding 20 mL of H2O and extracted with 2 × 20 mL of EtOAc. The combined organic layers were concentrated under vacuum to give 180 mg (98%) of the title compound as an off-white solid. LC-MS (ES, m / z): 445

[0620] Step 4. Synthesis of 1-[1-(4-fluorophenyl)piperidin-4-yl]-3-(5-hydroxypyridin-2-yl)urea [Chemistry] To a stirred solution of the product from the previous step (180 mg, 0.40 mmol) in THF (2 mL), 2N aqueous HCl solution (1 mL) was added dropwise. The resulting solution was stirred at room temperature for 2 h and then concentrated under vacuum. The crude product (180 mg) was purified by preparative-HPLC under the conditions of instrument “A”; column “A”; mobile phase, 10 mM aqueous NH4HCO3 solution, and ACN (from 25.0% ACN to a maximum of 54.0% in 8 min); detector, UV254 / 220 nm to give 50.5 mg (38%) of the title compound as an off-white solid.

[0621] LC-MS: (ES, m / z): 331 1 1H NMR (300 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.76 (s, 1H), 7.89 (s, 1H), 7.69 (d, J = 2.8 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.12 (dd, J = 8.9, 2.9 Hz, 1H), 7.08 - 6.88 (m, 4H), 3.67 (s, 1H), 3.42 (m, 2H), 2.82 (m, 2H), 1.91 (m, 2H), 1.58 - 1.44 (m, 2H).

[0622] Example 52 1-[1-(4-Chlorophenyl)piperidin-4-yl]-3-(5-hydroxypyridin-2-yl)urea

Chemical formula

Chemical formula

[0623] Step 2. Synthesis of 1-(4-Chlorophenyl)piperidin-4-amine

Chemical formula

[0624] Step 3: Synthesis of 3-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]-1-[1-(4-chlorophenyl)piperidin-4-yl]urea

Chem.

[0625] LC-MS: (ES, m / z): 461 Step 4. Synthesis of 1-[1-(4-chlorophenyl)piperidin-4-yl]-3-(5-hydroxypyridin-2-yl)urea

Chem.

[0626] LC-MS: (ES, m / z): 347 11H NMR (300 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.77 (s, 1H), 7.89 (s, 1H), 7.69 (d, J = 2.9 Hz, 1H), 7.32 - 7.10 (m, 4H), 6.94 (d, J = 8.7 Hz, 2H), 3.69 (s, 1H), 3.52 (m, 2H), 2.87 (m, 2H), 1.90 (m, 2H), 1.46 (m, 2H).

[0627] Scheme VII Example 53 1-(4-Fluorophenyl)piperidin-4-yl N-(5-hydroxypyridin-2-yl)carbamate

Chemical formula

Chemical formula

[0628] LC-MS: (ES, m / z): 196 11H NMR (300 MHz, DMSO-d6) δ 7.09~6.97 (m, 2H), 6.97~6.87 (m, 2H), 4.65 (d, J = 4.2 Hz, 1H), 4.09 (q, J = 5.3 Hz, 1H), 3.41 (dt, J = 11.7, 4.3 Hz, 2H), 3.16 (d, J = 5.1 Hz, 2H), 2.76 (ddd, J = 12.7, 10.1, 3.1 Hz, 2H), 1.46 (dtd, J = 13.0, 9.9, 3.8 Hz, 2H).

[0629] Step 2.1 - Synthesis of (4-fluorophenyl)piperidin-4-yl N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]carbamate

Chemical Structure

[0630] LC-MS: (ES, m / z): 446 11H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 7.88 (dd, J = 3.0, 0.6 Hz, 1H), 7.71 (d, J = 8.9 Hz, 1H), 7.32 (dd, J = 8.9, 3.0 Hz, 1H), 7.01 (ddt, J = 19.6, 6.9, 2.4 Hz, 4H), 4.83 (dq, J = 8.5, 4.1 Hz, 1H), 3.43 (d, J = 6.2 Hz, 1H), 2.99 (ddd, J = 12.4, 8.9, 3.2 Hz, 3H), 1.99 (d, J = 4.5 Hz, 2H), 1.82 - 1.65 (m, 2H), 0.96 (s, 9H), 0.19 (s, 6H).

[0631] Step 3.1 - Synthesis of (4-Fluorophenyl)piperidin-4-yl N-(5-Hydroxypyridin-2-yl)carbamate

Chemical Structure

[0632] LC-MS: (ES, m / z): 332 1 1H NMR (300 MHz, DMSO-d6) δ 9.69 (s, 1H), 9.51 (s, 1H), 7.79 (dd, J = 3.0, 0.7 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.16 (dd, J = 8.9, 3.0 Hz, 1H), 7.08 - 6.89 (m, 4H), 4.79 (dq, J = 8.5, 4.2 Hz, 1H), 3.47 - 3.35 (m, 2H), 2.95 (ddd, J = 12.4, 9.1, 3.2 Hz, 2H), 1.95 (s, 2H), 1.69 (dtd, J = 12.5, 8.8, 3.7 Hz, 2H).

[0633] Example 54 1-(2,4-Difluorophenyl)piperidin-4-yl N-(5-hydroxypyridin-2-yl)carbamate

Chemical formula

Chemical formula

[0634] LC-MS: (ES, m / z): 214 1 1H NMR (300 MHz, DMSO-d6) δ 7.21~6.91 (m, 3H), 4.68 (d, J = 4.2 Hz, 1H), 3.59 (dq, J = 8.7, 4.4 Hz, 1H), 3.14 (dt, J = 10.1, 4.2 Hz, 2H), 2.75~2.67 (m, 2H), 1.86~1.80 (m, 2H), 1.53 (ddt, J = 12.7, 9.2, 4.7 Hz, 2H).

[0635] Step 2. Synthesis of 1-(2,4-difluorophenyl)piperidin-4-yl N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]carbamate

Chemical formula

[0636] LC-MS: (ES, m / z): 464 1 1H NMR (300 MHz, DMSO-d6) δ 9.92 (s, 1H), 7.86 (dd, J = 3.0, 0.7 Hz, 1H), 7.73 - 7.64 (m, 1H), 7.30 (dd, J = 8.9, 3.0 Hz, 1H), 7.25 - 6.93 (m, 3H), 4.79 (dt, J = 8.4, 4.3 Hz, 1H), 3.25 - 3.11 (m, 2H), 2.87 (t, J = 9.2 Hz, 2H), 1.99 (s, 2H), 1.77 (td, J = 8.8, 4.0 Hz, 2H), 0.93 (s, 9H), 0.17 (s, 6H).

[0637] Step 3. Synthesis of 1-(2,4-difluorophenyl)piperidin-4-yl N-(5-hydroxypyridin-2-yl)carbamate

Chemical formula

[0638] LC-MS: (ES, m / z): 350 1 1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 9.55 (s, 1H), 7.81 (d, J = 2.9 Hz, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.26 - 7.16 (m, 2H), 7.16 - 7.09 (m, 1H), 7.09 - 6.93 (m, 1H), 4.79 (tt, J = 8.2, 3.9 Hz, 1H), 3.19 (dt, J = 11.0, 4.4 Hz, 2H), 2.89 (td, J = 8.9, 4.6 Hz, 2H), 2.02 (d, J = 12.1 Hz, 2H), 1.76 (dtd, J = 12.4, 8.6, 3.6 Hz, 2H).

[0639] Example 55 1-(4-Chlorophenyl)piperidin-4-yl N-(5-hydroxypyridin-2-yl)carbamate

Chemical formula

Chemical formula

[0640] LC-MS: (ES, m / z): 212 1 H NMR (300 MHz, DMSO-d6) δ 7.29~7.10 (m, 2H), 7.03~6.85 (m, 2H), 4.76~4.56 (m, 1H), 4.09 (s, 1H), 3.49 (dt, J = 12.7, 4.4 Hz, 2H), 2.83 (ddd, J = 12.9, 10.0, 3.1 Hz, 2H), 1.89~1.71 (m, 2H), 1.43 (dtd, J = 13.0, 9.8, 3.8 Hz, 2H).

[0641] Step 2. Synthesis of 1-(4-chlorophenyl)piperidin-4-yl N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]carbamate

Chemical Structure

[0642] LC-MS: (ES, m / z): 462 1 H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 7.88 (d, J = 2.9 Hz, 1H), 7.71 (d, J = 8.9 Hz, 1H), 7.32 (dd, J = 9.0, 3.0 Hz, 1H), 7.23 (d, J = 2.2 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 6.97 (td, J = 4.8, 2.5 Hz, 2H), 4.85 (dt, J = 8.4, 4.4 Hz, 1H), 3.57~3.48 (m, 2H), 3.25~2.82 (m, 2H), 1.98 (d, J = 9.4 Hz, 2H), 1.92~1.47 (m, 2H), 0.95 (s, 9H), 0.19 (s, 6H).

[0643] Step 3. Synthesis of 1-(4-chlorophenyl)piperidin-4-yl N-(5-hydroxypyridin-2-yl)carbamate

Chemical Structure

[0644] LC-MS: (ES, m / z): 348 1 1H NMR (300 MHz, DMSO-d6) δ 9.69 (s, 1H), 9.53 (s, 1H), 7.82~7.75 (m, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.26~7.11 (m, 3H), 7.01~6.90 (m, 2H), 4.80 (dt, J = 8.4, 4.3 Hz, 1H), 3.54~3.42 (m, 2H), 3.10~2.95 (m, 2H), 1.93 (m, 2H), 1.68 (td, J = 8.8, 4.0 Hz, 2H).

[0645] Example 56 1-(5-Fluoropyridin-2-yl)piperidin-4-yl N-(5-hydroxypyridin-2-yl)

Chemical Structure

Chemical Structure

[0646] LC-MS: (ES, m / z): 197 Step 2. Synthesis of 1-(5-fluoropyridin-2-yl)piperidin-4-yl N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]carbamate

Chemical Structure

[0647] LC-MS: (ES, m / z): 447 Step 3. Synthesis of 1-(5-fluoropyridin-2-yl)piperidin-4-yl N-(5-hydroxypyridin-2-yl)carbamate [Chem.] To a solution of the product (200 mg, 0.45 mmol) from the previous step in THF (2 mL), 2N aqueous HCl solution (1 mL) was added dropwise at room temperature. The resulting solution was stirred at room temperature for 2 hours and then concentrated under vacuum. The crude product (200 mg) was purified by preparative-HPLC under the conditions of instrument "A"; column "A"; mobile phase, 10 mM aqueous NH4HCO3 solution, and ACN (25.0% ACN with a maximum of 56.0% in 8 minutes); detector, UV254 / 220 nm to obtain 31.9 mg (21%) of the title compound as an off-white solid.

[0648] LC-MS: (ES, m / z): 333.3 1 1H NMR (300 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.55 (s, 1H), 8.06 (d, J = 3.1 Hz, 1H), 7.78 (d, J = 2.9 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.47 (ddd, J = 9.3, 8.3, 3.2 Hz, 1H), 7.16 (dd, J = 8.9, 3.0 Hz, 1H), 6.89 (dd, J = 9.4, 3.4 Hz, 1H), 4.85 (dt, J = 8.6, 4.5 Hz, 1H), 3.92 - 3.80 (m, 2H), 3.28 - 3.22 (m, 2H), 1.95 - 1.84 (m, 2H), 1.59 - 1.54 (m, 2H).

[0649] Example 57 1-[4-(Trifluoromethyl)phenyl]piperidin-4-yl N-(5-hydroxypyridin-2-yl)carbamate [Chem.] Step 1. Synthesis of 1-[4-(trifluoromethyl)phenyl]piperidin-4-ol [Chem.] A solution of 1-fluoro-4-(trifluoromethyl)benzene (820 mg, 5.00 mmol), piperidin-4-ol (505 mg, 4.99 mmol), and DIEA (1.29 g, 9.98 mmol) in dry DMSO (20 mL) was stirred at 80 °C for 16 h, then cooled to room temperature and extracted with 2 × 60 mL of EtOAc. The combined organic layers were concentrated under vacuum and purified by silica gel chromatography using EtOAc / hexane (2:1) to afford 460 mg (38%) of the title compound as an off-white solid.

[0650] LC-MS: (ES, m / z): 246 1 H NMR (300 MHz, DMSO-d6) δ 7.52~7.42 (m, 2H), 7.03 (d, J = 8.8 Hz, 2H), 4.70 (d, J = 4.3 Hz, 1H), 4.09 (q, J = 5.3 Hz, 1H), 3.66 (dd, J = 8.7, 4.4 Hz, 2H), 2.99 (ddd, J = 13.1, 9.9, 3.1 Hz, 2H), 1.86~1.68 (m, 2H), 1.41 (dtd, J = 12.9, 9.5, 3.8 Hz, 2H).

[0651] Step 2. Synthesis of 1-[4-(trifluoromethyl)phenyl]piperidin-4-yl N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]carbamate

Chemical Structure

[0652] LC-MS: (ES, m / z): 496 Step 3. Synthesis of 1-[4-(trifluoromethyl)phenyl]piperidin-4-yl N-(5-hydroxypyridin-2-yl)carbamate

Chemical formula

[0653] LC-MS: (ES, m / z): 382 11H NMR (300 MHz, DMSO-d6) δ 9.71 (s, 1H), 9.53 (s, 1H), 7.79 (d, J = 3.0 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.17 (dd, J = 8.9, 3.0 Hz, 1H), 7.06 (d, J = 8.6 Hz, 2H), 4.86 (dt, J = 8.2, 4.8 Hz, 1H), 3.70 - 3.58 (m, 2H), 3.27 - 3.12 (m, 2H), 1.93 (s, 2H), 1.64 (m, 2H).

[0654] Example 58 1-(2,4-Dichlorophenyl)piperidin-4-yl N-(5-hydroxypyridin-2-yl)carbamate [Chemical formula] Step 1. Synthesis of 1-(2,4-dichlorophenyl)piperidin-4-ol [Chemical formula] A solution of piperidin-4-ol (1.01 g, 9.99 mmol), 2,4-dichloro-1-fluorobenzene (1.65 g, 10.00 mmol), and DIEA (2.58 g) in dry DMSO (20 mL) was stirred at 80 °C for 16 h, then cooled and extracted with 2 × 50 mL of EtOAc. The combined organic layers were concentrated under vacuum and purified by silica gel chromatography using EtOAc / hexane (2:1) to give 110 mg (4%) of the title compound as an off-white solid.

[0655] LC-MS: (ES, m / z): 246 11H NMR (300 MHz, DMSO-d6) δ 7.50 (d, J = 2.5 Hz, 1H), 7.32 (dd, J = 8.6, 2.5 Hz, 1H), 7.14 (d, J = 8.7 Hz, 1H), 4.70 (d, J = 4.2 Hz, 1H), 3.61 (tt, J = 8.6, 4.3 Hz, 1H), 3.13 (dt, J = 10.2, 4.2 Hz, 2H), 2.70 (ddd, J = 12.1, 9.7, 2.9 Hz, 2H), 1.91 - 1.72 (m, 2H), 1.54 (dtd, J = 12.7, 9.2, 3.6 Hz, 2H).

[0656] Step 2.1 - Synthesis of (2,4-dichlorophenyl)piperidin-4-yl N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]carbamate

Chemical Structure

[0657] Step 3.1 - Synthesis of (2,4-dichlorophenyl)piperidin-4-yl N-(5-hydroxypyridin-2-yl)carbamate

Chemical Structure

[0658] LC-MS: (ES, m / z): 382 1 H NMR (300 MHz, DMSO-d6) δ 9.72 (s, 1H), 9.55 (s, 1H), 7.79 (d, J = 2.9 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.52 (d, J = 2.5 Hz, 1H), 7.35 (dd, J = 8.6, 2.5 Hz, 1H), 7.25 - 7.0 (m, 2H), 4.80 (tt, J = 8.1, 3.9 Hz, 1H), 3.23 - 3.09 (m, 2H), 2.86 (ddd, J = 11.8, 8.6, 3.1 Hz, 2H), 2.00 (ddt, J = 10.0, 6.9, 4.2 Hz, 2H), 1.75 (dtd, J = 12.2, 8.4, 3.5 Hz, 2H).

[0659] Example 59 1-(Pyridin-2-yl)piperidin-4-yl N-(5-hydroxypyridin-2-yl)carbamate

Chemical formula

Chemical formula

[0660] LC-MS: (ES, m / z): 179 1 1H NMR (400 MHz, DMSO-d6) δ 8.08 (ddd, J = 4.9, 2.1, 0.9 Hz, 1H), 7.49 (ddd, J = 8.9, 7.1, 2.1 Hz, 1H), 6.81 (dd, J = 8.6, 0.9 Hz, 1H), 6.57 (ddd, J = 7.1, 4.8, 0.8 Hz, 1H), 4.67 (d, J = 4.3 Hz, 1H), 4.04~3.93 (m, 2H), 3.69 (tq, J = 8.5, 4.1 Hz, 1H), 3.05 (ddd, J = 13.3, 10.2, 3.1 Hz, 2H), 1.76 (dqd, J = 10.0, 3.6, 1.7 Hz, 2H), 1.40~1.29 (m, 2H).

[0661] Step 2. Synthesis of 1-(pyridin-2-yl)piperidin-4-yl N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]carbamate

Chemical Structure

[0662] LC-MS: (ES, m / z): 429 1 H NMR (300 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.09 (ddd, J = 4.9, 2.1, 0.8 Hz, 1H), 7.94~7.81 (m, 1H), 7.77~7.66 (m, 1H), 7.50 (ddd, J = 8.9, 7.1, 2.0 Hz, 1H), 7.38~7.28 (m, 1H), 6.85 (d, J = 8.6 Hz, 1H), 6.59 (ddd, J = 7.1, 4.9, 0.8 Hz, 1H), 4.88 (dt, J = 8.5, 4.4 Hz, 1H), 4.02~3.86 (m, 2H), 3.31 (m, 2H), 1.92 (d, J = 12.9 Hz, 2H), 1.57 (dtd, J = 12.7, 8.8, 3.8 Hz, 2H), 0.93 (d, J = 2.7 Hz, 9H), 0.17 (d, J = 3.6 Hz, 6H).

[0663] Step 3. Synthesis of 1-(pyridin-2-yl)piperidin-4-yl N-(5-hydroxypyridin-2-yl)carbamate

Chemical Structure

[0664] LC-MS: (ES, m / z): 315 1 1H NMR (300Mhz, DMSO-d6) δ 9.70 (s, 1H), 9.52 (s, 1H), 8.09 (ddd, J = 4.9, 2.0, 0.8 Hz, 1H), 7.79 (d, J = 2.9 Hz, 1H), 7.59 (d, J = 8.9Hz, 1H), 7.50 (ddd, J = 8.9, 7.1, 2.1 Hz, 1H), 7.16 (dd, J = 8.9, 3.0 Hz, 1H), 6.89~6.79 (m, 1H), 6.59 (ddd, J = 7.1, 4.8, 0.8 Hz, 1H), 4.87 (tt, J = 8.3, 3.9Hz, 1H), 3.94 (dt, J = 13.3, 4.8Hz, 2H), 3.36~3.21 (m, 2H), 1.98~1.83 (m, 2H), 1.56 (dtd, J = 12.7, 8.8, 3.7Hz, 2H).

[0665] Example 60 1-[5-(Trifluoromethyl)pyridin-2-yl]piperidin-4-yl N-(5-hydroxypyridin-2-yl)carbamate

Chemical formula

Chemical formula

[0666] LC-MS: (ES, m / z): 247 Step 2.1 - Synthesis of [5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]carbamate

Chemical formula

[0667] LC-MS: (ES, m / z): 497 Step 3.1 - Synthesis of [5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl N-(5-hydroxypyridin-2-yl)carbamate

Chemical formula

[0668] LC-MS: (ES, m / z): 383.0 1 H NMR (300Mhz, DMSO-d6) δ 9.72 (s, 1H), 9.54 (s, 1H), 8.39 (s, 1H), 7.79~7.76 (m, 2H), 7.59 (d, J = 8.9 Hz, 1H), 7.16 (dd, J = 8.9, 3.0Hz, 1H), 6.99 (d, J = 9.1Hz, 1H), 4.91 (dt, J = 8.0, 4.5 Hz, 1H), 4.00 (d, J = 13.6 Hz, 2H), 3.55~3.42 (m, 2H), 1.99~1.91 (m, 2H), 1.64~1.50 (m, 2H).

[0669] Scheme VIII Example 61 N-(5-Hydroxypyridin-2-yl)-4-(propan-2-yl)benzene-1-sulfonamide

Chemical formula

Chemical formula

[0670] LC-MS (ES, m / z): 406 Step 2: Synthesis of N-(5-hydroxypyridin-2-yl)-4-(propan-2-yl)benzene-1-sulfonamide

Chemical Structure

[0671] LC-MS: (ES, m / z): 292 1 1H NMR (300 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.64 (s, 1H), 7.79~7.70 (m, 3H), 7.41 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.8, 3.0 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 2.94 (m, 1H), 1.19 (d, 7 = 6 Hz, 6H).

[0672] Example 62 4-tert-Butyl-N-(5-hydroxypyridin-2-yl)benzene-1-sulfonamide [Chemistry] Step 1: Synthesis of 4-tert-butyl-N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]benzene-1-sulfonamide [Chemistry] A solution of 5-[(tert-butyldimethylsilyl)oxy]pyridin-2-amine (224 mg, 1.00 mmol, 1.00 equiv) and 4-tert-butylbenzen-1-sulfonyl chloride (232 mg, 1.00 mmol, 1.00 equiv) in pyridine (5 mL) was stirred at room temperature for 4 hours. The resulting mixture was concentrated under vacuum and purified by silica gel chromatography using EtOAc / hexane (1:2) to afford 230 mg (55%) of the title compound as a white solid.

[0673] LC-MS: (ES, m / z): 421 Step 2: Synthesis of 4-tert-butyl-N-(5-hydroxypyridin-2-yl)benzene-1-sulfonamide [Chemistry] A solution of the product from the previous step (230 mg, 0.55 mmol, 1.00 equiv) in 2N HCl (1 mL) and THF (2 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. The crude product was purified by preparative-HPLC under the conditions of instrument “B”; column, SunFire C18 OBD preparative column, 100 Å, 5 μm, 19 mmX250 mm; mobile phase, water (0.1% FA), and ACN (30.0% ACN with a maximum of 80.0% in 7 minutes); detector, uv254 / 220 nm to afford 128.2 mg (77%) of the title compound as a white solid.

[0674] LC-MS: (ES, m / z): 306 11H NMR (300 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.64 (s, 1H), 7.78 - 7.72 (m, 2H), 7.61 - 7.54 (m, 2H), 7.15 (dd, J = 8.8, 3.0 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 1.27 (s, 9H).

[0675] Example 63 Benzyl 4 - [(5 - hydroxypyridin - 2 - yl)sulfamoyl]piperidine - 1 - carboxylate

Chemical formula

Chemical formula

[0676] LC - MS: (ES, m / z): 506 Step 2. Synthesis of benzyl 4 - [(5 - hydroxypyridin - 2 - yl)sulfamoyl]piperidine - 1 - carboxylate

Chemical formula

[0677] LC-MS: (ES, m / z): 392 1 1H NMR (300 MHz, DMSO-d6) δ 9.80 (s, 2H), 7.80 (d, J = 2.9 Hz, 1H), 7.42 - 7.24 (m, 5H), 7.16 (dd, J = 8.8, 3.0 Hz, 1H), 6.92 (d, J = 8.7 Hz, 1H), 5.06 (s, 2H), 4.06 (d, J = 13.2 Hz, 2H), 3.64 - 3.56 (m, 1H), 2.84 (s, 2H), 1.99 m, 2H), 1.51 (m, 2H).

[0678] Example 64 N-(5-Hydroxypyridin-2-yl)-1-phenylpiperidine-4-sulfonamide

Chemical formula

Chemical formula

[0679] LC-MS: (ES, m / z): 506 Step 2. Synthesis of N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]piperidine-4-sulfonamide

Chemical Structure

[0680] LC-MS: (ES, m / z): 372 1 1H NMR (300Mhz, DMSO-d6) δ 7.86 (d, J = 2.9 Hz, 1H), 7.28 (dd, J = 8.8, 3.0Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 3.53 (t, J = 11.9 Hz, 1H), 3.20~2.99 (m, 2H), 2.59~2.51 (m, 2H), 1.93 (d, J = 12.5 Hz, 2H), 1.60 (qd, J = 12.1, 3.9 Hz, 2H), 0.93 (s, 9H), 0.17 (s, 6H).

[0681] Step 3. Synthesis of N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]-1-phenylpiperidine-4-sulfonamide

Chem.

[0682] LC-MS: (ES, m / z): 448 Step 4. Synthesis of N-(5-hydroxypyridin-2-yl)-1-phenylpiperidine-4-sulfonamide

Chem.

[0683] LC-MS: (ES, m / z): 334 11H NMR (300 MHz, methanol-d4) δ 7.78 (d, J = 2.9 Hz, 1H), 7.28 - 7.11 (m, 3H), 7.05 (dd, J = 8.8, 0.7 Hz, 1H), 7.02 - 6.92 (m, 2H), 6.82 (t, J = 7.4 Hz, 1H), 3.77 (d, J = 12.6 Hz, 2H), 3.45 (tt, J = 12.0, 3.8 Hz, 1H), 2.70 (m, 2H), 2.19 (d, J = 12.6 Hz, 2H), 1.94 (m, 2H).

[0684] Example 65 1-Benzyl-N-(5-hydroxypyridin-2-yl)piperidine-4-sulfonamide

Chemical Structure

Chemical Structure

[0685] LC-MS: (ES, m / z): 462 11H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 7.95 (s, 1H), 7.92 - 7.86 (m, 1H), 7.36 - 7.19 (m, 6H), 6.97 (dd, J = 8.7, 0.6 Hz, 1H), 3.45 (s, 2H), 2.73 (d, J = 0.6 Hz, 4H), 1.92 (s, 2H), 1.74 - 1.60 (m, 2H), 0.94 (s, 9H), 0.19 (s, 6H).

[0686] Step 2.1 - Synthesis of Benzyl - N-(5 - hydroxypyridin - 2 - yl)piperidine - 4 - sulfonamide

Chemical Structure

[0687] LC - MS: (ES, m / z): 348 1 1H NMR (400 MHz, DMSO - d6) δ 9.70 (br, 2H), 7.82 (d, J = 2.9 Hz, 1H), 7.39 - 7.21 (m, 5H), 7.16 (dd, J = 8.8, 2.9 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 3.45 (s, 2H), 3.31 (m, 1H), 2.88 (m, 2H), 1.91 (m, 4H), 1.65 (m, 2H).

[0688] Example 66 1 - (4 - fluorophenyl) - N-(5 - hydroxypyridin - 2 - yl)piperidine - 4 - sulfonamide

Chemical Structure

Chemical formula

[0689] LC-MS (ES, m / z): 506 Step 2. Synthesis of N-[5-[(tert-Butyldimethylsilyl)oxy]pyridin-2-yl]piperidine-4-sulfonamide

Chemical formula

[0690] LC-MS (ES, m / z): 372 Step 3. Synthesis

Chemical formula

[0691] LC-MS (ES, m / z): 466 Step 4. Synthesis of 1-(4-fluorophenyl)-N-(5-hydroxypyridin-2-yl)piperidine-4-sulfonamide

Chemical Structure

[0692] LC-MS (ES, m / z): 352 1 1H NMR (300 Mhz, methanol-d4) δ 7.83 (dd, J = 3.0, 0.7 Hz, 1H), 7.22 (dd, J = 8.8, 3.0 Hz, 1H), 7.08 (dd, J = 8.8, 0.7 Hz, 1H), 7.04~6.89 (m, 4H), 3.67 (d, J = 12.4 Hz, 2H), 3.46 (m, 1H), 2.69 (m, 2H), 2.22 (d, J = 12.6 Hz, 2H), 2.09~1.87 (m, 2H).

[0693] Example 67 1-(5-Chloropyridin-2-yl)-N-(5-hydroxypyridin-2-yl)piperidine-4-sulfonamide

Chemical formula

Chemical formula

[0694] Step 2. Synthesis of 1-(5-Chloropyridin-2-yl)-N-(5-hydroxypyridin-2-yl)piperidine-4-sulfonamide

Chemical formula

[0695] LC-MS (ES, m / z): 318 1 1H NMR (300 MHz, DMSO-d6) δ 9.89 (br, 2H), 8.10 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 3.0 Hz, 1H), 7.58 (dd, J = 9.2, 2.8 Hz, 1H), 7.19 (dd, J = 8.8, 3.0 Hz, 1H), 6.93 (m, 2H), 4.35 (d, J = 13.2 Hz, 2H), 3.68 (tt, J = 12.3, 3.7 Hz, 1H), 2.88 (t, J = 12.6 Hz, 2H), 2.11~1.96 (m, 2H), 1.60 (qd, J = 12.6, 3.9 Hz, 2H).

[0696] Example 68 1-(4-Chlorophenyl)-N-(5-hydroxypyridin-2-yl)piperidine-4-sulfonamide

Chemical Structure

Chemical Structure

[0697] LC-MS (ES, m / z): 482 Step 2. Synthesis of 1-(4-Chlorophenyl)-N-(5-hydroxypyridin-2-yl)piperidine-4-sulfonamide [Chem.] A solution of the product (180 mg, 0.37 mmol) from the previous step in 2N HCl aqueous solution (3 mL) and THF (3 mL) was stirred at room temperature for 2 hours and then concentrated under vacuum. The crude product (180 mg) was purified by preparative-HPLC under the conditions of instrument "A"; column "D"; mobile phase, 10 mM NH4HCO3 aqueous solution, and ACN (holding 25.0% ACN for 7 minutes); detector, UV254 / 220 nm to obtain 98 mg (71%) of the title compound as an off-white solid.

[0698] LC-MS (ES, m / z): 368 1 1H NMR (300 MHz, DMSO-d6) δ 9.88 (br, 2H), 7.84 (d, J = 2.9 Hz, 1H), 7.28 - 7.14 (m, 3H), 7.02 - 6.88 (m, 3H), 3.80 (m, 2H), 3.57 (m, 1H), 2.73 (m, 2H), 2.11 - 1.96 (m, 2H), 1.73 (m, 2H).

[0699] Example 69 N-(5-Hydroxypyridin-2-yl)-1-[4-(trifluoromethyl)phenyl]piperidine-4-sulfonamide [Chem.] Step 1. Synthesis of N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]-1-[4-(trifluoromethyl)phenyl]piperidine-4-sulfonamide [Chem.] N-[5-[(tert-Butyldimethylsilyl)oxy]pyridin-2-yl]piperidine-4-sulfonamide (200 mg, 0.54 mmol), 1-bromo-4-(trifluoromethyl)benzene (215 mg, 0.96 mmol), NaOtBu (156 mg), RuPhos (2.5 mg), 3G RuPhox Pd catalyst (4.5 mg), and a solution of toluene (5 mL) were stirred at 80 °C for 16 h, then extracted with 2 × 30 mL of EtOAc. The combined organic layers were concentrated under vacuum and purified by silica gel chromatography using EtOAc / hexane (1 / 2), to give 115 mg (41%) of the title compound as a pale yellow solid. LC-MS: (ES, m / z): 516

[0700] Step 2. Synthesis of N-(5-hydroxypyridin-2-yl)-1-[4-(trifluoromethyl)phenyl]piperidine-4-sulfonamide

Chemical Structure

[0701] LC-MS (ES, m / z): 402 1 1H NMR (300 MHz, DMSO-d6) δ 9.86 (br, 2H), 7.84 (d, J = 2.9 Hz, 1H), 7.49 (d, J = 8.5 Hz, 2H), 7.20 (dd, J = 8.8, 3.0 Hz, 1H), 7.02 (m, 3H), 3.99 (m, 2H), 3.66 m, 1H), 2.88 m, 2H), 2.11~1.98 (m, 2H), 1.70 (m, 2H).

[0702] Example 70 N-(5-Hydroxypyridin-2-yl)-6-methylheptane-1-sulfonamide

Chemical Structure

Chemical Structure

[0703] Step 2. Synthesis of 6-methylheptane-1-sulfonyl chloride

Chemical Structure

[0704] Step 3. Synthesis of N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]-6-methylheptane-1-sulfonamide

Chemical Structure

[0705] LC-MS: (ES, m / z): 401 Step 4. Synthesis of N-(5-hydroxypyridin-2-yl)-6-methylheptane-1-sulfonamide

Chemical formula

[0706] LCMS: (ES, m / z): 287 1 1H NMR (300 MHz, methanol-d4) δ 7.84 (d, J = 3.0 Hz, 1H), 7.20 (dd, J = 8.8, 3.0 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 3.31 (m, 2H), 1.80 (m, 2H), 1.51 (m, 1H), 1.45~1.23 (m, 4H), 1.17 (dd, J = 8.4, 5.9 Hz, 2H), 0.87 (d, J = 6.6 Hz, 6H).

[0707] Example 71 4-(4-Chlorophenyl)-N-(5-hydroxypyridin-2-yl)piperidine-1-sulfonamide [Chemistry] Step 1.4 - Synthesis of (4-chlorophenyl)piperidine-1-sulfonyl chloride [Chemistry] To a solution of 4-(4-chlorophenyl)piperidine (500 mg, 2.56 mmol) in ACN (5 mL) was added SO2Cl2 (2.06 g) dropwise at 0 °C. The resulting solution was stirred at room temperature for 16 h and then concentrated under vacuum to give 500 mg (67%) of the title compound as an off-white solid.

[0708] Step 2. Synthesis of N-[5-[(tert-butyldimethylsilyl)oxy]pyridin-2-yl]-4-(4-chlorophenyl)piperidine-1-sulfonamide [Chemistry] To a solution of the product from the previous step (244 mg, 1.09 mmol) in pyridine (5 mL) was added 4-(4-chlorophenyl)piperidine-1-sulfonyl chloride (500 mg, 1.70 mmol) dropwise with stirring at 0 °C. The resulting solution was stirred at room temperature for 2 h and then concentrated under vacuum and purified by silica gel chromatography using EtOAc / hexane (1:1) to give 80 mg (15%) of the title compound as an off-white solid.

[0709] LC-MS: (ES, m / z): 482 Step 3. Synthesis of 4-(4-chlorophenyl)-N-(5-hydroxypyridin-2-yl)piperidine-1-sulfonamide [Chemistry] A solution of the product from the previous step (80 mg, 0.17 mmol) in 2N aqueous HCl (1 mL) and THF (2 mL) was It was stirred at room temperature for 2 hours and then concentrated under vacuum. The crude product (80 mg) was purified by preparative-HPLC under the conditions of equipment "B"; column "D"; mobile phase, water (0.1% FA) and ACN (33.0% ACN with a maximum of 65.0% in 7 minutes), and 18.8 mg (31%) of the title compound was obtained as an off-white solid.

[0710] LC-MS: (ES, m / z): 368 1 1H NMR (300 MHz, DMSO-d6) δ 10.33~9.38 (m, 2H), 7.84 (d, J = 2.9 Hz, 1H), 7.39~7.31 (m, 2H), 7.25~7.18 (m, 3H), 7.06 (d, J = 8.8 Hz, 1H), 3.81~3.63 (m, 2H), 2.80 (m, 2H), 2.60 (m, 1H), 1.86~1.67 (m, 2H), 1.48 (m, 2H).

[0711] Scheme X Example 72 N-(5-Hydroxypyridin-2-yl)-2-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)acetamide

Chemical formula

Chemical formula

[0712] LC-MS: (ES, m / z): 374.2 Step 2. Synthesis of N-(5-(tert-butyldimethylsilyloxy)pyridin-2-yl)-4-(4-fluorophenyl)piperazine-1-sulfonamide

Chemical Structure

[0713] LC-MS: (ES, m / z): 467.1 Step 3. Synthesis of N-(5-hydroxypyridin-2-yl)-2-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)acetamide

Chemical Structure

[0714] LC-MS: (ES, m / z): 353.1 1 1H NMR (400 Mhz, DMSO-d6) δ 9.74 (s, 2H), 7.80 (d, J = 2.9 Hz, 1H), 7.19 (dd, J = 8.8, 3.0 Hz, 1H), 7.09 - 7.00 (m, 3H), 6.97 - 6.90 (m, 2H), 3.27 - 3.18 (m, 4H), 3.11 - 3.02 (m, 4H).

[0715] Example 73 4-(5-Chloropyridin-2-yl)-N-(5-hydroxypyridin-2-yl)piperazine-1-sulfonamide

Chemical formula

Chemical formula

[0716] LC-MS: (ES, m / z): 484.3 Step 2. Synthesis of 4-(5-chloropyridin-2-yl)-N-(5-hydroxypyridin-2-yl)piperazine-1-sulfonamide

Chemical Structure

[0717] LC-MS: (ES, m / z): 370.1 1 1H NMR (400 Mhz, DMSO-d6) δ 9.91 (br, 2H), 8.11 (d, J = 2.7 Hz, 1H), 7.76 (d, J = 2.9 Hz, 1H), 7.62 (dd, J = 9.1, 2.7 Hz, 1H), 7.17 (dd, J = 8.8, 2.9 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 9.1 Hz, 1H), 3.49 (m, 4H), 3.18 (m, 4H).

[0718] Example 74 4-(4-Chlorophenyl)-N-(5-hydroxypyridin-2-yl)piperazine-1-sulfonamide

Chem.

Chem.

[0719] Step 2. Synthesis of 4-(4-chlorophenyl)-N-(5-hydroxypyridin-2-yl)piperazine-1-sulfonamide

Chem.

[0720] LC-MS: (ES, m / z): 369.1 1 1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.72 (s, 1H), 7.80 (d, J = 3.0 Hz, 1H), 7.26 - 7.21 (m, 2H), 7.19 (dd, J = 8.8, 3.0 Hz, 1H), 7.05 (d, J = ...

Claims

1. A pharmaceutical composition for treating Des1-mediated disorders in a subject in need thereof, having the structural formula II: 【Chemical Formula 1】 wherein, W is -NH-, X is N, Y is selected from CH and N, R ５ is independently selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (aryl)alkyl, (heteroaryl)alkyl, (aryl)aryl, (heteroaryl)aryl, (aryl)heteroaryl, and (heteroaryl)heteroaryl, and is optionally substituted with one, two, or three R ６ groups; each R ６ is independently selected from alkoxy, alkyl, amino, carboxy, cyano, halo, haloalkoxy, haloalkyl, and hydroxy; n is selected from 1 and 2; a compound represented thereby or a salt thereof; and a pharmaceutically acceptable carrier.

2. The pharmaceutical composition according to claim 1, wherein the subject is a human.

3. The pharmaceutical composition according to claim 1, wherein the Des1-mediated disorder is a metabolic disorder.

4. The pharmaceutical composition according to claim 1, wherein the Des1-mediated disorder is a lipid storage disorder.

5. The pharmaceutical composition according to claim 1, wherein the Des1-mediated disorder is an autoimmune disease or a chronic inflammatory disease.

6. The pharmaceutical composition according to claim 1, wherein the Des1-mediated disorder is a cardiovascular disease.

7. The pharmaceutical composition according to claim 1, wherein the Des1-mediated disorder is ischemia / reperfusion injury.

8. The pharmaceutical composition according to claim 1, wherein the Des1-mediated disorder is fibrosis or a related disease.

9. The pharmaceutical composition according to claim 1, wherein the Des1-mediated disorder is cancer.

10. The pharmaceutical composition according to claim 9, further comprising a second therapeutic agent.

11. The pharmaceutical composition according to claim 10, wherein the second therapeutic agent is selected from a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a CD47 inhibitor, an indoleamine-2,3-dioxygenase inhibitor, and an arginase inhibitor.

12. The pharmaceutical composition according to claim 11, wherein the PD-1 inhibitor is selected from pembrolizumab, pidilizumab, AMP-224, AMP-514, PDR001, and nivolumab.

13. The pharmaceutical composition according to claim 11, wherein the PD-L1 inhibitor is selected from atezolizumab, avelumab, and durvalumab.

14. The pharmaceutical composition according to claim 11, wherein the CTLA-4 inhibitor is selected from ipilimumab.

15. The pharmaceutical composition according to claim 11, wherein the CD47 inhibitor is selected from CV1, Hu5F9-G4, CC-90002, and TTI-621.

16. The pharmaceutical composition according to claim 11, wherein the indoleamine-2,3-dioxygenase inhibitor is selected from 1-methyltryptophan, INCB024360, indoximod, NLG919, norharman, rosmarinic acid, epacadostat, and naboximod.

17. The pharmaceutical composition according to claim 11, wherein the arginase inhibitor is selected from CB-1158 and norvaline.

18. The pharmaceutical composition according to claim 10, wherein the second therapeutic agent is a DNA damaging agent.

19. The pharmaceutical composition according to claim 18, wherein the DNA damaging agent is selected from ionizing radiation, radiation-mimicking neocarzinostatin, platinates, topo I inhibitors, topo II inhibitors, antimetabolites, alkylating agents, alkyl sulfonates, or antibiotics.

20. The pharmaceutical composition according to claim 19, wherein the platinates are selected from cisplatin, oxaliplatin, carboplatin, nedaplatin, lobaplatin, triplatin tetranitrate, picoplatin, satraplatin, prolinidac, and alloplatin.

21. The pharmaceutical composition according to claim 19, wherein the topo I inhibitor is selected from camptothecin, topotecan, irinotecan / SN38, rubitecan, and belotecan.

22. The pharmaceutical composition according to claim 19, wherein the topo II inhibitor is selected from etoposide, daunorubicin, doxorubicin, aclarubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, zorubicin, and teniposide.

23. The pharmaceutical composition according to claim 19, wherein the antimetabolite is selected from aminopterin, methotrexate, pemetrexed, raltitrexed, pentostatin, cladribine, clofarabine, fludarabine, thioguanine, mercaptopurine, fluorouracil, capecitabine, tegafur, carmofur, floxuridine, cytarabine, gemcitabine, azacitidine, and hydroxyurea.

24. The pharmaceutical composition according to claim 19, wherein the alkylating agent is selected from mechlorethamine, cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, melphalan, prednimustine, bendamustine, uramustine, estramustine, carmustine, lomustine, semustine, fotemustine, nimustine, ranimustine, streptozocin, busulfan, mannosulfan, treosulfan, carboquone, thiotepa, triaziquone, triethylenemelamine, procarbazine, dacarbazine, temozolomide, altretamine, mitobronitol, actinomycin, bleomycin, mitomycin, and plicamycin.

25. The pharmaceutical composition according to claim 10, wherein the second therapeutic agent is a CHK1 inhibitor.

26. The pharmaceutical composition according to claim 25, wherein the CHK1 inhibitor is selected from MK-8776, LY2603618, V158411, PF-477736, UCN-01, and AZD7762.

27. The pharmaceutical composition according to claim 10, wherein the second therapeutic agent is an antagonist monoclonal antibody (mAb).

28. The pharmaceutical composition according to claim 27, wherein the antagonist mAb is selected from CTLA-4 mAb, PD-1 mAb, and PD-L1 mAb, CD47 mAb, and OX40 mAb.

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