SCARPELLI RITA (IT)
CILIBRASI VINCENZO (IT)
CAPUTO SAMANTHA (IT)
FONDAZIONE ST ITALIANO TECNOLOGIA (IT)
WO2015173168A1 | 2015-11-19 | |||
WO2015173169A1 | 2015-11-19 | |||
WO2016210120A1 | 2016-12-29 | |||
WO2016210116A1 | 2016-12-29 | |||
WO2013178576A1 | 2013-12-05 | |||
WO2015173169A1 | 2015-11-19 | |||
WO2016210116A1 | 2016-12-29 | |||
WO2016210120A1 | 2016-12-29 | |||
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WO2000037504A2 | 2000-06-29 | |||
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WO2012078855A1 | 2012-06-14 | |||
WO2015173168A1 | 2015-11-19 |
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EP1212422A2 | 2002-06-12 |
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 6 September 2011 (2011-09-06), XP002801131, retrieved from STN Database accession no. 1328872-77-0
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 5 September 2011 (2011-09-05), XP002801132, retrieved from STN Database accession no. 1328415-08-2
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 4 September 2011 (2011-09-04), XP002801133, retrieved from STN Database accession no. 1327787-21-2
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CLAIMS 1. A compound of formula (I): pharmaceutically acceptable salt thereof, wherein: monocyclic or bicyclic (e.g., fused, spiro, bridged) heterocyclylene containing at least one N (including the depicted nitrogen) that is optionally substituted (e.g., with one or more substituents each independently selected from C1-6alkyl and oxo); R1 is selected from the group consisting of hydrogen, C1-6alkyl, C1-6alkylene-NRa2, C1- 6alkylene-ORc, 3-7 membered heterocyclyl, phenyl, C3-7cycloalkyl, and 5-6 membered heteroaryl; R7 and R8 are independently, for each occurrence, selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, and halogen; or R7 and R8 can be taken together to form C3- 7cycloalkylene; R9 is selected from the group consisting of hydrogen, C1-6alkyl, and halogen; Ra is hydrogen or C1-6alkyl; Rc is selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, 3-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, and C1-6alkylene-N(Ra)2; and n is an integer selected from 0 to 6, wherein when n is an integer selected from 1 to 6, W is selected from the group consisting of hydrogen, halogen, phenyl, 5-6 membered heteroaryl, C3-7cycloalkyl, 3-7 membered heterocyclyl, O-(C1-6alkyl), O-(C1-6haloalkyl), -O-phenyl, and O-(C1-6alkylene)-phenyl; and when n is 0, W is selected from the group consisting of hydrogen, C3-7cycloalkyl, 3-7 membered saturated heterocyclyl, O-(C1-6alkyl), O-(C1-6haloalkyl), -O-phenyl, and O-(C1- 6alkylene)-phenyl; wherein any aforementioned 3-7 membered heterocyclyl and phenyl are optionally substituted, and wherein the compound is not a compound selected from the group consisting of: , 2. The compound of claim 1, wherein the compound is a compound of formula (I-a): pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1. 3. The compound of claim 1 or 2, wherein is a monocyclic heterocyclylene. 4. The compound of any one of claims 1-3, wherein is selected from the group consisting of: wherein R2, R3, R2’ and R3’ are independently selected from hydrogen or C1-6alkyl, or R2 and R3 or R2’ and R3’ can be taken together to form C3-7cycloalkylene, 3-7 membered heterocyclylene, or oxo; or R4 and R5 are independently selected from hydrogen and C1-6alkyl, or R4 and R5 can be taken together to form oxo; R4’ and R5’ are independently selected from hydrogen and C1-6alkyl, or R4’ and R5’ can be taken together to form oxo; X is selected from the group consisting of CH2, NRa, and O; Xa is selected from CH or N; R10 is hydrogen or methyl; Ra is hydrogen or C1-6alkyl; indicates a single bond or double bond, and when a single bond, Xb is selected from the group consisting of CH2, NRa, and O, and when a double bond, Xb is CH; and m is 0 or 1. 5. The compound of claim 4, wherein Xa is CH. 6. The compound of claim 4 or 5, wherein Xb is CH2 or CH. 7. The compound of any one of claims 4-6, wherein X is CH2. 8. The compound of any one of claims 4-6, wherein X is O. 9. The compound of any one of claims 4-8, wherein at least one of R2 and R3 is methyl. 10. The compound of any one of claims 4-8, wherein at least one of R2, R3, R2’ and R3’ is methyl. 11. The compound of any one of claims 4-8, wherein R2 and R3 are methyl. 12. The compound of any one of claims 4-8, wherein R2 and R3 are methyl, and R2’ and R3’ are hydrogen. 13. The compound of any one of claims 4-8, wherein R2 and R3 are independently hydrogen or methyl. 14. The compound of any one of claims 4-8, wherein R2, R3, and R2’ and R3’ are independently hydrogen or methyl. 15. The compound of any one of claims 4-8, wherein R2 and R3 are taken together to form C3-7cycloalkylene, 3-7 membered heterocyclylene, or oxo. 16. The compound of claim 15, wherein R2 and R3 are taken together to form cyclopropylene, 4-membered heterocyclylene, or oxo. 17. The compound of any one of claims 4-8, wherein R2 and R2’ are taken together to form a 5-7-membered heterocycle, and R3 and R3’ are hydrogen. 18. The compound of any one of claims 4-17, wherein R4 and R5 are hydrogen or taken together to form oxo. 19. The compound of any one of claims 4-17, wherein R4, R5, R4’ and R5’ are hydrogen. 20. The compound of any one of claims 4-17, wherein R2 and R3 are methyl, and R2’, R3’, R4, R5, R4’ and R5’ are hydrogen. 21. The compound of any one of claims 4-20, wherein R2 and R3 are methyl, and R4, R5, R4’ and R5’ are hydrogen. 22. The compound of any one of claims 4-20, wherein R2 and R3 are methyl, R2’, R3’, R4, and R5 are hydrogen, and R4’ and R5’ are taken together to form oxo. 23. The compound of any one of claims 4-22, wherein m is 1. 24. The compound of any one of claims 4-23, wherein R10 is hydrogen. 25. The compound of claim 1, wherein the compound is a compound of formula (II): pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1. 26. The compound of claim 1, wherein the compound is a compound of formula (II-a): pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1. 27. The compound of claim 1, wherein the compound is a compound of formula (III): pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1. 28. The compound of claim 1, wherein the compound is a compound of formula (III-a): pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1. 29. The compound of claim 1, wherein the compound is a compound of formula (IV): pharmaceutically acceptable salt thereof, wherein the variables are as defined in claim 1. 30. The compound of claim 1, wherein the compound is a compound of formula (IV-a): tically acceptable salt thereof, wherein the variables are as defined in claim 1. 31. The compound of claim 1 or 2, wherein is a bicyclic heterocyclylene. 32. The compound of any one of claims 1, 2, and 31, wherein is a spiro-, fused-, or bridged-bicyclic heterocyclylene. 33. The compound of any one of claims 1, 2, 31, and 32, wherein is selected from wherein Xa is selected from N or CH; p, p’, q, q’, r, r’, t, t’, and s are independently selected from 1 or 2. 34. The compound of claim 33, wherein selected from the group consisting of f claim 33 or 34, wherein is . 36. The compound of claim 1, wherein the compound is a compound of formula (I-b): compound of formula (I-c): pharmaceutically acceptable salt thereof, wherein: is a monocyclic or bicyclic (e.g., fused, spiro, bridged) saturated heterocyclylene containing at least one N (including the depicted nitrogen) that is optionally substituted (e.g., with one or more substituents each independently selected from C1-6alkyl and oxo); wherein, R1 is selected from the group consisting of hydrogen, C1-6alkyl, C1-6alkylene-NRa2, C1- 6alkylene-ORc, 3-7 membered heterocyclyl, phenyl, C3-7cycloalkyl, and 5-6 membered heteroaryl; R7 and R8 are independently, for each occurrence, selected from the group consisting of hydrogen, C1-6alkyl, C1-6haloalkyl, and halogen; or R7 and R8 can be taken together to form C3- 7cycloalkylene; Ra is hydrogen or C1-6alkyl; and Rc is selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C3-7cycloalkyl, 3-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, and C1-6alkylene-N(Ra)2; n is an integer selected from 0 to 6; wherein when n is an integer selected from 1 to 6, W is selected from the group consisting of hydrogen, halogen, phenyl, 5-6 membered heteroaryl, C3-7cycloalkyl, 3-7 membered heterocyclyl, O-(C1-6alkyl), O-(C1-6haloalkyl), -O-phenyl, and O-(C1-6alkylene)-phenyl; and when n is 0, W is selected from the group consisting of hydrogen, C3-7cycloalkyl, 3-7 membered saturated heterocyclyl, O-(C1-6alkyl), O-(C1-6haloalkyl), -O-phenyl, and O-(C1- 6alkylene)-phenyl; wherein any aforementioned 3-7 membered heterocyclyl and phenyl are optionally substituted, wherein, when and n is 0 to 6, W is not hydrogen; when not phenyl; and when not C3-7cycloalkyl. 37. The compound of claim 1, wherein the compound is a compound of (I-d): pharmaceutically acceptable salt thereof, wherein: is a monocyclic or bicyclic (e.g., bridged) saturated heterocyclylene containing at least one N (including the depicted nitrogen) that is optionally substituted (e.g., with one or more substituents each independently selected from C1-6alkyl); R1 is C1-6alkyl; W is a phenyl; and n is 4. 38. The compound of any one of claims 1, 36, and 37, wherein is selected from the group consisting of: . 39. The compound of any one of claims 1-36 and 38, wherein R1 is selected from the group consisting of hydrogen, C1-6alkyl, C1-6alkylene-NRa2, and 3-7 membered heterocyclyl optionally substituted with methyl. 40. The compound of any one of claims 1-36 and 38, wherein R1 is hydrogen or C1-6alkyl. 41. The compound of any one of claims 1-36 and 38, wherein R1 is selected from methyl and hydrogen. 42. The compound of any one of claims 1-36 and 38, wherein R1 is C1-6alkyl. 43. The compound of any one of claims 1-38, wherein R1 is methyl. 44. The compound of any one of claims 1-36 and 38, wherein R1 is selected from the group consisting of methyl, hydrogen, -CH2CH2N(CH3)2, and . 45. The compound of any one of claims 1-36 and 38-44, wherein R7 and R8 are independently hydrogen or methyl. 46. The compound of any one of claims 1-36 and 38-44, wherein R7 and R8 are both hydrogen. 47. The compound of any one of claims 1-35 and 38-46, wherein R9 is hydrogen. 48. The compound of any one of claims 1-36 and 38-47, wherein n is an integer selected from 1 to 6 and W is selected from the group consisting of methyl, phenyl, 5-6 membered heteroaryl, C3-7cycloalkyl, 3-7 membered heterocyclyl, O-(C1-6alkyl), and O-(C1-6alkylene)- phenyl, wherein each aforementioned phenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of C1-6alkyl, halogen, and O-(C1-6alkyl). 49. The compound of any one of claims 1-36 and 38-47, wherein n is an integer selected from 1 to 6 and W is selected from the group consisting of methyl, phenyl, pyridazinyl, cyclohexyl, ethoxy, methoxy, cyclopropyl, and -O-CH2-phenyl, wherein each aforementioned phenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of C1-6alkyl, halogen, and O-(C1-6alkyl). 50. The compound of any one of claims 1-36 and 38-49, wherein W is methyl or phenyl. 51. The compound of any one of claims 1-36 and 38-49, wherein W is phenyl. 52. The compound of any one of claims 1-36 and 38-49, wherein W is methyl. 53. The compound of any one of claims 1-36 and 38-52, wherein n is 2, 3, or 4. 54. The compound of any one of claims 1-36 and 38-52, wherein n is 2. 55. The compound of any one of claims 1-36 and 38-52, wherein n is 4. 56. The compound of any one of claims 1-36 and 38-55, wherein any aforementioned phenyl or 3-7 membered heterocyclyl is optionally substituted with 1-4 substituents independently, for each occurrence, selected from the group consisting of C1-6alkyl, halogen, -O-C1-6alkyl, and - CH2N(Ra)2, wherein Ra is as defined in claim 1. 57. The compound of any one of claims 1-36 and 38-55, wherein any aforementioned phenyl or 3-7 membered heterocyclyl at W is optionally substituted with 1-3 substituents independently, for each occurrence, selected from the group consisting of C1-6alkyl, halogen, -O- C1-6alkyl, and -CH2N(Ra)2, wherein Ra is as defined in claim 1. 58. The compound of any one of claims 1-36 and 38-55, wherein any aforementioned phenyl at W is optionally substituted with 1-2 of methyl. 59. A pharmaceutical composition comprising the compound of any one of claims 1-58 and a pharmaceutically acceptable carrier. 60. A method of treating a subject with cancer and in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-58 or a pharmaceutical composition of claim 59. 61. A method of treating a subject with a lysosomal storage disorder and in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-58 or a pharmaceutical composition of claim 59. 62. A method of treating a subject with a neurodegenerative disorder and in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-58 or a pharmaceutical composition of claim 59. 63. The method of claim 60, wherein the cancer is melanoma. 64. The method of claim 61, wherein the lysosomal storage disorder is selected from the group consisting of : Krabbe disease, Fabry disease, Tay-Sachs disease, Pompe disease, Hunter’s syndrome, Niemann Pick disease Types A and B, and Gaucher disease. 65. The method of claim 64, wherein the lysosomal storage disorder is Gaucher disease. 66. The method of claim 62, wherein the neurodegenerative disorder is selected from the group consisting of: Alzheimer's disease, Parkinson’s disease, Huntington's disease, amyotrophic lateral sclerosis, Lewy body disease, dementia, and multiple system atrophy. 67. The method of claim 66, wherein the neurodegenerative disorder is Parkinson’s disease. 68. The method of claim 66, wherein the neurodegenerative disorder is Lewy body disease. 69. The method of claim 66, wherein the neurodegenerative disorder is dementia. 70. The method of claim 66, wherein the neurodegenerative disorder is multiple system atrophy. 71. A method of treating a subject with an inflammatory disorder and in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-58 or a pharmaceutical composition of claim 59. 72. The method of any one of claims 60-71, wherein the subject is human. 73. A compound of any one of claims 1-58 or a pharmaceutical composition of claim 59 for use in a method of treating a subject with cancer and in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound or the pharmaceutical composition. 74. A compound of any one of claims 1-58 or a pharmaceutical composition of claim 59 for use in a method of treating a subject with a lysosomal storage disorder and in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound or the pharmaceutical composition. 75. A compound of any one of claims 1-58 or a pharmaceutical composition of claim 59 for use in a method of treating a subject with a neurodegenerative disorder and in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound or the pharmaceutical composition. 76. A compound of any one of claims 1-58 or a pharmaceutical composition of claim 59 for use in a method of treating a subject with an inflammatory disorder and in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound or the pharmaceutical composition. 77. A compound of any one of claims 1-58 or a pharmaceutical composition of claim 59 for the manufacture of a medicament for treating a subject with cancer and in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound or the pharmaceutical composition. 78. A compound of any one of claims 1-58 or a pharmaceutical composition of claim 59 for the manufacture of a medicament for treating a subject with a lysosomal storage disorder and in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound or the pharmaceutical composition. 79. A compound of any one of claims 1-58 or a pharmaceutical composition of claim 59 for the manufacture of a medicament for treating a subject with a neurodegenerative disorder and in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound or the pharmaceutical composition. 80. A compound of any one of claims 1-58 or a pharmaceutical composition of claim 59 for the manufacture of a medicament for treating a subject with an inflammatory disorder and in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound or the pharmaceutical composition. |
[00294] The structures of the compounds of formula VI’a-i are as shown below: [00295] The structures of the compounds of formula VIIa-l are as shown below:
[00296] The structures of the compounds of formula VIIIa-k are as shown below: [00297] The structure of the compound of formula VII’a is as shown below: [00298] The structures of the compounds of formula IXa-k are as shown below: I Xi IXj IXk [00299] The structures of the compounds of formula Xa-c are as shown below: X a Xb Xc [00300] The structures of the compounds of formula XIa-m are as shown below:
X Ik XIl XIm The structures of the compounds of formula XIIa-n are as shown below: XIIk XIIl XIIm XIIn [00302] The structures of the compounds of formula XIIIa-c, XIVa-b, XVa-b, XVIa-b and XVIIa-b are as shown below:
[00303] The structures of the compounds of formula XVII’a and XVII’’a are as shown below: X VII'a XVII''a [00304] The structures of the compounds of formula XXa-g are as shown below:
XXd XXe XXf XXg [00305] The structures of the compounds of formula XXIa-b are as shown below: X XIa XXIb The structures of the compounds of formula XXIIa-f are as shown below: X XIId XXIIe XXIIf [00307] The structures of the compounds of formula XXIIIa-e are as shown below: X XIIIc XXIIId XXIIIe The structures of the compounds of formula XXIVa-f are as shown below: X XIVd XXIVe XXIVf [00309] The structures of the compounds of formula XXVIa, XXVIIa, XXVIIIa-b are as shown below:
X XVIIIa XXVIIIb The structures of the compounds of formula XXXa-k are as shown below: XXXj XXXk [00311] The structures of the compounds of formula XXX’a-c are as shown below: X XX'a XXX'b XXX'c . [00312] The structures of the compounds of formula XXX”a-c are as shown below: . [00313] The structures of the compounds of formula XXXIa-k are as shown below: . The structures of the compounds of formula XXXI’a-c are as shown below: X XXI'a XXXI'b XXXI'c . [00315] The structures of the compounds of formula XXXVII”a-c are as shown below: XXVII''a XXVII''b XXVII''c . [00316] The structures of the compounds of formula XXXIIa-k are as shown below:
X XXIIj XXXIIk [00317] The structures of the compounds of formula XXXII’a-c are as shown below: XXXII'a XXXII'b XXXII'c . The structures of the compounds of formula XXXII”a-c are as shown below: XXXII''a XXXII''b XXXII''c . [00319] The structures of the compounds of formula XXXIIIa-j are as shown below: XXXIIIf XXXIIIg XXXIIIh XXXIIIi XXXIIIj [00320] The structures of the compounds of formula XXXVa-l are as shown below: [00321] The structures of the compounds of formula XXXVIIa and XXXVIIIa are as shown below: X XXVIIa XXXVIIIa [00322] The structures of the compounds of formula XXXIII’a-c, XXXIV’a-c, and XXXV’a-c are as shown below:
XXXV'a XXXV'b XXXV'c [00323] The structures of the compounds of formula XXXIII”a-c and XXXV”a-c are as shown below: [00324] The structures of the compounds of formula XXXVIa-m are as shown below:
[00325] The structures of the compounds of formula XXXVI’a-c and XXXVI”a-c are as shown below: X XXVI''a XXXVI''b XXXVI''c . Part – Preparation of Specific N-heterocyclic Compounds [00326] Exemplary procedures for preparing specific N-heterocyclic carboxamides are provided below. The following examples describe the multistep synthesis of imidazole carboxamides and intermediates. The various steps, including the synthesis of intermediates, are discussed in more detail below. Example 1: 4-(2-Oxo-3H-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)piperidine -1-carboxamide tert-Butyl 4-(3-hydroxy-4-nitrophenyl)-3,6-dihydro-2H-pyridine-1-carbox ylate (VIIb) [00327] Following general procedure A (step 3), VIa (2.5 g, 8.07 mmol) and 5-bromo-2- nitrophenol (1.6 g, 7.34 mmol) afforded VIIb as a yellow solid (1.93 g, 82%). 1 H NMR (400 MHz, DMSO-d6) d 10.89 (s, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.18– 7.00 (m, 2H), 6.36 (bs, 1H), 4.04 (d, J = 2.9 Hz, 2H), 3.54 (t, J = 5.7 Hz, 2H), 2.49–2.39 (m, 2H), 1.43 (s, 9H). UPLC/MS (method B): Rt 1.48 min. MS (ES) C 16 H 20 N 2 O 5 requires 320, found 321 [M+H] + . tert-Butyl 4-(4-amino-3-hydroxy-phenyl)piperidine-1-carboxylate (VIIIb) [00328] Following general procedure B (method A), VIIb (0.250 g, 0.780 mmol) afforded VIIIb which was used in the next step without further purification. UPLC/MS (method A): Rt 1.98 min. MS (ES) C16H24N2O3 requires 292, found 293 [M+H] + . tert-Butyl 4-(4-amino-3-hydroxyphenyl)piperidine-1-carboxylate (IXb) [00329] Following general procedure B, (method A, step 2), VIIIb (4.2 g, 13.11 mmol) afforded IXb as a white solid (3.9 g, 95%). UPLC/MS (method A): Rt 2.17 min. MS (ES) C 17 H 22 N 2 O 4 requires 318, found 319 [M+H] + . 6-(4-Piperidyl)-3H-1,3-benzoxazol-2-one hydrochloride (Xa) [00330] Following general procedure C (step 2), IXb (3.9 g, 12.45 mmol) afforded Xa as a white solid (3.1 g, 99%). UPLC/MS (method A): Rt 0.91 min. MS (ES) C 12 H 14 N 2 O 2 requires 218, found 219 [M+H] + . 4-(2-Oxo-3H-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)piperidine -1-carboxamide [00331] Following general procedure D (Method A), Xa (0.280 g, 1.28 mmol). and 4- phenylbutyl isocyanate (0.247 g, 1.41 mmol) afforded the title compound as a white solid (0.050 g, 16%). 1 H NMR (400 MHz, CDCl 3 ) d 9.48 (bs, 1H), 7.31–7.26 (m, 2H), 7.24–7.14 (m, 3H), 7.11–6.91 (m, 3H), 4.63 (br s, 1H), 4.08 (d, J = 12.9 Hz, 2H), 3.40–3.21 (m, 2H), 2.90 (t, J = 12.6 Hz, 2H), 2.78–2.58 (m, 3H), 1.94–1.83 (m, 2H), 1.74–1.54 (m, 6H). UPLC/MS (method A): Rt 2.30 min. MS (ES) C 23 H 27 N 3 O 3 requires 393, found 394 [M+H] + . Example 2: 4-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)pipe ridine-1- carboxamide Benzyl 4-hydroxy-4-(2-oxo-3H-1,3-benzoxazol-6-yl)piperidine-1-carbo xylate (XIIIa) [00332] Following general procedure G, Vb (1.0 g, 4.49 mmol) and 6-bromo-3H-1,3- benzoxazol-2-one (0.4 g, 1.87 mmol) afforded XIIIa as a white solid (0.39 g, 57%). UPLC/MS (method A): Rt 1.83 min. MS (ES) C 20 H 20 N 2 O 5 requires 368, found 369 [M+H] + . Benzyl 4-(2-oxo-3H-1,3-benzoxazol-6-yl)-3,6-dihydro-2H-pyridine-1-c arboxylate (XIVa) [00333] To a solution of XIIIa (0.380 g, 1.03 mmol.) in THF (0.1 M) was added p-TsOH (0.191 g, 1.03 mmol) and the reaction mixture was stirred at reflux for 4h. Then, the reaction mixture was quenched with saturated aq. NaHCO 3 solution, extracted with EA, washed with brine, dried over Na 2 SO 4 and concentrated to afford XIVa which was used in the next step without further purification (0.330 g, 91%). 1 H NMR (400 MHz, DMSO-d6) d 7.40–7.30 (m, 7H), 7.22 (dd, J = 8.2, 1.7 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.13 (bs, 1H), 5.12 (s, 2H), 4.15– 4.05 (m, 2H), 3.65–3.55 (m, 2H). UPLC/MS (method A): Rt 2.15 min. MS (ES) C20H18N2O4 requires 350, found 351 [M+H] + . hydro-2H-pyridine-1-carboxylate [00334] Following general procedure C (step 1), XIVa (0.355 g, 1.01 mmol) and CH 3 I (0.215 g, 1.52 mmol) afforded XVa which was used in the next step without further purification. UPLC/MS (method A): Rt 2.31 min. MS (ES) C21H20N2O4 requires 364, found 365 [M+H] + . Benzyl 4-(2-oxo-3H-1,3-benzoxazol-6-yl)piperidine-1-carboxylate (XIIb) [00335] A suspension of XVa (0.360 g, 0.98 mmol, 1.0 eq.) in THF/MeOH (8:2, 0.1 M) was hydrogenated with the H-Cube apparatus using 10% Pd/C catalyst at RT. After complete conversion the solvent was evaporated under reduced pressure. The residue was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) d 7.21 (d, J = 1.4 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.09 (dd, J = 8.1, 1.5 Hz, 1H), 3.32 (s, 3H), 3.30–3.10 (bs, 1H), 3.05– 2.95 (m, 2H), 2.65–2.55 (m, 3H), 1.75–1.65 (m, 2H), 1.60–1.40 (m, 2H). UPLC/MS (method A): Rt 1.10 min. MS (ES) C H N + 1 3 16 2 O 2 requires 232, found 233 [M+H] . [00336] Following general procedure D (Method A), XIIb (0.09 g, 0.39 mmol) and 4- phenylbutyl isocyanate (0.075 g, 0.43 mmol) afforded the title compound as a white solid (0.104 g, 65%). 1 H NMR (400 MHz, CDCl3) d 7.35–7.25 (m, 2H), 7.25–7.15 (m, 3H), 7.07 (d, J = 1.6 Hz, 1H), 7.05 (dd, J = 8.0, 1.6 Hz, 1H), 6.91 (d, J = 7.9 Hz, 1H), 4.80–4.40 (m, 1H), 4.15–4.05 (m, 1H), 3.40 (s, 3H), 3.30 (t, J = 7.1 Hz, 2H), 2.89 (td, J = 12.9, 2.6 Hz, 2H), 2.80–2.60 (m, 3H), 1.90–1.80 (m, 2H), 1.75–1.50 (m, 6H). UPLC/MS (method A): Rt 2.21 min. MS (ES) C24H29N3O3 requires 407, found 408 [M+H] + . Example 3: N-iso-Butyl 4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)piperidine-1-carboxami de [00337] Following general procedure D (Method B), XIIb (0.063 g, 0.23 mmol) and isobutyl amine (0.050 g, 0.69 mmol) afforded the title compound as a white solid (0.058 g, 76%). 1 H NMR (400 MHz, CDCl 3 ) d 7.05 (d, J = 1.6 Hz, 1H), 7.03 (dd, J = 8.1, 1.6 Hz, 1H), 6.90 (s, 1H), 4.70–4.50 (m, 1H), 4.15–4.05 (m, 1H), 3.38 (s, 3H), 3.30 (t, J = 7.1 Hz, 2H), 2.88 (td, J = 13.1, 2.6 Hz, 2H), 2.75–2.45 (m, 1H), 1.90–1.80 (m, 2H), 1.80–1.70 (m, 1H), 1.70–1.50 (m, 3H), 0.92 (d, J = 6.7 Hz, 6H). UPLC/MS (method A): Rt 1.88 min. MS (ES) C 18 H 25 N 3 O 3 requires 331, found 332 [M+H] + . Example 4: N-(2-Cyclopropylethyl)-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl )piperidine-1- carboxamide [00338] Following general procedure D (Method C), XIIb (0.030 g, 0.064 mmol) and 2- cyclopropylethanamine hydrochloride (0.020 g, 0.168 mmol) afforded the title compound as a white solid (0.011 g, 50%). 1 H NMR (400 MHz, CDCl 3 ) d 7.11–7.03 (m, 2H), 6.91 (d, J = 8.0 Hz, 1H), 4.85 (br s, 1H), 4.13–4.01 (m, 2H), 3.41 (s, 3H), 3.38 (t, J = 7.0 Hz, 2H), 2.93 (td, J = 12.9, 2.6 Hz, 2H), 2.73 (tt, J = 12.2, 3.6 Hz, 1H), 1.95–1.85 (m, 2H), 1.80–1.63 (m, 3H), 1.47 (q, J = 7.0 Hz, 2H), 0.78–0.65 (m, 1H), 0.54–0.45 (m, 2H), 0.15–0.08 (m, 2H). UPLC/MS (method A): Rt 1.82 min. MS (ES) C19H25N3O3 requires 343, found 344 [M+H] + . Example 5: N-Cyclohexyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)piperidin e-1-carboxamide [00339] Following general procedure D (Method A), XIIb (0.050 g, 0.19 mmol) and cyclohexyl isocyanate (0.026 g, 0.21 mmol) afforded the title compound as a white solid (0.045 g, 68%). 1 H NMR (400 MHz, CDCl3) d 7.17–7.00 (m, 2H), 6.91 (d, J = 7.9 Hz, 1H), 4.44 (bs, 1H), 4.08 (d, J = 13.0 Hz, 2H), 3.79–3.59 (m, 1H), 3.41 (s, 3H), 2.89 (t, J = 12.0 Hz, 2H), 2.71 (tt, J = 12.2, 3.7 Hz, 1H), 2.07–1.94 (m, 2H), 1.93–1.81 (m, 2H), 1.78–1.59 (m, 5H), 1.49–1.32 (m, 2H), 1.26–1.05 (m, 3H). UPLC/MS (method A): Rt 1.99 min. MS (ES) C20H27N3O3 requires 357, found 358 [M+H] + . Example 6: 4-[3-(1-Methyl-4-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]-N-(4- phenylbutyl)piperidine-1-carboxamide tert-Butyl 4-[3-hydroxy-4-[(1-methyl-4-piperidyl)amino]phenyl]piperidin e-1-carboxylate [00340] To a solution of VIIIb (0.228 g, 0.78 mmol) in DCE (0.2 M), NaOAc (0.032 g, 0.39 mmol), glacial AcOH (0.02 mL, 0.39 mmol), N-methyl-4-piperidone (0.132 g, 1.17 mmol) and NaBH(AcO)3 (0.25 g, 1.17 mmol) were added and the mixture was stirred at RT for 2h and then diluted with EA, washed with saturated aq. NaHCO 3 solution, brine and dried over Na 2 SO 4 . After evaporation of the solvent, the residue was used in the next step without further purification. UPLC/MS (method A): Rt 1.83 min. MS (ES) C22H35N3O3 requires 389, found 390 [M+H] + . tert-Butyl 4-[3-(1-methyl-4-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]piperi dine-1-carboxylate (XIc) [00341] Following general procedure B (step 2), tert-butyl 4-[3-hydroxy-4-[(1-methyl-4- piperidyl)amino]phenyl]piperidine-1-carboxylate (0.220 g, 0.780 mmol) afforded XIc as a white solid (0.170 g, 52%). 1 H NMR (400 MHz, CDCl 3 ) d 7.33–7.27 (m, 1H), 7.08 (d, J = 1.6 Hz, 1H), 7.02 (dd, J = 8.2, 1.7 Hz, 1H), 4.40–4.16 (m, 3H), 3.13 (d, J = 11.5 Hz, 2H), 2.91–2.75 (m, 2H), 2.73–2.64 (m, 1H), 2.57–2.48 (m, 2H), 2.44 (s, 3H), 2.37–2.20 (m, 2H), 1.98–1.77 (m, 4H), 1.68–1.53 (m, 2H), 1.50 (s, 9H). UPLC/MS (method A): Rt 1.98 min. MS (ES) C23H33N3O4 requires 415, found 416 [M+H] + . 3-(1-Methyl-4-piperidyl)-6-(4-piperidyl)-1,3-benzoxazol-2-on e dihydrochloride (XIIc) [00342] Following general procedure C (step 2), XIc (0.170 g, 0.409 mmol) afforded XIIc as a brownish solid (0.158 g, 99%). 1 H NMR (400 MHz, DMSO-d 6 ) d 11.41 (s, 1H), 9.35–8.85 (m, 2H), 7.75 (d, J = 8.2 Hz, 1H), 7.24 (d, J = 1.5 Hz, 1H), 7.08 (dd, J = 8.3, 1.6 Hz, 1H), 4.47 (tt, J = 12.4, 4.3 Hz, 1H), 3.56–3.47 (m, 2H), 3.35–3.29 (m, 2H), 3.20 (dt, J = 13.8, 10.8 Hz, 2H), 3.04–2.84 (m, 3H), 2.86–2.69 (m, 5H), 2.06–1.95 (m, 2H), 1.96–1.85 (m, 4H). UPLC/MS (method A): Rt 1.14 min. MS (ES) C13H16N2O2 requires 315, found 316 [M+H] + . 4-[3-(1-Methyl-4-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]-N-(4- phenylbutyl)piperidine-1- carboxamide [00343] Following general procedure D (Method A), XIIc (0.060 g, 0.16 mmol) and 4- phenylbutyl isocyanate (0.029 g, 0.17 mmol) afforded the title compound as a white solid (0.035 g, 46%). 1 H NMR (400 MHz, CDCl 3 ) d 7.33–7.26 (m, 2H), 7.26–7.13 (m, 4H), 7.07 (s, 1H), 7.00 (d, J = 8.2 Hz, 1H), 4.51 (s, 1H), 4.34–4.16 (m, 1H), 4.07 (d, J = 13.1 Hz, 2H), 3.29 (q, J = 6.6 Hz, 2H), 3.06 (d, J = 11.5 Hz, 2H), 2.87 (t, J = 12.1 Hz, 2H), 2.77–2.60 (m, 3H), 2.54–2.33 (m, 5H), 2.25–2.10 (m, 2H), 1.94–1.78 (m, 4H), 1.74–1.52 (m, 6H). UPLC/MS (method A): Rt 2.25 min. MS (ES) C29H38N4O3 requires 490, found 491 [M+H] + . Example 7: 4-(3-Methyl-2-oxo-1,3-benzoxazol-7-yl)-N-(4-phenylbutyl)pipe ridine-1- carboxamide tert-Butyl 4-hydroxy-4-(2-oxo-3H-1,3-benzoxazol-7-yl)piperidine-1-carbo xylate (XIIIb) [00344] Following general procedure G, Va (2.2 g, 11.21 mmol) and 7-bromo-3H-1,3- benzoxazol-2-one (1.0 g, 4.67 mmol) afforded XIIIb as a white solid (1.07 g, 68 %). UPLC/MS (method A): Rt 1.75 min. MS (ES) C17H22N2O5 requires 334, found 335 [M+H] + . 7-(1,2,3,6-Tetrahydropyridin-4-yl)-3H-1,3-benzoxazol-2-one (XVIa) [00345] To a solution of XIIIb (1.0 g, 3.21 mmol) in toluene (0.1 M) was added TFA (5.0 mL, 29.94 mmol) and the reaction mixture was stirred at reflux for 2h. Then, the reaction mixture was quenched with saturated aq. NaHCO3 solution, extracted with EA, washed with brine, dried over Na2SO4 and concentrated to afford XVIa which was used in the next step without further purification. UPLC/MS (method A): Rt 0.95 min. MS (ES) C 12 H 12 N 2 O 2 requires 216, found 217 [M+H] + . tert-Butyl 4-(2-oxo-3H-1,3-benzoxazol-7-yl)-3,6-dihydro-2H-pyridine-1-c arboxylate (XVIIa) [00346] To a solution of XVIa (0.172 g, 0.79 mmol) in THF (0.1 M) ws added Boc2O (0.190 g, 0.87 mmol) in the presence of Et 3 N (0.167 mL, 1.19 mmol) and the reaction mixture was stirred at RT for 1h. Then, the reaction mixture was diluted with EA, washed with saturated aqueous NaHCO3 solution, brine, dried over Na2SO4 and concentrated to afford XVIIa as a white solid (0.227 g, 90%). 1 H NMR (400 MHz, DMSO-d6) d 11.66 (s, 1H), 7.15–7.10 (m, 1H), 7.06 (dd, J = 8.1, 1.4 Hz, 1H), 6.99 (dd, J = 7.5, 1.3 Hz, 1H), 6.40-6.28 (m, 1H), 4.15–3.95 (m, 1H), 3.55 (t, J = 5.7 Hz, 2H), 1.43 (s, 9H). UPLC/MS (method A): Rt 2.14 min. MS (ES) C17H20N2O4 requires 316, found 317 [M+H] + . tert-Butyl 4-(2-oxo-3H-1,3-benzoxazol-7-yl)piperidine-1-carboxylate (IXa) [00347] A suspension of XVIIa (0.225 g, 0.71 mmol, 1.0 eq.) in MeOH (0.1 M) was hydrogenated with the H-Cube apparatus using 10% Pd/C catalyst at RT and full H 2 mode. After complete conversion the solvent was evaporated under reduced pressure and the residue was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) d 11.57 (s, 1H), 7.08 (t, J = 7.8 Hz, 1H), 6.96 (dd, J = 8.3, 1.3 Hz, 1H), 6.93 (dd, J = 7.6, 1.2 Hz, 1H), 4.20– 3.95 (m, 2H), 3.10–2.70 (m, 3H), 1.80–1.70 (m, 2H), 1.68–1.52 (m, 2H), 1.42 (s, 9H). UPLC/MS (method A): Rt 2.17 min. MS (ES) C 17 H 22 N 2 O 4 requires 318, found 319 [M+H] + . tert-Butyl 4-(3-methyl-2-oxo-1,3-benzoxazol-7-yl)piperidine-1-carboxyla te (XIa) [00348] Following general procedure C (step 1), IXa (0.219 g, 0.69 mmol) and MeI (0.18 g, 1.04 mmol) afforded XIa which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) d 7.18 (t, J = 7.8 Hz, 1H), 7.10 (dd, J = 7.8, 1.3 Hz, 1H), 7.03 (dd, J = 7.9, 1.3 Hz, 1H), 4.15–4.00 (m, 2H), 3.33 (s, 3H), 3.10–2.70 (m, 3H), 3.05–2.75 (m, 3H), 1.80– 1.70 (m, 2H), 1.70–1.55 (m, 2H), 1.43 (s, 9H). UPLC/MS (method A): Rt 2.38 min. MS (ES) C18H24N2O4 requires 332, found 333 [M+H] + . 3-Methyl-7-(4-piperidyl)-1,3-benzoxazol-2-one hydrochloride (XIIa) [00349] Following general procedure C (step 2), XIa (0.212 g, 0.64 mmol) afforded XIIa which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) d 9.09 (bs, 1H), 8.89 (bs, 1H), 7.22 (t, J = 7.8 Hz, 1H), 7.15 (dd, J = 7.8, 1.2 Hz, 1H), 6.99 (dd, J = 7.9, 1.3 Hz, 1H), 3.40–3.35 (m, 1H), 3.34 (s, 3H), 3.20–3.10 (m, 1H), 3.10–3.95 (m, 2H), 2.10– 1.95 (m, 4H). UPLC/MS (method A): Rt 1.12 min. MS (ES) C 13 H 16 N 2 O 2 requires 232, found 233 [M+H] + . 4-(3-Methyl-2-oxo-1,3-benzoxazol-7-yl)-N-(4-phenylbutyl)pipe ridine-1-carboxamide [00350] Following general procedure D (Method A), XIIa (0.080 g, 0.30 mmol) and 4- phenylbutyl isocyanate (0.033 g, 0.33 mmol) afforded the title compound as a white solid (0.045 g, 88%). 1 H NMR (400 MHz, CDCl 3 ) d 7.35–7.25 (m, 2H), 7.24–7.11 (m, 4H), 6.97 (dd, J = 8.0, 1.1 Hz, 1H), 6.86 (dd, J = 7.8, 1.1 Hz, 1H), 4.65–4.45 (m, 1H), 4.15–4.00 (m, 2H), 3.42 (s, 3H), 3.32–3.25 (m, 2H), 3.15–3.05 (m, 1H), 3.00–2.85 (m, 2H), 2.75–2.65 (m, 2H), 2.00–1.85 (m, 2H), 1.85–1.65 (m, 6H), 1.65–1.50 (m, 2H). UPLC/MS (method A): Rt 2.27 min. MS (ES) C24H29N3O3 requires 407, found 408 [M+H] + . Example 8: N-iso-Butyl-4-(3-methyl-2-oxo-1,3-benzoxazol-7-yl)piperidine -1-carboxamide [00351] Following general procedure D (Method B), using XIIa (0.080 g, 0.29 mmol) and isobutyl amine (0.064 g, 0.736 mmol) afforded the title compound as a white solid (0.065 g, 68%). 1 H NMR (400 MHz, CDCl3) d 7.14 (t, J = 7.9 Hz, 1H), 6.99–6.91 (m, 1H), 6.83 (dd, J = 7.8, 1.1 Hz, 1H), 4.70–4.50 (m, 1H), 4.15–4.00 (m, 2H), 3.39 (s, 3H), 3.15–3.00 (m, 3H), 2.95– 2.85 (m, 2H), 1.95–1.85 (m, 2H), 1.85–1.60 (m, 3H), 0.92 (d, J = 6.7 Hz, 6H). UPLC/MS (method A): Rt 1.92 min. MS (ES) C18H25N3O3 requires 331, found 332 [M+H] + . Example 9: 4-(3-Methyl-2-oxo-1,3-benzoxazol-5-yl)-N-(4-phenylbutyl)pipe ridine-1- carboxamide tert-Butyl 4-(4-hydroxy-3-nitrophenyl)-3,6-dihydro-2H-pyridine-1-carbox ylate (VIIc) [00352] Following general procedure A (step 3), VIa (0.92 g, 2.98 mmol) and 4-bromo-2- nitrophenol (0.50 g, 2.29 mmol) afforded VIIc as a yellow oil (0.68 g, 92%). 1 H NMR (400 MHz, CDCl3) d 10.56 (s, 1H), 8.09 (d, J = 2.3 Hz, 1H), 7.67 (dd, J = 8.8, 2.4 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 6.10 (bs, 1H), 4.17–4.04 (m, 2H), 3.68 (t, J = 5.7 Hz, 2H), 2.60–2.38 (m, 2H), 1.52 (s, 9H). UPLC/MS (method B): Rt 1.05 min. MS (ES) C 16 H 20 N 2 O 5 requires 320, found 321 [M+H] + . tert-Butyl 4-(3-amino-4-hydroxyphenyl)piperidine-1-carboxylate (VIIIc) [00353] Following general procedure B(method A), VIIc (0.300 g, 0.937 mmol) afforded VIIIc which was used in the next step without further purification. UPLC/MS (method A): Rt 1.98 min. MS (ES) C16H24N2O3 requires 292, found 293 [M+H] + . tert-Butyl 4-(2-oxo-3H-1,3-benzoxazol-5-yl)piperidine-1-carboxylate (IXc) [00354] Following general procedure B (step 2), VIIIc (0.277 g, 0.95 mmol) afforded IXc as a colorless oil (0.220 g, 74%). 1 H NMR (400 MHz, CDCl3) d 8.11 (s, 1H), 7.15 (d, J = 8.3 Hz, 1H), 6.97 (dd, J = 8.4, 1.7 Hz, 1H), 6.92 (d, J = 1.7 Hz, 1H), 4.28 (dd, J = 10.6, 3.0 Hz, 2H), 2.82 (td, J = 13.2, 2.6 Hz, 2H), 2.68 (tt, J = 12.2, 3.6 Hz, 1H), 1.90–1.80 (m, 2H), 1.66–1.59 (m, 2H), 1.51 (s, 9H). UPLC/MS (method A): Rt 2.20 min. MS (ES) C17H22N2O4 requires 318, found 319 [M+H] + . tert-Butyl 4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)piperidine-1-carboxyla te (XId) [00355] Following general procedure C (step 1), IXc (0.220 g, 0.691 mmol) and MeI (0.146 g, 1.037 mmol) afforded XId which was used in the next step without purification. 1 H NMR (400 MHz, CDCl 3 ) d 7.14 (d, J = 8.2 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.82 (s, 1H), 4.29 (d, J = 12.1 Hz, 2H), 3.41 (s, 3H), 2.83 (t, J = 12.4 Hz, 2H), 2.77 – 2.63 (m, 1H), 1.95 – 1.78 (m, 2H), 1.75 – 1.57 (m, 2H), 1.51 (s, 9H). UPLC/MS (method B): Rt 1.20 min. MS (ES) C 18 H 24 N 2 O 4 requires 332, found 333 [M+H] + . 3-Methyl-5-(4-piperidyl)-1,3-benzoxazol-2-one hydrochloride (XIId) [00356] Following general procedure C (step 2), XId (0.210 g, 0.632 mmol) afforded XIId as a brownish solid (0.160 g, 94%). 1 H NMR (400 MHz, DMSO-d6) d 9.41 – 8.89 (m, 2H), 7.29 (d, J = 8.2 Hz, 1H), 7.11 (d, J = 1.7 Hz, 1H), 6.99 (dd, J = 8.3, 1.7 Hz, 1H), 3.40 – 3.35 (m, 2H), 3.34 (s, 3H), 3.08 – 2.81 (m, 3H), 2.01 – 1.81 (m, 4H). UPLC/MS (method A): Rt 1.14 min. MS (ES) C13H16N2O2 requires 232, found 233 [M+H] + . 4-(3-Methyl-2-oxo-1,3-benzoxazol-5-yl)-N-(4-phenylbutyl)pipe ridine-1-carboxamide [00357] Following general procedure D (method A), XIId (0.060 g, 0.19 mmol) and 4- phenylbutyl isocyanate (0.036 g, 0.21 mmol) afforded the title compound as a white solid (0.042 g, 54%). 1 H NMR (400 MHz, CDCl3) d 7.35–7.27 (m, 2H), 7.25–7.17 (m, 3H), 7.14 (d, J = 8.2 Hz, 1H), 6.96 (dd, J = 8.3, 1.7 Hz, 1H), 6.81 (d, J = 1.7 Hz, 1H), 4.59 (br s, 1H), 4.08 (d, J = 13.0 Hz, 2H), 3.41 (s, 3H), 3.31 (t, J = 7.1 Hz, 2H), 2.91 (td, J = 12.9, 2.6 Hz, 2H), 2.80–2.60 (m, 3H), 1.98–1.83 (m, 2H), 1.81–1.51 (m, 6H). UPLC/MS (method A): Rt 2.25 min. MS (ES) C24H29N3O3 requires 407, found 408 [M+H] + . Example 10: 4-(3-Methyl-2-oxo-1,3-benzoxazol-4-yl)-N-(4-phenylbutyl)pipe ridine-1- carboxamide tert-Butyl 4-(3-hydroxy-2-nitrophenyl)-3,6-dihydro-2H-pyridine-1-carbox ylate (VIId) [00358] Following general procedure A (step 3), VI’a (1.85 g, 5.96 mmol) and 3-bromo-2- nitrophenol (1.0 g, 4.59 mmol) afforded VIId as a pale yellow solid (1.42 g, 97%). 1 H NMR (400 MHz, CDCl 3 ) d 10.20 (s, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.11 (dd, J = 8.5, 1.5 Hz, 1H), 6.78 (dd, J = 7.5, 1.4 Hz, 1H), 5.56 (bs, 1H), 4.13 – 3.88 (m, 2H), 3.68 (t, J = 5.5 Hz, 2H), 2.28 (s, 2H), 1.52 (s, 9H). UPLC/MS (method B): Rt 1.05 min. MS (ES) C16H20N2O5 requires 320, found 321 [M+H] + . tert-Butyl 4-(2-amino-3-hydroxy-phenyl)piperidine-1-carboxylate (VIIId) [00359] Following general procedure B (method A), VIId (0.510 g, 1.56 mmol) afforded VIIId which was used in the next step without further purification. UPLC/MS (method A): Rt 2.01 min. MS (ES) C16H24N2O3 requires 292, found 293 [M+H] + . tert-Butyl 4-(2-oxo-3H-1,3-benzoxazol-4-yl)piperidine-1-carboxylate (IXd) [00360] Following general procedure B (step 2), VIId (0.465 g, 1.59 mmol) afforded IXd as a white solid (0.190 g, 37%). 1 H NMR (400 MHz, CDCl3) d 10.53 (s, 1H), 7.14 – 7.09 (m, 2H), 7.07– 7.00 (m, 1H), 4.31 (d, J = 13.1 Hz, 2H), 3.05– 2.74 (m, 3H), 1.90 (d, J = 10.9 Hz, 2H), 1.79–1.62 (m, 2H), 1.52 (s, 9H). UPLC/MS (method A): Rt 2.24 min. MS (ES) C 17 H 22 N 2 O 4 requires 318, found 336 [M+NH4] + . tert-Butyl 4-(3-methyl-2-oxo-1,3-benzoxazol-4-yl)piperidine-1-carboxyla te (XIe) [00361] Following general procedure C (step 1), IXd (0.16 g, 0.487 mmol) and MeI (0.10 g, 0.73 mmol) afforded XIe which used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 ) d 7.15 – 6.99 (m, 3H), 4.33 (d, J = 13.3 Hz, 2H), 3.67 (s, 3H), 3.29– 3.16 (m, 1H), 2.90– 2.78 (m, 2H), 1.92 – 1.70 (m, 4H), 1.51 (s, 9H). UPLC/MS (method B): Rt 1.20 min. MS (ES) C18H24N2O4 requires 332, found 333 [M+H] + . 3-Methyl-4-(4-piperidyl)-1,3-benzoxazol-2-one hydrochloride (XIIe) [00362] Following general procedure C (step 2), XIe (0.154 g, 0.46 mmol) afforded XIIe as a white solid (0.120 g, 97%). 1 H NMR (400 MHz, DMSO-d 6 ) d 9.38 – 9.00 (m, 2H), 7.22 (dd, J = 7.8, 1.2 Hz, 1H), 7.15 (t, J = 7.9 Hz, 1H), 7.08 (dd, J = 8.0, 1.3 Hz, 1H), 3.59 (s, 3H), 3.55 – 3.43 (m, 1H), 3.38 – 3.31 (m, 2H), 3.21 – 2.98 (m, 2H), 2.14 – 1.80 (m, 4H). UPLC/MS (method B): Rt 1.14 min. MS (ES) C 13 H 16 N 2 O 2 requires 232, found 233 [M+H] + . 4-(3-Methyl-2-oxo-1,3-benzoxazol-4-yl)-N-(4-phenylbutyl)pipe ridine-1-carboxamide [00363] Following general procedure D (Method A), XIIe (0.050 g, 0.16 mmol) and 4- phenylbutyl isocyanate (0.030 g, 0.17 mmol) afforded the title compound as a white solid (0.057 g, 89%). 1 H NMR (400 MHz, CDCl3) d 7.55–6.79 (m, 9H), 4.54 (s, 1H), 4.13 (d, J = 13.0 Hz, 2H), 3.66 (s, 3H), 3.423.12 (m, 3H), 2.91 (t, J = 12.7 Hz, 2H), 2.68 (t, J = 7.5 Hz, 2H), 2.00– 1.46 (m, 9H). UPLC/MS (method A): Rt 2.27 min. MS (ES) C 24 H 29 N 3 O 3 requires 407, found 408 [M+H] + . Example 11: 3-(2-Oxo-3H-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)piperidine -1- carboxamide 6-Piperidin-1-ium-3-yl-3H-1,3-benzoxazol-2-one hydrochloride (Xb) [00364] Following general procedure C (step 2), IXe (0.192 g, 0.6 mmol) afforded Xb as a white solid (0.150 g, 98%) and used in the next step without further purification. UPLC/MS (method A): Rt 1.06 min. MS (ES) C H N O requ + 1 2 15 2 2 ires 219, found 220 [M+H] . 3-(2-Oxo-3H-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)piperidine -1-carboxamide [00365] Following general procedure D (Method A), Xb (0.06 g, 0.31 mmol) and 4- phenylbutyl isocyanate (0.05 g, 0.31 mmol) afforded the title compound as a white solid (0.060 g 49%) 1 H NMR (400 MHz DMSO-d 6 ) d 1151 (s 1H) 730 – 711 (m 6H) 706 – 695 (m 2H), 6.46 (bs, 1H), 4.08 – 3.89 (m, 2H), 3.08 – 3.00 (m, 2H), 2.74 – 2.53 (m, 5H), 1.90 – 1.81 (m, 1H), 1.69 – 1.34 (m, 7H). UPLC/MS (method B): Rt 0.79 min. MS (ES) C 23 H 27 N 3 O 3 requires 393, found 394 [M+H] + . Example 12: 3-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)pipe ridine-1- carboxamide tert-Butyl 5-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyridine-1-car boxylate (VIb) [00366] Following general procedure A (step 1), Vc (1.0 g, 5.02 mmol) afforded VIb as a colorless oil (0.90 g, 54%). 1 H NMR (400 MHz, CDCl3) d 5.92 (t, J = 4.0 Hz, 1H), 4.13–3.83 (m, 2H), 3.49 (t, J = 5.6 Hz, 2H), 2.38–2.09 (m, 2H), 1.47 (s, 9H). UPLC/MS (method B): Rt 1.77 min. MS (ES) C 11 H 16 F 3 NO 5 S requires 331, found 332 [M+H] + . tert-Butyl 5-(3-hydroxy-4-nitrophenyl)-3,6-dihydro-2H-pyridine-1-carbox ylate (VIIe) [00367] Following general procedure A, VIb (0.90 g, 2.7 mmol) and 5-bromo-2-nitrophenol (0.650 g, 3.27 mmol) afforded VIIe as a yellow solid (0.460 g, 55%). 1 H NMR (400 MHz, CDCl3) d 10.64 (s, 1H), 8.06 (d, J = 8.9 Hz, 1H), 7.10 (s, 1H), 7.01 (dd, J = 8.9, 2.0 Hz, 1H), 6.49- 6.43 (m, 1H), 4.26 (s, 2H), 3.56 (t, J = 5.7 Hz, 2H), 2.37 (s, 2H), 1.50 (s, 9H). UPLC/MS (method B): Rt 1.86 min. MS (ES) C 16 H 20 N 2 O 5 requires 320, found 321 [M+H] + . tert-Butyl 3-(4-amino-3-hydroxyphenyl)piperidine-1-carboxylate (VIIIe) [00368] Following general procedure B (Method A), VIIe (0.45 g, 1.41 mmol) afforded VIIIe which was used in the next step without further purification. UPLC/MS (method B): Rt 0.73 min. MS (ES) C16H24N2O3 requires 292, found 293 [M+H] + . tert-Butyl 3-(2-oxo-3H-1,3-benzoxazol-6-yl)piperidine-1-carboxylate (IXe) [00369] Following general procedure B (step 2), VIIIe (0.270 g, 0.92 mmol) afforded IXe as a white solid (0.190 g, 64%). 1 H NMR (400 MHz, CDCl 3 ) d 10.04 (s, 1H), 7.02 (s, 1H), 6.99– 6.91 (m, 2H), 4.20–4.03 (m, 2H), 2.79–2.57 (m, 3H), 2.00–1.92 (m, 1H), 1.77–1.68 (m, 1H), 1.63–1.46 (m, 2H), 1.44 (s, 9H). UPLC/MS (method A): Rt 0.94 min. MS (ES) C17H22N2O4 requires 318, found 319 [M+H] + . tert-Butyl 3-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)piperidine-1-carboxyla te (XIf) [00370] Following general procedure C (step 1), IXf (0.400 g, 1.25 mmol) and MeI (0.27 g, 1.88 mmol) afforded XIf which was used in the next step without purification. 1 H NMR (400 MHz, CDCl3) d 7.10–7.08 (m, 1H), 7.06 (dd, J = 8.0, 1.5 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 4.24–4.05 (m, 2H), 3.38 (s, 3H), 2.81–2.61 (m, 3H), 2.01 (d, J = 9.2 Hz, 1H), 1.80–1.72 (m, 1H), 1.68–1.53 (m, 2H), 1.47 (s, 9H). UPLC/MS (method A): Rt 2.37 min. MS (ES) C18H24N2O4 requires 332, found 333 [M+H] + . 3-Methyl-6-piperidin-1-ium-3-yl-1,3-benzoxazol-2-one hydrochloride (XIIf) [00371] Following general procedure C (step 2), XIf (0.340 g, 1.024 mmol) afforded XIIf as a white solid (0.260 g, 99%). 1 H NMR (400 MHz, DMSO-d 6 ) d 9.16 (d, J = 85.0 Hz, 2H), 7.33 (d, J = 1.3 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.15 (dd, J = 8.1, 1.5 Hz, 1H), 3.31–3.20 (m, 2H), 3.09–2.96 (m, 2H), 2.94–2.77 (m, 1H), 1.93–1.61 (m, 4H). UPLC/MS (method A): Rt 1.16 min. MS (ES) C 13 H 16 N 2 O 2 requires 233, found 234 [M+H] + . 3-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)pipe ridine-1-carboxamide [00372] Following general procedure D (Method A), XIIf (0.08 g, 0.32 mmol) and 4- phenylbutyl isocyanate (0.06 g, 0.37 mmol) afforded the title compound as a white solid (0.107 g, 79%). 1 H NMR (400 MHz, CDCl 3 ) d 7.30–7.23 (m, 2H), 7.21–7.13 (m, 3H), 7.10–7.04 (m, 2H), 6.92–6.85 (m, 1H), 4.52 (bs, 1H), 4.11–3.98 (m, 1H), 3.88 (d, J = 12.8 Hz, 1H), 3.38 (s, 3H), 3.26 (t, J = 7.1 Hz, 2H), 2.88–2.78 (m, 1H), 2.78–2.69 (m, 2H), 2.64 (t, J = 7.5 Hz, 2H), 2.13–1.98 (m, 1H), 1.79 (ddd, J = 13.6, 8.5, 5.5 Hz, 1H), 1.72–1.49 (m, 6H). UPLC/MS (method A): Rt 2.29 min. MS (ES) C24H29N3O3 requires 407, found 408 [M+H] + . Example 13: 3-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-pentyl-piperidine-1 -carboxamide [00373] Following general procedure D (Method A), XIIf (0.060 g, 0.22 mmol) and n-pentyl isocyanate (0.053 g, 0.45 mmol) afforded the title compound as white solid (0.040 g, 53%). 1 H NMR (400 MHz, CDCl3) d 7.11–7.08 (m, 2H), 6.89 (d, J = 7.9 Hz, 1H), 4.60 (bs, 1H), 4.04 (t, J = 9.3 Hz, 1H), 3.89 (d, J = 13.1 Hz, 1H), 3.39 (s, 3H), 3.23 (t, J = 7.2 Hz, 2H), 2.85 (td, J = 12.8, 2.9 Hz, 1H), 2.80–2.71 (m, 2H), 2.11–1.98 (m, 1H), 1.89–1.57 (m, 3H), 1.51 (p, J = 7.3 Hz, 2H), 1.32 (tp, J = 7.2, 4.2, 3.5 Hz, 4H), 0.90 (t, J = 6.9 Hz, 3H). UPLC/MS (method A): Rt 2.29 min. MS (ES) C 19 H 27 N 3 O 3 requires 345, found 346 [M+H] + . Example 14: N-(2-Ethoxyethyl)-3-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)pipe ridine-1- carboxamide [00374] Following general procedure D (Method A), XIIf (0.090 g, 0.33 mmol) and 1- ethoxy-2-isocyanate (0.090 g, 0.99 mmol) afforded the title compound as a white powder (0.015 g, 13%). 1 H NMR (400 MHz, CDCl3) d 7.14–7.04 (m, 2H), 6.89 (d, J = 7.9 Hz, 1H), 3.75 (t, J = 14.7 Hz, 2H), 3.39 (s, 3H), 3.22 (qd, J = 7.0, 2.3 Hz, 4H), 2.88–2.78 (m, 2H), 2.78–2.67 (m, 1H), 2.09–1.97 (m, 1H), 1.89–1.74 (m, 1H), 1.72–1.54 (m, 2H), 1.13 (t, J = 7.1 Hz, 6H). UPLC/MS (method A): Rt 1.66 min. MS (ES) C18H25N3O4 requires 347, found 348 [M+H]. Example 15: 5-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)-3,6 -dihydro-2H- pyridine-1-carboxamide tert-Butyl 3-hydroxy-3-(2-oxo-3H-1,3-benzoxazol-6-yl)piperidine-1-carbo xylate (XIIIc) [00375] Following general procedure G, Vc (2.52 g, 12.63 mmol) and 6-bromo-3H-1,3- benzoxazol-2-one (2.46 g, 12.34 mmol) afforded XIIIc as a white solid (0.950 g, 69 %). 1H NMR (400 MHz, DMSO-d6) d 11.54 (bs, 1H), 7.41 (d, J = 1.5 Hz, 1H), 7.30 (dd, J = 8.2, 1.6 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 5.00 (s, 1H), 3.83–3.48 (m, 2H), 3.04–2.84 (m, 1H), 1.97–1.60 (m, 4H) 1.39 (s, 9H), 0.86 (t, J = 6.8 Hz, 1H). UPLC/MS (method A): Rt 1.76 min. MS (ES) C17H22N2O5 requires 334, found 333 [M-H]-. 6-(1,2,3,6-Tetrahydropyridin-5-yl)-3H-1,3-benzoxazol-2-one (XVIb) [00376] To a solution of XIIIc (0.93g, 2.69 mmol) in toluene (0.1 M) p-TsOH (0.850 g, 4.49 mmol) was added and the reaction mixture was stirred at reflux for 1h. Then, the reaction mixture was quenched with saturated aqueous NaHCO3 solution, extracted with EA, washed with brine, dried over Na 2 SO 4 and concentrated to afford XVIb which was used in the next step without purification. UPLC/MS (method A): Rt 0.83 min. MS (ES) C12H12N2O2 requires 216, found 215 [M-H]-. tert-Butyl 5-(2-oxo-3H-1,3-benzoxazol-6-yl)-3,6-dihydro-2H-pyridine-1-c arboxylate(XVIIb) [00377] To a solution of XVIb (0.580 g, 2.69 mmol) and Et3N (1.50 mL, 10.76 mmol in DCM (0.1M) Boc2O (0.590 g, 3.0 mmol) was added and the reaction mixture was stirred at RT for 10 min. Then, the reaction mixture was diluted with EA, washed with saturated aq. NaHCO 3 solution, brine, dried over Na2SO4 and concentrated to afford example XVIIb as a white solid (0.340 g, 40%). 1 H NMR (400 MHz, CDCl3) d 8.60 (bs, 1H), 7.22 (s, 1H), 7.18–7.11 (m, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.31–5.82 (m, 1H), 4.31–4.20 (m, 2H), 3.55 (t, J = 5.8 Hz, 2H), 2.32 (d, J = 4.0 Hz, 2H), 1.50 (s, 9H). UPLC/MS (method A): Rt 2.13 min. MS (ES) C17H20N2O4 requires 316, found 317 [M+H] + .
tert-Butyl 5-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-3,6-dihydro-2H-pyridi ne-1-carboxylate (XVII’a) [00378] Following general procedure C, XVII’ (0.06 g, 0.24 mmol) and MeI (0.05 g, 0.36 mmol) afforded XVII’a which was used in the next step without purification. UPLC/MS (method A): Rt 2.29 min. MS (ES) C18H22N2O4 requires 330, found 331 [M+H] + . 3-Methyl-6-(1,2,3,6-tetrahydropyridin-5-yl)-1,3-benzoxazol-2 -one hydrochloride (XVI’’a) [00379] Following general procedure C, XVII’ (0.058 g, 0.17 mmol) afforded XVI’’a, which was used in the next step without further purification. UPLC/MS (method A): Rt 1.16 min. MS (ES) C13H14N2O2 requires 230, found 231 [M+H] + . 5-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)-3,6 -dihydro-2H-pyridine-1- carboxamide [00380] Following general procedure D (Method A), XVI’’ (0.047 g, 0.17 mmol) and 4- phenylbutyl isocyanate (0.06 g, 0.34 mmol) afforded the title compound as a white solid (0.039 g, 57%). 1H NMR (400 MHz, CDCl 3 ) d 7.46–7.08 (m, 8H), 6.93 (d, J = 8.0 Hz, 1H), 6.19-6.14 (m, 1H), 4.21 (s, 2H), 3.52 (t, J = 5.6 Hz, 2H), 3.42 (s, 3H), 3.32 (t, J = 6.9 Hz, 2H), 2.67 (t, J = 7.4 Hz, 2H), 2.36 (s, 2H), 1.70 (dt, J = 14.8, 7.0 Hz, 2H), 1.61 (q, J = 7.3 Hz, 2H). UPLC/MS (method A): Rt 2.29 min. MS (ES) C 24 H 27 N 3 O 3 requires 405, found 406 [M+H] + . Example 16: 2-methyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4- phenylbutyl)piperidine-1-carboxamide tert-Butyl-2-methyl-4-(trifluoromethylsulfonyloxy)-3,6-dihyd ro-2H-pyridine-1-carboxylate (VIc) [00381] Following general procedure A (step 1), Vd (0.213 g, 1.0 mmol afforded Vic as a colorless oil (1:1 regioisomeric mixture, 0.290 g, 84%). 1 H NMR (400 MHz, CDCl 3 ) d 5.78– 5.67 (m, 1H), 4.83–4.56 (m, 1H), 4.42 (d, J = 18.9 Hz, 0.5H), 4.35–4.17 (m, 0.5H), 3.69–3.57 (m, 0.5H), 2.99 (t, J = 12.7 Hz, 0.5H), 2.81 (ddq, J = 16.9, 6.7, 3.4 Hz, 0.5H), 2.58 (dddt, J = 17.1, 11.5, 5.8, 2.7 Hz, 0.5H), 2.25–2.15 (m, 0.5H), 2.11–2.05 (m, 0.5H), 1.47 (s, 4.5H), 1.47 (s, 4.5H), 1.24 (d, J = 6.8 Hz, 1.5H), 1.18 (d, J = 6.9 Hz, 1.5H). UPLC/MS (method B): Rt 1.59 min. MS (ES) C12H18F3NO5S requires 345, found 346 [M+H] + . tert-Butyl-4-(3-hydroxy-4-nitrophenyl)-2-methyl-3,6-dihydro- 2H-pyridine-1-carboxylate (VIIf) [00382] Following general procedure A, VIc (0.290 g, 0.84 mmol) and 5-bromo-2- nitrophenol (0.087 g, 0.76 mmol) afforded VIIf as a yellow solid (6:4 regioisomeric mixture, 0.206 g, 73%). 1 H NMR (400 MHz, CDCl3) d 10.66 (s, 0.4H), 10.65 (s, 0.6H), 8.06 (d, J = 8 Hz, 0.4H), 8.05 (d, J = 8 Hz, 0.6H), 7.12–7.08 (m, 1H), 7.05–6.98 (m, 1H), 6.29–6.23 (m, 0.4H), 6.23–6.16 (m, 0.6H), 4.79–4.57 (m, 1H), 4.51–4.37 (m, 0.4H), 4.34–4.20 (m, 0.6H), 3.80–3.71 (m, 0.4H), 3.03–2.89 (m, 0.6H), 2.85–2.75 (m, 0.4H), 2.63–2.50 (m, 0.6H), 2.37–2.29 (m, 0.6H), 2.24 (d, J = 16.6 Hz, 0.4H), 1.49 (s, 5.4H), 1.49 (s, 3.6H), 1.28 (d, J = 6.8 Hz, 1.8H), 1.15 (d, J = 6.8 Hz, 1.2H). UPLC/MS (method B): Rt 1.59 min. MS (ES) C 17 H 22 N 2 O 5 requires 334, found 333 [M-H]-. tert-Butyl 4-(4-amino-3-hydroxyphenyl)-2-methylpiperidine-1-carboxylate (VIIIf) [00383] Following general procedure B, (Method A, step 1), VIIf (0.2 g, 0.6 mmol) afforded VIIIf which was used in the next step without further purification. UPLC/MS (method A): Rt 2.04 min. MS (ES) C17H26N2O3 requires 306, found 307 [M+H] + . tert-Butyl 2-methyl-4-(2-oxo-3H-1,3-benzoxazol-6-yl)piperidine-1-carbox ylate (IXf) [00384] Following general procedure B (step 2), VIIIf (0.184 g, 0.6 mmol) afforded IXf as a colorless oil (0.157 g, 79%). UPLC/MS (method B): Rt 0.97 min. MS (ES) C18H24N2O4 requires 332, found 333 [M+H] + . tert-Butyl 2-methyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)piperidine-1- carboxylate (XIg) [00385] Following general procedure C (step 1), IXf (0.157 g, 0.47 mmol) and MeI (0.1 g, 0.705 mmol) afforded XIg which was used in the next step without purification. UPLC/MS (method B): Rt 1.28 min. MS (ES) C19H26N2O4 requires 346, found 347 [M+H] + . 3-Methyl-6-(2-methyl-4-piperidyl]-1,3-benzoxazol-2-one hydrochloride (XIIg) [00386] Following general procedure C (step 2), XIg (0.163 g, 0.47 mmol) afforded XIIg which was used in the next step without further purification. UPLC/MS (method A): Rt 1.12 min. MS (ES) C14H18N2O2 requires 246, found 247 [M+H] + . 2-Methyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylb utyl)piperidine-1- carboxamide [00387] Following general procedure D (Method A), XIIg (0.140 g, 0.40 mmol) and 4- phenylbutyl isocyanate (0.09 g, 0.52 mmol) afforded the title compound as a white solid (70:30, cis/trans diastereomeric mixture, 0.140 g, 71%). 1 H NMR (400 MHz, DMSO-d6) d 7.31–7.06 (m, 8H), 6.38 (t, J = 5.6 Hz, 0.3H), 6.28 (t, J = 5.6 Hz, 0.7H), 4.44–4.31 (m, 0.3H), 3.93–3.79 (m, 1H), 3.62 (ddd, J = 13.8, 7.1, 3.4 Hz, 0.7H), 3.33 (s, 3H), 3.20–3.10 (m, 0.7H), 3.10–2.96 (m, 1.3H), 2.96–2.81 (m, 0.3H), 2.70–2.62 (m, 0.7H), 2.58 (t, J = 7.7 Hz, 2H), 1.98 (dq, J = 15.7, 7.8 Hz, 0.7H), 1.83–1.33 (m, 7.3H), 1.13 (d, J = 6.8 Hz, 0.9H), 1.08 (d, J = 6.2 Hz, 2.1H). UPLC/MS (method B): Rt 1.06 min. MS (ES) C 25 H 31 N 3 O 3 requires 421, found 422 [M+H] + . Example 17: (2R)-2-Methyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4- phenylbutyl)piperidine-1-carboxamide tert-Butyl- (2R)-2-methyl-4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H- pyridine-1- carboxylate (VId) [00388] Following general procedure A, Ve (0.427g, 2.0 mmol) afforded VId as a colorless oil (1:1 regioisomeric mixture, 0.5 g, 73%). 1 H NMR (400 MHz, CDCl 3 ) d 5.81–5.58 (m, 1H), 4.84–4.54 (m, 1H), 4.48–4.34 (m, 0.5H), 4.33–4.10 (m, 0.5H), 3.69–3.58 (m, 0.5H), 2.98 (t, J = 11.3 Hz, 0.5H), 2.80 (ddq, J = 16.7, 6.7, 3.4 Hz, 0.5H), 2.58 (dddd, J = 14.5, 11.5, 6.2, 3.1 Hz, 0.5H), 2.20 (dd, J = 16.8, 3.4 Hz, 0.5H), 2.13–1.92 (m, 0.5H), 1.51–1.43 (m, 9H), 1.25–1.19 (m, 1.5H), 1.17 (d, J = 6.9 Hz, 1.5H). UPLC/MS (method B): Rt 1.59 min. MS (ES) C12H18F3NO5S requires 345, found 346 [M+H] + . tert-Butyl- (2R)-4-(3-hydroxy-4-nitrophenyl)-2-methyl-3,6-dihydro-2H-pyr idine-1- carboxylate (VIIg) [00389] Following general procedure A, VId (1.10 g, 2.63 mmol) and 5-bromo-2-nitrophenol (0.520 g, 2.37 mmol) afforded VIIg as a yellow oil (1:1 regioisomeric mixture, 0.544 g, 62%). 1 H NMR (400 MHz, CDCl 3 ) d 10.64 (bs, 1H), 8.05 (d, J = 8.9 Hz, 1H), 7.10 (d, J = 1.9 Hz, 1H), 7.01 (dd, J = 8.9, 2.0 Hz, 1H), 6.22–6.17 (m, 1H), 4.78–4.54 (m, 1H), 4.38–4.15 (m, 1H), 3.03– 2.87 (m, 1H), 2.63–2.50 (m, 1H), 2.39–2.29 (m, 1H), 1.49 (s, 9H), 1.28 (d, J = 6.8 Hz, 3H). UPLC/MS (method B): Rt 1.33 min, 1.55 min. MS (ES) C17H22N2O5 requires 334, found 335 [M+H] + . tert-Butyl (2R)-4-(4-amino-3-hydroxyphenyl)-2-methylpiperidine-1-carbox ylate (VIIIg) [00390] Following general procedure B, (Method A, step 1), VIIg (0.544 g, 1.63 mmol) afforded VIIIg which was used in the next step without further purification. UPLC/MS (method A): Rt 2.00 min. MS (ES) requires 306, found 307 [M+H] + . tert-Butyl (2R)-2-methyl-4-(2-oxo-3H-1,3-benzoxazol-6-yl)piperidine-1-c arboxylate (IXg) [00391] Following procedure B (step 2), VIIIh (0.490 g, 1.6 mmol) afforded IXg as a yellow oil (0.400 g, 75%). 1 H NMR (400 MHz, CDCl3) d 8.16 (s, 1H), 7.07–7.05 (m, 1H), 7.04–7.01 (m, 1H), 6.90–6.86 (m, 1H), 4.00–3.92 (m, 1H), 3.81 (dd, J = 13.9, 7.5, 2.9 Hz, 1H), 3.24 (ddd, J = 14.0, 9.8, 6.5 Hz, 1H), 2.77 (qd, J = 11.5, 10.5, 3.0 Hz, 1H), 2.16 (tt, J = 12.9, 6.4 Hz, 1H), 1.90 (ddd, J = 13.2, 6.0, 2.7 Hz, 1H), 1.79 (td, J = 13.1, 5.4 Hz, 1H), 1.56 (dddd, J = 13.4, 10.2, 7.4, 4.2 Hz, 1H), 1.48 (s, 9H), 1.20 (d, J = 6.3 Hz, 3H). UPLC/MS (method A): Rt 2.17 min. MS (ES) C18H24N2O4 requires 332, found 333 [M+H] + . tert-Butyl (2R)-2-methyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)piperidi ne-1-carboxylate (XIh) [00392] Following general procedure C (step 1), IXg (0.610 g, 1.81 mmol) and MeI (0.39 g, 2.72 mmol) afforded XIh which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 ) d 7.07–7.04 (m, 1H), 7.04–6.99 (m, 1H), 6.91–6.82 (m, 1H), 4.56–4.45 (m, 1H), 4.02–3.88 (m, 1H), 3.80 (ddd, J = 13.9, 6.4, 3.7 Hz, 1H), 3.38 (d, J = 2.0 Hz, 3H), 3.28– 3.16 (m, 1H), 2.77 (dd, J = 12.3, 7.4 Hz, 1H), 2.24–2.07 (m, 1H), 1.89 (ddq, J = 9.6, 4.5, 1.7 Hz, 1H), 1.60–1.51 (m, 1H), 1.48 (d, J = 1.9 Hz, 9H), 1.20 (dd, J = 6.4, 1.7 Hz, 3H). UPLC/MS (method B): Rt 1.23 min. MS (ES) C19H26N2O4 requires 346, found 347 [M+H] + . 3-Methyl-6-[(2R)-2-methyl-4-piperidyl]-1,3-benzoxazol-2-one hydrochloride (XIIh) [00393] Following general procedure C (step 2), XIh (0.070 g, 0.2 mmol) afforded XIIh which was purified by trituration with Et2O (0.055 g, 97%). UPLC/MS (method A): Rt 1.08, 1.17 min. MS (ES) C 14 H 18 N 2 O 2 requires 246, found 247 [M+H] + . (2R)-2-Methyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-ph enylbutyl)piperidine-1- carboxamide [00394] Following general procedure D (Method A), XIIh (0.050 g, 0.17 mmol) and 4- phenylbutyl isocyanate (0.07 g, 0.40 mmol) afforded the title compound as a white solid (70:30, cis /trans diastereomeric mixture, 0.040 g, 52%). 1 H NMR (400 MHz, DMSO-d 6 ) d 7.30–7.22 (m, 4.38H), 7.22–7.06 (m, 7.30H), 6.38 (t, J = 5.4 Hz, 1H), 6.28 (t, J = 5.5 Hz, 1H), 4.42–4.33 (m, 0.3H), 3.92–3.80 (m, 1.3 H), 3.62 (ddd, J = 3.3, 6.9, 13.6 Hz, 1H), 3.31 (s, 4.28H), 3.14 (ddd, J = 14.2, 9.5, 6.2 Hz, 1H), 3.09–3.03 (m, 2.6H), 3.00–2.91 (m, 0.3H), 2.91–2.80 (m, 0.4H), 2.66 (dq, J = 12.9, 7.4, 5.7 Hz, 1H), 2.58 (t, J = 7.5 Hz, 3H), 1.98 (dq, J = 16.1, 7.6 Hz, 1H), 1.84–1.36 (m, 9.8H), 1.13 (d, J = 6.8 Hz, 1.18H), 1.08 (d, J = 6.3 Hz, 3H). UPLC/MS (method A): Rt 2.23 min. MS (ES) C 25 H 31 N 3 O 3 requires 421, found 422 [M+H] + . Example 18: (2R)-2-Methyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(2- phenylethyl)piperidine-1-carboxamide [00395] Following general procedure D (Method A), XIIh (0.050 g, 0.18 mmol) and 2- phenylethyl isocyanate (0.09 g, 0.36 mmol) afforded the title compound as a white solid (70:30, cis /trans diastereomeric mixture, 0.060 g, 90%). 1 H NMR (400 MHz, DMSO-d6) d 7.32–7.24 (m, 4.41H), 7.23–7.07 (m, 7.14H), 6.50 (d, J = 5.2 Hz, 0.45H), 6.36 (t, J = 5.4 Hz, 1H), 4.38 (s, 0.46H), 3.94–3.81 (m, 1.48H), 3.72–3.52 (m, 1.13H), 3.31 (s, 3H), 3.29–3.08 (m, 4.29H), 3.00– 2.81 (m, 1H), 2.78–2.68 (m, 2.8H), 2.70–2.59 (m, 1.33H), 2.03–1.89 (m, 1H), 1.84–1.57 (m, 3.5H), 1.55–1.39 (m, 1.6H), 1.13 (d, J = 6.8 Hz, 1.23H), 1.08 (d, J = 6.3 Hz, 3H). UPLC/MS (method A): Rt 2.03 min. MS (ES) C 23 H 27 N 3 O 3 requires 393, found 394 [M+H] + . Example 19: N-iso-Butyl (2R)-methyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)piperidine -1- carboxamide [00396] Following general procedure D (Method B), XIIh (0.050 g, 0.18 mmol) and isobutylamine (0.04 g, 0.54 mmol) afforded the title compound as a white solid (70:30, cis /trans diastereomeric mixture, 0.050 g, 76%). 1 H NMR (400 MHz, DMSO-d6) d 7.26 (s, 1H), 7.18– 7.07 (m, 2H), 6.40 (t, J = 5.6 Hz, 0.3H), 6.31 (t, J = 5.6 Hz, 1H), 4.47–4.35 (m, 0.3H,), 3.95– 3.91 (m, 0.3H), 3.91–3.80 (m, 1H), 3.65 (ddd, J = 13.6, 6.9, 3.5 Hz, 1H), 3.32 (s, 3H), 3.18 (ddd, J = 14.1, 9.3, 6.1 Hz, 1H), 3.01–2.93 (m, 0.3H,), 2.92–2.75 (m, 2.8H), 2.74–2.60 (m, 1H), 1.99 (dq, J = 15.9, 7.6 Hz, 1H), 1.85–1.58 (m, 4H), 1.58–1.46 (m, 1H), 1.49–1.39 (m, 0.3H), 1.15 (d, J = 6.8 Hz, 1.2H), 1.11 (d, J = 6.3 Hz, 3H), 0.83 (d, J = 6.7 Hz, 6H), 0.82 (d, J = 6.7 Hz, 2.6H). UPLC/MS (method A): Rt 1.93 min. MS (ES) C 19 H 27 N 3 O 3 requires 345, found 346 [M+H] + . Example 20: (2S)- methyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4- phenylbutyl)piperidine-1-carboxamide tert-Butyl (2S)-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropy ridine-1(2H)- carboxylate (VIe) [00397] Following general procedure A (step 1), Vf (0.213 g, 1.0 mmol) afforded VIe as a colorless oil (1:1 regioisomeric mixture, 0.320 g, 93%). 1 H NMR (400 MHz, CDCl 3 ) d 5.78– 5.67 (m, 1H), 4.83–4.56 (m, 1H), 4.42 (d, J = 18.9 Hz, 0.5H), 4.35–4.17 (m, 0.5H), 3.69–3.57 (m, 0.5H), 2.99 (t, J = 12.7 Hz, 0.5H), 2.81 (ddq, J = 16.9, 6.7, 3.4 Hz, 0.5H), 2.58 (dddt, J = 17.1, 11.5, 5.8, 2.7 Hz, 0.5H), 2.25 – 2.15 (m, 0.5H), 2.11 – 2.05 (m, 0.5H), 1.47 (s, 4.5H), 1.47 (s, 4.5H), 1.24 (d, J = 6.8 Hz, 1.5H), 1.18 (d, J = 6.9 Hz, 1.5H). UPLC/MS (method B): Rt 1.61 min. MS (ES) C12H18F3NO5S requires 345, found 346 [M+H] + . tert-Butyl (2S)-4-(3-hydroxy-4-nitrophenyl)-2-methyl-3,6-dihydro-2H-pyr idine-1- carboxylate (VIIh) [00398] Following general procedure A (step 2), VIe (0.32 g, 0.93 mmol), and 5-bromo-2- nitrophenol (0.223 g, 1.02 mmol) afforded VIIh as a yellow solid (60:40 regioisomeric mixture, 0.115 g, 37%). 1 H NMR (400 MHz, CDCl 3 ) d 10.66 (s, 0.4H), 10.65 (s, 0.6H), 8.06 (d, J = 8 Hz, 0.4H), 8.05 (d, J = 8 Hz, 0.6H), 7.12 – 7.08 (m, 1H), 7.05 – 6.98 (m, 1H), 6.29 – 6.23 (m, 0.4H), 6.23 – 6.16 (m, 0.6H), 4.79 – 4.57 (m, 1H), 4.51 – 4.37 (m, 0.4H), 4.34 – 4.20 (m, 0.6H), 3.80 – 3.71 (m, 0.4H), 3.03 – 2.89 (m, 0.6H), 2.85 – 2.75 (m, 0.4H), 2.63 – 2.50 (m, 0.6H), 2.37 – 2.29 (m, 0.6H), 2.24 (d, J = 16.6 Hz, 0.4H), 1.49 (s, 5.4H), 1.49 (s, 3.6H), 1.28 (d, J = 6.8 Hz, 1.8H), 1.15 (d, J = 6.8 Hz, 1.2H). UPLC/MS (method B): Rt 1.59 min. MS (ES) C17H22N2O5 requires 334, found 333 [M-H]-. tert-Butyl 4-(4-amino-3-hydroxyphenyl)-(2S)-methylpiperidine-1-carboxyl ate (VIIIh) [00399] Following general procedure B (Method A, step 1), VIIh (0.215 g, 0.64 mmol) afforded VIIIh which was used in the next step without further purification. UPLC/MS (method A): Rt 2.04 min. MS (ES) C17H26N2O3 requires 306, found 307 [M+H] + . tert-Butyl (2S)-methyl-4-(2-oxo-3H-1,3-benzoxazol-6-yl)piperidine-1-car boxylate (IXh) [00400] Following general procedure B (step 2), VIIIh (0.196 g, 0.64 mmol) afforded IXh as a colorless oil (0.105 g, 49%). 1 H NMR (400 MHz, CDCl3) d 7.67 (br s, 1H), 7.06 (s, 1H), 7.02– 6.91 (m, 2H), 4.02–3.91 (m, 1H), 3.81 (ddd, J = 13.9, 7.5, 3.3 Hz, 1H), 3.25 (ddd, J = 13.9, 9.7, 6.4 Hz, 1H), 2.84–2.72 (m, 1H), 2.25–2.10 (m, 1H), 1.95–1.87 (m, 1H), 1.87–1.74 (m, 1H), 1.64–1.54 (m, 1H), 1.49 (s, 9H), 1.21 (d, J = 6.4 Hz, 3H). UPLC/MS (method B): Rt 0.97 min. MS (ES) C 18 H 24 N 2 O 4 requires 332, found 333 [M+H] + . tert-Butyl (2S)-methyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)piperidine -1-carboxylate [00401] Following general procedure C (step 1), IXh (0.105 g, 0.32 mmol) and MeI (0.77 g, 0.47 mmol) afforded XIi which was used in the next step without further purification. UPLC/MS (method B): Rt 1.28 min. MS (ES) C19H26N2O4 requires 346, found 347 [M+H] + . 6-[(2S)- Methyl-4-piperidyl]-3H-1,3-benzoxazol-2-one hydrochloride (XIIi) [00402] Following general procedure C (step 2), IXh (0.100 g, 0.290 mmol) afforded XIIi which was used in the next step without further purification (70:30, cis /trans diastereomeric mixture, white solid). 1 H NMR (400 MHz, DMSO-d6) d 9.33–8.62 (m, 2H), 7.28–7.07 (m, 3H), 3.68–3.54 (m, 0.3H), 3.35 (m overlapped with H 2 O signal, 0.7H), 3.32 (s, 3H), 3.29–3.18 (m, 0.7H), 3.18–3.03 (m, 0.9H), 3.03–2.87 (m, 1.4H), 2.13–2.01 (m, 0.3H), 2.00–1.87 (m, 2H), 1.87–1.73 (m, 1H), 1.65 (q, J = 12.6 Hz, 0.7H), 1.37 (d, J = 6.9 Hz, 0.9H), 1.27 (d, J = 6.4 Hz, 2.1H). UPLC/MS (method A): Rt 1.12 min. MS (ES) C14H18N2O2 requires 246, found 247 [M+H] + . (2S)-Methyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phen ylbutyl)piperidine-1- carboxamide [00403] Following general procedure D (Method A), XIIi (0.030 g, 0.122 mmol) and 4- phenylbutyl isocyanate (0.023 g, 0.134 mmol) afforded the title compound as a white solid (70:30, cis /trans diastereomeric mixture, 0.038 g, 74%). 1 H NMR (400 MHz, DMSO-d6) d 7.31–7.06 (m, 8H), 6.38 (t, J = 5.6 Hz, 0.3H), 6.28 (t, J = 5.6 Hz, 0.7H), 4.44–4.31 (m, 0.3H), 3.93–3.79 (m, 1H), 3.62 (ddd, J = 13.8, 7.1, 3.4 Hz, 0.7H), 3.33 (s, 3H), 3.20–3.10 (m, 0.7H), 3.10–2.96 (m, 1.3H), 2.96–2.81 (m, 0.3H), 2.70–2.62 (m, 0.7H), 2.58 (t, J = 7.7 Hz, 2H), 1.98 (dq, J = 15.7, 7.8 Hz, 0.7H), 1.83–1.33 (m, 7.3H), 1.13 (d, J = 6.8 Hz, 0.9H), 1.08 (d, J = 6.2 Hz, 2.1H). UPLC/MS (method B): Rt 1.06 min. MS (ES) C 25 H 31 N 3 O 3 requires 421, found 422 [M+H] + . Example 21: (2S)-Methyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(2- phenylethyl)piperidine-carboxamide [00404] Following general procedure D (Method A), XIIi (0.015 g, 0.05 mmol) and 2- phenylethyl isocyanate (0.009 g, 0.0009 mL, 0.064 mmol) afforded the title compound as a white solid (0.011 g, 64%). 1H NMR (400 MHz, DMSO-d 6 ) d 7.34–7.24 (m, 3H), 7.23–7.09 (m, 5H), 6.37 (t, J = 5.5 Hz, 1H), 3.87 (dt, J = 10.1, 6.2 Hz, 1H), 3.64 (ddd, J = 14.0, 7.2, 3.3 Hz, 1H), 3.31 (s, 3H), 3.29–3.20 (m, 2H), 3.20–3.10 (m, 1H), 2.75 (t, J = 7.4 Hz, 2H), 2.70–2.60 (m, 1H), 2.04–1.91 (m, 1H), 1.84–1.75 (m, 1H), 1.64 (td, J = 12.8, 9.9 Hz, 1H), 1.50 (dddd, J = 13.3, 9.8, 6.1, 3.3 Hz, 1H), 1.09 (d, J = 6.2 Hz, 3H). UPLC/MS (method A): Rt 2.04 min. MS (ES) C23H27N3O3 requires 393, found 394 [M+H] + . Example 22: N-iso-Butyl (2S)-methyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)piperidine -1- carboxamide [00405] Following general procedure D (Method B), XIIi (0.020 g, 0.07 mmol) and isobutyl amine (0.015 g, 0.21 mmol) afforded the title compound as a white solid (0.012 g, 50%). 1 H NMR (400 MHz, DMSO-d 6 ) d 7.28–7.24 (m, 1H), 7.17–7.08 (m, 2H), 6.31 (t, J = 5.7 Hz, 1H), 3.86 (dt, J = 10.0, 6.2 Hz, 1H), 3.64 (ddd, J = 13.8, 7.0, 3.6 Hz, 1H), 3.31 (s, 3H), 3.17 (ddd, J = 13.8, 9.3, 6.0 Hz, 1H), 2.90 (ddd, J = 12.8, 6.9, 5.8 Hz, 1H), 2.80 (ddd, J = 12.8, 7.0, 5.5 Hz, 1H), 2.72–2.60 (m, 1H), 2.05–1.92 (m, 1H), 1.83–1.75 (m, 1H), 1.75–1.58 (m, 2H), 1.52 (dddd, J = 13.3, 9.8, 6.0, 3.6 Hz, 1H), 1.10 (d, J = 6.2 Hz, 3H), 0.83 (d, J = 6.7 Hz, 6H). UPLC/MS (method A): Rt 1.90 min. MS (ES) C 19 H 27 N 3 O 3 requires 345, found 346 [M+H] + . Example 23: 2,2-Dimethyl-4-(2-oxo-3H-1,3-benzoxazol-6-yl)-N-(4-phenylbut yl)piperidine- 1-carboxamide tert-Butyl 2,2-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydrop yridine-1(2H)- carboxylate (VIf) [00406] Following general procedure A (step 1), Vg (0.227g, 1.0 mmol) afforded VIf as a colorless oil (0.328 g, 91%). 1 H NMR (400 MHz, CDCl3) d 5.77 (tt, J = 3.8, 1.2 Hz, 1H), 4.07 (dt, J = 3.8, 2.6 Hz, 2H), 2.39 (dt, J = 2.6, 1.4 Hz, 2H), 1.49 (s, 6H), 1.46 (s, 9H). UPLC/MS (method B): Rt 1.92 min. MS (ES) C 13 H 20 F 3 NO 5 S requires 359, found 360 [M+H] + . tert-Butyl 4-(3-hydroxy-4-nitrophenyl)-6,6-dimethylcyclohex-3-ene-1-car boxylate (VIIi) [00407] Following general procedure A (step 2), VIf (0.328 g, 0.91 mmol) and 5-bromo-2- nitrophenol (0.179 g, 0.82 mmol) afforded VIIi as a yellow solid (0.300 g, 46%). 1 H NMR (400 MHz, CDCl3) d 10.66 (s, 1H), 8.06 (d, J = 8.9 Hz, 1H), 7.10 (d, J = 1.9 Hz, 1H), 7.03 (dd, J = 8.9, 2.0 Hz, 1H), 6.41 (tt, J = 4.4, 1.0 Hz, 1H), 4.12 (m, 2H), 2.50 (m, 2H), 1.49 (s, 8H), 1.47 (s, 6H). UPLC/MS (method B): Rt 1.82 min. MS (ES) C 18 H 24 N 2 O 5 requires 348, found 349 [M+H] + . tert-Butyl 4-(4-amino-3-hydroxyphenyl)-2,2-dimethylpiperidine-1-carboxy late (VIIIi) [00408] Following general procedure B (Method A, step 1), VIIi (0.168 g, 0.48 mmol) afforded VIIIi which was used in the next step without further purification. UPLC/MS (method A): Rt 0.96 min. MS (ES) C 18 H 28 N 2 O 3 requires 320, found 321 [M+H] + . tert-Butyl 2,2-dimethyl-4-(2-oxo-3H-1,3-benzoxazol-6-yl)piperidine-1-ca rboxylate (IXi) [00409] Following general procedure B (step 2), VIIi (0.169 g, 0.53 mmol) afforded IXi as a white solid (0.176 g, 59%). 1 H NMR (400 MHz, CDCl3) d 7.94 (s, 1H), 7.07 (s, 1H), 7.02–6.94 (m, 2H), 3.98 (dt, J = 13.7, 4.7 Hz, 1H), 3.19 (ddd, J = 14.0, 10.7, 3.7 Hz, 1H), 2.92–2.79 (m, 1H), 2.00–1.92 (m, 1H), 1.74 (t, J = 13.2 Hz, 1H), 1.69–1.58 (m, 2H), 1.54 (s, 6H), 1.48 (s, 9H). UPLC/MS (method A): Rt 2.36 min. MS (ES) C 19 H 26 N 2 O 4 requires 346, found 347 [M+H] + . 6-(2,2-dimethyl-4-piperidyl)-3H-1,3-benzoxazol-2-one (Xc) [00410] Following general procedure C (step 2), Xc (0.100 g, 0.290 mmol). The residue was used in the next step without further purification (white solid). UPLC/MS (method A): Rt 1.07 min. MS (ES) C 14 H 18 N 2 O 2 requires 246, found 247 [M+H] + . 2,2-Dimethyl-4-(2-oxo-3H-1,3-benzoxazol-6-yl)-N-(4-phenylbut yl)piperidine-1- carboxamide [00411] Following general procedure D (Method A), Xc (0.035 g, 0.36 mmol.) and 4- phenylbutyl isocyanate (0.024 g, 0.14 mmol) afforded the title compound as a white solid (0.006 g, 10%). 1 H NMR (400 MHz, CDCl3) d 8.85 (s, 1H), 7.30–7.27 (m, 1H), 7.21–7.14 (m, 4H), 7.08 (s, 1H), 7.00 (s, 2H), 4.54 (t, J = 6.3 Hz, 1H), 3.52 (dt, J = 10.8, 6.7 Hz, 1H), 3.31–3.10 (m, 3H), 2.93–2.78 (m, 1H), 2.64 (t, J = 7.5 Hz, 2H), 2.01–1.88 (m, 1H), 1.77–1.46 (m, 7H), 1.57 (s, 3H), 1.40 (s, 3H).UPLC/MS (method B): Rt 1.09 min. MS (ES) C 25 H 31 N 3 O 3 requires 421, found 422 [M+H] + . Example 24: 2,2-Dimethyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4- phenylbutyl)piperidine-1-carboxamide tert-Butyl 2,2-dimethyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)piperidin e-1-carboxylate (XIj) [00412] Following general procedure C (step 1), IXi (0.117 g, 0.34 mmol) and MeI (0.082 g, 0.51 mmol) afforded XIj which was used in the next step without purification. UPLC/MS [00413] Following general procedure C (step 2), XIj (0.122 g, 0.34 mmol) afforded XIIj as a white solid (0.90 g, 90%). UPLC/MS (method A): Rt 1.15 min. MS (ES) C15H20N2O2 requires 260, found 261 [M+H] + . 2,2-Dimethyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phe nylbutyl)piperidine-1- carboxamide [00414] Following general procedure D (Method A), XIIj (0.080 g, 0.27 mmol) and 4- phenylbutyl isocyanate (0.052 g, 0.29 mmol) afforded the compound as a white solid (0.066 g, 57%). 1 H NMR (400 MHz, DMSO-d6) d 7.31–7.24 (m, 3H), 7.23–7.10 (m, 5H), 6.47 (t, J = 5.5 Hz, 1H), 3.61 (dt, J = 12.9, 4.0 Hz, 1H), 3.33 (s, 3H), 3.06–2.97 (m, 3H), 2.85 (tt, J = 12.1, 3.8 Hz, 1H), 2.58 (t, J = 7.6 Hz, 2H), 1.85–1.79 (m, 1H), 1.65–1.49 (m, 5H), 1.46 (s, 3H), 1.41 (m, 2H), 1.31 (s, 3H). UPLC/MS (method A): Rt 2.45 min. MS (ES) C26H33N3O3 requires 435, found 436 [M+H] + . Example 25: 2,2-Dimethyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(2- phenylethyl)piperidine-1-carboxamide [00415] Following general procedure D (Method A), XIIj (0.012 g, 0.04 mmol) and 2- phenylethyl isocyanate (0.007 g, 0.048 mmol) afforded the title compound as a white solid (0.007 g, 45%). 1 H NMR (400 MHz, DMSO-d6) d 7.33–7.24 (m, 3H), 7.23–7.08 (m, 5H), 6.56 (t, J = 5.5 Hz, 1H), 3.59 (dt, J = 12.9, 4.1 Hz, 1H), 3.33 (s, 3H), 3.27–3.13 (m, 2H), 2.97 (td, J = 12.3, 3.0 Hz, 1H), 2.85 (tt, J = 12.1, 3.8 Hz, 1H), 2.78–2.63 (m, 2H), 1.85–1.76 (m, 1H), 1.66– 1.49 (m, 3H), 1.47 (s, 3H), 1.32 (s, 3H). UPLC/MS (method A): Rt 2.25 min. MS (ES) C 24 H 29 N 3 O 3 requires 407, found 408 [M+H] + . Example 26: 2,2-Dimethyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(3- [00416] Following general procedure D (Method A), XIIj (0.030 g, 0.106 mmol) and 3- phenylpropyl isocyanate (0.031 g, 0.13 mmol) afforded the title compound as a white solid (0.025 g, 56%). 1 H NMR (400 MHz, DMSO-d6) d 7.32–7.23 (m, 3H), 7.23–7.08 (m, 5H), 6.52 (br s, 1H), 3.62 (dt, J = 12.9, 4.1 Hz, 1H), 3.32 (s, 3H), 3.09–2.93 (m, 3H), 2.85 (tt, J = 12.5, 4.0 Hz, 1H), 2.56 (t, J = 7.7 Hz, 2H), 1.87–1.78 (m, 1H), 1.75–1.49 (m, 5H), 1.46 (s, 3H), 1.31 (s, 3H). UPLC/MS (method A): Rt 2.32 min. MS (ES) C25H31N3O3 requires 421, found 422 [M+H] + . Example 27: N-(2-Benzyloxyethyl)-2,2-dimethyl-4-(3-methyl-2-oxo-1,3-benz oxazol-6- yl)piperidine-1-carboxamide [00417] Following general procedure D, XIIj (0.032 g, 0.103 mmol) and 2- benzyloxyethanamine (0.042 g, 0.83 mmol) afforded the title compound as a white solid (0.022 g, 46%). 1 H NMR (400 MHz, DMSO-d 6 ) d 7.39–7.23 (m, 6H), 7.18–7.08 (m, 2H), 6.51 (t, J = 5.6 Hz, 1H), 4.47 (s, 2H), 3.62 (dt, J = 12.9, 4.1 Hz, 1H), 3.43 (t, J = 6.1 Hz, 2H), 3.19 (qd, J = 6.0, 3.6 Hz, 2H), 3.06–2.95 (m, 1H), 2.84 (ddt, J = 12.2, 7.7, 3.9 Hz, 1H), 1.87–1.76 (m, 1H), 1.66–1.48 (m, 3H), 1.46 (s, 3H), 1.31 (s, 3H). UPLC/MS (method A): Rt 2.20 min. MS (ES) C25H31N3O4 requires 437, found 438 [M+H] + . [00418] Following general procedure D (Method A), XIIj (0.025 g, 0.08 mmol) and penthyl isocyanate (0.011 g, 0.095 mmol) afforded the title compound as a white solid (0.019 g, 58%). 1 H NMR (400 MHz, DMSO-d 6 ) d 7.19–7.07 (m, 2H), 6.43 (t, J = 5.5 Hz, 1H), 3.60 (dt, J = 12.8, 4.0 Hz, 1H), 3.33 (s, 3H), 3.04–2.90 (m, 3H), 2.84 (ddd, J = 12.3, 8.3, 3.8 Hz, 1H), 1.86–1.77 (m, 1H), 1.66–1.48 (m, 3H), 1.45 (s, 3H), 1.43–1.35 (m, 2H), 1.34–1.18 (m, 7H), 0.86 (t, J = 7.0 Hz, 3H). UPLC/MS (method A): Rt 2.30 min. MS (ES) C 21 H 31 N 3 O 3 requires 373, found 374 [M+H] + . Example 29: N-(2-Cyclopropylethyl)-2,2-dimethyl-4-(3-methyl-2-oxo-1,3-be nzoxazol-6- [00419] Following general procedure D (Method C), XIIj (0.055 g, 0.18 mmol) and 2- cyclopropylethanamine hydrochloride (0.029 g, 0.24 mmol) afforded the title compound as a white solid (0.007 g, 10%). 1 H NMR (400 MHz, DMSO-d6) d 7.25 (s, 1H), 7.20–7.10 (m, 2H), 6.45 (t, J = 5.5 Hz, 1H), 3.62 (dt, J = 13.0, 4.1 Hz, 1H), 3.13–2.94 (m, 3H), 2.85 (tt, J = 12.1, 3.8 Hz, 1H), 1.89–1.76 (m, 1H), 1.67–1.49 (m, 3H), 1.46 (s, 3H), 1.38–1.25 (m, 5H), 0.74–0.57 (m, 1H), 0.47–0.30 (m, 2H), 0.11–0.08 (m, 2H). UPLC/MS (method A): Rt 2.14 min. MS (ES) C21H29N3O3 requires 371, found 372 [M+H] + . Example 30: N-(3-methoxypropyl)-2,2-dimethyl-4-(3-methyl-2-oxo-1,3-benzo xazol-6- [00420] Following general procedure D (Method B), XIIj (0.030 g, 0.101 mmol) and 3- methoxypropyl amine (0.054 g, 0.61 mmol) afforded the title compound as a white solid (0.008 g, 21%). 1 H NMR (400 MHz, DMSO-d6) d 7.25 (d, J = 1.4 Hz, 1H), 7.18–7.09 (m, 2H), 6.44 (t, J = 5.4 Hz, 1H), 3.60 (dt, J = 12.9, 4.1 Hz, 1H), 3.35–3.31 (m, 5H), 3.22 (s, 3H), 3.06–2.96 (m, 3H), 2.84 (ddd, J = 12.3, 8.3, 3.8 Hz, 1H), 1.87–1.77 (m, 1H), 1.67–1.48 (m, 6H), 1.46 (s, 3H), 1.31 (s, 3H). UPLC/MS (method A): Rt 1.81 min. MS (ES) C20H29N3O4 requires 375, found 376 [M+H] + . Example 31: N-(4-Cyclopropylbutyl)-2,2-dimethyl-4-(3-methyl-2-oxo-1,3-be nzoxazol-6- yl)piperidine-1-carboxamide [00421] Following general procedure D (Method C), XXIIj (0.052 g, 0.17 mmol) and 4- cyclopropylbutan-1-amine (0.038 g, 0.34 mmol) afforded the title compound as a white solid (0.019 g, 27%). 1 H NMR (400 MHz, DMSO-d6) d 7.25 (s, 1H), 7.20–7.06 (m, 2H), 6.44 (t, J = 5.6 Hz, 1H), 3.61 (d, J = 12.8 Hz, 1H), 3.07–2.91 (m, 3H), 2.85 (t, J = 12.3 Hz, 1H), 1.90–1.76 (m, 1H), 1.67–1.50 (m, 3H), 1.46 (s, 3H), 1.37 (d, J = 41.4 Hz, 7H), 1.23–1.13 (m, 2H), 0.79– 0.54 (m, 1H), 0.45–0.31 (m, 2H), 0.08–0.05 (m, 2H). UPLC/MS (method A): Rt 2.42 min. MS (ES) C23H33N3O3 requires 399, found 400 [M+H] + . Example 32: 4-[3-[2-(Dimethylamino)ethyl]-2-oxo-1,3-benzoxazol-6-yl]-2,2 -dimethyl-N-(4- phenylbutyl)piperidine-1-carboxamide tert-Butyl 4-[3-[2-(dimethylamino)ethyl]-2-oxo-1,3-benzoxazol-6-yl]-2,2 -dimethyl- piperidine-1-carboxylate (XIk) [00422] To a solution of IXi (0.080 g, 0.23 mmol) in DMF (0.2 M) was added K2CO3 (0.095 g, 0.69 mmol) and 1,2-dibromoethane (0.349 g, 1.84 mmol) at RT and the reaction was stirred at 60°C for 3h. The mixture was poured into ice and the precipitate was filtered off, solubilized in DCM and dried over Na2SO4. After evaporation of the solvent, tert-butyl 4-[3-(2-bromoethyl)-2- oxo-1,3-benzoxazol-6-yl]-2,2-dimethyl-piperidine was used in the next step without further purification. 1 H NMR (400 MHz,CDCl 3 ) d 7.11–7.08 (m, 1H), 7.07–7.03 (m, 1H), 7.01–6.96 (m, 1H), 4.21 (t, J = 6.5 Hz, 2H), 3.98 (dt, J = 13.7, 4.7 Hz, 1H), 3.70–3.63 (m, 5H), 3.19 (ddd, J = 14.0, 10.7, 3.7 Hz, 1H), 2.87–2.81 (m, 1H), 2.01–1.91 (m, 1H), 1.56 (s, 3H), 1.48 (s, 9H), 1.37 (s, 3H). UPLC/MS (method B): Rt 1.84 min. MS (ES) C 21 H 29 BrN 2 O 4 requires 453, found 454 [M+H] + . [00423] To a solution of tert-butyl 4-[3-(2-bromoethyl)-2-oxo-1,3-benzoxazol-6-yl]-2,2- dimethyl-piperidine (0.104 g, 0.23 mmol) in DMF (0.2 M) was added K 2 CO 3 (0.095 g, 0.69 mmol) and dimethylamine (0.103 g, 2.3 mmol) and the reaction was stirred at 60°C for 2h and then cooled to RT, poured into ice and the precipitate was filtered off. The residue was used in the next step without further purification. 1 H NMR (400 MHz,CDCl 3 ) d 7.46 (d, J = 8.1 Hz, 1H), 714–707 (m 2H) 450 (t J = 72 Hz 2H) 398 (dt J = 137 47 Hz 1H) 344–333 (m 2H) 3.18 (ddd, J = 14.0, 10.7, 3.7 Hz, 1H), 2.87 (s, 6H), 1.99–1.91 (m, 1H), 1.73 (t, J = 13.1 Hz, 1H), 1.64–1.59 (m, 1H), 1.56 (s, 3H), 1.48 (s, 10H), 1.37 (s, 3H). UPLC/MS (method A): Rt 2.24 min. MS (ES) C23H35N3O4 requires 417, found 418 [M+H] + . [00424] Following general procedure C (step 2), XIk (0.096 g, 0.23 mmol) afforded XIIk as a yellow solid (0.085 g, 95%). 1 H NMR (400 MHz, DMSO-d6) d 10.57–10.16 (m, 1H), 9.30–8.95 (m, 2H), 7.42–7.36 (m, 1H), 7.25 (s, 1H), 7.16–7.09 (m, 1H), 4.23 (t, J = 6.3 Hz, 2H), 3.48–3.42 (m, 2H), 3.21–3.02 (m, 3H), 2.88–2.82 (m, 6H), 1.96–1.72 (m, 4H), 1.39 (s, 6H). UPLC/MS (method A): Rt 1.00 min. MS (ES) C18H27N3O2 requires 317, found 318 [M+H] + . 4-[3-[2-(Dimethylamino)ethyl]-2-oxo-1,3-benzoxazol-6-yl]-2,2 -dimethyl-N-(4- phenylbutyl)piperidine-1-carboxamide [00425] Following general procedure D (Method A), XIIk (0.040 g, 0.103 mmol) and 4- phenylbutyl isocyanate (0.019 g, 0.113 mmol) afforded the title compound as a gummy solid (0.009 g, 18%). 1 H NMR (400 MHz, DMSO-d 6 ) d 7.31–7.13 (m, 7H), 7.09 (dd, J = 8.2, 1.6 Hz, 1H), 6.46 (t, J = 5.5 Hz, 1H), 3.88 (t, J = 6.3 Hz, 2H), 3.60 (dt, J = 12.8, 4.1 Hz, 1H), 3.07–2.92 (m, 3H), 2.89–2.78 (m, 1H), 2.62–2.53 (m, 4H), 2.16 (s, 6H),1.86–1.77 (m, 1H), 1.67–1.48 (m, 5H), 1.45 (s, 3H), 1.43–1.35 (m, 2H), 1.30 (s, 3H). UPLC/MS (method A): Rt 2.17 min. MS (ES) C29H40N4O3 requires 492, found 493 [M+H] + . Example 33: 3-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)-8- azabicyclo[3.2.1]octane-8-carboxamide tert-Butyl 3-(trifluoromethylsulfonyloxy)-8-azabicyclo[3.2.1]oct-3-ene- 8-carboxylate (VIg) [00426] Following general procedure A (step 1), Vi (0.95 g, 4.2 mmol) afforded VIg as a colorless oil (1.24 g, 83%). 1 H NMR (400 MHz, CDCl 3 ) d 6.09 (d, J = 4.0 Hz, 1H), 4.46 (s, 2H), 3.21–2.90 (m, 1H), 2.23 (s, 1H), 2.09 (d, J = 16.4 Hz, 1H), 2.05–1.94 (m, 2H), 1.85–1.65 (m, 1H), 1.46 (s, 9H). UPLC/MS (method B): Rt 1.61 min. MS (ES) C13H18F3NO5S requires 357, found 358 [M+H] + . tert-Butyl 3-(3-hydroxy-4-nitrophenyl)-8-azabicyclo[3.2.1]oct-3-ene-8-c arboxylate (VIIj) [00427] Following general procedure A (step 2), VIg (0.60 g, 1.7 mmol) and 5-bromo-2- nitrophenol (0.33 g, 1.53 mmol) afforded VIIj as yellow solid (0.33 g, 56%). 1 H NMR (400 MHz, CDCl 3 ) d 10.62 (s, 1H), 8.02 (d, J = 8.9 Hz, 1H), 7.06 (d, J = 1.7 Hz, 1H), 7.00 (dd, J = 9.0, 1.9 Hz, 1H), 6.67 (d, J = 5.1 Hz, 1H), 4.59–4.43 (m, 2H), 3.08 (d, J = 15.5 Hz, 1H), 2.31– 2.13 (m, 2H), 2.10–1.86 (m, 2H), 2.03–1.86 (m, 2H), 1.73–1.64 (m, 1H), 1.45 (s, 9H). UPLC/MS (method B): Rt 1.46 min. MS (ES) C 18 H 22 N 2 O 5 requires 346, found 347 [M+H] + . tert-Butyl- 3-(4-amino-3-hydroxyphenyl)-8-azabicyclo[3.2.1]octane-8-carb oxylate (VIIIj) [00428] Following general procedure B (Method A, step 1), VIIj (0.33 g, 0.96 mmol) afforded VIIIj which was used in the next step without further purification. UPLC/MS (method A): Rt 2.01 min. MS (ES) C18H26N2O3 requires 318, found 319 [M+H] + . tert-Butyl 3-(2-oxo-3H-1,3-benzoxazol-6-yl)-8-azabicyclo[3.2.1]octane-8 -carboxylate (IXj) [00429] Following general procedure B (step 2), VIIIj (0.300 g, 0.94 mmol) afforded IXj as a yellow oil (0.050 g, 15%). 1 H NMR (400 MHz, CDCl 3 ) d 8.52 (s, 1H), 7.10–6.91 (m, 3H), 4.43– 4.20 (m, 2H), 2.74–2.40 (m, 3H), 2.09–1.96 (m, 2H), 1.64–1.57 (m, 2H), 1.55–1.44 (m, 2H), 1.43 (s, 3H), 1.24 (s, 6H). UPLC/MS (method A): Rt 2.18 min. MS (ES) C19H24N2O4 requires 344, found 345 [M+H] + . tert-Butyl 3-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-8-azabicyclo[3.2.1]oc tane-8-carboxylate (XIl) [00430] Following general procedure C (step 1), IXj (0.050 g, 0.13 mmol) and MeI (0.03 g, 0.2 mmol) afforded XIl which was used in the next step without further purification. UPLC/MS (method A): Rt 2.39 min. MS (ES) C 20 H 26 N 2 O 4 requires 358, found 359 [M+H] + . 6-(8-Azabicyclo[3.2.1]octan-3-yl)-3-methyl-1,3-benzoxazol-2- one hydrochloride (XIIl) [00431] Following general procedure C (step 2), XIl (0.06 g, 0.167 mmol) afforded XIIl as a white solid (0.04 g, 92%). (UPLC/MS (method A): Rt 1.10 min. MS (ES) C 15 H 18 N 2 O 2 requires 258, found 259 [M+H] + . 3-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)-8-a zabicyclo[3.2.1]octane-8- carboxamide [00432] Following general procedure D (Method A), XIIl (0.045 g, 0.14 mmol) and 4- phenylbutyl isocyanate (0.05 g, 0.28 mmol) afforded the title compound as a white solid (85:15, endo:exo stereoisomers, 0.035 g, 62%). 1 H NMR (400 MHz, DMSO-d 6 ) d 7.29–7.21 (m, 3.4H), 7.21–7.07 (m, 5.0H), 7.05–7.00 (m, 1.2H), 6.45 (t, J = 5.7 Hz, 1H), 6.44 – 6.42 (m, 0.15H), 4.26–4.17 (m, 2.3H), 3.31–3.29 (m, 3.5H), 3.20–3.12 (m, 0.2H), 3.09 (q, J = 6.7 Hz, 2H), 2.63– 2.56 (m, 2.3H), 2.55–2.45 (m, 1H), 2.30 (dt, J = 14.5, 7.5 Hz, 2H), 1.92–1.65 (m, 3.3H), 1.65– 1.52 (m, 4.8H), 1.50–1.40 (m, 4.4H). UPLC/MS (method A): Rt 2.20 min. MS (ES) C 26 H 31 N 3 O 3 requires 433, found 434 [M+H]. Example 34: 8-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)-2-o xa-5- azaspiro[3.5]nonane-5-carboxamide Benzyl 8-(trifluoromethylsulfonyloxy)-2-oxa-5-azaspiro[3.5]non-7-en e-5-carboxylate (VIh) [00433] Following general procedure A, Vi (0.246 g, 0.89 mmol) afforded VIh as a colorless oil (0.220 g, 61%). 1 H NMR (400 MHz, CDCl 3 ) d 7.42–7.28 (m, 5H), 5.78 (tt, J = 3.2, 1.4 Hz, 1H), 5.13 (s, 2H), 4.82 (d, J = 6.6 Hz, 2H), 4.31 (s, 2H), 4.08 (q, J = 2.8 Hz, 2H), 2.95 (s, 2H). UPLC/MS (method B): Rt 1.24 min. MS (ES) C16H16F3NO6S requires 407, found 408 [M+H] + . Benzyl 8-(3-hydroxy-4-nitro-phenyl)-2-oxa-5-azaspiro[3.5]non-7-ene- 5-carboxylate (VIIk) [00434] Following general procedure A, VIh (0.220 g, 0.54 mmol) and 5-bromo-2-nitro- phenol (0.141 g, 0.65 mmol) afforded VIlk as a yellow oil (0.192 g, 90%). 1 H NMR (400 MHz, CDCl3) d 10.63 (s, 1H), 8.10–8.03 (m, 1H), 7.41–7.30 (m, 5H), 7.11 (d, J = 2.0 Hz, 1H), 7.00 (dd, J = 8.9, 2.0 Hz, 1H), 6.27-6.18 (m, 1H), 5.12 (s, 2H), 4.89 (d, J = 6.5 Hz, 2H), 4.31 (s, 2H), 4.18 (q, J = 2.8 Hz, 2H), 3.01 (s, 2H). UPLC/MS (method B): Rt 1.12 min. MS (ES) C 21 H 20 N 2 O 6 requires 396, found 395 [M-H]-. Benzyl 8-(4-amino-3-hydroxy-phenyl)-2-oxa-5-azaspiro[3.5]non-7-ene- 5-carboxylate (VII’a) [00435] Following general procedure B, step 1 (Method C), VIIk (0.182 g, 0.46 mmol) afforded VII’a which was used in the next step without further purification. UPLC/MS (method A): Rt 1.86 min. MS (ES) C 21 H 22 N 2 O 4 requires 366, found 367 [M+H] + . Benzyl 8-(2-oxo-3H-1,3-benzoxazol-6-yl)-2-oxa-5-azaspiro[3.5]non-7- ene-5-carboxylate (XIVb) [00436] Following general procedure B, step 2, VII’a (0.287 g, 0.46 mmol) afforded XIVb as a colorless oil (0.106 g, 56%). 1 H NMR (400 MHz, CDCl3) d 8.44 (br s, 1H), 7.41–7.30 (m, 5H), 7.24–7.22 (m, 1H), 7.18 (dd, J = 8.2, 1.7 Hz, 1H), 7.05–7.00 (m, 1H), 6.01-5.94 (m, 1H), 5.13 (s, 2H), 4.90 (d, J = 6.4 Hz, 2H), 4.33 (s, 2H), 4.18–4.13 (m, 2H), 3.01 (s, 2H). UPLC/MS (method A): Rt 1.96 min. MS (ES) C22H20N2O5 requires 392, found 393 [M+H] + . Benzyl 8-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-2-oxa-5-azaspiro[3.5] non-7-ene-5- carboxylate (XVb) [00437] Following general procedure C, step 1, XIVb (0.106 g, 0.27 mmol) and MeI (0.350 g, 2.16 mmol) afforded XVb which was used in the next step without purification. 1 H NMR (400 MHz, CDCl3) d 7.42–7.32 (m, 5H), 7.25–7.20 (m, 2H), 6.95 (d, J = 8.0 Hz, 1H), 6.01-5.94 (m, 1H), 5.15 (s, 2H), 4.92 (d, J = 6.4 Hz, 2H), 4.35 (s, 2H), 4.16 (d, J = 3.1 Hz, 2H), 3.44 (s, 3H), 3.04 (s, 2H). UPLC/MS (method A): Rt 2.13 min. MS (ES) C 23 H 22 N 2 O 5 requires 406, found 407 [M+H] + . 3-Methyl-6-(2-oxa-5-azaspiro[3.5]nonan-8-yl)-1,3-benzoxazol- 2-one (XIIm) [00438] Following general procedure B, (Method E), XIVb (0.110 g, 0.27 mmol) afforded XIIm which was used in the next step without purification. 1 H NMR (400 MHz, CDCl3) d 7.12– 7.02 (m, 2H), 6.95–6.86 (m, 1H), 4.68 (d, J = 6.2 Hz, 1H), 4.58 (dd, J = 6.2, 1.5 Hz, 1H), 3.39 (s, 3H), 3.10 (ddd, J = 11.9, 4.1, 2.5 Hz, 1H), 2.79 (td, J = 12.0, 2.7 Hz, 1H), 2.62 (tt, J = 12.4, 3.6 Hz, 1H), 2.39–2.27 (m, 1H), 1.86–1.55 (m, 5H). UPLC/MS (method A): Rt 1.05 min. MS (ES) C15H18N2O3 requires 274, found 275 [M+H] + . 8-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)-2-o xa-5-azaspiro[3.5]nonane-5- carboxamide [00439] Following general procedure D (Method A), XIIm (0.030 g, 0.11 mmol) and 4- phenylbutyl isocyanate (0.021 g, 0.12 mmol) afforded the title compound as a white solid (0.016 g, 36%). 1 H NMR (400 MHz, DMSO-d6) d 7.29–7.22 (m, 2H), 7.20–7.11 (m, 5H), 7.06 (dd, J = 8.1, 1.6 Hz, 1H), 6.77 (t, J = 5.6 Hz, 1H), 4.70 (d, J = 7.1 Hz, 1H), 4.49–4.37 (m, 2H), 4.19 (d, J = 7.0 Hz, 1H), 3.73 (d, J = 15.1 Hz, 1H), 3.32 (s, 3H), 3.13 (dt, J = 12.9, 6.5 Hz, 1H), 3.05–2.90 (m, 2H), 2.70–2.54 (m, 3H), 2.24–2.12 (m, 1H), 1.97–1.86 (m, 1H), 1.62–1.50 (m, 3H), 1.49– 1.38 (m, 2H), 1.31 (td, J = 12.7, 3.5 Hz, 1H). UPLC/MS (method A): Rt 2.08 min. MS (ES) C 26 H 31 N 3 O 4 requires 449, found 450 [M+H] + . Example 35: 4-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-2-oxo-N-(4-phenylbuty l)piperidine-1- carboxamide tert-Butyl 4-(3-benzyloxy-4-nitro-phenyl)-6-oxo-2,3-dihydropyridine-1-c arboxylate (VIIl) [00440] Following general procedure A, VI’i (0.96 g, 0.297 mmol) and 2-benzyloxy-4- bromo-1-nitrobenzene (0.100 g, 0.327 mmol) afforded VIIl as a yellow solid (0.102 g, 74%). 1 H NMR (400 MHz, CDCl 3 ) d 7.92 (d, J = 8.5 Hz, 1H), 7.52–7.47 (m, 2H), 7.43 (ddd, J = 7.5, 6.6, 1.4 Hz, 2H), 7.40–7.35 (m, 1H), 7.22 (d, J = 1.8 Hz, 1H), 7.16 (dd, J = 8.4, 1.8 Hz, 1H), 6.33- 6.30 (m, 1H), 5.30 (s, 2H), 4.02 (t, J = 6.4 Hz, 2H), 2.78 (td, J = 6.5, 1.4 Hz, 2H), 1.59 (s, 9H). UPLC/MS (method B): Rt 2.55 min. MS (ES) C 23 H 24 N 2 O 6 requires 424, found 425 [M+H] + . (VIIIk) [00441] Following general procedure B (Method A), VIIl (0.50 g, 1.18 mmol) afforded VIIIk which was used in the next step without further purification. UPLC/MS (method A): Rt 1.65 min. MS (ES) C16H22N2O4 requires 306, found 307 [M+H] + . tert-Butyl [00442] Following general procedure B, VIIIk (0.360 g, 1.18 mmol) afforded IXk as a yellow oil (0.300 g, 70%). UPLC/MS (method A): Rt 1.77 min. MS (ES) C17H20N2O5 requires 332, found 333 [M+H] + . tert-Butyl 4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-2-oxo-piperidine-1-ca rboxylate (XIm) [00443] Following general procedure C, IXk (0.310 g, 0.93 mmol) and CH 3 I (0.2 g, 0.09 mL, 1.4 mmol) afforded XIm as a white solid. 1 H NMR (400 MHz, CDCl 3 ) d 7.10–7.05 (m, 1H), 7.03–7.00 (m, 1H), 6.92 (d, J = 8.0 Hz, 1H), 3.88 (ddd, J = 12.9, 5.0, 4.1 Hz, 1H), 3.61 (ddd, J = 12.9, 10.9, 4.3 Hz, 1H), 3.39 (s, 3H), 3.22–3.09 (m, 1H), 2.84 (ddd, J = 17.1, 5.4, 2.0 Hz, 1H), 2.59 (dd, J = 17.1, 11.2 Hz, 1H), 2.27–2.15 (m, 1H), 1.95 (dtd, J = 13.6, 11.0, 5.0 Hz, 1H), 1.54 (s, 9H). UPLC/MS (method A): Rt 1.94 min. MS (ES) C18H22N2O5 requires 346, found 345 [M+H] + . 3-Methyl-6-(2-oxo-4-piperidyl)-1,3-benzoxazol-2-one (XIIn) [00444] Following general procedure C, XIm (0.045 g, 0.130 mmol) afforded XIIn as a white solid (0.028 g, 87%). 1 H NMR (400 MHz, DMSO-d6) d 7.65 (s, 1H), 7.31 (d, J = 1.4 Hz, 1H), 7.21–7.12 (m, 2H), 3.32 (s, 3H), 3.21 (qd, J = 6.6, 4.1 Hz, 2H), 3.12–3.01 (m, 1H), 2.43–2.23 (m, 2H), 1.93–1.78 (m, 2H). (UPLC/MS (method A): Rt 1.21 min. MS (ES) C 13 H 14 N 2 O 3 requires 246, found 247 [M+H] + . 4-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-2-oxo-N-(4-phenylbuty l)piperidine-1-carboxamide [00445] Following general procedure D (Method A), XIIn (0.025 g, 0.102 mmol) and 4- phenylbutyl isocyanate (0.02 g, 0.112 mmol) the title compound as a white solid (0.030 g, 70%). 1 H NMR (400 MHz, CDCl3) d 9.40–9.30 (m, 1H), 7.30–7.27 (m, 1H), 7.21–7.14 (m, 3H), 7.08– 7.05 (m, 1H), 7.03–7.00 (m, 1H), 6.92 (d, J = 8.0 Hz, 1H), 4.16 (ddd, J = 13.7, 5.0, 4.2 Hz, 1H), 3.63 (ddd, J = 13.6, 10.9, 4.3 Hz, 1H), 3.40 (s, 3H), 3.34 (q, J = 6.6 Hz, 2H), 3.24–3.05 (m, 1H), 2.88 (ddd, J = 17.7, 5.8, 2.0 Hz, 1H), 2.69–2.50 (m, 3H), 2.24 (dtd, J = 14.2, 4.2, 2.0 Hz, 1H), 1.91 (dtd, J = 13.8, 11.0, 5.0 Hz, 1H), 1.74–1.59 (m, 4H). UPLC/MS (method A): Rt 2.36 min. MS (ES) C24H27N3O4 requires 421, found 422 [M+H]. Example 36: 2-(2-Oxo-3H-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)piperidine -1- carboxamide tert-Butyl N-[5-oxo-5-(2-oxo-3H-1,3-benzoxazol-6-yl)pentyl]carbamate (XXIIa) [00446] Following general procedure G, XXa (2.8 g, 14.0 mmol) and 6-bromo-3H-1,3- benzoxazol-2-one (0.6 g, 2.80 mmol) afforded XXIIa as a white powder (0.594 g, 63%). 1 H NMR (400 MHz, DMSO-d 6 ) d 11.99 (bs, 1H), 7.85–7.80 (m, 2H), 7.19 (d, J = 8.6 Hz, 1H), 6.79 (t, J = 5.8 Hz, 1H), 3.05–2.85 (m, 4H), 1.65–1.50 (m, 2H), 1.50–1.40 (m, 2H), 1.37 (s, 9H). UPLC/MS (method A): Rt 1.84 min. MS (ES) C17H22N2O5 requires 334, found 335 [M+H] + . 6-(2-Piperidyl)-3H-1,3-benzoxazol-2-one (XXIIIa) [00447] To a suspension of XXIIa (0.297 g, 0.89 mmol) in DCM (0.1 M) was added TFA (20 g 178 mmol) and the reaction mixture was stirred at RT for 1h After evaporation of the solvent, the residue was used in the next step without further purification. UPLC/MS (method A): Rt 0.89 min. MS (ES) C 12 H 14 N 2 O 3 requires 234, found 235 [M+H] + . [00448] To a solution of compound from Step 1 in ACN (0.1 M) was added NaBH(OAc)3 (0.566 g, 2.67 mmol) and the reaction mixture was stirred at RT for 30 min and then quenched with the addition of MeOH and diluted with EA. The organic phase was washed with a saturated aqueous NaHCO 3 solution, brine and dried over Na 2 SO 4 . After evaporation of the solvent, the residue was purified by SCX to afford XXIIIa. UPLC/MS (method A): Rt 0.94 min. MS (ES) C 12 H 14 N 2 O 2 requires 218, found 219 [M+H] + . 2-(2-Oxo-3H-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)piperidine -1-carboxamide [00449] Following general procedure D (Method A), XXIIIa (0.025 g, 0.1 mmol) and 4- phenylbutyl isocyanate (0.018 g, 0.1 mmol) afforded the title compound as a white solid (0.086 g, 91%). 1 H NMR (400 MHz, DMSO-d6) d 11.55 (s, 1H), 7.26 (dd, J = 7.9, 6.9 Hz, 2H), 7.16 (dt, J = 7.9, 1.4 Hz, 3H), 7.05 (d, J = 8.1 Hz, 2H), 6.95 (dd, J = 8.0, 1.4 Hz, 1H), 6.49 (t, J = 5.5 Hz, 1H), 5.35–5.30 (m, 1H), 3.86 (d, J = 13.4 Hz, 1H), 3.15–3.00 (m, 2H), 2.75–2.60 (m, 1H), 2.60–2.50 (m, 2H), 2.27 (d, J = 13.9 Hz, 1H), 1.80–1.65 (m, 1H), 1.60–1.20 (m, 8H). UPLC/MS (method A): Rt 2.07 min. MS (ES) C 23 H 27 N 3 O 3 requires 393, found 394 [M+H] + . Example 37: 2-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)pipe ridine-1- carboxamide tert-Butyl N-[5-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-5-oxo-pentyl]carba mate (XXIVa) [00450] Following general procedure C (step 1), XXIIa (0.030 g, 0.090 mmol) and CH3I (0.020 g, 0.14 mmol) afforded XXIVa which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) d 7.93 (dd, J = 8.2, 1.6 Hz, 1H), 7.88 (d, J = 1.5 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 6.79 (d, J = 6.5 Hz, 1H), 3.39 (s, 3H), 3.05–2.90 (m, 4H), 1.65–1.50 (m, 2H), 1.50–1.40 (m, 2H), 1.37 (s, 9H). UPLC/MS (method A): Rt 1.99 min. MS (ES) C 18 H 24 N 2 O 5 requires 348, found 349 [M+H] + . 3-Methyl-6-(2-piperidyl)-1,3-benzoxazol-2-one (XXVa) [00451] To a suspension of XXIVa (0.10 g, 0.28 mmol) in DCM (0.1 M) was added TFA (0.43 mL, 5.6 mmol) and the reaction mixture was stirred at RT for 1h. After evaporation of the solvent, the residue was used in the next step without further purification. UPLC/MS (method A): Rt 1.07 min. MS (ES) C18H24N2O5 requires 248, found 249 [M+H] + . [00452] To a solution of compound from Step 1 (0.070 g, 0.28 mmol) in ACN (0.1 M) was added NaBH(OAc)3 (0.178g, 0.84 mmol) and the reaction mixture was stirred at RT for 30 min and then quenched with MeOH, diluted with EA, washed with saturated aq. NaHCO3 solution, brine and dried over Na 2 SO 4 . After evaporation of the solvent, the residue was purified by SCX to afford XXVa (0.062 g, 92%). 1 H NMR (400 MHz, DMSO-d6) d 9.35 (s, 1H), 7.65 (d, J = 1.5 Hz, 1H), 7.44 (dd, J = 8.1, 1.6 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H) 4.30–4.25 (m, 1H), 3.35 (s, 3H), 3.10–2.95 (m, 1H), 2.00–1.75 (m, 6H), 1.70–1.50 (m, 1H). UPLC/MS (method A): Rt 1.07 min. MS (ES) C 13 H 16 N 2 O 2 requires 232, found 233 [M+H] + . [00453] Following general procedure D (Method A), XXVa (0.070 g, 0.026 mmol) and 4- phenylbutyl isocyanate (0.050 g, 0.29 mmol) afforded the title compound as a white solid (0.098 g, 93%). 1 H NMR (400 MHz, CDCl 3 ) d 9.78 (s, 1H), 7.35–7.25 (m, 2H), 7.25–7.15 (m, 3H), 7.00 (s, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 5.35–5.25 (m, 1H), 4.75–4.65 (m, 1H), 3.82 (d, J = 12.9 Hz, 1H), 3.32 (d, J = 6.5 Hz, 2H), 3.04 (td, J = 13.3, 12.2, 3.7 Hz, 1H), 2.63 (t, J = 7.4 Hz, 2H), 2.25–2.15 (m, 1H), 2.05–1.90 (m, 2H), 1.90–1.85 (m, 1H), 1.75–1.50 (m, 7H), 1.50–1.35 (m, 1H). UPLC/MS (method A): Rt 2.23 min. MS (ES) C24H29N3O3 requires 407, found 408 [M+H] + . Example 38: 3-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)morp holine-4- carboxamide tert-Butyl N-[2-[2-oxo-2-(2-oxo-3H-1,3-benzoxazol-6-yl)ethoxy]ethyl]car bamate (XXIId) [00454] Following general procedure G, XXe (1.18 g, 5.84 mmol) and 6-bromo-3H-1,3- benzoxazol-2-one (0.250 g, 1.17 mmol) afforded XXIId as a white solid (0.233 g, 59%). 1 H NMR (400 MHz, CDCl 3 ) d 9.42 (s, 1H), 7.89–7.74 (m, 2H), 7.18 (d, J = 8.1 Hz, 1H), 5.25 (bs, 1H), 4.78 (s, 2H), 3.70 = 5.1 Hz, 2H), 3.42 (t, J = 5.1 Hz, 2H), 1.47 (s, 9H). UPLC/MS (method A): Rt 1.64 min. MS (ES) C 16 H 20 N 2 O 6 requires 336, found 337 tert-Butyl N-[2-[2-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-2-oxo-ethoxy]et hyl]carbamate (XXIVd) [00455] To a solution (0.2 M) of XXIId (0.130 g, 0.39 mmol) in anydrous DMF was added MeI (0.110 g, 0.77 mmol) and K 2 CO 3 (0.040 g, 0.29 mmol) and the reaction mixture was stirred at RT for 3h. The reaction mixture was diluted with DCM, washed with brine, dried over Na2SO4 and concentrated to afford XXIVd which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 ) d 7.89 (d, J = 7.6 Hz, 1H), 7.82 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 5.15 (bs, 1H), 4.77 (s, 2H), 3.68 (t, J = 5.1 Hz, 2H), 3.48 (s, 3H), 3.40 (d, J = 5.3 Hz, 2H), 1.47 (s, 9H). UPLC/MS (method A): Rt 1.78 min. MS (ES) C17H22N2O6 requires 350, found 351 [M+H] + . 3-Methyl-6-morpholin-3-yl-1,3-benzoxazol-2-one (XXVd) [00456] To a suspension of XXIVd (0.110 g, 0.314 mmol) in DCM (0.1 M) was added TFA (0.537 g, 0.36 mL, 4.71 mmol) and the reaction mixture was stirred at RT for 1h. After evaporation of the solvent, the residue was used in the next step without further purification. UPLC/MS (method A): Rt 0.95 min. MS (ES) C12H14N2O3 requires 250, found 251 [M+H] + . [00457] To a solution of compound from Step 1 in ACN (0.1 M) was added NaBH(OAc)3 (0.2 g, 0.942 mmol) and the reaction mixture was stirred at RT for 30 min and then quenched with the addition of MeOH and diluted with EA. The organic phase was washed with saturated aq. NaHCO3 solution, brine and dried over Na2SO4 and concentrated to afford XXVd which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) d 9.87 (s, 2H), 7.69 (d, J = 1.6 Hz, 1H), 7.49 (dd, J = 8.1, 1.6 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 4.50 (dd, J = 10.7, 3.7 Hz, 1H), 4.11–3.73 (m, 4H), 3.36 (s, 3H), 3.30–3.18 (m, 2H). UPLC/MS (method A): Rt 0.91 min. MS (ES) C 12 H 14 N 2 O 3 .ClH requires 234, found 235 [M+H] + . [00458] Following general procedure D (Method A), XXVd (0.052 g, 0.19 mmol) and 4- phenylbutyl isocyanate (0.037 g, 0.21 mmol) afforded the title compound as a white solid (0.067 g, 84%). 1 H NMR (400 MHz, DMSO-d6) d 7.34–7.23 (m, 3H), 7.22–7.09 (m, 5H), 6.56 (t, J = 5.5 Hz, 1H), 5.10 (d, J = 3.3 Hz, 1H), 4.28 (d, J = 11.9 Hz, 1H), 3.91–3.58 (m, 3H), 3.44 (td, J = 11.5, 3.1 Hz, 1H), 3.32 (s, 3H), 3.19–2.88 (m, 3H), 2.59–2.52 (m, 2H), 1.59–1.35 (m, 4H). UPLC/MS (method A): Rt 2.01 min. MS (ES) C23H27N3O4 requires 409, found 410 [M+H] + . Example 39: 2-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)pipe razine-1- carboxamide Benzyl N-[2-(tert-butoxycarbonylamino)ethyl]-N-[2-oxo-2-(2-oxo-3H-1 ,3-benzoxazol-6- yl)ethyl]carbamate (XXIIb) [00459] Following general procedure G, XXb (0.640 g, 1.91 mmol) and 6-bromo-3H-1,3- benzoxazol-2-one (0.1 g, 0.47 mmol) afforded XXIIb as a white solid (0.158 g, 71%). 1H NMR (400 MHz, DMSO-d6) d 7.90–7.80 (m, 2H), 7.45–7.30 (m, 3H), 7.30–7.15 (m, 4H), 6.85–6.65 (m, 1H), 5.20–4.95 (m, 2H), 4.90–4.75 (m, 2H), 3.45–3.30 (m, 2H), 3.20–3.05 (m, 2H), 1.37 (s, 9H). UPLC/MS (method A): Rt 2.07 min. MS (ES) C24H27N3O7 requires 469, found 470 [M+H] + . tert-Butyl N-[5-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-5-oxo-pentyl]carba mate (XXIVb) [00460] Following general procedure C (step 1), XXIIb (0.150 g, 0.32 mmol) and MeI (0.091 g, 0.64 mmol) afforded XXIVb which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) d 7.95–7.70 (m, 2H), 7.45–7.30 (m, 3H), 7.30–7.20 (m, 2H), 7.10–7.00 (m, 1H), 5.25–5.00 (m, 3H), 4.80–4.60 (m, 2H), 3.60–3.50 (m, 2H), 3.48 (s, 3H), 3.40–3.20 (m, 2H), 1.42 (s, 9H). UPLC/MS (method A): Rt 2.19 min. MS (ES) C 25 H 29 N 3 O 7 requires 483, found 484 3-Methyl-6-(2-piperidyl)-1,3-benzoxazol-2-one (XXVb) [00461] To a suspension of XXIVb (0.145 g, 0.30 mmol) in DCM (0.1 M) was added TFA (0.684g, 6.0 mmol) and the reaction mixture was stirred at RT for 1h. After evaporation of the solvent, the residue was used in the next step without further purification. UPLC/MS (method A): Rt 1.53 min. MS (ES) C 20 H 21 N 3 O 5 requires 383, found 384 [M+H] + . [00462] To a solution of compound from Step 1 in ACN (0.1 M) was added NaBH(OAc)3 (0.191 g, 0.90 mmol) and the reaction mixture was stirred at RT for 30 min and then quenched with the addition of MeOH and diluted with EA. The organic phase was washed with saturated aq. NaHCO3 solution, brine, dried over Na2SO4 and concentrated to afford XXVb which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) d 7.40–7.30 (m, 6H), 7.23 (dd, J = 8.0, 1.5 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 5.16 (s, 2H), 4.25–4.10 (m, 2H), 3.85–3.70 (m, 1H), 3.39 (s, 3H), 3.20–3.00 (m, 2H), 3.00–2.70 (m, 2H), 2.30–2.10 (bs, 1H). UPLC/MS (method A): Rt 1.70 min. MS (ES) C 20 H 21 N 3 O 4 requires 367, found 368 [M+H] + . Benzyl 3-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-4-(4-phenylbutylcarba moyl)piperazine-1- carboxylate (XXVIIIa) [00463] Following general procedure D (Method A), XXVb (0.110 g, 0.030 mmol) and 4- phenylbutyl isocyanate (0.060 g, 0.33 mmol) afforded XXVIIIa as a white solid (0.137 g, 84%). 1 H NMR (400 MHz, CDCl 3 ) d 7.40–7.25 (m, 7H), 7.20–7.05 (m, 5H), 6.90–6.70 (m, 1H), 5.20– 5.10 (m, 2H), 5.10–4.95 (m, 1H), 4.35–4.15 (m, 1H), 4.10–3.90 (m, 1H), 3.90–3.55 (m, 2H), 3.50–3.40 (m, 3H), 3.34 (s, 3H), 3.30–3.10 (m, 2H), 2.65–2.45 (m, 2H), 1.60–1.35 (m, 4H). UPLC/MS (method A): Rt 2.29 min. MS (ES) C 31 H 34 N 4 O 5 requires 542, found 543 [M+H] + . 2-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)pipe razine-1-carboxamide [00464] Following general procedure B (method B), XXVIIIa (0.135 g, 0.25 mmol) afforded the title compound as a white solid (0.069, 68%). 1 H NMR (400 MHz, DMSO-d 6 ) d 7.30 (s, 1H), 7.25 (dd, J = 8.5, 6.5 Hz, 2H), 7.19–7.10 (m, 5H), 6.45 (t, J = 5.5 Hz, 1H), 5.11 (s, 1H), 3.66 (dd, J = 12.6, 3.7 Hz, 1H), 3.40–3.30 (m, 1H), 3.38 (s, 3H), 3.15–2.95 (m, 2H), 2.95–2.85 (m, 2H), 2.85–2.75 (m, 2H), 2.65–2.55 (m, 3H), 1.60–1.30 (m, 4H). UPLC/MS (method A): Rt 1.66 min. MS (ES) C 23 H 28 N 4 O 3 requires 408, found 409 [M+H] + . Example 40: 4-Methyl-2-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4- phenylbutyl)piperazine-1-carboxamide [00465] To a solution of 2-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl) piperazine-1-carboxamide (0.030 g, 0.073 mmol) in ACN (0.2 M) was added formaldehyde (37% aq. solution; 0.008 g, 0.28 mmol) and NaBH(AcO) 3 (0.30 g, 0.14 mmol) and the mixture was stirred at RT for 2h and then diluted with EA, washed with saturated aq. NaHCO3 solution, brine and dried over Na2SO4. The solvent was reduced in vacuo to afford the title compound as a white solid (0.029 g, 94%). 1 H NMR (400 MHz, CDCl 3 ) d 7.40–7.35 (m, 1H), 7.30–7.20 (m, 4H), 7.20–7.15 (m, 1H), 7.15–7.10 (m, 2H), 6.85 (d, J = 8.1 Hz, 1H), 5.25 (s, 1H), 4.50–4.35 (m, 1H), 3.64 (d, J = 13.1 Hz, 1H), 3.34 (s, 3H), 3.30–3.05 (m, 3H), 2.85–2.70 (m, 1H), 2.65–2.55 (m, 2H), 2.55–2.45 (m, 1H), 2.31 (s, 3H), 2.25–2.10 (m, 1H), 1.70–1.45 (m, 4H). UPLC/MS (method A): Rt 1.87 min. MS (ES) C24H30N4O3 requires 422, found 423 [M+H] + . Example 41: 4-Methyl-3-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4- phenylbutyl)piperazine-1-carboxamide Benzyl 4-methyl-3-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)piperazine-1- carboxylate (XXVIa) [00466] To a solution of XXVb (0.050 g, 0.13 mmol) in ACN (0.2 M) 37 % aqueous solution of formaldehyde (0.016 g, 0.039 mL, 0.52 mmol) and NaBH(AcO)3 (0.055 g, 0.26 mmol) were added. The mixture was stirred at RT for 2h and then diluted with EA, washed with saturated aqueous NaHCO3 solution, brine, dried over Na2SO4 and concentrated to afford XXVIa which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 ) d 7.45–7.30 (m, 5H), 7.25–7.15 (m, 1H), 6.91 (d, J = 7.9 Hz, 1H), 5.15 (s, 2H), 4.15–4.00 (m, 2H), 3.40 (s, 3H), 3.35–3.05 (m, 1H), 3.05–2.75 (m, 3H), 2.40–2.15 (m, 1H), 2.05 (s, 3H), 1.90–1.50 (m, 1H). UPLC/MS (method A): Rt 2.03 min. MS (ES) C21H23N3O4 requires 381, found 382 [M+H] + . 3-Methyl-6-(1-methylpiperazin-2-yl)-1,3-benzoxazol-2-one (XXVIIa) [00467] Following general procedure B (method A), XXVIa (0.044 g, 0.12 mmol) afforded XXVIIa which was used in the next step without further purification. UPLC/MS (method A): Rt 0.94 min. MS (ES) C13H17N3O2 requires 247, found 248 [M+H] + . 4-Methyl-3-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylb utyl)piperazine-1- carboxamide [00468] Following general procedure D (Method A), XXVIIa (0.025 g, 0.10 mmol) and 4- phenylbutyl isocyanate (0.019 g, 0.11 mmol) afforded the title compound as a white solid (0.021 g, 50%). 1 H NMR (400 MHz, CDCl3) d 7.30–7.25 (m, 3H), 7.25–7.20 (m, 1H), 7.20–7.15 (m, 3H), 6.92 (d, J = 7.9 Hz, 1H), 4.45–4.35 (m, 1H), 3.90–3.70 (m, 2H), 3.39 (s, 3H), 3.30–3.20 (m, 2H), 3.20–3.10 (m, 1H), 3.05–2.90 (m, 2H), 2.90–2.75 (m,1H), 2.70–2.60 (m, 2H), 2.40–2.02 (m, 1H), 2.05 (s, 3H), 1.75–1.50 (m 4H). UPLC/MS (method A): Rt 1.99 min. MS (ES) C 24 H 30 N 4 O 3 requires 422, found 423 [M+H] + . Example 42: 3,3-Dimethyl-5-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phe nylbutyl) morpholine-4-carboxamide tert-Butyl 3,3-dimethyl-5-oxo-morpholine-4-carboxylate (XXf) [00469] To a solution of 5,5-dimethylmorpholinone (1.0 g, 7.8 mmol) in anhydrous THF (0.3M) nBuLi was added dropwise (2.5 M in hexanes, 3.41 mL) at - 78°C under N 2 atmosphere. After 30 min, a solution of Boc2O (6.75 g, 30.96 mmol) in anhydrous THF was added at -78°C. The reaction mixture was allowed to warm to RT overnight, diluted with EA, washed with saturated aqueous NaHCO 3 solution, brine, dried over Na 2 SO 4 and concentrated to afford XXf as white solid (1.6 g, 90%). 1 H NMR (400 MHz, CDCl3) d 4.20 (s, 2H), 3.58 (s, 2H), 1.54 (s, 9H), 1.44 (s, 6H). UPLC/MS (method A): Rt 1.78 min. MS (ES) C11H19NO4 requires 229, found 230 [M+H] + . [2-(tert-Butoxycarbonylamino)-2-methyl-propyl]-N-methoxy-N-m ethyl-carbamate (XXIa) [00470] Step 1: To a solution of XXf (1.6 g, 6.98 mmol) in THF:H 2 O (3:1, 0.3 M) was added LiOH (0.334 g, 13.94 mmol) and the reaction mixture was stirred 3 h at RT and then diluted with DCM. The pH of the aqueous layer was adjusted to about 4 using 5% aq. citric acid. The aqueous layer was extracted with DCM and dried over Na 2 SO 4 to afford 2-[2-(tert- butoxycarbonylamino)-2-methyl-propoxy]acetic acid which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) d 8.24 (bs, 1H), 3.52 (s, 2H), 3.19 (s, 2H), 1.35 (s, 9H), 1.17 (s, 6H). UPLC/MS (method A): Rt 1.23 min. MS (ES) C 11 H 21 NO 5 requires 247, found 248 [M+H] + , 246 [M-H]-. [00471] Step 2: To a solution of 2-[2-(tert-butoxycarbonylamino)-2-methyl-propoxy]acetic acid (0.500 g, 2.02 mmol) in DMF (0.3M) N,O-dimethylhydroxylamine hydrochloride (0.250 g, 2.42 mmol), HATU (0.920 g, 2.42 mmol) and DIPEA (1.86 mL, 2.63 mmol) were added. The reaction mixture was stirred on at RT, diluted with EA, washed with saturated aq. NH4Cl solution, brine, dried over Na2SO4 and concentrated to afford XXIa as a white solid (0.56 g, 96%). 1 H NMR (400 MHz, CDCl 3 ) d 5.58 (bs, 1H), 4.29 (s, 2H), 3.66 (s, 3H), 3.43 (s, 2H), 3.17 (s, 3H), 1.42 (s, 9H), 1.31 (s, 6H). UPLC/MS (method A): Rt 1.88 min. MS (ES) C 13 H 26 N 2 O 5 requires 290, found 291 [M-H] + . tert-Butyl N-[1,1-dimethyl-2-[2-oxo-2-(2-oxo-3H-1,3-benzoxazol-6-yl)eth oxy]ethyl] carbamate(XXIIe) [00472] Following general procedure G, XXIa (0.500 g, 1.72 mmol) and 6-bromo-3H-1,3- benzoxazol-2-one (0.250 g, 1.17 mmol) afforded XXIIe as a transparent oil (0.120 g, 30%). 1 H NMR (400 MHz, CDCl3) d 9.98 (bs, 1H), 7.79 (dd, J = 1.9, 10.2 Hz, 2H), 7.15 (d, J = 8.1 Hz, 1H), 4.75 (s, 2H), 3.54 (s, 2H), 1.44 (s, 9H), 1.32 (s, 6H). UPLC/MS (method A): Rt 1.96 min. MS (ES) C + 1 8 H 24 N 2 O 6 requires 364, found 363 [M-H] . tert-Butyl N-[1,1-dimethyl-2-[2-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-2- oxo- ethoxy]ethyl]carbamate (XXIVe) [00473] To a solution of XXIIe (0.120 g, 0.33 mmol) in anydrous DMF (0.1 M) MeI (0.12 g, 0.83 mmol, 0.05 mL) and K 2 CO 3 (0.030 g, 0.25 mmol) were added and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted DCM, brine, dried over Na2SO4 and concentrated to afford XXIVe which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 ) d 7.87 (dd, J = 8.2, 1.5 Hz, 1H), 7.80 (d, J = 1.3 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 5.09 (bs, 1H), 4.73 (s, 2H), 3.53 (s, 2H), 3.45 (s, 3H), 1.43 (s, 9H), 1.32 (s, 6H). UPLC/MS (method A): Rt 2.18 min. MS (ES) C19H26N2O6 requires 378, found 379 [M+H] + . 3-Methyl-6-(5,5-dimethylmorpholin-3-yl)-1,3-benzoxazol-2-one trifluoroacetic acid (XXVe) [00474] Step 1: To a suspension of XXIVe (0.174 g, 0.24 mmol) in DCM (0.1 M) TFA (0.155 g, 0.4 mL, 4.80 mmol) was added and the reaction mixture was stirred at RT for 1h. After evaporation of the solvent, the residue was used in the next step without further purification. UPLC/MS (method A): Rt 1.63 min. MS (ES) C 14 H 16 N 2 O 3 requires 260, found 261 [M+H] + . [00475] Step 2: To a solution of compound from Step 1 in DCE (0.1 M) NaBH(OAc)3 (0.152 g, 0.72 mmol) was added and the reaction mixture was stirred at RT for 30 min and then quenched with the addition of MeOH. The solvent was removed under reduced pressure and the crude was used in the next step without further purification. UPLC/MS (method A): Rt 1.05 min. MS (ES) C14H18N2O3 requires 262, found 263 [M+H] + . 3,3-Dimethyl-5-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phe nylbutyl) morpholine-4- carboxamide Following general procedure D (Method A), XXVe (0.045 g, 0.12 mmol) and 4-phenylbutyl isocyanate (0.011 g, 0.06 mmol) afforded the title compound as a white solid (0.013 g, 25%). 1 H NMR (400 MHz, DMSO-d6) d 7.34–7.30 (m, 1H), 7.30–7.00 (m, 8H), 4.46 (dd, J = 9.6, 3.9 Hz, 1H), 3.75 (dd, J = 11.2, 3.9 Hz, 1H), 3.47–3.33 (m, 3H), 2.87 (ddq, J = 25.9, 13.2, 6.6 Hz, 2H), 2.44–2.36 (m, 2H), 1.40–1.16 (m, 10H). UPLC/MS (method A): Rt 2.19 min. MS (ES) C25H31N3O4 requires 437, found 438 [M+H] + . Example 43: 3,3-Dimethyl-5-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4- phenylbutyl) [00476] Following general procedure D (Method A), XXVe (0.015 g, 0.04 mmol) and n- pentyl isocyanate (0.011 g, 0.04 mmol) afforded the title compound as a white solid (0.010 g, 60%). 1 H NMR (400 MHz, DMSO-d 6 ) d 7.34–7.31 (m, 1H), 7.24–7.17 (m, 1H), 7.14 (d, J = 8.1 Hz, 1H), 7.03 (t, J = 5.8 Hz, 1H), 4.44 (dd, J = 9.8, 4.0 Hz, 1H), 3.75 (dd, J = 11.1, 4.0 Hz, 1H), 3.47–3.28 (m, 6H), 2.98–2.71 (m, 2H), 1.22 (d, J = 8.4 Hz, 5H), 1.20–0.82 (m, 7H), 0.71 (t, J = 7.3 Hz, 3H). UPLC/MS (method A): Rt 2.03 min. MS (ES) C20H29N3O4 requires 375, found 376 [M+H] + . Example 44: 2-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)pyrr olidine-1- carboxamide tert-Butyl N-[4-oxo-4-(2-oxo-3H-1,3-benzoxazol-6-yl)butyl]carbamate (XXIIf) [00477] Following general procedure G, XXg (1.30 g, 7.0 mmol) and 6-bromo-3H-1,3- benzoxazol-2-one (0.300 g, 1.40 mmol) afforded XXIIf as a transparent oil (0.225 g, 50%). 1 H NMR (400 MHz, DMSO-d 6 ) d 7.87–7.66 (m, 2H), 7.23–7.14 (m, 1H), 6.90–6.78 (m, 1H), 3.67– 3.57 (m, 2H), 3.06–2.90 (m, 2H), 1.86–1.59 (m, 2H), 1.36 (s, 9H). UPLC/MS (method A): Rt 1.74 min. MS (ES) C H N O requires 320, foun - 1 6 20 2 5 d 321 [M-H] tert-Butyl N-[4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-4-oxo-butyl]carbam ate (XXIVf) [00478] To a solution of XXIIf (0.100 g, 0.31 mmol) in anydrous DMF (0.1 M) CH 3 I (0.07 g, 0.47 mmol) and K 2 CO 3 (0.032 g, 0.23 mmol) were added and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted DCM, brine, dried over Na2SO4 and concentrated to afford XXIVf which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) d 7.94–7.89 (m, 1H), 7.85–7.83 (m, 1H), 7.42–7.33 (m, 1H), 6.90– 6.85 (m, 1H), 3.38 (s, 3H), 3.05–2.95 (m, 4H), 1.78–1.66 (m, 2H), 1.37 (s, 9H). UPLC/MS (method A): Rt 1.90 min. MS (ES) C17H22N2O5 requires 334, found 335 [M+H] + . 3-Methyl-6-pyrrolidin-2-yl-1,3-benzoxazol-2-one trifluoroacetic acid (XXVf) [00479] To a suspension of XXIVf (0.095 g, 0.28 mmol) in DCM (0.1 M) TFA (0.648 g, 0.4 mL, 5.70 mmol) was added and the reaction mixture was stirred at RT for 1h. After concentration the residue was used in the next step without further purification. UPLC/MS (method A): Rt 1.01 min. MS (ES) C12H14N2O3 requires 234, found 235 [M+H] + . To a solution of compound from Step 1 in DCE (0.1 M) NaBH(OAc)3 (0.178 g, 0.56 mmol) was added. The reaction mixture was stirred at RT for 30 min and then quenched with the addition of MeOH. The solvent was removed under reduced pressure and triturated with Et2O to afford XXVf as a white solid (0.091 g, 97%). 1 H NMR (400 MHz, DMSO-d6) d 9.59 (bs, 1H), 8.75 (bs, 1H), 7.54– 7.51 (m, 1H), 7.40–7.15 (m, 2H), 4.67–4.54 (m, 1H), 3.37 (s, 3H), 3.36–3.25 (m, 2H), 2.42–2.30 (m, 1H), 2.20–1.90 (m, 2H). UPLC/MS (method A): Rt 0.97 min. MS (ES) C 12 H 14 N 2 O 2 requires 218, found 219 [M+H] + . 2-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)pyrr olidine-1-carboxamide [00480] Following general procedure D (Method A), XXVf (0.090 g, 0.27 mmol) and 4- phenylbutyl isocyanate (0.053 g, 0.30 mmol) afforded the title compound as a white solid (0.094 g, 89%). 1 H NMR (400 MHz, CDCl 3 ) d 7.47–7.40 (m, 2H), 7.37–7.32 (m, 1H), 7.30–7.25 (m, 4H), 7.07–7.02 (m, 1H), 5.01–4.95 (m, 1H), 3.87–3.76 (m, 2H), 3.51 (s, 3H), 3.42–3.25 (m, 2H), 2.75–2.65 (m, 2H), 2.61–2.48 (m, 1H), 2.18–1.94 (m, 4H), 1.71–1.54 (m, 4H). UPLC/MS (method A): Rt 2.07 min. MS (ES) C23H27N3O3 requires 393, found 394 [M+H]. Example 45: 4-(2-Oxo-3H-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)piperazine -1- carboxamide tert-Butyl 4-(3-hydroxy-4-nitrophenyl)piperazine-1-carboxylate (XXXIa) [00481] Following general procedure F, XXXa (3.56 g, 19.14 mmol) and 5-fluoro-2- nitrophenol (2.0 g, 12.73 mmol) afforded XXXIa as a yellow solid. The residue was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) d 10.95 (s, 1H), 7.89 (d, J = 9.7 Hz, 1H), 6.64 (dd, J = 9.7, 2.8 Hz, 1H), 6.42 (d, J = 2.7 Hz, 1H), 3.54–3.41 (m, 8H), 1.43 (s, 9H). UPLC/MS (method A): Rt 2.36 min. MS (ES) C15H21N3O5 requires 323, found 324 [M+H] + . tert-Butyl 4-(4-amino-3-hydroxyphenyl)piperazine-1-carboxylate (XXXIIa) [00482] Following general procedure B (Method A, step 1), XXXIa (4.1 g, 12.73 mmol) afforded XXXIIa which was used in the next step without further purification. UPLC/MS (method A): Rt 1.77 min. MS (ES) C 15 H 23 N 3 O 3 requires 293, found 294 [M+H] + . tert-Butyl 4-(2-oxo-3H-1,3-benzoxazol-6-yl)piperazine-1-carboxylate (XXXIIIa) [00483] Following general procedure B (step 2), XXXIIa (3.7 g, 12.73 mmol) afforded XXXIIIa as a pink solid (3.05 g, 75%). 1 H NMR (400 MHz, DMSO-d6) d 11.34 (s, 1H), 7.00 (d, J = 2.2 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 6.74 (dd, J = 8.6, 2.3 Hz, 1H), 3.57–3.41 (m, 4H), 3.08–2.93 (m, 4H), 1.42 (s, 9H). UPLC/MS (method A): Rt 2.01 min. MS (ES) C 16 H 21 N 3 O 4 requires 319, found 320 [M+H] + . 6-Piperazin-1-yl-3H-1,3-benzoxazol-2-one hydrochloride (XXXIVa) [00484] Following general procedure C (step 2), XXXIIIa (0.070 g, 0.274 mmol) afforded XXXIVa as a gray solid (0.056 g, 93%). 1 H NMR (600 MHz, DMSO-d6) d 11.47 (s, 1H), 9.24 (s, 2H), 7.07 (d, J = 2.2 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 6.79 (dd, J = 8.5, 2.3 Hz, 1H), 3.39– 3.27 (m, 4H), 3.25–3.18 (m, 4H). UPLC/MS (method B): Rt 1.34 min. MS (ES) C 11 H 13 N 3 O 2 requires 219, found 220 [M+H] + . 4-(2-Oxo-3H-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)piperazine -1-carboxamide [00485] Following general procedure D (Method A), XXXVIa (0.050 g, 0.18 mmol) and 4- phenylbutyl isocyanate (0.06 g, 0.35 mmol) afforded the title compound as a white solid (0.030 g, 48%). 1 H NMR (400 MHz, DMSO-d6) d 11.17 (s, 1H), 7.31–7.22 (m, 2H), 7.22–7.12 (m, 3H), 7.00 (d, J = 2.3 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 6.75 (dd, J = 8.6, 2.3 Hz, 1H), 6.56 (t, J = 5.5 Hz, 1H), 3.41 (t, J = 5.1 Hz, 4H), 3.12–2.92 (m, 6H), 2.58 (t, J = 7.5 Hz, 2H), 1.65–1.49 (m, 2H), 1.49–1.35 (m, 2H). UPLC/MS (method A): Rt 1.94 min. MS (ES) C22H26N4O3 requires 394, found 395 [M+H] + , 393 [M-H]-. Example 46: 4-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)pipe razine-1- carboxamide tert-Butyl 4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)piperazine-1-carboxyla te (XXXVa) [00486] Following general procedure C (step 1), XXXIIIa (0.065 g, 0.204 mmol) and MeI (0.116 g, 0.814 mmol) afforded XXXVa as a pink solid (0.055 g, 82%). The residue was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) d 7.03–6.73 (m, 3H), 3.76–3.55 (m, 4H), 3.39 (s, 3H), 3.10 (q, J = 5.1 Hz, 4H), 1.51 (s, 9H). UPLC/MS (method A): Rt 2.09 min. MS (ES) C 17 H 23 N 3 O 4 requires 333, found 334 [M+H] + . 3-Methyl-6-piperazin-1-yl-1,3-benzoxazol-2-one hydrochloride (XXXVIa) [00487] Following general procedure C (step 2), XXXVa (0.052 g, 0.156 mmol) afforded XXXVIa as a gray solid (0.045 g, 95%). 1 H NMR (400 MHz, DMSO-d 6 ) d 9.31 (br s, 2H), 7.20–7.08 (m, 2H), 6.88 (dd, J = 8.6, 2.3 Hz, 1H), 3.41–3.28 (m, 7H), 3.21 (q, J = 4.8 Hz, 4H). UPLC/MS (method A): Rt 0.91 min. MS (ES) C12H15N3O2 requires 233, found 234 [M+H] + . 4-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)pipe razine-1-carboxamide [00488] Following general procedure D (Method A), XXXVIa (0.040 g, 0.131 mmol) and 4- phenylbutyl isocyanate (0.025 g, 0.144 mmol) afforded the title compound as a white solid (0.040 g, 75%). 1 H NMR (400 MHz, CDCl 3 ) d 7.34–7.25 (m, 2H), 7.24–7.15 (m, 3H), 6.94–6.84 (m, 2H), 6.84–6.74 (m, 1H), 4.53 (t, J = 5.7 Hz, 1H), 3.64–3.48 (m, 4H), 3.39 (s, 3H), 3.35–3.24 (m, 2H), 3.18–3.03 (m, 4H), 2.67 (t, J = 7.5 Hz, 2H), 1.81–1.64 (m, 2H), 1.64–1.52 (m, 2H). UPLC/MS (method A): Rt 2.05 min. MS (ES) C 23 H 28 N 4 O 3 requires 408, found 409 [M+H] + . Example 47: 4-[3-[2-(Dimethylamino)ethyl]-2-oxo-1,3-benzoxazol-6-yl]-N-( 4- phenylbutyl)piperazine-1-carboxamide tert-Butyl 4-[3-[2-(dimethylamino)ethyl]-2-oxo-1,3-benzoxazol-6-yl]pipe razine-1- carboxylate (XXXVb) [00489] Step 1: To a solution of XXXIIIa (0.250 g, 0.78 mmol) in DMF (0.2 M) was added K2CO3 (0.325 g, 2.35 mmol) and 1,2-dibromoethane (0.054 mL, 6.26 mmol) at RT and the reaction was stirred at 60°C for 3h. The mixture was poured into ice and the precipitate was filtered, solubilized in DCM and dried over Na2SO4. After evaporation of the solvent, tert-butyl 4-[3-(2-bromoethyl)-2-oxo-1,3-benzoxazol-6-yl]piperazine-1-c arboxylate was used in the next step without further purification (0.294 g, 88%). 1 H NMR (400 MHz,CDCl 3 ) d 7.02–6.89 (m, 2H), 6.88–6.76 (m, 1H), 4.22 (t, J = 6.6 Hz, 2H), 3.74–3.53 (m, 6H), 3.18–2.99 (m, 4H), 1.51 (s, 9H). UPLC/MS (method A): Rt 2.30 min. MS (ES) C18H24BrN3O4 requires 425, found 426 [M+H] + . [00490] Step 2: To a solution of the compound from Step 1 (0.080 g, 0.19 mmol) in DMF (0.2 M) was added K2CO3 (0.078 g, 0.56 mmol) and NHMe2 (0.94 mL, 1.877 mmol) at RT and the reaction was stirred at 60°C for 2h and then cooled to RT, poured into ice and the precipitate was filtered off. The residue was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) d 7.02 (d, J = 8.5 Hz, 1H), 6.88 (d, J = 2.2 Hz, 1H), 6.78 (dd, J = 8.5, 2.3 Hz, 1H), 4.02 (t, J = 6.9 Hz, 2H), 3.66–3.56 (m, 4H), 3.14–3.03 (m, 4H), 2.82 (t, J = 6.0 Hz, 2H), 2.44 (s, 6H), 1.51 (s, 9H). UPLC/MS (method A): Rt 1.69 min. MS (ES) C 20 H 30 N 4 O 4 requires 390, found 391 [M+H] + . 3-[2-(Dimethylamino)ethyl]-6-piperazin-1-yl-1,3-benzoxazol-2 -one dihydrochloride (XXXVIb) [00491] Following general procedure C (step 2), XXXVb (0.055 g, 0.141 mmol) afforded XXXVIb as a gray solid (0.050 g, 98%). 1 H NMR (400 MHz, DMSO-d 6 ) d 10.70 (br s, 1H), 9.45 (br s, 2H), 7.34 (d, J = 8.6 Hz, 1H), 7.16 (d, J = 2.2 Hz, 1H), 6.89 (dd, J = 8.6, 2.3 Hz, 1H), 4.22 (t, J = 6.3 Hz, 2H), 3.49–3.37 (m, 2H), 3.39–3.28 (m, 4H), 3.25–3.15 (m, 4H), 2.85 (s, 3H), 2.83 (s, 3H). UPLC/MS (method A): Rt 0.46 min. MS (ES) C 15 H 22 N 4 O 2 requires 290, found 291 [M+H] + . 4-[3-[2-(Dimethylamino)ethyl]-2-oxo-1,3-benzoxazol-6-yl]-N-( 4-phenylbutyl)piperazine-1- carboxamide [00492] Following general procedure D (Method A), XXXVIb (0.048 g, 0.132 mmol) and 4- phenylbutyl isocyanate (0.025 g, 0.145 mmol) afforded the title compound as a white solid (0.040 g, 65%). 1 H NMR (400 MHz, DMSO-d6) d 7.33–7.23 (m, 2H), 7.25–7.11 (m, 4H), 7.06 (d, J = 2.2 Hz, 1H), 6.82 (dd, J = 8.7, 2.3 Hz, 1H), 6.56 (t, J = 5.5 Hz, 1H), 3.86 (t, J = 6.2 Hz, 2H), 3.55–3.36 (m, 4H), 3.25–2.88 (m, 6H), 2.63–2.52 (m, 4H), 2.16 (s, 6H), 1.67–1.50 (m, 2H), 1.50–1.35 (m, 2H). UPLC/MS (method A): Rt 1.80 min. MS (ES) C26H35N5O3 requires 465, found 466 [M+H] + . Example 48: (2R)-2-Methyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4- phenylbutyl)piperazine-1-carboxamide tert-Butyl (2R)-4-(3-hydroxy-4-nitrophenyl)-2-methylpiperazine-1-carbox ylate (XXXIb) [00493] Following general procedure F, XXXb (0.89 g, 4.77 mmol) and 5-fluoro-2- nitrophenol (0.5 g, 3.18 mmol) afforded XXXIb as an orange solid (0.865 g, 81%). 1 H NMR (400 MHz, CDCl3) d 11.25 (s, 1H), 7.96 (d, J = 9.6 Hz, 1H), 6.37 (dd, J = 9.7, 2.7 Hz, 1H), 6.25 (d, J = 2.7 Hz, 1H), 4.38–4.26 (m, 1H), 3.91 (dt, J = 13.6, 4.0 Hz, 1H), 3.80–3.69 (m, 1H), 3.67– 3.57 (m, 1H), 3.42–3.30 (m, 2H), 3.19 (ddd, J = 12.3, 10.3, 3.8 Hz, 1H), 1.48 (s, 9H), 1.20 (d, J = 6.7 Hz, 3H). UPLC/MS (method A): Rt 2.39 min. MS (ES) C16H23N3O5 requires 337, found 338 [M+H] + . tert-Butyl (2R)-4-(4-amino-3-hydroxyphenyl)-2-methylpiperazine-1-carbox ylate (XXXIIb) [00494] Following general procedure B (Method A), XXXIb (0.400 g, 1.186 mmol) afforded XXXIIb which was used in the next step without further purification. UPLC/MS (method A): Rt 1.82 min. MS (ES) C 16 H 25 N 3 O 3 requires 307, found 308 [M+H] + . tert-Butyl (2R)-2-methyl-4-(2-oxo-3H-1,3-benzoxazol-6-yl)piperazine-1-c arboxylate (XXXIIIb) [00495] Following general procedure B (step 2), XXXIIb (0.365 g, 1.186 mmol) afforded XXXIIIb as a pink solid (0.192 g, 49%). 1 H NMR (400 MHz, CDCl3) d 8.61 (bs, 1H), 7.00–6.91 (m, 1H), 6.90–6.82 (m, 1H), 6.80–6.70 (m, 1H), 4.36 (s, 1H), 3.97 (d, J = 13.2 Hz, 1H), 3.39 (d, J = 11.8 Hz, 1H), 3.34–3.20 (m, 2H), 2.99–2.88 (m, 1H), 2.83–2.68 (m, 1H), 1.49 (s, 9H), 1.34 (d, J = 6.8 Hz, 3H). UPLC/MS (method A): Rt 2.07 min. MS (ES) C17H23N3O4 requires 333, found 334 [M+H] + . tert-Butyl (2R)-2-methyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)piperazi ne-1-carboxylate (XXXVc) [00496] Following general procedure C (step 1), XXXIIIb (0.192 g, 0.58 mmol) and MeI (0.14 g, 0.86 mmol) afforded XXXVc as a white solid (0.160 g, 79%). 1 H NMR (400 MHz, CDCl3) d 7.05–6.66 (m, 3H), 4.37 (s, 1H), 3.98 (d, J = 13.1 Hz, 1H), 3.45–3.20 (m, 5H), 3.02– 2.90 (m, 1H), 2.86–2.70 (m, 1H), 1.49 (s, 9H), 1.36 (d, J = 6.6 Hz, 3H). UPLC/MS (method A): Rt 2.26 min. MS (ES) C18H25N3O4 requires 347, found 348 [M+H] + . 3-Methyl-6-[(3R)-3-methylpiperazin-1-yl]-1,3-benzoxazol-2-on e hydrochloride (XXXVIc) [00497] Following general procedure C (step 2), XXXVb (0.160 g, 0.46 mmol) afforded XXXVIc as a white solid (0.09 g, 68%). 1 H NMR (400 MHz, CDCl 3 ) d 9.98–9.17 (m, 2H), 7.25–7.10 (m, 2H), 6.98–6.83 (m, 1H), 3.75–3.59 (m, 2H), 3.41–3.25 (m, 5H), 3.16–2.94 (m, 2H), 2.87–2.74 (m, 1H), 1.31 (d, J = 6.5 Hz, 3H). UPLC/MS (method A): Rt 0.99 min. MS (ES) C 13 H 17 N 3 O 2 requires 247, found 248 [M+H] + . (2R)-2-Methyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-ph enylbutyl)piperazine-1- carboxamide [00498] Following general procedure D (Method A), XXXVIc (0.03 g, 0.160 mmol) and 4- phenylbutyl isocyanate (0.020 g, 0.12 mmol) afforded the title compound as a white solid (0.013 g, 29%). 1 H NMR (400 MHz, DMSO-d6) d 7.31–7.23 (m, 2H), 7.22–7.13 (m, 3H), 7.09 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 2.2 Hz, 1H), 6.81 (dd, J = 8.6, 2.3 Hz, 1H), 6.47 (t, J = 5.5 Hz, 1H), 4.26–4.17 (m, 1H), 3.78 (d, J = 13.1 Hz, 1H), 3.48 (d, J = 11.5 Hz, 1H), 3.39 (d, J = 11.7 Hz, 1H), 3.29 (s, 3H), 3.12–2.98 (m, 3H), 2.72 (dd, J = 11.8, 3.7 Hz, 1H), 2.61–2.54 (m, 2H), 2.54– 2.52 (m, 1H), 1.60–1.50 (p, J = 7.0 Hz, 2H), 1.42 (p, J = 7.0 Hz, 2H), 1.16 (d, J = 6.6 Hz, 3H). UPLC/MS (method A): Rt 2.16 min. MS (ES) C24H30N4O3 requires 422, found 423 [M+H] + . Example 49: (2S)-2-Methyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4- phenylbutyl)piperazine-1-carboxamide tert-Butyl (2S)-4-(3-hydroxy-4-nitrophenyl)-2-methylpiperazine-1-carbox ylate (XXXIc) [00499] Following general procedure F, XXXc (1.27 g, 6.36 mmol) and 5-fluoro-2- nitrophenol (0.5 g, 3.18 mmol) afforded XXXIc as a yellow solid. The residue was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 ) d 11.25 (s, 1H), 7.96 (d, J = 9.6 Hz, 1H), 6.36 (dd, J = 9.7, 2.7 Hz, 1H), 6.25 (d, J = 2.7 Hz, 1H), 4.37–4.27 (m, 1H), 3.91 (dt, J = 13.4, 3.7 Hz, 1H), 3.75 (dt, J = 12.4, 3.4 Hz, 1H), 3.62 (dd, J = 13.3, 2.0 Hz, 1H), 3.42–3.29 (m, 2H), 3.19 (td, J = 11.5, 10.5, 3.8 Hz, 1H), 1.48 (s, 9H), 1.20 (d, J = 6.7 Hz, 3H). UPLC/MS (method B): Rt 1.26 min. MS (ES) C 16 H 23 N 3 O 5 requires 337, found 338 [M+H] + . tert-Butyl (2S)-4-(4-amino-3-hydroxyphenyl)-2-methylpiperazine-1-carbox ylate (XXXIIc) [00500] Following general procedure B (Method A), XXXIc (1.43 g, 4.24 mmol) afforded which XXXIIc was used in the next step without further purification. UPLC/MS (method A): Rt 1.84 min. MS (ES) C 16 H 25 N 3 O 3 requires 307, found 308 [M+H] + . tert-Butyl (2S)-2-methyl-4-(2-oxo-3H-1,3-benzoxazol-6-yl)piperazine-1-c arboxylate [00501] Following general procedure B (step 2), XXXIIc (1.29 g, 4.24 mmol) afforded XXXIIIc as a pink solid (0.260 g, 20%). 1 H NMR (400 MHz, CDCl3) d 9.71 (s, 1H), 6.96 (d, J = 8.5 Hz, 1H), 6.81 (d, J = 1.9 Hz, 1H), 6.71 (dd, J = 8.5, 2.0 Hz, 1H), 4.35 (s, 1H), 3.95 (d, J = 13.3 Hz, 1H), 3.43–3.31 (m, 1H), 3.31–3.18 (m, 2H), 2.90 (dd, J = 11.8, 3.8 Hz, 1H), 2.71 (td, J =11.6, 3.5 Hz, 1H), 1.48 (s, 9H), 1.31 (d, J = 6.7 Hz, 3H). UPLC/MS (method A): Rt 2.08 min. MS (ES) C17H23N3O4 requires 333, found 334 [M+H] + . tert-Butyl (2S)-2-methyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)piperazi ne-1-carboxylate (XXXVd) [00502] Following general procedure C (step 1), XXXIIIe (0.260 g, 0.78 mmol) and MeI (0.55 g, 3.90 mmol) afforded XXXVd as a pink solid. The residue was used in the next step without further purification. UPLC/MS (method A): Rt 2.27 min. MS (ES) C18H25N3O4 requires 347, found 348 [M+H] + . 3-Methyl-6-[(3S)-3-methylpiperazin-1-yl]-1,3-benzoxazol-2-on e hydrochloride (XXXVId) [00503] Following general procedure C (step 2), XXXVc (0.310 g, 0.89 mmol) afforded XXXVId as a gray solid (0.245 g, 97%). 1 H NMR (400 MHz, DMSO-d6) d 9.76–9.58 (m, 1H), 9.49–9.27 (m, 1H), 7.16–7.10 (m, 2H), 6.88 (dd, J = 8.5, 2.2 Hz, 1H), 3.74–3.59 (m, 2H), 3.42– 3.26 (m, 2H), 3.30 (s, 3H), 3.16–2.94 (m, 2H), 2.85–2.74 (m, 1H), 1.31 (d, J = 6.5 Hz, 3H). (UPLC/MS (method A): Rt 0.96 min. MS (ES) C 13 H 17 N 3 O 2 requires 247, found 248 [M+H] + . (2S)-2-Methyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-ph enylbutyl)piperazine-1- carboxamide [00504] Following general procedure D (Method A), XXXVId (0.050 g, 0.18 mmol) and 4- phenylbutyl isocyanate (0.06 g, 0.35 mmol) afforded the title compound as a white solid (30 mg, 45%). 1 H NMR (400 MHz, DMSO-d6) d 7.27 (t, J = 7.4 Hz, 2H), 7.22–7.13 (m, 3H), 7.09 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 2.1 Hz, 1H), 6.81 (dd, J = 8.6, 2.2 Hz, 1H), 6.47 (t, J = 5.4 Hz, 1H), 4.26–4.17 (m, 1H), 3.82–3.74 (m, 1H), 3.51–3.44 (m, 1H), 3.43–3.35 (m, 1H), 3.29 (s, 3H), 3.14–2.96 (m, 3H), 2.72 (dd, J = 11.8, 3.6 Hz, 1H), 2.62–2.54 (m, 2H), 2.55–2.52 (m, 1H), 1.55 (p, J = 7.3, 8.0 Hz, 2H), 1.42 (p, J = 7.0 Hz, 2H), 1.16 (d, J = 6.6 Hz, 3H). UPLC/MS (method A): Rt 2.17 min. MS (ES) C 24 H 30 N 4 O 3 requires 422, found 423 [M+H] + . Example 50: 2,2-Dimethyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4- phenylbutyl)piperazine-1-carboxamide tert-Butyl 4-(3-hydroxy-4-nitrophenyl)-2,2-dimethylpiperazine-1-carboxy late (XXXId) [00505] Following general procedure F, XXXd (0.6 g, 2.8 mmol) and 5-fluoro-2-nitrophenol (0.66 g, 4.2 mmol) afforded XXXId as a yellow solid (0.436 g, 83%). 1 H NMR (400 MHz, CDCl 3 ) 11.33 (s, 1H), 7.97 (d, J = 9.6 Hz, 1H), 6.30 (dd, J = 9.7, 2.7 Hz, 1H), 6.15 (d, J = 2.7 Hz, 1H), 3.88 (t, J = 5.7 Hz, 2H), 3.59–3.46 (m, 4H), 1.50 (s, 9H), 1.42 (s, 6H). d UPLC/MS (method A): Rt 2.51 min. MS (ES) C17H25N3O5 requires 351, found 352 [M+H] + . tert-Butyl 4-(4-amino-3-hydroxyphenyl)-2,2-dimethyl-piperazine-1-carbox ylate (XXXIId) [00506] Following general procedure B (Method C), XXXId (0.436 g, 1.24 mmol) afforded XXXIId which was used in the next step without further purification. UPLC/MS (method A): Rt 1.64 min. MS (ES) C17H27N3O3 requires 321, found 322 [M+H] + . tert-Butyl 2,2-dimethyl-4-(2-oxo-3H-1,3-benzoxazol-6-yl)piperazine-1-ca rboxylate (XXXIIId) [00507] Following general procedure B (step 2), XXXIId (0.4 g, 1.24 mmol) and CDI (1.01 g, 6.2 mmol) afforded XXIIId as a lilac solid (0.316 g, 73%). 1 H NMR (400 MHz, CDCl 3 ) d 8.30 (s, 1H), 6.92 (d, J = 8.6 Hz, 1H), 6.77–6.71 (m, 1H), 6.65–6.56 (m, 1H), 3.81 (t, J = 8.0 Hz, 2H), 3.35 (t, J = 5.5 Hz, 2H), 3.21 (s, 2H), 1.50 (s, 9H), 1.46 (s, 6H). UPLC/MS (method A): Rt 2.28 min. MS (ES) C 18 H 25 N 3 O 4 requires 347, found 348 [M+H] + . tert-Butyl 2,2-dimethyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)piperazin e-1-carboxylate (XXXVe) [00508] Following general procedure C (step 1), XXXIIId (0.100 g, 0.288 mmol) and MeI (0.031 mL, 0.434 mmol) afforded XXXVe which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 ) d 6.82 (d, J = 8.5 Hz, 1H), 6.68 (d, J = 2.3 Hz, 1H), 6.57 (dd, J = 8.6, 2.3 Hz, 1H), 3.78 (t, J = 5.6 Hz, 2H), 3.35 (s, 3H), 3.32 (t, J = 5.6 Hz, 2H), 3.20 (s, 2H), 1.49 (s, 9H), 1.44 (s, 6H. UPLC/MS (method A): Rt 2.58 min. MS (ES) C19H27N3O4 requires 361, found 362 [M+H] + . 6-(3,3-Dimethylpiperazin-1-yl)-3-methyl-1,3-benzoxazol-2-one hydrochloride (XXXVIe) [00509] Following general procedure C (step 2), XXXVe (0.104 g, 0.288 mmol) afforded XXXVIe which was used in the next step without further purification 1 H NMR (400 MHz, DMSO-d6) 1 H NMR (400 MHz, DMSO-d6) d 9.44–9.28 (m, 2H), 7.13 (d, J = 8.5 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H), 6.85 (dd, J = 8.6, 2.3 Hz, 1H), 3.30 (s, 3H), 3.29–3.20 (m, 4H), 3.13 (s, 2H), 1.40 (s, 6H). d UPLC/MS (method A): Rt 1.17 min. MS (ES) C 14 H 19 N 3 O 2 requires 261, found 262 [M+H] + . 2,2-Dimethyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phe nylbutyl)piperazine-1- carboxamide [00510] Following general procedure D (Method A), XXXVIe (0.05 g, 0.172 mmol) and 4- phenylbutyl isocyanate (0.036 g, 0.260 mmol) afforded the title compound as a white solid (0.045 g, 60%). 1 H NMR (400 MHz, DMSO-d6) d 7.31–7.25 (m, 2H), 7.22–7.15 (m, 3H), 7.07 (d, J = 8.6 Hz, 1H), 6.93 (d, J = 2.2 Hz, 1H), 6.69 (dd, J = 8.6, 2.3 Hz, 1H), 6.36 (t, J = 5.5 Hz, 1H), 3.46 (t, J = 5.5 Hz, 2H), 3.29 (s, 3H), 3.23–3.14 (m, 4H), 3.09 (s, 2H), 3.02 (q, J = 6.6 Hz, 2H), 2.58 (t, J = 7.6 Hz, 2H), 1.56 (p, J = 7.5 Hz, 2H), 1.43 (p, J = 7.6 Hz, 2H), 1.37 (s, 6H). UPLC/MS (method A): Rt 2.32 min. MS (ES) C25H32N4O3 requires 436, found 437 [M+H] + . Example 51: 2,2-Dimethyl-4-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(2- [00511] Following general procedure D (Method A), XXXVIe (0.028 g, 0.090 mmol) and 4- phenylethyl isocyanate (0.010 g, 0.070 mmol) afforded the title compound as a white solid (0.022 g, 57%). 1 H NMR (400 MHz, DMSO-d 6 ) d 7.37–7.27 (m, 2H), 7.25–7.14 (m, 3H), 7.07 (d, J = 8.6 Hz, 1H), 6.93 (d, J = 2.3 Hz, 1H), 6.70 (dd, J = 8.7, 2.3 Hz, 1H), 6.46 (t, J = 5.4 Hz, 1H), 3.45 (t, J = 5.5 Hz, 2H), 3.26–3.16 (m, 4H), 3.10 (s, 2H), 2.78–2.68 (m, 2H), 1.37 (s, 6H). UPLC/MS (method A): Rt 2.13 min. MS (ES) C 23 H 28 N 4 O 3 requires 408, found 409 [M+H] + . Example 52: N-(4-Cyclopropylbutyl)-2,2-dimethyl-4-(3-methyl-2-oxo-1,3-be nzoxazol-6- yl)piperazine-1-carboxamide [00512] Following general procedure D (Method C), XXXVIe (0.040 g, 0.130 mmol) and 4- cyclopropylbutan-1-amine (0.029 g, 0.256 mmol) afforded the title compound as a white solid (0.026 g, 49%). 1 H NMR (400 MHz, DMSO-d 6 ) d 7.07 (d, J = 8.6 Hz, 1H), 6.93 (d, J = 2.3 Hz, 1H), 6.70 (dd, J = 8.6, 2.3 Hz, 1H), 6.34 (t, J = 5.4 Hz, 1H), 3.47 (t, J = 5.5 Hz, 2H), 3.29 (s, 3H), 3.19 (t, J = 5.5 Hz, 2H), 3.09 (s, 2H), 2.98 (q, J = 6.6 Hz, 2H), 1.49–1.38 (m, 2H), 1.38 (s, 6H), 1.38–1.28 (m, 2H), 1.18 (q, J = 7.0 Hz, 2H), 0.73–0.59 (m, 1H), 0.47–0.28 (m, 2H), 0.08– 0.09 (m, 2H). UPLC/MS (method A): Rt 2.30 min. MS (ES) C 22 H 32 N 4 O 3 requires 400, found 401 [M+H] + . Example 53: N-(2-Cyclopropylethyl)-2,2-dimethyl-4-(3-methyl-2-oxo-1,3-be nzoxazol-6- yl)piperazine-1-carboxamide [00513] Following general procedure D (Method C), XXXVIe (0.040 g, 0.130 mmol) and 2- cyclopropylethanamine (0.022 g, 0.258 mmol) afforded the title compound as a white solid (0.012 g, 24%). 1 H NMR (400 MHz, DMSO-d6) d 7.07 (d, J = 8.5 Hz, 1H), 6.93 (d, J = 2.2 Hz, 1H), 6.69 (dd, J = 8.6, 2.3 Hz, 1H), 6.34 (t, J = 5.4 Hz, 1H), 3.47 (t, J = 5.4 Hz, 2H), 3.29 (s, 3H), 3.19 (t, J = 5.5 Hz, 2H), 3.14–2.97 (m, 4H), 1.37 (s, 6H), 1.35–1.26 (m, 2H), 0.80–0.56 (m, 1H), 0.51–0.24 (m, 2H), 0.12–0.15 (m, 2H). UPLC/MS (method A): Rt 2.01 min. MS (ES) C 20 H 28 N 4 O 3 requires 372, found 373 [M+H] + . Example 54: 2,2-Dimethyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-pentyl -piperazine-1- carboxamide [00514] Following general procedure D (Method A), XXXVIe (0.028 g, 0.090 mmol) and butyl isocyanate (0.010 g, 0.070 mmol) afforded the title compound as a white solid (0.022 g, 57%). 1 H NMR (400 MHz, DMSO-d6) d 7.25 (d, J = 1.4 Hz, 1H), 7.18–7.09 (m, 2H), 6.44 (t, J = 5.4 Hz, 1H), 3.60 (dt, J = 12.9, 4.1 Hz, 1H), 3.35–3.31 (m, 5H), 3.22 (s, 3H), 3.06–2.96 (m, 3H), 2.84 (ddd, J = 12.3, 8.3, 3.8 Hz, 1H), 1.87–1.77 (m, 1H), 1.67–1.48 (m, 6H), 1.46 (s, 3H), 1.31 (s, 3H). UPLC/MS (method A): Rt 1.81 min. MS (ES) C20H29N3O4 requires 375, found 376 [M+H] + . Example 55: N-(2-Ethoxyethyl)-2,2-dimethyl-4-(3-methyl-2-oxo-1,3-benzoxa zol-6- yl)piperazine-1 carboxamide [00515] Following general procedure D (Method B), XXXVIe (0.029 g, 0.097 mmol) and 2- ethoxyethylamine (0.052 g, 0.585 mmol) afforded the title compound as a white solid (0.002 g, 6%). 1 H NMR (400 MHz, CDCl3) d 6.83 (d, J = 8.5 Hz, 1H), 6.71 (d, J = 2.3 Hz, 1H), 6.59 (dd, J = 8.6, 2.3 Hz, 1H), 4.87 (s, 1H), 3.65–3.60 (m, 2H), 3.56 – 3.49 (m, 4H), 3.42 (q, J = 5.1 Hz, 2H), 3.36 (s, 3H), 3.34–3.28 (m, 2H), 3.13 (s, 2H), 1.49 (s, 6H), 1.21 (t, J = 7.0 Hz, 3H). UPLC/MS (method A): Rt 1.77 min. MS (ES) C 19 H 28 N 4 O 4 requires 376, found 377 [M+H] + . Example 56: N-(3-Methoxypropyl)-2,2-dimethyl-4-(3-methyl-2-oxo-1,3-benzo xazol-6- yl)piperazine-1-carboxamide [00516] Following general procedure D (Method B), XXXVIe (0.025 g, 0.084 mmol) and 3- methoxypropylamine (0.045 g, 0.504 mmol) afforded the title compound as a white solid (0.012 g, 38%). 1 H NMR (400 MHz, CDCl 3 ) d 6.82 (d, J = 8.5 Hz, 1H), 6.71 (d, J = 2.3 Hz, 1H), 6.59 (dd, J = 8.5, 2.3 Hz, 1H), 5.22 (s, 1H), 3.62–3.57 (m, 2H), 3.52 (t, J = 5.6 Hz, 2H), 3.38–3.32 (m, 2H), 3.36 (s, 3H), 3.35 (s, 3H), 3.32–3.27 (m, 2H), 3.13 (s, 2H), 1.81 (p, J = 5.8 Hz, 2H), 1.49 (s, 6H). UPLC/MS (method A): Rt 1.73 min. MS (ES) C 19 H 28 N 4 O 4 requires 376, found 377 [M+H] + . Example 57: N-(2-Benzyloxyethyl)-2,2-dimethyl-4-(3-methyl-2-oxo-1,3-benz oxazol-6- yl)piperazine-1-carboxamide [00517] Following general procedure D (Method C), XXXVIe (0.044 g, 0.148 mmol) and 2- benzyloxyethanamine (0.068 g, 0.450 mmol) afforded the title compound as a white solid (0.028 g, 43%). 1 H NMR (400 MHz, DMSO-d6) d 7.43–7.23 (m, 5H), 7.07 (d, J = 8.6 Hz, 1H), 6.93 (d, J = 2.3 Hz, 1H), 6.69 (dd, J = 8.6, 2.3 Hz, 1H), 6.43 (t, J = 5.5 Hz, 1H), 4.49 (s, 2H), 3.46 (dt, J = 17.1, 5.7 Hz, 4H), 3.29 (s, 3H), 3.26–3.16 (m, 4H), 3.11 (s, 2H), 1.37 (s, 6H). UPLC/MS (method A): Rt 2.07 min. MS (ES) C24H30N4O4 requires 438, found 437 [M-H]-. Example 58: 4-[3-[2-(Dimethylamino)ethyl]-2-oxo-1,3-benzoxazol-6-yl]-2,2 -dimethyl-N-(4- phenylbutyl)piperazine-1-carboxamide tert-Butyl 4-[3-[2-(dimethylamino)ethyl]-2-oxo-1,3-benzoxazol-6-yl]-2,2 -dimethyl- piperazine-1-carboxylate (XXXVf) [00518] Step 1: To a solution of XXXd (0.080 g, 0.23 mmol) in DMF (0.2 M) were added K2CO3 (0.095 g, 0.69 mmol) and 1,2-dibromoethane (0.346 g, 1.84 mmol) at RT and the reaction was stirred at 60°C for 3h. The mixture was poured into ice and the precipitate was filtered, solubilized in DCM and dried over Na 2 SO 4 . After evaporation of the solvent, tert-butyl 4-[3-(2-bromoethyl)-2-oxo-1,3-benzoxazol-6-yl]-2,2-dimethylp iperazine-1-carboxylate was used in the next step without further purification. 1 H NMR (400 MHz,CDCl3) d 6.92 (d, J = 8.6 Hz, 1H), 6.71 (d, J = 2.3 Hz, 1H), 6.59 (dd, J = 8.6, 2.4 Hz, 1H), 4.18 (t, J = 6.6 Hz, 2H), 3.80 (dd, J = 6.3, 5.0 Hz, 2H), 3.65 (t, J = 6.6 Hz, 2H), 3.34 (t, J = 5.6 Hz, 2H), 3.22 (s, 2H), 1.49 (s, 9H), 1.45 (s, 6H). UPLC/MS (method A): Rt 2.60 min. MS (ES) C20H28BrN3O4 requires 454, found 455 [M+H] + . [00519] Step 2: To a solution of tert-butyl 4-[3-(2-bromoethyl)-2-oxo-1,3-benzoxazol-6-yl]- 2,2-dimethylpiperazine-1-carboxylate (0.105 g, 0.23 mmol) in DMF (0.2 M) were added K2CO3 (0.095 g, 0.69 mmol) and NHMe 2 (2M in THF, 1.0 mL, 2.3 mmol) at RT and the reaction was stirred at 60°C for 2h and then cooled to RT, poured into ice and the precipitate was filtered. The residue was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) d 7.29 (s, 1H), 6.63 (d, J = 2.3 Hz, 1H), 6.57 (dd, J = 8.6, 2.4 Hz, 1H), 4.37 (s, 2H), 3.78 (t, J = 5.6 Hz, 2H), 3.32 (t, J = 5.6 Hz, 2H), 3.23 (s, 2H), 2.86–2.57 (m, 8H), 1.49 (s, 9H), 1.42 (s, 6H). UPLC/MS (method A): Rt 2.05 min. MS (ES) C22H34N4O4 requires 418, found 419 [M+H] + . 3-[2-(Dimethylamino)ethyl]-6-(3,3-dimethylpiperazin-1-yl)-1, 3-benzoxazol-2-one [00520] Following general procedure C (step 2), XXXVf (0.096 g, 0.23 mmol) afforded XXXVIf as a gray solid (0.068 g, 76%). 1 H NMR (400 MHz, DMSO-d6) d 10.19 (bs, 2H), 9.32 (bs, 2H), 7.29 (d, J = 8.2 Hz, 1H), 7.14 (d, J = 2.2 Hz, 1H), 6.87 (dd, J = 8.6, 2.2 Hz, 1H), 4.20 (t, J = 6.1 Hz, 2H), 3.53–3.39 (s, 2H), 3.43 (m, 2H), 3.31–3.20 (m, 4H), 3.14 (s, 2H), 2.90–2.80 (m, 6H), 1.40 (s, 6H). UPLC/MS (method A): Rt 0.92 min. MS (ES) C17H26N4O2 requires 318, found 319 [M+H] + . 4-[3-[2-(Dimethylamino)ethyl]-2-oxo-1,3-benzoxazol-6-yl]-2,2 -dimethyl-N-(4- phenylbutyl)piperazine-1-carboxamide [00521] Following general procedure D (method A), XXXVIf (0.035 g, 0.09 mmol) and 4- phenylbutyl isocyanate (0.017 g, 0.096 mmol) afforded the title compound as a white solid (0.012 g, 27%). 1 H NMR (400 MHz, DMSO-d 6 ) d 7.27 (t, J = 7.5 Hz, 2H), 7.21–7.09 (m, 3H), 6.91 (d, J = 2.3 Hz, 1H), 6.67 (dd, J = 8.7, 2.3 Hz, 1H), 6.35 (t, J = 5.5 Hz, 1H), 3.84 (t, J = 6.2 Hz, 2H), 3.45 (t, J = 5.5 Hz, 2H), 3.18 (t, J = 5.4 Hz, 2H), 3.07 (s, 2H), 3.01 (td, J = 7.0, 5.4 Hz, 2H), 2.62–2.51 (m, 4H), 2.16 (s, 6H), 1.61–1.50 (m, 2H), 1.42 (q, J = 7.4 Hz, 2H), 1.36 (s, 6H). UPLC/MS (method A): Rt 2.05 min. MS (ES) C28H39N5O3 requires 493, found 494 [M+H] + . Example 59: 2,6-Dimethyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4- phenylbutyl)piperazine-1-carboxamide tert-Butyl 4-(3-hydroxy-4-nitrophenyl)-2,6-dimethyl-piperazine-1-carbox ylate (XXXIe) [00522] Step 1: Following general procedure F, XXXe (0.78 g, 6.81 mmol) and 5-fluoro-2- nitrophenol (1.0 g, 6.4 mmol) afforded 5-(3,5-dimethylpiperazin-1-yl)-2-nitrophenol as a white powder. The residue was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) d 7.93 (d, J = 9.7 Hz, 1H), 6.43 (dd, J = 9.7, 2.7 Hz, 1H), 6.29 (d, J = 2.7 Hz, 1H), 3.76 (dd, J = 12.6, 2.0 Hz, 2H), 2.94 (dtt, J = 12.6, 6.3, 3.2 Hz, 2H), 2.56 (dd, J = 12.6, 10.7 Hz, 2H), 1.15 (d, J = 6.3 Hz, 6H). UPLC/MS (method A): Rt 1.19 min. MS (ES) C 12 H 17 N 3 O 3 requires 251, found 252 [M+H] + . [00523] Step 2: To a solution of 5-(3,5-dimethylpiperazin-1-yl)-2-nitrophenol (1.0 g, 3.98 mmol) in THF (0.1 M) was added Boc 2 O (0.87g, 3.98 mmol) in the presence of Et 3 N (0.050 g, 0.7 mL, 4.78 mmol) and the reaction mixture was stirred at RT for 1h. Then, the reaction mixture was diluted with EA, washed with saturated aqueous NaHCO3 solution, brine and dried over Na 2 SO 4 . After evaporation of the solvent, the residue was purified by column chromatography (SiO2), eluting with Cy/EA (7:3) to afford XXXIe as an orange oil (0.9 g, 64%). UPLC/MS (method A): Rt 2.50 min. MS (ES) C17H25N3O5 requires 351, found 352 [M+H] + . tert-Butyl 4-(4-amino-3-hydroxyphenyl)-2,6-dimethylpiperazine-1-carboxy late (XXXIIe) [00524] Following general procedure B (Method C), XXXIe (0.70 g, 1.99 mmol) afforded XXXIIe was used in the next step without further purification. UPLC/MS (method A): Rt 1.62 min. MS (ES) C17H27N3O3 requires 321, found 322 [M+H] + . tert-Butyl 2,6-dimethyl-4-(2-oxo-3H-1,3-benzoxazol-6-yl)piperazine-1-ca rboxylate (XXXIIIe) [00525] Following general procedure B (step 2), XXXIIe (0.6 g, 1.86 mmol) afforded XXXIIIe as a pink oil (0.5 g, 72%). 1 H NMR (400 MHz, CDCl 3 ) d 8.69 (bs, 1H), 6.96 (d, J = 8.48 Hz, 1H), 6.84 (d, J = 2.1 Hz, 1H), 6.74 (dd, J = 8.5, 2.2 Hz, 1H), 6.82 (q, J = 6.8 Hz, 2H), 3.24 (d, J = 11.7 Hz, 2H), 2.87 (dd, J = 11.7, 4.3 Hz, 2H), 1.50 (s, 9H), 1.37 (d, J = 6.8 Hz, 6H). UPLC/MS (method A): Rt 2.22 min. MS (ES) C 18 H 25 N 3 O 4 requires 347, found 348 [M+H] + . tert-Butyl 2,6-dimethyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)piperazin e-1-carboxylate (XXXVg) [00526] Following general procedure C (step 1), XXXIIIe (0.2 g, 0.58 mmol) and MeI (0.41 g, 2.90 mmol) afforded XXXVg as a white solid (0.19 g, 91%). UPLC/MS (method B): Rt 1.30 min. MS (ES) C 19 H 27 N 3 O 4 requires 361, found 362 [M+H] + . 6-(3,5-Dimethylpiperazin-1-yl)-3-methyl-1,3-benzoxazol-2-one hydrochloride (XXXVIg) [00527] Following general procedure C (step 2), XXXVe (0.190 g, 0.53 mmol) afforded XXXVIg which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) d 9.96–9.80 (m, 1H), 9.35–9.18 (m, 1H), 7.15 (s, 1H), 7.13 (d, J = 6.7 Hz, 1H), 6.90 (dd, J = 8.6, 2.3 Hz, 1H), 3.72 (d, J = 11.3 Hz, 2H), 3.39–3.28 (m, 2H), 3.29 (s, 3H), 2.83–2.74 (m, 2H), 1.32 (d, J = 6.5 Hz, 6H). UPLC/MS (method A): Rt 1.03 min. MS (ES) C 14 H 19 N 3 O 2 requires 261, found 262 [M+H] + . 2,6-Dimethyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phe nylbutyl)piperazine-1- carboxamide [00528] Following general procedure D (Method A), XXXVIg (0.040 g, 0.12 mmol) and 4- phenylbutyl isocyanate (0.040 g, 0.04 mL, 0.24 mmol) afforded the title compound as white solid (0.030 g mg, 50%). 1 H NMR (400 MHz, CDCl3) d 7.32–7.25 (m, 2H), 7.21–7.15 (m, 2H), 6.87–6.82 (m, 2H), 6.76 (dd, J = 8.4, 1.7 Hz, 1H), 4.45–4.36 (m, 1H), 4.18–4.08 (m, 2H), 3.37 (s, 3H), 3.31 (q, J = 6.5 Hz, 2H), 3.25 (d, J = 11.6 Hz, 2H), 2.89 (dd, J = 11.3, 3.8 Hz, 2H), 2.66 (t, J = 7.5 Hz, 2H), 1.62 (ddt, J = 36.2, 14.4, 7.3 Hz, 4H), 1.39 (d, J = 6.8 Hz, 6H). UPLC/MS (method A): Rt 2.27 min. MS (ES) C25H32N4O3 requires 436, found 437 [M+H] + . Example 60: 7-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)-4,7 - diazaspiro[2.5]octane-4-carboxamide tert-Butyl 7-(3-hydroxy-4-nitrophenyl)-4,7-diazaspiro[2.5]octane-4-carb oxylate (XXXIf) [00529] Following general procedure F, XXXf (0.30 g, 1.4 mmol) and 5-fluoro-2-nitrophenol (0.33 g, 2.1 mmol) afforded XXXIf as an orange solid (0.471 g, 96%). 1 H NMR (400 MHz, CDCl 3 ) d 11.19 (s, 1H), 7.94 (d, J = 9.7 Hz, 1H), 6.37 (dd, J = 9.7, 2.8 Hz, 1H), 6.25 (d, J = 2.7 Hz, 1H), 3.72–3.67 (m, 2H), 3.48–3.41 (m, 2H), 3.23 (s, 2H), 1.48 (s, 9H), 1.12–1.05 (m, 2H), 0.87–0.82 (m, 2H). UPLC/MS (method A): Rt 1.48 min. MS (ES) C17H23N3O5 requires 349, found 350 [M+H] + . tert-Butyl 7-(4-amino-3-hydroxy-phenyl)-4,7-diazaspiro[2.5]octane-4-car boxylate (XXXIIf) [00530] Following general procedure B (Method C), XXXIf (0.47 g, 1.35 mmol) afforded XXXIIf which was used in the next step without further purification. UPLC/MS (method A): Rt 1.65 min. MS (ES) C17H25N3O3 requires 319, found 320 [M+H] + . tert-Butyl 7-(2-oxo-3H-1,3-benzoxazol-6-yl)-4,7-diazaspiro[2.5]octane-4 -carboxylate (XXXIIIf) [00531] Following general procedure B, XXXIIf (0.43 g, 1.35 mmol) and CDI (1.09 g, 6.75 mmol) afforded XXIIIf as a pink solid (0.192 g, 50%). 1 H NMR (400 MHz, DMSO-d 6 ) d 11.28 (bs, 1H), 6.95 (d, J = 2.3 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 6.68 (dd, J = 8.6, 2.3 Hz, 1H), 3.61– 3.51 (m, 2H), 3.08–2.98 (m, 2H), 2.88 (s, 2H), 1.40 (s, 9H), 0.97–0.89 (m, 2H), 0.86–0.78 (m, 2H). UPLC/MS (method A): Rt 2.08 min. MS (ES) C 18 H 23 N 3 O 4 requires 345, found 346 [M+H] + . tert-Butyl 7-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-4,7-diazaspiro[2.5]oc tane-4-carboxylate (XXXVh) [00532] Following general procedure C, XXXIIIf (0.050 g, 0.15 mmol) and CH3I (0.036 g, 0.016 mL, 0.22 mmol) afforded XXXVh which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) d 7.07 (d, J = 8.6 Hz, 1H), 7.01 (d, J = 2.2 Hz, 1H), 6.78 (dd, J = 8.6, 2.3 Hz, 1H), 3.61–3.54 (m, 2H), 3.28 (s, 3H), 3.08–3.01 (m, 2H), 2.91 (s, 2H), 1.40 (s, 9H), 0.96–0.90 (m, 2H), 0.87–0.81 (m, 2H). UPLC/MS (method A): Rt 2.27 min. MS (ES) C 19 H 25 N 3 O 4 requires 359, found 360 [M+H] + . 6-(4,7-Diazaspiro[2.5]octan-7-yl)-3-methyl-1,3-benzoxazol-2- one hydrochloride (XXXVIh) [00533] Following general procedure C, XXXVf (0.053 g, 0.15 mmol) afforded XXXVIh which was used in the next step without further purification 1 H NMR (400 MHz, DMSO-d 6 ) d 9.73 (bs, 2H), 7.12 (d, J = 8.6 Hz, 1H), 7.10 (d, J = 2.2 Hz, 1H), 6.85 (dd, J = 8.6, 2.3 Hz, 1H), 3.41–3.33 (m, 2H), 3.30 (s, 3H), 3.23 (s, 2H), 1.14–1.09 (m, 2H), 0.94–0.86 (m, 2H). UPLC/MS (method A): Rt 104 min MS (ES) C 14 H 17 N 3 O 2 requires 259 found 260 [M+H] + 7-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)-4,7 -diazaspiro[2.5]octane-4- carboxamide (Example 60) [00534] Following general procedure D (Method A), XXXVIf (0.028 g, 0.095 mmol) and 4- phenylbutyl isocyanate (0.020 g, 0.114 mmol) afforded the title compound as a white solid (0.014 g, 34%). 1 H NMR (400 MHz, DMSO-d6) d 7.25–7.19 (m, 2H), 7.17–7.12 (m, 3H), 7.07 (d, J = 8.6 Hz, 1H), 6.98 (d, J = 2.3 Hz, 1H), 6.75 (dd, J = 8.6, 2.3 Hz, 1H), 6.34 (t, J = 5.8 Hz, 1H), 3.60 (s, 2H), 3.28 (s, 3H), 3.10 (q, J = 6.5 Hz, 2H), 2.99–2.93 (m, 2H), 2.91 (s, 2H), 2.55 (t, J = 7.5 Hz, 2H), 1.58–1.37 (m, 4H), 0.97–0.79 (m, 4H). UPLC/MS (method A): Rt 2.19 min. MS (ES) C 25 H 30 N 4 O 3 requires 434, found 435 [M+H] + . Example 61: 3-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)-3,8 - diazabicyclo[3.2.1]octane-8-carboxamide tert-Butyl 3-(3-hydroxy-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (XXXIg) [00535] Following general procedure F, XXXg (0.99 g, 4.66 mmol) and 5-fluoro-2- nitrophenol (0.95 g, 6.06 mmol) afforded XXXIg as a yellow solid (1.63 g, 94%). 1 H NMR (400 MHz, CDCl 3 ) d 11.20 (s, 1H), 7.98 (d, J = 9.6 Hz, 1H), 6.41 (dd, J = 9.7, 2.8 Hz, 1H), 6.30 (d, J = 2.7 Hz, 1H), 4.52–4.28 (m, 2H), 3.59 (d, J = 2.2 Hz, 1H), 3.56 (d, J = 2.2 Hz, 1H), 3.25 (s, 1H), 3.22 (s, 1H), 2.09–1.93 (m, 2H), 1.81–1.71 (m, 2H), 1.51 (s, 9H). UPLC/MS (method A): Rt 2.44 min. MS (ES) C17H23N3O5 requires 349, found 350 [M+H] + . tert-Butyl 3-(4-amino-3-hydroxyphenyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (XXXIIg) [00536] Following general procedure B (Method C), XXXIg (0.250 g, 0.72 mmol) afforded XXXIIg which was used in the next step without further purification. UPLC/MS (method A): Rt 1.85 min. MS (ES) C 17 H 25 N 3 O 3 requires 319, found 320 [M+H] + . tert-Butyl 3-(2-oxo-3H-1,3-benzoxazol-6-yl)-3,8-diazabicyclo[3.2.1]octa ne-8-carboxylate (XXXIIIg) [00537] Following general procedure B (step 2), XXXIIg (0.230 g, 0.720 mmol) afforded XXIXh as a light pink solid (0.134 g, 54%). 1 H NMR (400 MHz, CDCl3) d 8.34 (s, 1H), 6.94 (d, J = 8.7 Hz, 1H), 6.88 (s, 1H), 6.77 (d, J = 8.7 Hz, 1H), 4.61–4.35 (m, 2H), 3.48–3.28 (m, 2H), 3.14–3.01 (m, 2H), 2.06–1.97 (m, 4H), 1.50 (s, 9H). UPLC/MS (method A): Rt 2.09 min. MS (ES) C18H23N3O4 requires 345, found 346 [M+H] + . tert-Butyl 3-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-3,8-diazabicyclo[3.2. 1]octane-8- carboxylate (XXXVi) [00538] Following general procedure C (step 1), XXXIIIg (0.210 g, 0.608 mmol) and MeI (0.129 g, 0.912 mmol) afforded XXXVi as a white solid (0.180 g, 83%). 1 H NMR (400 MHz, CDCl3) d 6.91–6.81 (m, 2H), 6.81–6.72 (m, 1H), 4.50–4.26 (m, 2H), 3.38 (s, 3H), 3.37–3.30 (m, 2H), 3.14–2.88 (m, 2H), 2.07–1.91 (m, 4H). UPLC/MS (method A): Rt 2.28 min. MS (ES) C 19 H 25 N 3 O 4 requires 359, found 360 [M+H] + . 6-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-3-methyl-1,3-benzoxazo l-2-one hydrochloride (XXXVIi) [00539] Following general procedure C (step 2), XXXVi (0.175 g, 0.487 mmol) afforded XXXVIi as a white solid (0.045 g, 95%). 1 H NMR (400 MHz, DMSO-d6) d 9.66–9.37 (m, 2H), 7.11 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 2.3 Hz, 1H), 6.77 (dd, J = 8.6, 2.3 Hz, 1H), 4.13–4.08 (m, 2H), 3.60–3.50 (m, 2H), 3.30 (s, 3H), 3.16–3.08 (m, 2H), 2.06–1.86 (m, 4H). UPLC/MS (method A): Rt 1.07 min. MS (ES) C14H17N3O2 requires 259, found 260 [M+H] + . 3-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)-3,8 -diazabicyclo[3.2.1]octane-8- carboxamide [00540] Following general procedure D (Method A), XXXVIi (0.040 g, 0.120 mmol) and 4- phenylbutyl isocyanate (0.023 g, 0.132 mmol) afforded the title compound as a white solid (0.032 g, 61%). 1 H NMR (400 MHz, DMSO-d 6 ) d 7.27–7.20 (m, 2H), 7.20–7.11 (m, 3H), 7.07 (d, J = 8.6 Hz, 1H), 6.95 (d, J = 2.3 Hz, 1H), 6.71 (dd, J = 8.7, 2.3 Hz, 1H), 6.62 (t, J = 5.7 Hz, 1H), 4.43–4.23 (m, 2H), 3.37 (dd, J = 11.2, 2.4 Hz, 2H), 3.29 (s, 3H), 3.14–3.02 (m, 2H), 2.76 (dd, J = 11.1, 2.0 Hz, 2H), 2.60–2.52 (m, 2H), 1.85–1.66 (m, 4H), 1.61–1.48 (m, 2H), 1.48–1.35 (m, 2H). UPLC/MS (method A): Rt 2.15 min. MS (ES) C25H30N4O3 requires 434, found 435 Example 62: 8-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-7-oxo-N-(4-phenylbuty l)-2-oxa-5,8- diazaspiro[3.5]nonane-5-carboxamide Benzyl 7-oxo-2-oxa-5,8-diazaspiro[3.5]nonane-5-carboxylate (XXXh) [00541] To a solution of 2-oxa-5,8-diazaspiro[3.5]nonan-7-one (0.22 g, 1.55 mmol) and DIPEA (0.40 g, 3.10 mmol) in anydrous DCM (0.1 M) was added benzyl chloroformate (0.53 g, 3.10 mmol) at 0°C and the reaction mixture was stirred at RT for 2h. The reaction mixture was diluted with DCM, washed with a saturated aq. NaHCO 3 solution, brine and dried over Na 2 SO 4 to afford XXXh as a yellow solid (0.320 g, 75%). 1 H NMR (400 MHz, DMSO-d6) d 8.04 (s, 1H), 7.51–7.29 (m, 5H), 5.12 (s, 2H), 4.86 (d, J = 6.5 Hz, 2H), 4.27 (d, J = 6.5 Hz, 2H), 3.93 (s, 2H), 3.61 (d, J = 2.6 Hz, 2H). UPLC/MS (method A): Rt 1.41 min. MS (ES) C 14 H 16 N 2 O 4 requires 276, found 277 [M+H] + . Benzyl 8-(3-benzyloxy-4-nitrophenyl)-7-oxo-2-oxa-5,8-diazaspiro[3.5 ]nonane-5-carboxylate (XXXIh) [00542] Following general procedure E, XXXh (0.215 g, 0.78 mmol) afforded XXXIh as a yellow solid (0.222 g, 56%). 1 H NMR (400 MHz, CDCl 3 ) d 7.98 (d, J = 8.8 Hz, 1H), 7.52–7.46 (m, 2H), 7.46–7.33 (m, 8H), 7.26 (d, J = 2.1 Hz, 1H), 6.96 (dd, J = 8.8, 2.2 Hz, 1H), 5.25 (s, 2H), 5.23 (s, 2H), 5.13 (d, J = 6.6 Hz, 2H), 4.39 (d, J = 6.7 Hz, 2H), 4.31 (s, 2H), 4.17 (s, 2H). UPLC/MS (method A): Rt 2.40 min. MS (ES) C 27 H 25 N 3 O 7 requires 503, found 504 [M+H] + . Benzyl 8-(4-amino-3-benzyloxyphenyl)-7-oxo-2-oxa-5,8-diazaspiro[3.5 ]nonane-5- carboxylate (XXXIIh) Following general procedure B (Method C), step 1 using XXXIh (0.265 g, 0.53 mmol). The residue was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 ) d 7.55–7.31 (m, 10H), 6.82–6.72 (m, 2H), 6.68 (dd, J = 8.2, 2.2 Hz, 1H), 5.21 (s, 2H), 5.09 (d, J = 13.4 Hz, 4H), 4.42 (d, J = 6.5 Hz, 2H), 4.27 (s, 2H), 4.10 (s, 2H), 3.93 (s, 2H), 3.81–3.73 (m, 1H), 1.92–1.83 (m, 1H). UPLC/MS (method A): Rt 2.15 min. MS (ES) C27H27N3O5 requires 473, found 474 [M+H] + . Benzyl 8-[4-[benzyl(methyl)amino]-3-benzyloxyphenyl]-7-oxo-2-oxa-5, 8- diazaspiro[3.5]nonane-5-carboxylate (XXXVIIa) [00543] To a solution of XXXIIh (0.240 g, 0.51 mmol) in DCE (0.1 M), benzaldehyde (0,10 g, 0.91 mmol) and TFA (0.014 g, 0.01 mL, 0.127 mmol) were added at RT followed by NaBH(AcO) 3 (0.32 g,1.52 mmol). After 2h additional NaBH(AcO) 3 (0.32 g, 1.52 mmol) was added followed by formaldehyde 37% in water (0.76 g, 25.34 mmol) and the reaction was stirred at RT for 2h. The reaction was quenched with MeOH (15 mL), then pH was neutralized with saturated aqueous NaHCO 3 solution, washed with brine and dried over Na 2 SO 4 to afford XXXVII as a white waxy solid (0.285 g, 94%). 1 H NMR (400 MHz, CDCl3) d 7.45–7.33 (m, 10H), 7.27–7.20 (m, 5H), 6.95 (d, J = 8.5 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 6.80 (dd, J = 8.4, 2.4 Hz, 1H), 5.22 (s, 2H), 5.18–5.05 (m, 4H), 4.43 (d, J = 6.6 Hz, 2H), 4.29 (s, 2H), 4.26 (s, 2H), 4.13 (s, 2H), 2.70 (s, 3H). UPLC/MS (method B): Rt 1.88 min. MS (ES) C35H35N3O5 requires 577, found 578 [M+H] + . 8-[3-Hydroxy-4-(methylamino)phenyl]-2-oxa-5,8-diazaspiro[3.5 ]nonan-7-one (XXXVIIIa) [00544] Following general procedure B (method E), XXXVIIa (0.285 g, 0.493 mmol) afforded XXXVIIIa which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) d 9.35 (s, 1H), 6.66–6.51 (m, 2H), 6.47–6.32 (m, 1H), 4.79 (bs, 1H), 4.49 (d, J = 6.2 Hz, 2H), 4.44 (d, J = 6.2 Hz, 2H), 3.76 (s, 2H), 3.38 (s, 2H), 2.72 (s, 3H). UPLC/MS (method A): Rt 1.01 min. MS (ES) C 13 H 17 N 3 O 3 requires 263, found 264 [M+H] + . 8-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-2-oxa-5,8-diazaspiro[ 3.5]nonan-7-one (XXXVIj) [00545] Following general procedure B, XXXVIIIa (0.129 g, 0.493 mmol) afforded XXXVIj as a white solid (0.030 g, 60%). 1 H NMR (400 MHz, CDCl3) d 7.20 (d, J = 1.9 Hz, 1H), 7.14 (dd, J = 8.3, 2.0 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 4.68 (d, J = 6.8 Hz, 2H), 4.66–4.59 (m, 2H), 3.99 (s, 2H), 3.78 (s, 2H), 3.44 (s, 3H). UPLC/MS (method A): Rt 0.95 min. MS (ES) C14H15N3O4 requires 289, found 290 [M+H] + . 8-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-7-oxo-N-(4-phenylbuty l)-2-oxa-5,8- diazaspiro[3.5]nonane-5-carboxamide [00546] Following general procedure D (Method A), XXXVIj (0.030 g, 0.101 mmol) and 4- phenylbutyl isocyanate (0.019 g, 0.111 mmol) afforded the title compound as a white solid (0.038 g, 80%). 1 H NMR (400 MHz, DMSO-d6) d 7.38 (d, J = 1.9 Hz, 1H), 7.31–7.22 (m, 3H), 7.23–7.09 (m, 4H), 6.99 (t, J = 5.5 Hz, 1H), 4.77 (d, J = 6.8 Hz, 2H), 4.45 (d, J = 6.9 Hz, 2H), 4.06 (d, J = 10.2 Hz, 4H), 3.36 (s, 3H), 3.08 (q, J = 6.5 Hz, 2H), 2.59 (t, J = 7.6 Hz, 2H), 1.65– 1.50 (m, 2H), 1.51–1.36 (m, 2H). UPLC/MS (method A): Rt 1.86 min. MS (ES) C25H28N4O5 requires 464, found 465 [M+H] + . Example 63: 4-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-3-oxo-N-(4-phenylbuty l)piperazine-1- carboxamide tert-Butyl 4-(3-benzyloxy-4-nitrophenyl)-3-oxopiperazine-1-carboxylate (XXXIi) [00547] Following general procedure E, XXXi (0.750 g, 3.83 mmol) and 2-benzyloxy-4- bromo-1-nitrobenzene (1.42 g, 4.6 mmol) afforded XXXIi as a yellow solid (0.750 g, 40%). 1 H NMR (400 MHz, CDCl3) d 7.94 (d, J = 8.8 Hz, 1H), 7.49–7.44 (m, 2H), 7.43–7.37 (m, 2H), 7.37–7.27 (m, 2H), 6.95 (dd, J = 8.8, 2.0 Hz, 1H), 5.22 (s, 2H), 4.27 (s, 2H), 3.82–3.71 (m, 4H), 1.50 (s, 9H). UPLC/MS (method A): Rt 2.34 min. MS (ES) C22H25N3O6 requires 427, found 428 tert-Butyl 4-(4-amino-3-hydroxyphenyl)-3-oxo-piperazine-1-carboxylate (XXXIIi) [00548] Following general procedure B (Method B), XXXIi (0.750g, 1.76 mmol) afforded XXXIIi which was used in the next step without further purification. UPLC/MS (method A): Rt 1.47 min. MS (ES) C 15 H 21 N 3 O 4 requires 307, found 308 [M+H] + . tert-Butyl 3-oxo-4-(2-oxo-3H-1,3-benzoxazol-6-yl)piperazine-1-carboxyla te (XXXIIIh) [00549] Following general procedure B (step 2), XXXIIi (0.54 g, 1.75 mmol) afforded XXXIIIh as a violet oil (0.40 g, 68%). 1 H NMR (400 MHz, CDCl 3 ) d 9.29 (bs, 1H), 7.11 (d, J = 1.8 Hz, 1H), 6.97 (dd, J = 8.3, 2.0 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 4.28 (s, 2H), 3.76 (dt, J = 41.9, 4.9 Hz, 4H), 1.51 (s, 9H). UPLC/MS (method A): Rt 1.58 min. MS (ES) C16H19N3O5 requires 333, found 334 [M+H] + . tert-Butyl 4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-3-oxo-piperazine-1-ca rboxylate (XXXVj) [00550] Following general procedure C (step 1), XXXIIIi (0.200 g, 0.6 mmol) and MeI (0.34 g, 2.40 mmol) afforded XXXVj as a whitish solid (0.200g, 99%). UPLC/MS (method A): Rt 1.72 min. MS (ES) C 19 H 27 N 3 O 4 requires 347, found 348 [M+H] + . 3-Methyl-6-(2-oxopiperazin-1-yl)-1,3-benzoxazol-2-one hydrochloride (XXXVIk) [00551] Following general procedure C (step 2), XXXVk (0.20 g, 0.6 mmol) afforded XXXVIk as white solid (0.150 g, 88%). UPLC/MS (method A): Rt 0.75 min. MS (ES) C 12 H 13 N 3 O 3 requires 247, found 248 [M+H] + . 4-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-3-oxo-N-(4-phenylbuty l)piperazine-1-carboxamide [00552] Following general procedure D (Method A), XXXVIk (0.050 g, 0.6 mmol) and 4- phenylbutyl isocyanate (0.34 g, 2.40 mmol) afforded the title compound as white solid (40 mg, 53%). 1 H NMR (400 MHz, CDCl 3 ) d 7.32–7.26 (m, 2H), 7.22–7.14 (m, 3H), 7.10 (d, J = 8.2 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 4.56 (bs, 1H), 4.13 (s, 2H), 3.78 (dd, J = 30.8, 4.8 Hz, 4H), 3.40 (s, 3H), 3.28 (t, J = 6.8 Hz, 2H), 2.64 (t, J = 7.4 Hz, 2H), 1.74–1.48 (m, 4H). UPLC/MS (method A): Rt 1.83 min. MS (ES) C 23 H 26 N 4 O 4 requires 422, found 423 [M+H] + . Example 64: 2,2-Dimethyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-3-oxo-N- (4-phenylbutyl) piperazine-1-carboxamide tert-Butyl 4-(4-amino-3-hydroxy-phenyl)-2,2-dimethyl-3-oxo-piperazine-1 -carboxylate [00553] Following general procedure F, XXXj (1.0 g, 4.4 mmol) and 2-benzyloxy-4-bromo- 1-nitrobenzene (1.6 g, 5.30 mmol) afforded XXXIj as a yellow solid (1.2 g, 60%). 1 H NMR (400 MHz, CDCl 3 ) d 7.94 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 7.1 Hz, 2H), 7.43–7.30 (m, 4H), 6.96 (dd, J = 8.8, 2.1 Hz, 1H), 5.24 (s, 2H), 3.90–3.49 (m, 4H), 1.76 (s, 6H), 1.53 (s, 9H). UPLC/MS (method A): Rt 2.63 min. MS (ES) C24H29N3O6 requires 455, found 456 [M+H] + . tert-Butyl 4-(4-amino-3-hydroxy-phenyl)-2,2-dimethyl-3-oxo-piperazine-1 -carboxylate (XXXIIj) [00554] Following general procedure B (Method A), XXXIj (0.3 g, 0.66 mmol) afforded XXXIIj which was used in the next step without further purification. UPLC/MS (method A): Rt 1.73 min. MS (ES) C 17 H 25 N 3 O 4 requires 335, found 336 [M+H] + . tert-Butyl 2,2-dimethyl-3-oxo-4-(2-oxo-3H-1,3-benzoxazol-6-yl)piperazin e-1-carboxylate (XXXIIIi) [00555] Following general procedure B, XXXIIj (0.22 g, 0.65 mmol) afforded XXXIIIi as a white solid (0.14 g, 59%). 1 H NMR (400 MHz, CDCl3) d 8.90 (bs, 1H), 7.09 (d, J = 1.6 Hz, 1H), 6.92 (dd, J = 8.3, 1.9 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 3.88–3.79 (m, 2H), 3.69 (dd, J = 5.9, 3.9 Hz, 2H), 1.79 (s, 6H), 1.53 (s, 9H). UPLC/MS (method A): Rt 1.89 min. MS (ES) C18H23N3O5 requires 365, found 366 [M+H] + . tert-Butyl 2,2-dimethyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-3-oxo-pi perazine-1- carboxylate (XXXVk) [00556] Following general procedure C, XXXIIIj (0.140 g, 0.38 mmol) and MeI (0.270 g, 1.90 mmol) afforded XXXVk which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) d 7.17 (d, J = 1.9 Hz, 1H), 7.09 (dd, J = 8.3, 1.9 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 3.81 (dd, J = 5.9, 3.8 Hz, 2H), 3.71 (dd, J = 5.9, 3.9 Hz, 2H), 3.40 (s, 3H), 1.75 (s, 6H), 1.52 (s, 9H). UPLC/MS (method A): Rt 2.01 min. MS (ES) C 19 H 25 N 3 O 5 requires 375, found 376 [M+H] + . 6-(3,3-Dimethyl-2-oxo-piperazin-1-yl)-3-methyl-1,3-benzoxazo l-2-one hydrochloride (XXXVIl) [00557] Following general procedure C, XXXVIl (0.174 g, 0.46 mmol) afforded XXXVIl as a white solid (0.110 g, 83%). UPLC/MS (method A): Rt 0.92 min. MS (ES) C 14 H 17 N 3 O 3 requires 275, found 276 [M+H] + . 2,2-Dimethyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-3-oxo-N- (4-phenylbutyl)piperazine-1- carboxamide [00558] Following general procedure D (Method A), XXXVIl (0.030 g, 0.096 mmol) and 4- phenylbutyl isocyanate (003 g 019 mmol) afforded the title compound as a white solid (0021 g, 50%). 1 H NMR (400 MHz, CDCl3) d 7.29 (dd, J = 8.4, 6.9 Hz, 2H), 7.23–7.14 (m, 4H), 7.10 (dd, J = 8.3, 2.0 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 4.63 (bs, 1H), 3.75 (dd, J = 6.2, 3.5 Hz, 2H), 3.68 (dd, J = 6.2, 3.5 Hz, 2H), 3.41 (s, 3H), 3.28 (t, J = 7.0 Hz, 2H), 2.66 (t, J = 7.4 Hz, 2H), 1.79 (s, 6H), 1.73–1.64 (m, 2H), 1.64–1.50 (m, 2H). UPLC/MS (method A): Rt 2.08 min. MS (ES) C 25 H 30 N 4 O 4 requires 450, found 451 [M+H] + . Example 65: 2,2-Dimethyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-5-oxo-N- (4-phenylbutyl) piperazine-1-carboxamide tert-Butyl 4-(3-benzyloxy-4-nitrophenyl)-2,2-dimethyl-5-oxopiperazine-1 -carboxylate (XXXIk) [00559] Following general procedure E, XXXk (0.1 g, 0.438 mmol) and 2-benzyloxy-4- bromo-1-nitrobenzene (0.162 g, 0.526 mmol) afforded XXXIk as a yellow solid (0.093 g, 47 %). 1 H NMR (400 MHz, CDCl3) d 7.95 (d, J = 8.8 Hz, 1H), 7.50–7.43 (m, 2H), 7.40 (m, J = 6.4, 1.0 Hz, 2H), 7.34 (m, 2H), 6.90 (dd, J = 8.8, 2.2 Hz, 1H), 5.25 (s, 2H), 4.25 (s, 2H), 3.63 (s, 2H), 1.50 (s, 9H), 1.48 (s, 6H). UPLC/MS (method A): Rt 2.57 min. MS (ES) C 24 H 29 N 3 O 6 requires 455, found 456 [M+H] + . tert-Butyl 4-(4-amino-3-hydroxyphenyl)-2,2-dimethyl-5-oxopiperazine-1-c arboxylate (XXXIIk) [00560] Following general procedure B (Method E), XXXIk (0.090 g, 0.198 mmol) afforded XXXIIk which used in the next step without further purification. UPLC/MS (method A): Rt 1.79 min. MS (ES) C 17 H 25 N 3 O 4 requires 335, found 336 [M+H] + . tert-Butyl 2,2-dimethyl-5-oxo-4-(2-oxo-3H-1,3-benzoxazol-6-yl)piperazin e-1-carboxylate (XXXIIIj) [00561] Following general procedure B, XXXIIk (0.211 g, 0.630 mmol) afforded XXXIIIj as a white solid (0.148 g, 0.410 mmol, 65%). 1 H NMR (400 MHz, CDCl 3 ) d 8.51 (s, 1H), 7.18 (d, J = 2.0 Hz, 1H), 7.03 (dd, J = 8.4, 2.0 Hz, 1H), 6.94 (d, J = 8.3 Hz, 1H), 4.25 (s, 2H), 3.63 (s, 2H), 1.53 (s, 6H), 1.51 (s, 9H). UPLC/MS (method A): Rt 1.92 min. MS (ES) C18H23N3O5 requires 361, found 362 [M+H] + . tert-Butyl 2,2-dimethyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-5-oxo-pi perazine-1- carboxylate (XXXVl) [00562] Following general procedure C, XXXIIIk (0.097 g, 0.268 mmol) afforded XXXVl which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 ) d 7.21 (d, J = 2.0 Hz, 1H), 7.14 (dd, J = 8.3, 2.0 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 4.23 (s, 2H), 3.64 (s, 2H), 3.41 (s, 3H), 1.53 (s, 6H), 1.50 (s, 9H). UPLC/MS (method A): Rt 2.03 min. MS (ES) C 19 H 25 N 3 O 5 requires 375, found 376 [M+H] + . 6-(5,5-Dimethyl-2-oxo-piperazin-1-yl)-3-methyl-1,3-benzoxazo l-2-one hydrochloride (XXXVIm) [00563] Following general procedure C, XXXVm (0.097g, 0.268 mmol) afforded XXXVIm as a white solid (0.067 g, 80%). UPLC/MS (method A): Rt 1.09 min. MS (ES) C14H17N3O3 requires 275, found 276 [M+H] + . 2,2-Dimethyl-4-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-5-oxo-N- (4-phenylbutyl)piperazine-1- carboxamide [00564] Following procedure D (Method A), XXXVIm (0.040 g, 0.128 mmol) afforded the title compound as a white solid (0.040 g, 0.089 mmol, 70%). 1 H NMR (400 MHz, DMSO-d6) d 7.38 (d, J = 1.9 Hz, 1H), 7.31–7.23 (m, 3H), 7.22–7.13 (m, 4H), 6.29 (t, J = 5.4 Hz, 1H), 4.00 (s, 2H), 3.68 (s, 2H), 3.34 (s, 3H), 3.03 (q, J = 6.5 Hz, 2H), 2.58 (t, J = 7.6 Hz, 2H), 1.56 (p, J = 7.2 Hz, 2H), 1.47–1.39 (m, 2H), 1.43 (s, 6H). UPLC/MS (method A): Rt 2.09 min. MS (ES) C25H30N4O4 requires 450, found 451 [M+H] + . Example 66: (3aS,6aR)- and (3aR, 6aS)-2-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4- phenylbutyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5- carboxamide tert-Butyl (3aS,6aR) and (3aR, 6aS)-2-(3-hydroxy-4-nitrophenyl)-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (XXXI’a) [00565] Following general procedure F, XXX’a (0.100 g, 0.471 mmol) and 5-fluoro-2- nitrophenol (0.074 g,0.471 mmol) afforded XXXI’a as a yellow solid (0.132 g, 80%). 1 H NMR (400 MHz, CDCl3) d 11.37 (s, 1H), 7.95 (d, J = 9.5 Hz, 1H), 6.15 (dd, J = 2.6, 9.5 Hz, 1H), 6.00 (d, J = 2.5 Hz, 1H), 3.67 (dd, J = 7.0, 11.1 Hz, 4H), 3.33 (dd, J = 4.1, 10.8 Hz, 4H), 3.12–2.93 (m, 2H), 1.46 (s, 9H). UPLC/MS (method A): Rt 2.31 min. MS (ES) C 17 H 23 N 3 O 5 requires 349, found 350 [M+H] + . tert-Butyl (3aS,6aR) and (3aR,6aS)-2-(4-amino-3-hydroxyphenyl)-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (XXXII’a) [00566] Following general procedure B (Method A), XXXI’a (0.132 g, 0.378 mmol) afforded XXXII’a which was used in the next step without further purification. UPLC/MS (method A): Rt 1.45 min. MS (ES) C17H25N3O3 requires 319, found 377 [M+ AcO]-. tert-Butyl (3aS,6aR)- and (3aR,6aS)-2-(2-oxo-3H-1,3-benzoxazol-6-yl)-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole- ’ [00567] Following general procedure B (step 2), XXXII’a (0.120 g, 0.378 mmol) afforded XXXIII’a as a purple solid (0.083 g, 63%). 1 H NMR (400 MHz, CDCl 3 ) d 8.56 (bs, 1H), 6.91 (d, J = 8.5 Hz, 1H), 6.50 (s, 1H), 6.35 (d, J = 7.6 Hz, 1H), 3.72–3.59 (m, 2H), 3.58–3.46 (m, 2H), 3.42–3.23 (m, 2H), 3.22–3.13 (m, 2H), 3.10–2.96 (m, 2H), 1.46 (s, 9H). UPLC/MS (method A): Rt 1.99 min. MS (ES) C 18 H 23 N 3 O 4 requires 345, found 346 [M+H] + . tert-Butyl (3aS,6aR)- and (3aR, 6aS)-2-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)- 1,3,3a,4,6,6a- hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (XXXV’a) [00568] Following general procedure C (step 1), XXXIII’a (0.035 g, 0.101 mmol) and MeI (0.072g, 0.505 mmol) afforded XXXV’a as a white solid (0.02g, 0.056 mmol, 55%). 1 H NMR (400 MHz, CDCl 3 ) d 6.80 (d, J = 8.5 Hz, 1H), 6.50 (d, J = 2.1 Hz, 1H), 6.37 (dd, J = 1.9, 8.5 Hz, 1H), 3.70–3.60 (m, 2H), 3.55–3.47 (m, 2H), 3.35 (s, 3H), 3.22–3.15 (m, 2H), 3.03–2.98 (m, 2H), 1.45 (s, 9H). UPLC/MS (method A): Rt 2.19 min. MS (ES) C 19 H 25 N 3 O 4 requires 359, found 360 [M+H] + 6-[(3aS,6aR)- and (3aR,6aS)-2,3,3a,4,6,6a-Hexahydro-1H-pyrrolo[3,4-c]pyrrol-5- yl]-3- methyl-1,3-benzoxazol-2-one hydrochloride (XXXVI’a) [00569] Following general procedure C (step 2), XXXV’a (0.20 g, 0.056 mmol) afforded XXXVI’a as a violet solid (0.010 g, 60%). UPLC/MS (method A): Rt 1.08 min. MS (ES) C14H17N3O2 requires 259, found 260 [M+H] + . (3aS,6aR)- and (3aR,6aS)-2-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenyl butyl)- 1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxamide [00570] Following general procedure D (Method A), XXXVI’a (0.010 g, 0.034 mmol) and 4- phenylbutyl isocyanate (0.010g, 0.062 mmol) afforded the title compound as white solid (10 mg, 71%). 1 H NMR (400 MHz, CDCl 3 ) d 7.28–7.23 (m, 2H), 7.17 (t, J = 7.3 Hz, 3H), 6.80 (d, J = 8.5 Hz, 1H), 6.47 (d, J = 2.2 Hz, 1H), 6.33 (dd, J = 2.2, 8.5 Hz, 1H), 4.17 (t, J = 5.51 Hz, 1H), 3.64 (dd, J = 7.4, 10.0 Hz, 2H), 3.51 (dd, J = 7.2, 9.3 Hz, 2H), 3.35 (s, 3H), 3.34 (dd, J = 4.0, 10.2 Hz, 2H), 3.27 (q, J = 7.0 Hz, 2H), 3.22 (dd, J = 3.8, 9.5 Hz, 2H), 3.14–3.02 (m, 2H), 2.65 (t, J = 7.5 Hz, 2H), 1.74–1.62 (m, 2H), 1.62–1.51 (m, 2H). UPLC/MS (method A): Rt 2.10 min. MS (ES) C25H30N4O3 requires 434, found 435 [M+H] + . Example 67: 7-(2-Oxo-3H-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)-2,7- diazaspiro[3.5]nonane-2-carboxamide 6-(2,7-Diazaspiro[3.5]nonan-7-yl)-3H-1,3-benzoxazol-2-one hydrochloride (XXXIV’’a) [00571] Following general procedure C, XXXII’’a (0.050 g, 0.139 mmol) afforded XXXIV’’a which was used in the next step without further purification. MS (ES) C 14 H 17 N 3 O 2 requires 259, found 260 [M+H] + . 7-(2-Oxo-3H-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)-2,7-diaza spiro[3.5]nonane-2- carboxamide [00572] Following general procedure D (Method A), XXXIV’’a (0.036 g, 0.139 mmol) and 4-phenylbutyl isocyanate (0.027 g, 0.152 mmol) afforded the title compound as a pinkish solid (0.022 g, 34%). 1 H NMR (400 MHz, DMSO-d6) d 11.25–10.26 (bs, 1H), 7.31–7.23 (m, 2H), 7.20–7.13 (m, 3H), 6.95 (d, J = 2.3 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 6.71 (dd, J = 8.6, 2.3 Hz, 1H), 6.20 (t, J = 5.8 Hz, 1H), 3.50 (s, 4H), 3.03–2.95 (m, 6H), 2.56 (t, J = 7.6 Hz, 2H), 1.80– 1.70 (m, 4H), 1.60–1.47 (m, 2H), 1.44–1.33 (m, 2H). UPLC/MS (method A): Rt 1.98 min. MS (ES) C25H30N4O3 requires 434, found 435 [M+H] + . Example 68: 7-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)-2,7 - diazaspiro[3.5]nonane-2-carboxamide tert-Butyl 7-(3-hydroxy-4-nitrophenyl)-2,7-diazaspiro[3.5]nonane-2-carb oxylate (XXXI’’a) [00573] Following general procedure F, XXX’’a (0.30 g, 1.33 mmol) and 5-fluoro-2- nitrophenol (0.312 g, 1.99 mmol) XXXI’’a as a yellow solid (0.387 g, 80%). 1 H NMR (400 MHz, CDCl3) 11.22 (s, 1H), 7.93 (d, J = 9.7 Hz, 1H), 6.43 (dd, J = 9.7, 2.7 Hz, 1H), 6.31 (d, J = 2.7 Hz, 1H), 3.70 (s, 4H), 3.46–3.36 (m, 4H), 1.89–1.79 (m, 4H), 1.45 (s, 9H). d UPLC/MS (method A): Rt 2.43 min. MS (ES) C18H25N3O5 requires 363, found 364 [M+H] + . tert-Butyl 7-(4-amino-3-hydroxyphenyl)-2,7-diazaspiro[3.5]nonane-2-carb oxylate (XXXII’’a) [00574] Following general procedure B (Method C), XXXI’’a (0.387 g, 1.07 mmol) afforded XXXII’’a which was used in the next step without further purification. UPLC/MS (method A): Rt 1.72 min. MS (ES) C18H27N3O3 requires 333, found 334 [M+H] + . tert-Butyl 7-(2-Oxo-3H-1,3-benzoxazol-6-yl)-2,7-diazaspiro[3.5]nonane-2 -carboxylate (XXXIII’’a) [00575] Following general procedure B, XXXII’’a (0.36 g, 1.07 mmol) and CDI (0.87 g, 5.35 mmol) afforded XXIII’’a as a pink solid (0.192 g, 50%). 1 H NMR (400 MHz, DMSO-d 6 ) d 11.26 (bs, 1H), 6.95 (d, J = 2.3 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 6.71 (dd, J = 8.6, 2.3 Hz, 1H), 3.58 (s, 4H), 3.00 (s, 4H), 1.77 (t, J = 5.5 Hz, 4H), 1.38 (s, 9H). UPLC/MS (method A): Rt 2.00 min. MS (ES) C 19 H 25 N 3 O 4 requires 359, found 360 [M+H] + . carboxylate [00576] Following general procedure C, XXXIII’’a (0.050 g, 0.14 mmol) and CH 3 I (0.023 g, 0.010 mL, 0.14 mmol) afforded XXXV’’a as a pink solid (0.026 g, 50%). 1 H NMR (400 MHz, DMSO-d6) d 7.06 (d, J = 8.6 Hz, 1H), 7.01 (d, J = 2.2 Hz, 1H), 6.80 (dd, J = 8.6, 2.3 Hz, 1H), 3.58 (s, 4H), 3.03 (s, 4H), 1.77 (t, J = 5.5 Hz, 4H), 1.38 (s, 9H). UPLC/MS (method A): Rt 2.20 min. MS (ES) C 20 H 27 N 3 O 4 requires 373, found 374 [M+H] + . 6-(2,7-Diazaspiro[3.5]nonan-7-yl)-3-methyl-1,3-benzoxazol-2- one hydrochloride (XXXVI’’a) [00577] Following general procedure C, XXXV’’a (0.026 g, 0.07 mmol) afforded XXXVI’’a which was used in the next step without further purification. UPLC/MS (method A): Rt 1.05 min. MS (ES) C15H19N3O2 requires 273, found 274 [M+H] + . 7-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)-2,7 -diazaspiro[3.5]nonane-2- carboxamide [00578] Following general procedure D (Method A), XXXVI’’a (0.024 g, 0.07 mmol) and 4- phenylbutyl isocyanate (0.015 g, 0.084 mmol) afforded the title compound as a white solid (0.022 g, 70%). 1 H NMR (400 MHz, DMSO-d6) d 7.31–7.24 (m, 2H), 7.21–7.14 (m, 3H), 7.06 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 2.2 Hz, 1H), 6.81 (dd, J = 8.6, 2.3 Hz, 1H), 6.20 (t, J = 5.8 Hz, 1H), 3.51 (s, 4H), 3.28 (s, 3H), 3.06–2.94 (m, 6H), 2.56 (t, J = 7.6 Hz, 2H), 1.76 (t, J = 5.5 Hz, 4H), 1.60–1.48 (m, 2H), 1.44–1.34 (m, 2H). UPLC/MS (method A): Rt 2.10 min. MS (ES) C26H32N4O3 requires 434, found 435 [M+H] + . Example 69: 2-(2-Oxo-3H-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)-2,7- diazaspiro[3.5]nonane-7-carboxamide tert-Butyl 2-(3-hydroxy-4-nitrophenyl)-2,7-diazaspiro[3.5]nonane-7-carb oxylate (XXXVII’’b) [00579] Following general procedure F, XXX’’b (0.3 g, 1.33 mmol) and 5-fluoro-2- nitrophenol (0.27 g, 1.72 mmol) afforded XXXVII’’b as a yellow solid (0.415 g, 86%). 1 H NMR (400 MHz, CDCl3) d 11.46 (s, 1H), 7.96 (d, J = 9.3 Hz, 1H), 5.97 (dd, J = 9.4, 2.4 Hz, 1H), 5.84 (d, J = 2.4 Hz, 1H), 3.80 (s, 4H), 3.50–3.40 (m, 4H), 1.91–1.77 (m, 4H).UPLC/MS (method A): Rt 2.51 min. MS (ES) C 18 H 25 N 3 O 5 requires 336, found 364 [M+H] + . tert-Butyl 2-(4-amino-3-hydroxyphenyl)-2,7-diazaspiro[3.5]nonane-7-carb oxylate (XXXII’’b) [00580] Following general procedure B (Method C), XXXI’’b (0.40 g, 1.10 mmol) afforded XXXII’’b which was used in the next step without further purification. UPLC/MS (method A): Rt 1.58 min. MS (ES) C18H27N3O3 requires 333, found 332 [M+H] + . tert-Butyl 2-(2-oxo-3H-1,3-benzoxazol-6-yl)-2,7-diazaspiro[3.5]nonane-7 -carboxylate (XXXIII’’b) [00581] Following general procedure B, XXXII’’b (0.37 g, 1.10 mmol) and CDI (0.89 g, 5.50 mmol) afforded XXXIII’’b as a pink solid (0.22 g, 56%). 1 H NMR (400 MHz, CDCl 3 ) d 8.36 (s, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.42 (s, 1H), 6.28 (d, J = 8.4 Hz, 1H), 3.66 (s, 4H), 3.55–3.38 (m, 4H), 1.90–1.77 (m, 4H), 1.49 (s, 9H). UPLC/MS (method A): Rt 2.11 min. MS (ES) C19H25N3O4 requires 359, found 360 [M+H] + . 6-(2,7-Diazaspiro[3.5]nonan-2-yl)-3H-1,3-benzoxazol-2-one hydrochloride (XXXIV’’b) [00582] Following general procedure C, XXXIII’’b (0.050 g, 0.139 mmol) afforded XXXIV’’b which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) d 11.37 (s, 1H), 8.94 (bs, 2H), 6.95 (d, J = 8.2 Hz, 1H), 6.60 (s, 1H), 6.35 (d, J = 8.3 Hz, 1H), 3.68 (s, 4H), 3.04 (s, 4H), 1.98 (t, J = 5.6 Hz, 4H). UPLC/MS (method A): Rt 0.89 min. MS (ES) C 14 H 17 N 3 O 2 requires 259, found 260 [M+H] + . 2-(2-Oxo-3H-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)-2,7-diaza spiro[3.5]nonane-7- carboxamide [00583] Following general procedure D (Method A), XXXIV’’b (0.036 g, 0.139 mmol) and 4-phenylbutyl isocyanate (0.027 g, 0.152 mmol) afforded the title compound as a pinkish solid (0.025 g, 41%). 1 H NMR (400 MHz, DMSO-d6) d 11.18 (bs, 1H), 7.32–7.24 (m, 2H), 7.23–7.13 (m, 3H), 6.88 (d, J = 8.3 Hz, 1H), 6.45 (t, J = 5.5 Hz, 1H), 6.41 (d, J = 2.1 Hz, 1H), 6.17 (dd, J = 8.4, 2.1 Hz, 1H), 3.52 (s, 4H), 3.29–3.20 (m, 4H), 3.04 (q, J = 6.8 Hz, 2H), 2.58 (t, J = 7.6 Hz, 2H), 1.72–1.61 (m, 4H), 1.61–1.47 (m, 2H), 1.47–1.34 (m, 2H).UPLC/MS (method A): Rt 2.06 min. MS (ES) C 25 H 30 N 4 O 3 requires 434, found 435 [M+H] + . Example 70: 2-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)-2,7 - diazaspiro[3.5]nonane-7-carboxamide [00584] Following general procedure C, XXXIII’’b (0.047 g, 0.131 mmol) and CH3I (0.020 g, 0.144 mmol) afforded XXXV’’b as a pink powder (0.037 g, 75%). 1 H NMR (400 MHz, CDCl 3 ) d 6.81 (d, J = 8.4 Hz, 1H), 6.41 (d, J = 2.1 Hz, 1H), 6.29 (d, J = 8.3 Hz, 1H), 3.64 (s, 4H), 3.50–3.40 (m, 4H), 3.37 (s, 3H), 1.88–1.75 (m, 4H), 1.49 (s, 9H). UPLC/MS (method A): Rt 2.31 min. MS (ES) C 20 H 27 N 3 O 4 requires 373, found 374 [M+H] + . 6-(2,7-Diazaspiro[3.5]nonan-2-yl)-3-methyl-1,3-benzoxazol-2- one hydrochloride (XXXVI’b) [00585] Following general procedure C, XXXV’’b (0.035 g, 0.094 mmol) afforded XXXVI’b as a white solid (0.035 g, quantitative). 1 H NMR (400 MHz, DMSO-d6) d 8.94 (bs, 2H), 7.10 (d, J = 8.4 Hz, 1H), 6.59 (d, J = 2.1 Hz, 1H), 6.37 (d, J = 8.4 Hz, 1H), 3.66 (s, 4H), 3.29 (s, 3H), 3.04 (s, 4H), 1.97 (t, J = 5.7 Hz, 4H).UPLC/MS (method A): Rt 1.08 min. MS (ES) C15H19N3O2 requires 273, found 274 [M+H] + . 2-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)-2,7 -diazaspiro[3.5]nonane-7- carboxamide [00586] Following general procedure D (Method A), XXXVI’’b (0.030 g, 0.097 mmol) and 4-phenylbutyl isocyanate (0.019 g, 0.107 mmol) afforded the title compound as a yellowish solid (32 mg, 70%). 1 H NMR (400 MHz, DMSO-d 6 ) d 7.28 (t, J = 7.5 Hz, 2H), 7.25–7.11 (m, 3H), 7.05 (d, J = 8.4 Hz, 1H), 6.53–6.41 (m, 2H), 6.25 (dd, J = 8.4, 2.1 Hz, 1H), 3.54 (s, 4H), 3.31– 3.22 (m, 9H), 3.04 (q, J = 6.6 Hz, 2H), 2.58 (t, J = 7.6 Hz, 2H), 1.64 (t, J = 5.5 Hz, 4H), 1.61– 1.49 (m, 2H), 1.48–1.34 (m, 2H). UPLC/MS (method A): Rt 2.19 min. MS (ES) C 26 H 32 N 4 O 3 requires 448, found 449 [M+H]. Example 71: 9-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)-3,9 - diazaspiro[5.5]undecane-3-carboxamide tert-Butyl 9-(3-hydroxy-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-ca rboxylate (XXXVII’’c) [00587] Following general procedure F, XXX’’c (0.40 g, 1.57 mmol) and 5-fluoro-2- nitrophenol (0.37 g, 2.36 mmol) afforded XXXVII’’c as an orange solid (0.595 g, 97%). 1 H NMR (400 MHz, CDCl3) d 11.28 (bs, 1H), 7.93 (d, J = 9.7 Hz, 1H), 6.41 (dd, J = 9.7, 2.7 Hz, 1H), 6.28 (d, J = 2.7 Hz, 1H), 3.51–3.33 (m, 8H), 1.66–1.61 (m, 4H), 1.50 (t, J = 5.9 Hz, 4H), 1.46 (s, 9H). UPLC/MS (method A): Rt 2.62 min. MS (ES) C 20 H 29 N 3 O 5 requires 391, found 392 [M+H] + . tert-Butyl 9-(4-amino-3-hydroxyphenyl)-3,9-diazaspiro[5.5]undecane-3-ca rboxylate (XXXII’’c) [00588] Following general procedure B (Method C), XXXI’’c (0.250 g, 0.64 mmol) afforded XXXII’’c which was used in the next step without further purification. UPLC/MS (method A): Rt 1.70 min. MS (ES) C 20 H 31 N 3 O 3 requires 361, found 362 [M+H] + . tert-Butyl 9-(2-oxo-3H-1,3-benzoxazol-6-yl)-3,9-diazaspiro[5.5]undecane -3-carboxylate (XXXIII’c) [00589] Following general procedure B, XXXII’’c (0.23 g, 0.64 mmol) and CDI (0.52 g, 3.2 mmol) afforded XXXIII’’c as a pink solid (0.106 g, 43%). 1 H NMR (400 MHz, CDCl 3 ) d 8.08 (bs, 1H), 6.91 (d, J = 8.5 Hz, 1H), 6.85 (d, J = 2.2 Hz, 1H), 6.74 (dd, J = 8.6, 2.3 Hz, 1H), 3.48– 3.36 (m, 4H), 3.14–3.07 (m, 4H), 1.70–1.63 (m, 4H), 1.58–1.54 (m, 2H), 1.52–1.47 (m, 2H), 1.46 (s, 9H). UPLC/MS (method A): Rt 2.19 min. MS (ES) C 21 H 29 N 3 O 4 requires 387, found 388 [M+H] + . tert-Butyl 9-(3-methyl-2-oxo-1,3-benzoxazol-6-yl)-3,9-diazaspiro[5.5]un decane-3- carboxylate (XXXV’c) [00590] Following general procedure C, XXXIII’’c (0.050 g, 0.13 mmol) and CH 3 I (0.042 g, 0.018 mL, 0.26 mmol) afforded XXXV’c which was used in the next step without further purification. UPLC/MS (method A): Rt 2.39 min. MS (ES) C22H31N3O4 requires 401, found 402 [M+H] + . 6-(3,9-Diazaspiro[5.5]undecan-3-yl)-3-methyl-1,3-benzoxazol- 2-one hydrochloride (XXXVI’’c) [00591] Following general procedure C, XXXVI’’c (0.042 g, 0.10 mmol) afforded XXXVI’’c which was used in the next step without further purification. UPLC/MS (method A): Rt 1.18 min MS (ES) C 17 H 23 N 3 O 2 requires 301, found 302 [M+H] + . 9-(3-Methyl-2-oxo-1,3-benzoxazol-6-yl)-N-(4-phenylbutyl)-3,9 -diazaspiro[5.5]undecane-3- carboxamide [00592] Following general procedure D (Method A), XXXVI’’c (0.034 g, 0.10 mmol) and 4- phenylbutyl isocyanate (0.052 g, 0.30 mmol) afforded the title compound as a white solid (0.016 g, 34%). 1 H NMR (400 MHz, CDCl 3 ) d 7.31–7.27 (m, 2H), 7.21–7.14 (m, 3H), 6.89–6.75 (m, 3H), 4.37 (t, J = 5.4 Hz, 1H), 3.36 (s, 3H), 3.35–3.31 (m, 4H), 3.26 (q, J = 6.6 Hz, 2H), 3.14– 3.08 (m, 4H), 2.64 (t, J = 7.5 Hz, 2H), 1.71–1.64 (m, 6H), 1.58–1.50 (m, 15H). UPLC/MS (method A): Rt 2.31 min. MS (ES) C 28 H 36 N 4 O 3 requires 476, found 477 [M+H] + . BIOLOGICAL ACTIVITY EVALUATION [00593] The ability of exemplary compounds to inhibit acid ceramidase was measured. Experimental procedures and results are provided below. Part I: Assay Procedure [00594] Cell lysates overexpressing acid ceramidase were used as the enzyme source for compound potency determination in a biochemical fluorescent assay. Briefly, compounds were preincubated with 10 mg protein of cell lysates in a dose-response manner for 1 hr at RT in the assay buffer containing 25 mM NaAC and 100 mM NaCl, pH 4.5. The reaction was initiated by the addition of substrate Rbm14-12 at a final concentration of 6.3 mM. The reaction was run at RT for 1 hr before it was stopped by the addition of the stopping buffer containing 20% methanol (v/v), 1 mg/ml NaIO 4 , 0.1 M glycine, pH 10.6. The samples were incubated with the stopping buffer at RT for 1 hr to allow the fluorescent product to be formed. Finally the plate was read with SpectraMax i3 plate reader (Molecular Devices) at ex360 nm and em446 nm. Data were collected and used to determine the IC50 values of compounds by curve fitting to the four-parameter inhibition equation. Part II: Results [00595] Human acid ceramidse (hACR) inhibition values for tested compounds are provided in Table 1 below, along with cLogP, and compound solubility in water. The symbol “A” indicates inhibition of less than 0.2 PM; the symbol “B” indicates inhibition in the range of 0.2 PM up to 1 PM; and the symbol “C” indicates inhibition of greater than 1 PM. TABLE 1
INCORPORATION BY REFERENCE [00596] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes. EQUIVALENTS [00597] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.
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