Macrocyclic urea orexin receptor agonists

Abstract

The present invention relates to macrocyclic urea compounds that are orexin receptor agonists. The present invention also relates to the use of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases involving the orexin receptors. The present invention also relates to compositions containing these compounds. The present invention also relates to the use of these compositions in the potential prevention or treatment of such diseases involving the orexin receptors.

Description

Background Technology

[0001] Orexin (hypothalamic secretions) comprises two neuropeptides produced in the hypothalamus: orexin A (OX-A) (a 33-amino acid peptide) and orexin B (OX-B) (a 28-amino acid peptide) (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexin regulates sleep and wakefulness, opening up potential new treatments for narcolepsy, idiopathic hypersomnia, excessive daytime sleepiness, shift worker sleep disorders, obstructive sleep apnea, and insomnia (Chemelli R. Metal., Cell, 1999, 98, 437-451). Orexin has been found to stimulate food consumption in rats, suggesting that these peptides act as mediators in a central feedback mechanism regulating feeding behavior (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexin has also been shown to play a role in arousal, mood, energy homeostasis, reward, learning, and memory (Peyron, et al., Journal of Neurosci., 1998, 18(23): 9996-100150; Harris, et al., Trends Neurosci., 2006, 29(10), 571-577). Two orexin receptors have been cloned and identified in mammals. They belong to the G protein-coupled receptor superfamily (Sakurai T. et al., Cell, 1998, 92, 573-585): the orexin-1 receptor (OX or OX1R) is partially selective for OX-A, and the orexin-2 receptor (OX2 or OX2R) can bind to OX-A and OX-B with similar affinity. It is believed that the physiological functions in which orexin is presumed to be involved are manifested through one or both of the two subtypes of orexin receptors, the OX1 receptor and the OX2 receptor. Summary of the Invention

[0002] This invention relates to macrocyclic urea compounds as orexin receptor agonists. The invention also relates to the use of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases involving orexin receptors. The invention further relates to compositions comprising these compounds. The invention also relates to the use of these compositions in the potential prevention or treatment of such diseases involving orexin receptors. Invention Details

[0004] This invention relates to compounds of formula I:

[0005]

[0006] in:

[0007] A is N or C(R) 8) n ;

[0008] D is N or C(R) 8) n ;

[0009] E is N or C(R) 8) n ;

[0010] G is N or C(R) 8) n ;

[0011] J is N or C(R) 8) n ;

[0012] W is N or C(R) 8) n ;

[0013] When J is N, m is 1, but when J is C(R) 8) n When m is 1 or 2;

[0014] n is 0 or 1;

[0015] X is either -O- or -CH2-;

[0016] Y is unsubstituted or selected from 1 to 3 elements of R. 4 The following groups are substituted by the following groups: phenyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyridofuranyl, oxazolyl, thiazolyl;

[0017] Z is

[0018] R is independently selected from H or C. 1-6 alkyl;

[0019] R 1 Selected from:

[0020] (1) Hydrogen,

[0021] (2)CN,

[0022] (3)-C(O)NR2-,

[0023] (4)-CH2OCH2CF3-,

[0024] (5)-CH2OCH2CHCF2-,

[0025] (6)C 1-6 Alkyl groups, which are unsubstituted or substituted by one to three independent substituents selected from the following.

[0026] aC 1-6 alkyl,

[0027] b. Halogen,

[0028] c. Hydroxyl group,

[0029] d. Unsubstituted or substituted with 1 to 3 substituents selected from halogens -OC 1-6 Alkyl, or unsubstituted or halogenated, C 1-6 Alkyl or fluorinated C 1-6 Alkyl-substituted C 3-6 cycloalkyl,

[0030] eC 3-6 Cycloalkyl groups, which are unsubstituted or have one to three R groups. 4 replace,

[0031] f. Heteroaryl, unsubstituted or with 1 to 3 R groups 4 replace,

[0032] g. Heterocyclic group, unsubstituted or surrounded by 1 to 3 R groups 4 replace,

[0033] h.CN, and

[0034] iS(O)2R;

[0035] R 2 Selected from

[0036] 1) Straight chain or branched chain C 1-10 Alkyl or C 4-8 alkenyl,

[0037] 2)-(CR2) 1-6 -O-(CR2) 1-6 -;

[0038] 3)-(CR2) 1-6 -N(R 9 )-(CR2) 1-6 -, where R 9 It is hydrogen or -C 1-6 Alkyl, wherein the -C 1-6 The alkyl group is either unsubstituted or substituted with a halogen.

[0039] 4)-(CR2) 1-6 C 3-6 Cycloalkyl-(CR2) 1-6 -, where -C 3-6 The cycloalkyl group is unsubstituted or converted to -C. 1-6 Alkyl or halogen substitution, and

[0040] 5) Unsubstituted or -C1-6 The following groups, alkyl or halogen-substituted, are piperidinyl, pyrrolyl, oxazolyl, oxadiazole, or thiazolyl rings;

[0041] R 3 Selected from direct key, -S-, -NR-, -OC 1-6 Alkyl-,-SC 1-6 Alkyl- and -S(O)2-C 1-6 alkyl-;

[0042] R 4 Selected from:

[0043] (1) Hydrogen,

[0044] (2) Hydroxyl group,

[0045] (3) Halogen,

[0046] (4)-C 1-6 Alkyl groups, which are unsubstituted or substituted with 1 to 6 fluorine atoms,

[0047] (5)-OC 1-6 Alkyl groups, which are unsubstituted or substituted with 1 to 6 fluorine atoms, and

[0048] (6)C 3-6 cycloalkyl;

[0049] R 5 and R 6 Selected independently from:

[0050] (1) Hydrogen, and

[0051] (2)-C 1-6 Alkyl group, wherein the alkyl group is unsubstituted or substituted by one to six independent substituents selected from halogens.

[0052] Or R 5 and R 6 The carbon atoms bonded to them can together form -C 3-6 Cycloalkyl groups;

[0053] R 7 Selected from:

[0054] (1) Hydrogen,

[0055] (2)-C 1-6 Alkyl groups, wherein the alkyl group is unsubstituted or substituted by 1 to 6 substituents independently selected from halogens, and

[0056] (3)-C 3-6 cycloalkyl, wherein the -C 3-6 The cycloalkyl group is unsubstituted or converted to -C. 1-6 Alkyl or halogen substitution;

[0057] R 8 Selected from:

[0058] (1) Hydrogen,

[0059] (2) Halogens, and

[0060] (3)-C 1-6 Alkyl group, wherein the alkyl group is unsubstituted or substituted by one to six substituents independently selected from halogens;

[0061] Or its pharmaceutically acceptable salt.

[0062] One embodiment of this application includes a compound of formula I':

[0063]

[0064] in:

[0065] A is either N or C;

[0066] D is N or C(R) 8) n ;

[0067] E is N or C(R) 8) n ;

[0068] G is N or C(R) 8) n ;

[0069] J is N or C(R) 8) n ;

[0070] W is N or C(R) 8) n ;

[0071] The condition is that 1, 2, 3 or 4 of A, D, E, G, J and W are N, and the remaining ones of A, D, E, G, J and W are not N;

[0072] N is 0 or 1;

[0073] X is either -O- or -CH2-;

[0074] Y is unsubstituted or selected from 1 to 3 elements of R. 4 The following groups are substituted by the following groups: phenyl, pyridinyl, pyrazinyl, pyridazinyl, pyridofuranyl, oxazolyl, thiazolyl;

[0075] Z is

[0076] R is independently selected from H or C. 1-6alkyl;

[0077] R 1 Selected from:

[0078] (1) Hydrogen,

[0079] (2)CN,

[0080] (3)-C(O)NR2,

[0081] (4)-CH2OCH2CF3-,

[0082] (5)-CH2OCH2CHCF2-,

[0083] (6)-C 1-6 Alkyl groups, which are unsubstituted or substituted by one to three independent substituents selected from the following.

[0084] aC 1-6 alkyl,

[0085] b. Halogen,

[0086] c. Hydroxyl group,

[0087] d. Unsubstituted or substituted with 1 to 3 substituents selected from halogens -OC 1-6 Alkyl groups, or unsubstituted or halogenated, C 1-6 Alkyl or fluorinated C 1-6 Alkyl-substituted C 3-6 cycloalkyl,

[0088] e.-C 3-6 Cycloalkyl groups, which are unsubstituted or have one to three R groups. 4 replace,

[0089] f. Heteroaryl, unsubstituted or with 1 to 3 R groups 4 replace,

[0090] g. Heterocyclic group, unsubstituted or surrounded by 1 to 3 R groups 4 replace,

[0091] h.CN, and

[0092] i.-S(O)2R;

[0093] R 2 Selected from

[0094] 1) Straight chain or branched chain C 1-10 Alkyl or C 4-8 alkenyl,

[0095] 2)-(CR2) 1-6 -O-(CR2) 1-6 -,

[0096] 3)-(CR2) 1-6 -N(R 9 )-(CR2) 1-6 -, where R 9 It is hydrogen or -C 1-6 Alkyl, wherein the -C 1-6 The alkyl group is either unsubstituted or substituted with a halogen.

[0097] 4)-(CR2) 1-6 C 3-6 Cycloalkyl-(CR2) 1-6 Wherein -C 3-6 The cycloalkyl group is unsubstituted or converted to -C. 1-6 Alkyl or halogen substitution, and

[0098] 5) Unsubstituted or -C 1-6 The following groups, alkyl or halogen-substituted, are piperidinyl, pyrrolyl, oxazolyl, oxadiazole, or thiazolyl rings;

[0099] R 3 Selected from direct key, -OC 1-6 Alkyl-,-SC 1-6 Alkyl groups and -S(O)2-C 1-6 alkyl-;

[0100] R 4 Selected from:

[0101] (1) Hydrogen,

[0102] (2) Hydroxyl group,

[0103] (3) Fluorine,

[0104] (4)-C 1-6 Alkyl groups, which are unsubstituted or substituted with 1 to 6 fluorine atoms, and

[0105] (5)-OC 1-6 Alkyl groups, which are unsubstituted or substituted with 1 to 6 fluorine atoms;

[0106] R 5 and R 6 Selected independently from:

[0107] (1) Hydrogen, and

[0108] (2)-C 1-6 Alkyl group, wherein the alkyl group is unsubstituted or substituted by one to six independent substituents selected from halogens.

[0109] Or R 5 and R 6 The carbon atoms bonded to them can together form -C 3-6Cycloalkyl groups;

[0110] R 7 Selected from:

[0111] (1)-C 1-6 Alkyl groups, wherein the alkyl group is unsubstituted or substituted by 1 to 6 substituents independently selected from halogens, and

[0112] (2)-C 3-6 cycloalkyl, wherein the -C 3-6 The cycloalkyl group is unsubstituted or converted to -C. 1-6 Alkyl or halogen substitution;

[0113] R 8 Selected from:

[0114] (1) Hydrogen,

[0115] (2) Halogens, and

[0116] (3)-C 1-6 Alkyl group, wherein the alkyl group is unsubstituted or substituted by one to six substituents independently selected from halogens;

[0117] Or its pharmaceutically acceptable salt.

[0118] In one embodiment of the invention, Y is selected from unsubstituted or by one to three molecules selected from R. 4 The following groups are substituted by the group: phenyl, pyridyl, pyridazinyl and pyrimidinyl.

[0119] One embodiment of the present invention includes a compound of formula Ia:

[0120]

[0121] in

[0122] Z represents a straight chain or a branched chain. 3-10 Alkyl or C 4-8 Alkenyl group, which is unsubstituted or substituted by 1 to 6 substituents selected from the following:

[0123] (1) Hydroxyl group,

[0124] (2) Halogen,

[0125] (3)C 1-6 Alkyl groups, which are unsubstituted or substituted with 1 to 6 substituents selected from: halogen, tetrahydrofuranyl, unsubstituted or substituted with 1 to 3 substituents selected from halogen -OC 1-6 Alkyl groups, or unsubstituted or with one to three atoms selected from halogens, C 1-6 Alkyl or fluorinated C 1-6 Alkyl substituents substituted C 3-6cycloalkyl,

[0126] (4)C 3-6 Cycloalkyl groups, which are unsubstituted or composed of 1 to 3 alkyl groups selected from halogens, C14, C24, C34, C44, C54, C6 ... 1-6 Alkyl or fluorinated C 1-6 Alkyl substituents,

[0127] (5)-OC 1-6 Alkyl groups, which are either unsubstituted or substituted with 1 to 3 halogens.

[0128] (6) Tetrahydrofuranyl,

[0129] (7) Tetrahydropyranyl,

[0130] (8) Isoxazolyl group, and

[0131] (9) Thiazole group;

[0132] And it can optionally be in C 3-10 The alkyl group contains a group selected from the following:

[0133] (1)-O-,

[0134] (2)-N(R 9 )-, where R 9 It is hydrogen or -C 1-6 Alkyl, wherein the -C 1-6 The alkyl group is either unsubstituted or substituted with a halogen.

[0135] (3)-C 3-6 cycloalkyl, wherein the -C 3-6 The cycloalkyl group is unsubstituted or converted to -C. 1-6 Alkyl or halogen substitution, and

[0136] (4) Unsubstituted or -C 1-6 The following groups, alkyl or halogen-substituted, are piperidinyl, pyrrolyl, oxazolyl, oxadiazole, or thiazolyl rings;

[0137] And the other substituents A, D, E, G, W, X, R 4 R 5 R 6 and R 7 Defined in this document; or its pharmaceutically acceptable salt.

[0138] One embodiment of the present invention includes a compound of formula Ia':

[0139]

[0140] Where D, Z, R4, R 5 R 6 and R 7Defined in this document; or its pharmaceutically acceptable salt.

[0141] One embodiment of the present invention includes a compound of formula Ia":

[0142]

[0143] Z is defined in this paper; or its pharmaceutically acceptable salt.

[0144] One embodiment of the present invention includes a compound of formula Ib:

[0145]

[0146] Where A, D, E, G, W, X, Z, R 4 R 5 R 6 and R 7 Defined in this document; or its pharmaceutically acceptable salt.

[0147] One embodiment of the present invention includes a compound of formula Ib':

[0148]

[0149] Where Z, R 4 R 5 R 6 and R 7 Defined in this document; or its pharmaceutically acceptable salt.

[0150] One embodiment of the present invention includes a compound of formula Ib":

[0151]

[0152] Ib”

[0153] Z is defined in this paper; or its pharmaceutically acceptable salt.

[0154] One embodiment of the present invention includes, wherein the group is:

[0155]

[0156] Selected from the following compounds:

[0157] A is either N or C;

[0158] D is N or C(R) 8) n ;

[0159] E is either N or C;

[0160] G is N or C(R) 8)n ;

[0161] J is N or C(R) 8) n ;

[0162] W is N or C(R) 8) n ;and

[0163] When J is N, m is 1, but when J is C(R) 8 ) n When m is 1 or 2.

[0164] One embodiment of the present invention includes a group thereof:

[0165]

[0166] Selected from the following compounds:

[0167]

[0168] One embodiment of the present invention includes a compound of formula I, wherein the group

[0169]

[0170] Selected from:

[0171]

[0172] One embodiment of the present invention includes a compound in which X is -O-. Another embodiment of the present invention includes a compound in which X is -CH2.

[0173] One embodiment of the present invention includes a compound wherein Y is selected from the following compounds:

[0174]

[0175] In one embodiment of the invention, Y is selected from one to three unsubstituted or substituted genes selected from R. 4 The group substituted with the following groups: phenyl, pyridyl, pyridazinyl, and pyrimidinyl. In one embodiment of the invention, Y is selected from unsubstituted or substituted 1 to 3 groups selected from R. 4 The following groups are substituted with the group: pyridyl, pyridazinyl, and pyrimidinyl. One embodiment of the invention comprises a compound wherein Y is phenyl, pyridyl, pyridazinyl, or pyrimidinyl. One embodiment of the invention comprises a compound wherein Y is phenylphenyl or pyridyl. In one embodiment, Y is phenyl. In one embodiment of the invention, Y is pyridyl.

[0176] One embodiment of the present invention includes wherein Z is Compounds.

[0177] In one embodiment of the present invention, R 1 Selected from

[0178] (1) Hydrogen,

[0179] (2)CN,

[0180] (3)-C(O)NR2,

[0181] (4)CH2OCH2CF3

[0182] (5)CH2OCH2CHCF2,

[0183] (6)C 1-6 Alkyl groups, which are unsubstituted or substituted by one to three independent substituents selected from the following.

[0184] aC 1-6 alkyl,

[0185] b. Halogens,

[0186] c. Hydroxyl group,

[0187] d. Unsubstituted or substituted with 1 to 3 substituents selected from halogens -OC 1-6 Alkyl groups, or unsubstituted or halogenated, C 1-6 Alkyl or fluorinated C 1-6 Alkyl-substituted C 3-6 cycloalkyl,

[0188] eC 3-6 Cycloalkyl groups, which are unsubstituted or have one to three R groups. 4 replace,

[0189] f. Heteroaryl, unsubstituted or with 1 to 3 R groups 4 replace,

[0190] g. Heterocyclic group, unsubstituted or surrounded by 1 to 3 R groups 4 replace,

[0191] h.CN, and

[0192] iS(O)2R.

[0193] In one embodiment of the invention, R 1 Selected from hydrogen, -C(O)NR2, CH2OCH2CF3, CH2OCH2CHCF2 and -C 1-6 Alkyl group, wherein the alkyl group is unsubstituted or substituted by one to three substituents independently selected from the following: C 1-6Alkyl, halogen, hydroxyl, CN, unsubstituted or with 1 to 3 R 4 Replacement C 3-6 Cycloalkyl groups, and unsubstituted or substituted with 1 to 3 substituents selected from halogens -OC 1-6 Alkyl, or unsubstituted or halogenated, C 1-6 Alkyl or fluorinated C 1-6 Alkyl-substituted C 3-6 Cycloalkyl. In one embodiment of the invention, R 1 Selected from hydrogen, -C(O)NR2, CH2OCH2CF3, CH2OCH2CHCF2 and -C 1-6 Alkyl group, wherein the alkyl group is unsubstituted or substituted by one to three substituents independently selected from the following: C 1-6 Alkyl, halogen, CN and unsubstituted or with 1 to 3 R 4 Replacement C 3-6 Cycloalkyl.

[0194] In one embodiment of the invention, R 2 Selected from

[0195] 1) Straight chain or branched chain C 1-10 Alkyl or C 4-8 alkenyl,

[0196] 2)(CR2) 1-6 -O-(CR2) 1-6 -;

[0197] 3)(CR2) 1-6 -N(R 9 )-(CR2) 1-6 -, where R 9 It is hydrogen or -C 1-6 Alkyl, wherein the -C 1-6 The alkyl group is either unsubstituted or substituted with a halogen.

[0198] 4)-(CR2) 1-6 C 3-6 Cycloalkyl-(CR2) 1-6 Wherein -C 3-6 The cycloalkyl group is unsubstituted or converted to -C. 1-6 Alkyl or halogen substitution, and

[0199] 5) Unsubstituted or -C 1-6 The following groups are alkyl or halogen-substituted: piperidinyl, pyrrolyl, oxazolyl, oxadiazolyl, or thiazolyl ring.

[0200] In one embodiment of the invention, R 2 Selected from straight chain or branched chain C 1-10 Alkyl or C4-8 Alkenyl; -(CR2) 1-6 -O-(CR2) 1-6 -;-(CR2) 1-6 -N(R 9 )-(CR2) 1-6 -, where R 9 It is hydrogen or -C 1-6 Alkyl group; and -(CR2) 1-6 C 3-6 Cycloalkyl-(CR2) 1-6 Wherein -C 3-6 The cycloalkyl group is unsubstituted or converted to -C. 1-6 Alkyl or halogen substitution. In one embodiment of the invention, R... 2 Selected from straight chain or branched chain C 1-10 Alkyl or C 4-8 Alkenyl, and -(CR2) 1-6 -O-(CR2) 1-6 -. In one implementation, R 2 Selected from straight chain or branched chain C 1-10 Alkyl groups and -(CR2) 1-6 -O-(CR2) 1-6 -

[0201] In one embodiment of the invention, R 3 Selected from direct key, -S-, -NR-, -OC 1-6 Alkyl, -SC 1-6 Alkyl groups and -S(O)2-C 1-6 Alkyl group. In one embodiment of the invention, R 3 Selected from direct bond and -OC 1-6 Alkyl group. In one embodiment of the invention, R 3 For direct keys.

[0202] One embodiment of the invention includes a straight or branched chain C in which Z is unsubstituted or substituted with a substituent selected from the following: 3-8 Alkyl or C 4-8 Alkenyl compounds:

[0203] (1) Fluorine,

[0204] (2)C 1-6 Alkyl groups, which are unsubstituted or substituted with the following groups: tetrahydrofuranyl, tetrahydropyranyl, 1 to 6 fluorine groups, or unsubstituted or substituted with C 1-6 Alkyl, fluorinated C 1-6 Alkyl or 1 to 6 fluorine-substituted C 3-6 cycloalkyl,

[0205] (3)C 3-6Cycloalkyl groups, which are unsubstituted or C-substituted. 1-6 Alkyl, fluorinated C 1-6 Alkyl groups or 1 to 6 fluorine-substituted groups, and

[0206] (4)-OC 1-6 Alkyl groups, which are unsubstituted or substituted with 1 to 6 fluorine atoms,

[0207] And it can optionally be in C 3-8 The alkyl group contains a group selected from the following:

[0208] (1)-O-,

[0209] (2)-N(R 9 )-, where R 9 It is hydrogen or -C 1-6 Alkyl, wherein the -C 1-6 The alkyl group is either unsubstituted or substituted with a halogen.

[0210] (3)-C 3-6 Cycloalkyl groups, wherein the -C 3-6 The cycloalkyl group is unsubstituted or converted to -C. 1-6 Alkyl or halogen substitution, and

[0211] (4) Unsubstituted or -C 1-6 The following groups are alkyl or halogen-substituted: piperidinyl, pyrrolyl, oxazolyl, oxadiazolyl, or thiazolyl ring.

[0212] One embodiment of the present invention includes Z being a straight chain or a branched chain C. 3-8 Alkyl or C 4-8 Alkenyl compounds, which are either unsubstituted or substituted with substituents selected from the following:

[0213] (1) Fluorine,

[0214] (2)C 1-6 Alkyl groups, which are unsubstituted or C-substituted. 3-6 Cycloalkyl or 1 to 6 fluorine-substituted,

[0215] (3)C 3-6 Cycloalkyl groups, which are unsubstituted or C-substituted. 1-6 Alkyl, fluorinated C 1-6 Alkyl groups or 1 to 6 fluorine-substituted groups, and

[0216] (4)-OC 1-6 Alkyl groups, which are unsubstituted or substituted with 1 to 6 fluorine atoms,

[0217] And it can optionally be in C 3-8 The alkyl group contains a group selected from the following:

[0218] (1)-O-,

[0219] (2)-N(R 9 )-, where R 9 It is hydrogen or -C 1-6 Alkyl, wherein the -C 1-6 Alkyl groups are either unsubstituted or substituted with halogens, and

[0220] (3)-C 3-6 Cycloalkyl groups, wherein the -C 3-6 The cycloalkyl group is unsubstituted or converted to -C. 1-6 Alkyl or halogen substitution.

[0221] One embodiment of the present invention includes Z being a straight chain or a branched chain C. 3-8 Alkyl compounds that are unsubstituted or substituted with substituents selected from the following:

[0222] (1) Fluorine,

[0223] (2)C 1-6 Alkyl groups, which are unsubstituted or substituted with 1 to 6 fluorine atoms, and which may optionally be C10-C6 ... 3-8 The alkyl group contains a group selected from the following:

[0224] (1)-O-,

[0225] (2)-N(R 9 )-, where R 9 It is hydrogen or -C 1-6 Alkyl, wherein the -C 1-6 The alkyl group is either unsubstituted or substituted with a halogen.

[0226] One embodiment of the present invention includes a compound wherein Z is selected from the following compounds:

[0227]

[0228] One embodiment of the present invention includes R 4 Selected from the following compounds:

[0229] (1)H,

[0230] (2)C 1-6 alkyl,

[0231] (3) Halogen,

[0232] (4)-OC 1-6 Alkyl groups, and

[0233] (5)C 3-6 Cycloalkyl.

[0234] One embodiment of the present invention includes R 4Selected from hydrogen, methyl, F, Cl, -OCH3 and C 3-6 Cycloalkyl compounds. One embodiment of the invention includes R... 4 A compound of hydrogen. One embodiment of the invention includes R... 4 A compound containing methyl groups. One embodiment of the invention includes R... 4 Compounds with -OCH3.

[0235] One embodiment of the present invention includes R 5 and R 6 The compounds are selected independently from the following:

[0236] (1) Hydrogen, and

[0237] (2)-C 1-6 Alkyl group, wherein the alkyl group is unsubstituted or substituted by one to six substituents independently selected from fluorine.

[0238] One embodiment of the present invention includes R 5 It is hydrogen and R 6 A compound of hydrogen. One embodiment of the invention includes R... 5 It is hydrogen and R 6 A compound containing methyl groups. One embodiment of the invention includes R... 5 It is hydrogen and R 6 It is a trifluoromethyl compound.

[0239] One embodiment of the present invention includes R 7 Selected from the following compounds:

[0240] (1) Hydrogen,

[0241] (2)-C 1-6 Alkyl groups, and

[0242] (3)-C 3-6 Cycloalkyl.

[0243] One embodiment of the present invention includes R 7 Compounds selected from hydrogen, methyl, and ethyl. One embodiment of the invention includes R... 7 It is a compound of ethyl group.

[0244] One embodiment of the present invention includes R 8 A compound of hydrogen. One embodiment of the invention includes R... 8 Compounds containing methyl groups.

[0245] Some embodiments of the present invention include compounds selected from the compounds described herein or pharmaceutically acceptable salts thereof.

[0246] Some embodiments of the present invention include compounds selected from the following:

[0247] (10R,E)-9-ethyl-10-methyl-3-oxa-7,9-diaza-2(6,8)-imidazo[1,2-a]pyrazin-1(1,3)-benzo-4(1,3)-cyclopentacyclodeca-8-one;

[0248] (12R)-13-ethyl-12-methyl-12,13,16,17,19,20-hexahydro-6,22-(azeno))-11,7-(metheno)imidazo[1,2-o][1,18,4,6,15]cycloicosin-14(15H)-one;

[0249] (12R)-13-ethyl-12-methyl-18-(propyl-2-yl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[1,2-r][1,4,7,9,18]oxatetraazacycloeicosene-14-one;

[0250] (12R)-13-ethyl-12-methyl-12,13,15,16,17,18,21,22,22a,23-decahydro-14H,20H-6,25-(azaben)-11,7-(methylene)imidazo[1,2-s]pyrrolo[2,1-c][1,4,8,10,19]oxatetraazacyclotetradecene-14-one;

[0251] (7R)-8-ethyl-7-methyl-18-oxa-8,10,13,21,24,26-hexaazapentacyclo-[17.6.1.1~2,6~.1~13,17~.0~20,24~]octadec-1(25),2(28),3,5,19(26),20,22-heptaen-9-one;

[0252] (12R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,20,21-octahydro-14H-6,23-(azaene)-11,7-(methylene)imidazo[2,1-f][1,4,7,13,16,18]dioxatetraazacyclotetradecene-14-one;

[0253] (12R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,20,21-octahydro-14H-6,23-(azaene)-11,7-(methylene)imidazo[2,1-f][1,4,7,13,16,18]dioxatetraazacyclotetradecene-14-one;

[0254] (12R)-13-ethyl-8-methoxy-12-methyl-12,13,15,16,17,18,20,21-octahydro-14H-6,23-(azaene)-11,7-(methylene)imidazo[2,1-f][1,4,7,13,16,18]dioxatetraazacyclotetradecene-14-one;

[0255] (12R)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,20,21-hexahydro-19H-6,23-(azaene)-11,7-(methylene)imidazo[1,2-o][1,18,4,6,9,15]dioxatetraazacyclotetradecene-14(15H)-one;

[0256] (12R)-13-ethyl-8-methoxy-12,16-dimethyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0257] (12R)-13-ethyl-8-methoxy-12,16-dimethyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0258] (R,E)-4-ethyl-3-methyl-13-oxa-4,6,9-triaza-1(6,8)-imidazo[1,2-a]pyrazin-2(1,3)benzerocyclodeca-5-one;

[0259] (12R)-13-ethyl-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[1,2-s][1,4,8,10,19]oxatetraazacyclotetradecene-14(15H)-one;

[0260] (12R)-13-ethyl-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclic icosenoen-14(15H)-one;

[0261] (12R)-13-ethyl-12,19,19-trimethyl-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclic eicosene-14-one;

[0262] (12R)-13-ethyl-12-methyl-12,13,15,16,17,18,20,21-octahydro-14H-6,23-(azaene)-11,7-(methylene)imidazo[2,1-f][1,4,7,16,18]dioxatriazacyclotetradecene-14-one;

[0263] (12R)-13,18-diethyl-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15,18]oxatetraazacyclotetradecene-14(15H)-one;

[0264] (12R)-13-ethyl-12,18,21-trimethyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15,18]oxatetraazacyclotetradecene-14(15H)-one;

[0265] (12R)-13-ethyl-12-methyl-12,13,16,17,20,21-hexahydro-19H-6,23-(azaben)-11,7-(methylene)imidazo[1,2-o][1,18,4,6,15]dioxatriazacyclotetradecene-14(15H)-one;

[0266] (12R)-13-ethyl-12,16-dimethyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclic icosenoen-14(15H)-one;

[0267] (12R)-13-ethyl-12-methyl-16-(1,3-thiazolyl-4-yl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclotetradecene-14(15H)-one;

[0268] (12R)-13-ethyl-12-methyl-16-(1,3-thiazolyl-4-yl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclotetradecene-14(15H)-one;

[0269] (12R)-13-ethyl-12-methyl-16-(1,2-oxazol-3-yl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclotetradecene-14(15H)-one;

[0270] (12R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,20,21-hexahydro-19H-6,23-(azaene)-11,7-(methylene)imidazo[1,2-o][1,18,4,6,9,15]dioxatetraazacyclotetradecene-14(15H)-one;

[0271] (12R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,20,21-hexahydro-19H-6,23-(azaene)-11,7-(methylene)imidazo[1,2-o][1,18,4,6,9,15]dioxatetraazacyclotetradecene-14(15H)-one;

[0272] (R,27E,62Z)-10-ethyl-11-methyl-3-oxa-8,10-diaza-6(4,2)-thiazoza-2(6,8)-imidazo[1,2-a]pyrazin-1(1,3)benzacycloundecanone-9-one;

[0273] (R,27E,54Z)-10-ethyl-11-methyl-3-oxa-8,10-diaza-5(3,5)-oxadiaza-2(6,8)-imidazo[1,2-a]pyrazin-1(1,3)benzacycloundecanone-9-one;

[0274] (3R,E)-4-ethyl-3,9-dimethyl-8-(trifluoromethyl)-12-oxa-4,6,9-triaza-1(6,8)-imidazo[1,2-a]pyrazin-2(1,3)benzerocyclododecano-5-one;

[0275] (3R,E)-4-ethyl-3,9-dimethyl-8-(trifluoromethyl)-13-oxa-4,6,9-triaza-1(6,8)-imidazo[1,2-a]pyrazin-2(1,3)benzerocyclodeca-5-one;

[0276] (3R,7R,E)-4-ethyl-22-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-12-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(3,5-pyridazine-cyclododecano-5-one;

[0277] (3R,7R,E)-4-ethyl-22-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(3,5)pyridinium ring tridecanone;

[0278] (12S,16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacycloeicosene-14-one;

[0279] (12R,16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacycloeicosene-14-one;

[0280] (12S,16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0281] (17E,3R,7S,9Z)-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-12-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(1,3-benzylcyclododecano-9-en-5-one;

[0282] (3R,7R,E)-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-12-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(1,3-benzylcyclododecano-5-one;

[0283] (16S,18Z)-13-ethyl-8-methoxy-12-(trifluoromethyl)-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,20-hexahydro-14H-6,22-(azaene)-11,7-(methylene)[1,2,4]triazolo[5,1-c][1,4,10,13,15]oxatetraazacycloeicosene-14-one;

[0284] (16R)-13-ethyl-8-methoxy-12-(trifluoromethyl)-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)[1,2,4]triazolo[5,1-c][1,4,10,13,15]oxatetraazacycloeicosene-14-one;

[0285] (16R)-13-ethyl-8-methoxy-12-(trifluoromethyl)-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)[1,2,4]triazolo[5,1-c][1,4,10,13,15]oxatetraazacycloeicosene-14-one;

[0286] 13-Ethyl-8-methoxy-12-(trifluoromethyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)[1,2,4]triazolo[5,1-c][1,4,10,13,15]oxatetraazacycloeicosene-14-one;

[0287] (16R)-13-ethyl-8-methoxy-2-methyl-12-(trifluoromethyl)-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacycloeicosene-14-one;

[0288] (16R)-13-ethyl-8-methoxy-2-methyl-12-(trifluoromethyl)-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacycloeicosene-14-one;

[0289] (16R)-13-ethyl-8-methoxy-12,16-bis(trifluoromethyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)[1,2,4]triazolo[5,1-c][1,4,10,13,15]oxatetraazacycloeicosene-14-one;

[0290] (16R)-13-ethyl-8-methoxy-16-(2,2,2-trifluoroethyl)-12-(trifluoromethyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)[1,2,4]triazolo[5,1-c][1,4,10,13,15]oxatetraazacycloeicosene-14-one;

[0291] (16R)-13-ethyl-8-methoxy-12,16-bis(trifluoromethyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacycloeicosene-14-one;

[0292] (16R)-13-ethyl-8-methoxy-12,16-bis(trifluoromethyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacycloeicosene-14-one;

[0293] (12S,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacycloeicosene-14-one;

[0294] (12R,18Z)-13-ethyl-12,17-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,20-hexahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclic eicosene-14-one;

[0295] (12R,18Z)-13-ethyl-12,17-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,20-hexahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclic eicosene-14-one;

[0296] (12R,18Z)-13-ethyl-12,17-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,20-hexahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclic eicosene-14-one;

[0297] (12R)-13-ethyl-12,17-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclic eicosene-14-one;

[0298] (12R)-13-ethyl-12,17-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclic eicosene-14-one;

[0299] (12R)-13-ethyl-12,17-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclic eicosene-14-one;

[0300] (12R)-13-ethyl-12,17-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclic eicosene-14-one;

[0301] (16R)-13-ethyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclic eicosene-14-one;

[0302] (16R)-13-ethyl-8-methoxy-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclic eicosene-14-one;

[0303] (16R)-13-ethyl-8-methoxy-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacycloeicosene-14-one;

[0304] (3R,7R,E)-4-ethyl-22-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-12-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(3,5-pyridazinecyclododecano-5-one;

[0305] (3R,7R,E)-4-ethyl-22-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(3,5-pyridone-cyclotridefan-5-one;

[0306] (3R,E)-4-ethyl-3,9-dimethyl-7-(3,3,3-trifluoropropyl)-12-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(1,3-benzylcyclododecano-5-one;

[0307] (12R)-13-ethyl-12-methyl-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclic eicosene-14-one;

[0308] (7R)-8-ethyl-14,14-difluoro-3-methoxy-7-methyl-11-(3,3,3-trifluoropropyl)-17-oxa-5,8,10,20,23,25-hexaazatetracyclo[16.6.1.12,6.019,23]hexacarbon-1(24),2(26),3,5,18(25),19,21-heptaen-9-one;

[0309] (7R)-8-ethyl-14,14-difluoro-3-methoxy-7-methyl-11-(3,3,3-trifluoropropyl)-17-oxa-5,8,10,20,23,25-hexaazatetracyclo[16.6.1.12,6.019,23]hexacarbon-1(24),2(26),3,5,18(25),19,21-heptaen-9-one;

[0310] (7R)-8-ethyl-14,14-difluoro-3-methoxy-7-methyl-11-(3,3,3-trifluoropropyl)-17-oxa-5,8,10,20,23,25-hexaazatetracyclo[16.6.1.12,6.019,23]hexacarbon-1(24),2(26),3,5,18(25),19,21-heptaen-9-one;

[0311] (3R,7R,E)-4-ethyl-23-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyridazine-2(2,6)pyridazine-cyclotridefan-5-one;

[0312] (16R)-13-ethyl-8-methoxy-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,9,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0313] (12R)-13,16-diethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0314] (12R)-13,16-diethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0315] (12R)-13-ethyl-8-methoxy-12-methyl-16-(2-methylpropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetraenocene-14(15H)-one;

[0316] (12R)-13-ethyl-8-methoxy-12-methyl-16-(2-methylpropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetraenocene-14(15H)-one;

[0317] (12R)-13-ethyl-8-methoxy-12-methyl-16-propyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0318] (12R)-13-ethyl-8-methoxy-12-methyl-16-propyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0319] (12R)-16-(cyclopropylmethyl)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0320] (12R)-16-(cyclopropylmethyl)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0321] (12R)-13-ethyl-8-methoxy-16-(2-methoxyethyl)-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0322] (12R)-13-ethyl-8-methoxy-16-(2-methoxyethyl)-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0323] (12R)-16-cyclopropyl-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0324] (12R)-16-cyclopropyl-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0325] (12R)-13-ethyl-8-methoxy-16-(methoxymethyl)-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0326] (12R)-13-ethyl-8-methoxy-16-(methoxymethyl)-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0327] (12R)-16-[(2,2-difluorocyclopropyl)methyl]-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0328] (12R)-16-[(2,2-difluorocyclopropyl)methyl]-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0329] (12R)-16-[(2,2-difluorocyclopropyl)methyl]-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azane)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacycloteicosyneo-14(15H)-one;

[0330] (12R)-16-[(2,2-difluorocyclopropyl)methyl]-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0331] (12R)-13-ethyl-8-methoxy-16-(3-methoxypropyl)-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0332] (12R)-13-ethyl-8-methoxy-16-(3-methoxypropyl)-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0333] (12R)-16-(cyclobutylmethyl)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0334] (12R)-16-(cyclobutylmethyl)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0335] (12R)-16-(ethoxymethyl)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0336] (12R)-16-(ethoxymethyl)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0337] (12R)-16-tert-butyl-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0338] (12R)-16-tert-butyl-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0339] (12R)-13-ethyl-16-(2-ethylbutyl)-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0340] (12R)-13-ethyl-16-(2-ethylbutyl)-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0341] (12R)-16-(cyclopentylmethyl)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0342] (12R)-16-(cyclopentylmethyl)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0343] (12R)-13-ethyl-8-methoxy-12-methyl-16-{[1-(trifluoromethyl)cyclopropyl]methyl}-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0344] (12R)-13-ethyl-8-methoxy-12-methyl-16-{[1-(trifluoromethyl)cyclopropyl]methyl}-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0345] (12R)-13-ethyl-8-methoxy-12-methyl-16-[(tetrahydrofuran-3-yl)methyl]-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0346] (12R)-13-ethyl-8-methoxy-12-methyl-16-[(tetrahydrofuran-3-yl)methyl]-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0347] (12R)-13-ethyl-8-methoxy-12-methyl-16-(tetrahydropyran-4-yl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacycloteicosene-14(15H)-one;

[0348] (12R)-13-ethyl-8-methoxy-12-methyl-16-(tetrahydropyran-4-yl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacycloteicosene-14(15H)-one;

[0349] (12R)-16-[(3,3-difluorocyclobutyl)methyl]-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0350] (12R)-16-[(3,3-difluorocyclobutyl)methyl]-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0351] (12R)-16-{[1-(difluoromethyl)cyclopropyl]methyl}-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0352] (12R)-16-{[1-(difluoromethyl)cyclopropyl]methyl}-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0353] (12R)-13-ethyl-16-(3-fluoro-3-methylbutyl)-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetraenocene-14(15H)-one;

[0354] (12R)-13-ethyl-16-(3-fluoro-3-methylbutyl)-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetraenocene-14(15H)-one;

[0355] (12R)-13-ethyl-16-(3-fluorobutyl)-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetraenocene-14(15H)-one;

[0356] (12R)-13-ethyl-16-(3-fluorobutyl)-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetraenocene-14(15H)-one;

[0357] (12R)-13-ethyl-8-methoxy-12-methyl-16-[2-(trifluoromethoxy)ethyl]-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0358] (12R)-13-ethyl-8-methoxy-12-methyl-16-[2-(trifluoromethoxy)ethyl]-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0359] (9R,E)-12-ethyl-13-methyl-9-(3,3,3-trifluoropropyl)-3-oxa-10,12-diaza-1(7,5)-furano[3,2-b]pyridazo-2(6,8-imidazo[1,2-a]pyrazine-11-one;

[0360] (10R)-7-ethyl-6,19-dimethyl-10-(3,3,3-trifluoropropyl)-6,7,10,11,12,13,14,15-octahydro-23,17-(azaene)-5,24-(methylene)furano[2,3-h]imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-8(9H)-one;

[0361] (10R)-7-ethyl-6,19-dimethyl-10-(3,3,3-trifluoropropyl)-6,7,10,11,12,13,14,15-octahydro-23,17-(azaene)-5,24-(methylene)furano[2,3-h]imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-8(9H)-one;

[0362] (10R)-7-ethyl-6,20-dimethyl-10-(3,3,3-trifluoropropyl)-6,7,10,11,12,13,14,15-octahydro-23,17-(azaene)-5,24-(methylene)furano[2,3-h]imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-8(9H)-one;

[0363] (10R)-7-ethyl-6,20-dimethyl-10-(3,3,3-trifluoropropyl)-6,7,10,11,12,13,14,15-octahydro-23,17-(azaene)-5,24-(methylene)furano[2,3-h]imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-8(9H)-one;

[0364] (12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(trifluoromethyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0365] (12R,16R)-13-ethyl-8,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,9,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0366] (12R,16R)-13-ethyl-8,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0367] (15R)-12-ethyl-7-methoxy-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-10,6-(azaene)-5,22-(methylene)pyrazolo[1,5-c][1,3,9,13,15]oxatetraazacyclotetraenocene-13(14H)-one;

[0368] (15R)-12-ethyl-7-methoxy-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-10,6-(azaene)-5,22-(methylene)pyrazolo[1,5-c][1,3,9,13,15]oxatetraazacyclotetraenocene-13(14H)-one;

[0369] (12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20,21,22-decahydro-14H-6,23-(azaene)-11,7-(methylene)imidazo[1,2-l][1,3,6,12]tetraazacyclotetradecene-14-one;

[0370] (12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)[1,2,4]triazolo[5,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0371] (12R,16R)-16-(3,3-difluorobutyl)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,9,13,15]oxatetraazacyclotetraenocene-14(15H)-one;

[0372] (12R,16R)-16-(3,3-difluorobutyl)-13-ethyl-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0373] (12R)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0374] (12R,16R)-13-ethyl-8-methoxy-5,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,9,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0375] (12R,16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,5,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0376] (15R)-12-ethyl-7-methoxy-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-5,22-(azaene)-10,6-(methylene)pyrazolo[1,5-c][1,3,10,13,15]oxatetraazacyclotetraenocene-13(14H)-one;

[0377] (15R)-12-ethyl-7-methoxy-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-5,22-(azaene)-10,6-(methylene)pyrazolo[1,5-c][1,3,10,13,15]oxatetraazacyclotetraenocene-13(14H)-one;

[0378] (12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(methylene)imidazo[2,1-c][1,4,5,9,13,15]oxapentazone-14(15H)-one;

[0379] (16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(azaben)imidazo[2,1-c][1,4,13,15]oxatriazacyclotetradecene-14(15H)-one;

[0380] (12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(methylene)imidazo[2,1-c][1,4,9,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0381] (16R)-13-ethyl-10,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,8,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0382] (16R)-13-ethyl-10,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,8,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0383] (12S,16R)-13-ethyl-8,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(azaene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0384] (12R,16R)-13-ethyl-8,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(azaene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0385] (15R)-12-ethyl-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-6,22-(azaene)-7,10-cyclothionidazo[2,1-c][1,4,8,12,14]oxatetraazacycloeicosene-13(14H)-one;

[0386] (15R)-12-ethyl-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-6,22-(azaene)-7,10-cyclothionidazo[2,1-c][1,4,8,12,14]oxatetraazacycloeicosene-13(14H)-one;

[0387] (15R)-12-ethyl-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-6,22-(azaene)-7,10-cyclothionidazo[2,1-c][1,4,9,12,14]oxatetraazacycloeicosene-13(14H)-one;

[0388] (16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(methylene)imidazo[2,1-c][1,4,8,10,13,15]oxapentazone-14(15H)-one;

[0389] (16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(methylene)imidazo[2,1-c][1,4,8,10,13,15]oxapentazone-14(15H)-one;

[0390] (12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(azaben)imidazo[2,1-c][1,4,13,15]oxatriazacyclotetradecene-14(15H)-one;

[0391] (11R,15R)-12-ethyl-7-methoxy-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-5,22-(azaene)-10,6-(methylene)pyrazolo[1,5-c][1,3,5,10,13,15]oxapentazone-13(14H)-one;

[0392] (12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(2,2,2-trifluoroethyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,5,9,13,15]oxapentazone-14(15H)-one;

[0393] (11R,15R)-12-ethyl-7-methoxy-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-5,22:10,6-di(methylene)pyrazolo[1,5-c][1,3,5,10,13,15]oxapentazone-13(14H)-one;

[0394] (12R,16R)-13-ethyl-12-methyl-16-(2,2,2-trifluoroethyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,5,10,13,15]oxapentazone-14(15H)-one;

[0395] (12R,16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,5,10,13,15]oxapentazone-14(15H)-one;

[0396] (12R,16R)-13-ethyl-12-methyl-16-(2,2,2-trifluoroethyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0397] (15R)-12-ethyl-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-6,22-(azaene)-7,10-epoxyimidazo[2,1-c][1,4,8,12,14]oxatetraazacycloeicosene-13(14H)-one;

[0398] (15R)-12-ethyl-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-6,22-(azaene)-7,10-epoxyimidazo[2,1-c][1,4,8,12,14]oxatetraazacycloeicosene-13(14H)-one;

[0399] (15R)-12-ethyl-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-6,22:10,7-di(azaben)imidazo[2,1-c][1,8,4,12,14]dioxatriazacycloeicosene-13(14H)-one;

[0400] (15R)-12-ethyl-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-6,22:10,7-di(azaben)imidazo[2,1-c][1,8,4,12,14]dioxatriazacycloeicosene-13(14H)-one;

[0401] (12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20,21,22-decahydro-14H-11,7-(azaene)-6,23-(methylene)imidazo[1,2-l][1,3,12]triazacyclic icosenoen-14-one;

[0402] (12S,16R)-13-ethyl-9,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0403] (12R,16R)-13-ethyl-9,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0404] (15R)-12-ethyl-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-6,22-(azaene)-7,10-epoxyimidazo[2,1-c][1,4,9,12,14]oxatetraazacycloeicosene-13(14H)-one;

[0405] (3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-14-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridazine-14-adenosine-5-one;

[0406] (3R,7R,E)-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridone-decaproic acid-5-one;

[0407] (3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone;

[0408] (12R,16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,8,10,13,15]oxapentazone-14(15H)-one;

[0409] (16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,8,10,13,15]oxapentazone-14(15H)-one;

[0410] (12S,16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,8,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0411] (12R,16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,8,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0412] (12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(2,2,2-trifluoroethyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0413] (12R,16S)-13-ethyl-8-methoxy-12-methyl-16-(trifluoromethyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0414] (12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,9,10,13,15]oxapentazone-14(15H)-one;

[0415] (12S,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(azaene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0416] (12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(azaben)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0417] (12S,16R)-13-ethyl-9,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,8,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0418] (12R,16R)-13-ethyl-9,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,8,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0419] (12S,16R)-13-ethyl-9,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,8,10,13,15]oxapentazone-14(15H)-one;

[0420] (12R,16R)-13-ethyl-9,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,8,10,13,15]oxapentazone-14(15H)-one;

[0421] (16R)-13-ethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one;

[0422] (3R,E)-7-(2,2-difluorobutyl)-4-ethyl-25,3-dimethyl-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridone-decaproic acid-5-one;

[0423] (3R,7R,E)-4-ethyl-25-methoxy-16,3-dimethyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(4,2)pyridone-2-pyridone-5-one;

[0424] (3R,7R,E)-4-ethyl-25-methoxy-17,3-dimethyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(4,2)pyridone-2-pyridone-5-one;

[0425] (R,E)-7-(3,3-difluorobutyl)-4-ethyl-22-methoxy-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(3,5)pyridone-2-triazin-5-one;

[0426] (3R,7R,E)-4-ethyl-7-(fluoromethyl)-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone;

[0427] (3R,7S,E)-7-(3,3-difluoropropyl)-4-ethyl-25-fluoro-3-methyl-10,13-dioxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(4,2)pyridone-2-pyridone-5-one;

[0428] (3R,7R,E)-25-chloro-7-(3,3-difluoropropyl)-4-ethyl-3-methyl-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone;

[0429] (3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-25,3-dimethyl-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridone-decaproic acid-5-one;

[0430] (3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-((R)-3,3,3-trifluoro-2-hydroxypropyl)-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone;

[0431] (3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-((S)-3,3,3-trifluoro-2-hydroxypropyl)-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone;

[0432] (3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-((R)-3,3,3-trifluoro-1-hydroxypropyl)-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone;

[0433] (3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-((S)-3,3,3-trifluoro-1-hydroxypropyl)-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone;

[0434] (3R,7S,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-10-thia-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone;

[0435] (3R,7S,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-10-thia-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone 10,10-dioxide;

[0436] (3R,7S,E)-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridone-decaproic acid-5-one;

[0437] (3R,7R,E)-4-ethyl-10-hydroxy-22,3-dimethyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(3,5)pyridinium ring tridecanone;

[0438] (3R,7R,Z)-4-ethyl-23-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-4,6-diaza-1(6,8)-imidazo[1,2-a]pyridazine-2(2,6-pyridazine-cyclododecano-5-one;

[0439] (3R,7R,E)-4-ethyl-23-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(2,6)pyrazin-cyclotridefan-5-one;

[0440] (3R,7R,E)-4-ethyl-26-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(5,7)-pyrazolo[1,5-a]pyridazine-2(5,3)-pyridazine heterocyclic tridecanone;

[0441] (3R,7S,E)-4-ethyl-8,8-difluoro-25-methoxy-3,7-dimethyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone;

[0442] (3R,7R,E)-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone;

[0443] (R,E)-4-ethyl-3,3-dimethyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone;

[0444] (3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-12-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone;

[0445] (3R,E)-4-ethyl-25-methoxy-3-methyl-12-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridazin-7(1,2)-cyclopropanecyclododecano-5-one;

[0446] (3R,7R,E)-7-(3,3-difluorobutyl)-4-ethyl-22,3-dimethyl-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(3,5)pyridone-1,3-dicyclodeca-5-one;

[0447] (3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyrimidine heterocyclic tridecanone;

[0448] (3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-22-methoxy-3-methyl-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(3,5)pyridinium ring tridecanone;

[0449] (3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-b]pyridazinza-2(4,2)-pyridinium ring tridecanone;

[0450] (3R,7S,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyridaz-2(4,2)pyridazine-1-tetrazan-5-one;

[0451] (3R,7R,E)-7-(2,2-difluoropropyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone;

[0452] (3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-(3-methylpyrazin-2-yl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone;

[0453] (3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-25,3-dimethyl-9,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridone-decaproic acid-5-one;

[0454] (3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-(2-(methanesulfonyl)ethyl)-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone;

[0455] (3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-25-methoxy-3-methyl-10,13-dioxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(4,2)pyridone-2-pyridone-5-one;

[0456] (3R,7R,E)-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(5,7)-pyrazolo[1,5-a]pyridazine-2(4,2)pyridazine-13-adenosine-5-one;

[0457] (3R,7R)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-quinolina-2(4,2)-pyridinium ring tridecanone;

[0458] (3R,7R,E)-3,4-dimethyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone;

[0459] (3R,7R,E)-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(5,3-pyridazin-hexacyclic tridecanone;

[0460] (3R,7R,E)-7-(3,3-difluorobutyl)-4-ethyl-15,3-dimethyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(2,4)pyridinium ring tridecanone;

[0461] (3R,7S,E)-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-10,13-dioxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(2,4-pyridinium ring tridecanone;

[0462] (3R,7R)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-naphthidia-2(4,2)-pyridazine-13-adenosine-5-one;

[0463] (3R,7S,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-naphthia-2(4,2)-pyridylidene-13-adenosine-9-en-5-one;

[0464] (3R,7S,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone;

[0465] (3R,7S,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-10,13-dioxa-4,6-diaza-1(5,7)-pyrazolo[1,5-c]pyrimidinazole-2(4,2)pyridone-decaproic acid-5-one;

[0466] (3R,7R,E)-4-ethyl-25-methoxy-12,3-dimethyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-b]pyridazinza-2(4,2)-pyridinium ring tridecanone;

[0467] (3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-25-methoxy-3-methyl-10,13-dioxa-4,6-diaza-1(5,7)-pyrazolo[1,5-c]pyrimidinazole-2(4,2)pyridone-decaproic acid-5-one;

[0468] (3R,7R,E)-4-ethyl-25-methoxy-13,3-dimethyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-b]pyridazinza-2(4,2)-pyridinium ring tridecanone;

[0469] (3R,E)-7-(3,3-difluorobutyl)-4-ethyl-25-methoxy-3-methyl-10,13-dioxa-4,6-diaza-1(7,5)-[1,2,4]triazolo[1,5-c]pyrimidinazole-2(4,2)-pyridazine-1-tetrazon-5-one;

[0470] (3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-25-methoxy-3-methyl-9,13-dioxa-4,6-diaza-1(5,7)-pyrazolo[1,5-c]pyrimidinazole-2(4,2)pyridone-decaproic acid-5-one;

[0471] (3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-25-methoxy-3-methyl-9,13-dioxa-4,6-diaza-1(5,7)-pyrazolo[1,5-c]pyrimidinazole-2(4,2)pyridone-decaproic acid-5-one;

[0472] (3R,7R,E)-7-(3,3-difluorobutyl)-4-ethyl-25-methoxy-15,3-dimethyl-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone;

[0473] (3R,7S,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-9,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[4,3-a]pyrazin-2(4,2)pyridinium ring tridecanone;

[0474] (3R,7S,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-9,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone;

[0475] (3R,7S,E)-4-ethyl-23-fluoro-3-methyl-7-(3,3,3-trifluoropropyl)-9,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone;

[0476] (3R,7R,E)-7-(3,3-difluorobutyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(7,5)-[1,2,4]triazolo[1,5-c]pyrimidinazole-2(4,2)-pyridazine-1-tetrazon-5-one;

[0477] (R,E)-4-ethyl-25-methoxy-3-methyl-14-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridazine-1,4-diazon-5-one;

[0478] (R,E)-4-ethyl-25-methoxy-3-methyl-11-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridazine-1 / undecano-5-one;

[0479] (7S,E)-4-ethyl-23-fluoro-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone;

[0480] (3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-3-methyl-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridone-decaproic acid-5-one;

[0481] (3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-3-methyl-10,13-dioxa-4,6-diaza-1(5,7)-pyrazolo[1,5-c]pyrimidinazole-2(4,2)pyridone-decaproic acid-5-one;

[0482] (3R,E)-7-(2-(difluoromethoxy)ethyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone;

[0483] (3R,E)-4-ethyl-7-((1-fluorocyclopropyl)methyl)-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone;

[0484] (3R,E)-7-(4,4-difluorobutyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone;

[0485] (3R,E)-4-ethyl-7-(isopropoxymethyl)-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone;

[0486] (3R,E)-7-(2,2-difluoroethyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone;

[0487] (3R,E)-4-ethyl-25-methoxy-3-methyl-7-(2,2,3,3-tetrafluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone;

[0488] (3R,E)-4-ethyl-25-methoxy-3-methyl-7-((2,2,2-trifluoroethoxy)methyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone;

[0489] (3R,E)-4-ethyl-25-methoxy-3-methyl-7-(tetrahydrofuran-3-yl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone;

[0490] (3R,E)-7-((2,2-difluoroethoxy)methyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone;

[0491] (3R,E)-4-ethyl-25-methoxy-7-(1-methoxyethyl)-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone;

[0492] (3R,E)-7-(2,2-difluorocyclopropyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)pyridinium ring tridecanone;

[0493] (3R,E)-4-ethyl-25-methoxy-3-methyl-7-(tetrahydrofuran-2-yl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)pyridinium ring tridecanone;

[0494] 2-((3R,E)-4-ethyl-25-methoxy-3-methyl-5-oxo-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridonecyclodeca-7-yl)acetonitrile;

[0495] (3R,E)-7-(3,3-difluorocyclobutyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone;

[0496] 3-((3R,E)-4-ethyl-25-methoxy-3-methyl-5-oxo-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium trideca-7-yl)propionitrile;

[0497] (3R,E)-25-cyclopropyl-7-(3,3-difluoropropyl)-4-ethyl-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridazine-1,3-dicyclodeca-5-one;

[0498] (3R,E)-25-chloro-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone;

[0499] (3R,E)-4-ethyl-25-fluoro-7-(methoxymethyl)-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone;

[0500] (3R,E)-7-(3,3-difluorobutyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(4,2)pyridone-2-pyridone-5-one;

[0501] (3R,E)-7-(3,3-difluoropropyl)-4-ethyl-25,3-dimethyl-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridone-13-adenosine-5-one;

[0502] (3R,E)-7-(3,3-difluoropropyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(4,2)pyridone-2-pyridone-5-one;

[0503] (3R,E)-7-(bicyclo[1.1.1]pent-1-ylmethyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(4,2)-pyridone-decaproic acid-5-one;

[0504] (3R,E)-7-(3,3-difluoropropyl)-4-ethyl-25-fluoro-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-b]pyridazinza-2(4,2)-pyridinium ring tridecanone;

[0505] (3R,E)-4-cyclopropyl-7-(3,3-difluoropropyl)-25-fluoro-3-methyl-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(4,2)pyridazine-13-adenosine-5-one;

[0506] (3R,E)-4-ethyl-25-methoxy-3-methyl-7-((1-methylcyclopropyl)methyl)-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(4,2)pyridone-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(4,2)-pyridone-13-adenosine-5-one;

[0507] (3R,E)-7-(2,2-difluoropropyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(4,2)pyridone-2-pyridone-5-one;

[0508] (3S,E)-7-(3,3-difluoropropyl)-4-ethyl-25-methoxy-3-(trifluoromethyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone;

[0509] (9R,13R,E)-14-cyclopropyl-12-ethyl-13-methyl-9-(3,3,3-trifluoropropyl)-3-oxa-10,12-diaza-1(5,2)-thiazoza-2(6,8)-imidazo[1,2-a]pyrazine-cyclotridefan-11-one;

[0510] (16E,22E,7R)-25-cyclopropyl-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-21H-13-oxa-4,6-diaza-1(5,7)-pyrazolo[1,5-a]pyridazine-2(1,3)pyrazolocyclic tridecanone;

[0511] (9R,13R,E)-14-cyclopropyl-12-ethyl-13-methyl-9-(3,3,3-trifluoropropyl)-3-oxa-10,12-diaza-1(5,2)-oxazozaza-2(6,8)-imidazo[1,2-a]pyrazine-cyclotridefan-11-one;

[0512] (3R,E)-4-ethyl-2 5 -Methoxy-3-methyl-7 4 -(trifluoromethyl)-11-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridazin-7(3,1)-pyrrolidone-1,1,2-a-cycloundecan-5-one;

[0513] (3R,E)-4-ethyl-7 4 7 4 -Difluoro-3-methyl-11-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-7(3,1)-pyrrolidone-2(1,3)benzacycloundecanone-5-one;

[0514] (3R,E)-4-ethyl-25-methoxy-3-methyl-7 4 -(trifluoromethyl)-12-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridazin-7(3,1)-pyrrolidone-1,2-a-cyclododecano-5-one;

[0515] (3R,E)-4-ethyl-2 2 -Methoxy-3-methyl-7-(2-methylthiazo-4-yl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(3,5)pyridone-decaproic acid-5-one;

[0516] (3R,E)-4-ethyl-2 5-Methoxy-3-methyl-7-(2-methylthiazo-5-yl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)pyridinium ring tridecanone;

[0517] (3R,E)-4-ethyl-2 5 -Methoxy-3-methyl-7-(1-methyl-1H-tetrazol-5-yl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)pyridinium ring tridecanone;

[0518] (3R,E)-4-ethyl-2 5 -Methoxy-3-methyl-7-(4-methylthiazo-2-yl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)pyridinium ring tridecanone;

[0519] (3R,E)-4-ethyl-2 5 -Methoxy-3-methyl-7-(1-methyl-1H-1,2,4-triazol-5-yl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)pyridinium ring tridecanone;

[0520] (1 7 E,3R,8E)-4-ethyl-11,11-difluoro-2 5 -Methoxy-3,7-dimethyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium-hexacyclic tridecane-8-en-5-one;

[0521] (3R,7S,E)-4-ethyl-11,11-difluoro-2 5 -Methoxy-3,7-dimethyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone;

[0522] (3'R,7'S,7'E,8'E)-4'-ethyl-5'-methoxy-3',7'-dimethyl-2,3,5,6-tetrahydrospiro[pyran-4,11'-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2-pyridinium tridecaneno]-8'-en-5'-one;

[0523] (3'R,7'S,E)-4'-ethyl-5'-methoxy-3',7'-dimethyl-2,3,5,6-tetrahydrospiro[pyran-4,11'-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2-pyridinium tridecanone]-5'-one;

[0524] (3R,E)-4-ethyl-2 5 -Methoxy-3-methyl-5-oxo-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazinaza-2(4,2)-pyridinium heterocyclic tridecanenoic acid-7-carboxynitrile; and

[0525] (3R,E)-4-ethyl-2 5 -Fluoro-3-methyl-5-oxo-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinehexacyclic tridecanedio-7-carboxamide;

[0526] Or its pharmaceutically acceptable salt.

[0527] Some embodiments of the present invention include compounds selected from the following example numbers: 110, 125, 129, 136, 142, 164, 165, 169, 174, and 179, or pharmaceutically acceptable salts thereof. In embodiments of the present invention, the compounds include example numbers 110, 136, 164, and 179, or pharmaceutically acceptable salts thereof.

[0528] Alternative embodiments of the present invention may also exclude any of the compounds listed above.

[0529] It should be understood that, unless otherwise stated, references to “Formula I” also include compounds of Formula I’, Formula Ia, Formula Ia’, Formula Ia”, Formula Ib, Formula Ib’ and Formula Ib”.

[0530] The compounds of this invention may contain one or more asymmetric centers, and thus may appear as racemic mixtures and racemic mixtures, single enantiomers, diastereomer mixtures, and single diastereomers. Additional asymmetric centers may be present depending on the nature of the different substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and it is intended to include all possible optical and diastereomers of the compounds in mixtures, as well as those that are pure or partially purified, within the scope of this invention. This invention is intended to include all such isomeric forms of these compounds. Similarly, this invention includes tautomeric forms of the compounds disclosed herein. Formula I represents the structure of such compounds without a specific stereochemistry. At least some of the chemical names of the compounds of this invention described in this application may have been automatically generated using commercially available chemical nomenclature software programs and have not been independently verified.

[0531] As is known in the art, the independent synthesis of these diastereomers or their chromatographic separation can be achieved by appropriately modifying the methods disclosed herein. Their absolute stereochemistry can be determined by X-ray crystallography of the crystalline products or, if necessary, by crystallization of crystalline intermediates derived from reagents containing asymmetric centers of known absolute configurations. Absolute stereochemistry can also be elucidated by other techniques known in the art, such as cryo-electron microscopy. Relative stereochemistry can be determined using nuclear magnetic resonance methods known in the art. Stereochemistry can be specified analogously based on the relative biological activity of a group of isomers, following the same trend established by a group of isomers with similar stereochemical definitions. If desired, racemic mixtures of compounds can be separated to isolate individual enantiomers. Separation can be carried out by methods well known in the art, such as coupling a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomer mixture, and then separating the individual diastereomers by standard methods, such as stepwise crystallization or chromatography. The coupling reaction is typically performed by generating a salt from an enantiomerically pure acid or base. The diastereomeric derivative can then be converted to a pure enantiomer by cleavage of the added chiral residue. Racemic mixtures of compounds can also be directly separated by chromatography using chiral stationary phases, methods well known in the art. The compounds of the present invention can also be separated by supercritical fluid chromatography (SFC), reversed-phase HPLC, or silica gel chromatography. Isomers are named according to the order in which they elute from the column (first, second, etc., eluted isomers, or using "A" and "B" or "a" and "b" as first, second, etc., eluted isomers), and examples are named Example #A and Example #B according to the order of elution from the purification system, etc. Those skilled in the art will understand that sometimes a peak may contain more than one isomer, and when split in half or further fractionated, multiple fractions of a peak may be produced and may not represent a single isomer. Furthermore, some separations require multiple rounds of purification using the same purification method and / or alternative purification systems. Additionally, mixtures can be mixtures of 2 to 8 stereoisomers. Alternatively, any enantiomer of the compound can be obtained by stereoselective synthesis using optically pure starting materials or reagents with known configurations, by methods well known in the art.

[0532] As will be understood by those skilled in the art, the term halogen or halo as used herein is intended to include fluorine, chlorine, bromine, and iodine. Similarly, C 1-6 , such as C 1-6 In alkyl groups, is defined as a group having 1, 2, 3, 4, 5, or 6 carbons arranged in a straight or branched chain, which makes C 1-6Alkyl groups specifically include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, secondary pentyl, hexyl, etc. A group designated as being independently substituted can be independently substituted by multiple such substituents.

[0533] This invention also includes all pharmaceutically acceptable isotopic variants of compounds of Formula I, in which one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from those normally found in nature. These compounds are identical to those disclosed herein, but one or more atoms are replaced by atoms having an atomic mass or mass number different from those normally found in nature. Examples of isotopes suitable for inclusion in compounds of this invention include isotopes of hydrogen such as… 2 H and 3 H, carbon isotopes such as 11 C 13 C and 14 C, isotopes of nitrogen such as 13 N and 15 N, isotopes of oxygen such as 15 O、 17 O and 18 O, phosphorus isotopes such as 32 P, isotopes of sulfur such as 35 S, isotopes of fluorine such as 18 F, isotopes of iodine such as 123 I and 125 I, isotopes of chlorine such as 36 Cl. Certain isotope-labeled compounds of Formula I, such as those containing radioactive isotopes, are useful in studies of drug and / or substrate tissue distribution. Radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) It is particularly useful for this purpose because it is easy to incorporate and detect. Heavier isotopes such as deuterium (i.e., 2 H) substitution may offer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirement, and may therefore be preferred in some cases. Using positron-emitting isotopes such as... 11 C, 18 F, 15 O and 13 Nitrogen substitution can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. Embodiments of the invention include compounds substituted with positron-emitting isotopes. 11 Compounds substituted with C isotopes. Embodiments of the invention include those using... 18Compounds substituted with the F isotope. In the compounds of this invention, atoms may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched with a specific isotope having the same atomic number but a different atomic mass or mass number than that of atoms predominantly found in nature. This invention aims to include all suitable isotopic variations of the compounds of this invention. For example, different isotopic forms of hydrogen (H) include protium (… 1 H) and deuterium ( 2 H). Protium is the main hydrogen isotope found in nature. Enriching deuterium can provide certain therapeutic advantages, such as increasing the in vivo half-life or reducing dosage requirements, or can provide compounds that can be used as standards for characterizing biological samples. The isotope-enriched compounds of the present invention can be prepared using conventional techniques well known to those skilled in the art, or by methods similar to those described in the schemes and examples herein, using appropriate isotope-enriching reagents and / or intermediates, without the need for unnecessary experiments.

[0534] Those skilled in the art will recognize those instances where the compounds of the present invention can form salts. In such cases, another embodiment provides a pharmaceutically acceptable salt of the compounds of the present invention. Therefore, unless otherwise stated, references to the compounds of the present invention herein should be understood to include references to their salts. The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable, non-toxic base or acid (including inorganic or organic bases and inorganic or organic acids). Furthermore, when the compounds of the present invention contain both a basic moiety (e.g., but not limited to pyridine or imidazole) and an acidic moiety (e.g., but not limited to carboxylic acids), zwitterions ("internal salts") can be formed, and these zwitterions are included in the present invention. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, ferric salts, ferrous salts, lithium salts, magnesium salts, ferric salts, divalent manganese salts, potassium salts, sodium salts, zinc salts, etc. Specific embodiments include ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts. Salts in solid form can exist in more than one crystal structure and can also exist as hydrates or solvates. Salts derived from pharmaceutically acceptable organic non-toxic alkaloids include the following: primary amines, secondary amines, and tertiary amines; substituted amines, including naturally occurring substituted amines; cyclic amines; and basic ion exchange resins (such as arginine, betaine, caffeine, choline, N,N′-diphenylethylenediamine, diethylamine, 2-diethylamineethanol, 2-dimethylamineethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, helapamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins), procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0535] When the compounds of the present invention are basic, the salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. These acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, viscous acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc. Specific embodiments include citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, fumaric acid, and tartaric acid. It should be understood that, as used herein, references to compounds of formula 1 also imply the inclusion of pharmaceutically acceptable salts. Salts of the compounds of the present invention can be formed by methods known to those skilled in the art, for example, by reacting the compounds of the present invention with a certain amount of an acid or base (e.g., an equal amount of acid or base) in a medium in which the salt is precipitated or in an aqueous medium, followed by lyophilization.

[0536] Examples of the invention are the embodiments and the use of the compounds disclosed herein. Specific compounds within the invention include compounds selected from those disclosed in the following embodiments, pharmaceutically acceptable salts thereof, and their single enantiomers or diastereomers.

[0537] This invention also relates to the use of the compounds disclosed herein as agonists of orexin receptor activity. The compounds of this invention and pharmaceutically acceptable salts thereof can be used in methods for inhibiting orexin receptor activity in individuals such as mammals, the methods comprising administering an amount of said compound. The compounds of this invention can be administered to a variety of other mammals besides primates, particularly humans. This invention relates to the therapeutic potential of the compounds of this invention or pharmaceutically acceptable salts thereof. This invention also relates to the use of the compounds of this invention or pharmaceutically acceptable salts thereof in the manufacture of medicaments for inhibiting orexin receptor activity or treating the disorders and diseases described herein in humans and animals.

[0538] Individuals to whom the compounds of the present invention are administered, or pharmaceutically acceptable salts thereof, are typically mammals, such as humans, males or females. The amount of the compound administered to the individual is sufficient to induce agonization of orexin receptors within that individual. In one embodiment, the amount of the compound may be an “effective amount,” wherein the compound of the present invention is administered in an amount that will elicit a biological or medical response in a tissue, system, animal, or human that is being sought by a researcher, veterinarian, physician, or other clinician. An effective amount does not necessarily include considerations of toxicity and safety in relation to the administration of the compound. It is recognized that those skilled in the art can influence said diseases by treating individuals currently suffering from neurological and psychiatric disorders associated with orexin receptor activation, or by preventingively treating individuals who may suffer from said diseases, using effective amounts of the compounds of the present invention. As used herein, the terms “treatment” and “treating” refer to all processes in which there may be a slowing, interruption, inhibition, control, or cessation of the progression of the neurological and psychiatric diseases described herein, but not necessarily the complete elimination of the impaired symptoms, as well as preventive treatment of the mentioned conditions, particularly in individuals susceptible to such diseases or disorders. The terms “application” and / or “administration” of a compound should be understood as meaning the intention to provide an individual with the compound or a prodrug of the present invention.

[0539] As used herein, the term "composition" is intended to include products containing a specified amount of a specified ingredient, and any product composed directly or indirectly of a specified amount of the specified ingredient. The term is intended to include products containing one or more active ingredients and an inert ingredient constituting a carrier, and any product resulting directly or indirectly from a combination, complexation, or aggregation of any two or more ingredients, or from the dissociation of one or more ingredients, or from other types of reactions or interactions of one or more ingredients. Therefore, compositions of the present invention include any composition prepared by mixing compounds of the present invention with a pharmaceutically acceptable carrier. "Pharmaceutically acceptable" means that the carrier, diluent, or excipient must be compatible with the other components of the formulation and harmless to its recipient.

[0540] The use of the compounds according to the invention as orexin receptor OX1R and / or OX2R agonists can be readily determined without the need for unnecessary experiments performed using methods well-known in the art. Both OX1R and / or OX2R G-coupled protein receptors (GPCRs) are coupled via the Gαq signaling pathway, ultimately promoting calcium mobilization by generating inositol triphosphate (IP3). IP-3 has a relatively short half-life and is rapidly metabolized to inositol monophosphate (IP-1), which can be readily detected using a commercially available assay kit (IP-One; Cisbio; catalog number 621PAPEC) in combination with cell lines expressing one or more target receptors of interest. The use of the compounds according to the invention as orexin receptor OX1R and / or OX2R agonists can be determined using this assay.

[0541] In a typical experiment, the activities of OX1 and OX2 receptor agonists are determined according to the following general experimental method. Chinese hamster ovary (CHO) cells expressing human OX1R and / or human OX2R are grown in Iscove-modified DMEM medium containing glutamax. TMThe culture medium contained 1% G418, 100 U / mL penicillin, 100 μg / mL streptomycin, and 10% qualified heat-inactivated fetal bovine serum (FBS). OX2R cells were seeded at 10,000 cells / well / 50 μL, and OX1R cells at 20,000 cells / well / 50 μL into 384-well white tissue culture plates (Greiner; catalog number 781080). All cell / culture medium reagents were from GIBCO-Invitrogen. The seeded cell plates were incubated at 37°C, 5% CO2, and 85% humidity for 20–24 hours. On the day of testing, using an acoustic liquid handling machine (ECHO; Labcyte), sufficient volumes of the test compound stock solution (10 mM in DMSO) or 100% DMSO were dispensed into all test wells of the 384-well diamond plate (Labcyte) to prepare 10 points of 1 / 2 logarithmic dilution at a final volume of 202.5 nL / well, thus preparing the test-ready compound plate. After completing the assay preparation, it is important to perform the following three steps with minimal delay: 1) Add 20 μl of 1× stimulation buffer to the compound plate using a Multidrop Combi (small box, Thermo Fisher Scientific, catalog number 24073290); 2) Remove the culture medium from the cell plate using a Bluewasher (slow rotation; BlueCatBio); 3) Add 14 μl of the compound / stimulation buffer mixture to the cell plate using a Bravo liquid processor (Agilent), and then incubate the cell plate at 37°C, 5% CO2, and 85% humidity for 1 or 2 hours (corresponding to OX1R and OX2R, respectively). During incubation, prepare the IP-1 assay reagent (38:1:1 lysis buffer:D2:AB-crypate reagent). Add 6 μl of the mixed assay reagent to the cell plate using a Multidrop Combi (small box, Thermo Fisher Scientific, catalog number 24073290), and incubate at room temperature and in the dark for 60 minutes. Fluorescence signals were detected using an Envision plate reader (Perkin Elmer) [LANCE / DELFIADual Enh (Em:APC 665; Ex:Cy5 620)].

[0542] For each compound, the data are suitable for four-parameter logistic fitting (ActivityBase software), EC 50The inflection point of the resulting curve is reported. The percentage effect of each test compound is determined as a percentage of the original sample value / mean maximum effect, where the mean maximum effect is derived from the average original value of 32 control wells per test plate (1 μM orexin A (catalog number 003-30) was used for human OX1R, and 1 μM of a reference compound with 100% activity previously established by comparison with orexin A was used for human OX2R). The inherent orexin receptor agonist activity of the compounds that can be used in this invention can be determined by these assays.

[0543] In the above IPOne assay, all the final compounds in the following examples exhibited orexin-2 receptor agonist activity, EC 50 The concentrations range from approximately 0.01 nM to 5000 nM. Additional data are provided in the examples below. Such results demonstrate the intrinsic activity of the compound as an agonist of orexin-1 and / or orexin-2 receptors. Generally, those skilled in the art will understand that if a substance exhibits EC50 activity in an IPOne assay... 50 If the concentration is less than about 50 μM, or more specifically less than about 1000 nM, the substance is considered to effectively stimulate orexin receptors.

[0544] Orexin receptors are associated with a wide range of biological functions. This suggests potential roles for these receptors in various disease processes in humans and other species. Therefore, the compounds of this invention are potentially useful for treating, preventing, improving, controlling, or reducing the risk of various diseases associated with orexin receptors, including one or more of the following conditions or diseases: narcolepsy, narcolepsy syndrome with narcolepsy-like symptoms, cataplexy in narcolepsy, excessive daytime sleepiness (EDS) in narcolepsy, excessive sleepiness, idiopathic excessive sleepiness, repetitive excessive sleepiness, intrinsic excessive sleepiness, excessive sleepiness with excessive daytime sleepiness, sleep disturbances, sleep apnea, insomnia, nocturnal myoclonus, disturbances of consciousness such as coma, REM sleep disturbances, jet lag syndrome, excessive daytime sleepiness, sleep disturbances in shift workers, and sleep disorders. Sleep disorders, sleep disturbances, excessive sleep associated with depression, mood / emotional disorders, Alzheimer's disease or cognitive impairment, Parkinson's disease, Guillain-Barré syndrome, Levin's syndrome, and age-related sleep disorders; Alzheimer's and sunset syndrome; conditions related to circadian rhythms and mental and physical disorders associated with cross-time zone travel and shift work arrangements; fibromyalgia; heart failure; diseases associated with bone loss; sepsis; syndromes characterized by non-recovery sleep and muscle pain or sleep apnea associated with breathing disorders during sleep; conditions due to decreased sleep quality; and other diseases associated with general orexin system dysfunction.

[0545] Therefore, in some embodiments, the present invention can provide methods for treating or controlling narcolepsy, narcolepsy syndrome with narcolepsy-like symptoms, cataplexy in narcolepsy, excessive daytime sleepiness (EDS) in narcolepsy, hypersomnia, idiopathic hypersomnia, repetitive hypersomnia, intrinsic hypersomnia, hypersomnia with excessive daytime sleepiness, sleep interruption, sleep apnea, altered consciousness, REM sleep interruption, jet lag, sleep disturbances in shift workers, sleep abnormalities, night terrors, insomnia associated with depression, affective / mood disorders, Alzheimer's disease, or cognitive impairment; treating or controlling sleep disturbances associated with neurological disorders (including neuropathic pain and restless legs syndrome); treating or controlling addiction disorders; treating or controlling the use and abuse of psychoactive substances; and enhancing cognitive function. The invention is intended to treat or control various conditions, including: improving memory; treating or controlling obesity; treating or controlling diabetes and appetite, taste, or eating disorders; treating or controlling insulin resistance syndrome; treating or controlling hypothalamic diseases; treating or controlling depression; treating, controlling, alleviating epilepsy, or reducing the risk of epilepsy, including absence epilepsy; treating or controlling pain, including neuropathic pain; treating or controlling Parkinson's disease; treating or controlling Guillain-Barré syndrome; treating or controlling Levin syndrome; treating or controlling psychosis; treating or controlling depression, mood disorders, mental disorders, and anxiety disorders; treating side effects or complications caused by anesthesia; reversing anesthesia after surgery; treating or controlling depression, including major depressive disorder and major depressive disorder; treating or controlling bipolar disorder; or treating, controlling, alleviating schizophrenia, or reducing the risk of schizophrenia, wherein the method comprises administering the compounds of the invention to an individual.

[0546] The compounds of this invention may also be potentially used to treat, prevent, improve, control, or reduce the risk of various other diseases related to orexin receptors, including one or more of the following conditions: improving sleep quality, enhancing sleep efficiency, increasing sleep maintenance; increasing the value calculated by dividing an individual's sleep time by the time it takes for an individual to attempt to fall asleep; improving sleep onset; reducing sleep latency or onset (time required to fall asleep); reducing difficulty falling asleep; increasing sleep continuity; reducing the number of awakenings during sleep; reducing intermittent awakenings during sleep; reducing nighttime awakenings; reducing the time spent awake after sleep onset; increasing total sleep time. Insomnia; reducing sleep fragmentation; altering the time, frequency, or duration of REM sleep cycles (bouts); altering the time, frequency, or duration of slow-wave (i.e., stage 3 or 4) sleep cycles; increasing the amount and proportion of stage 2 sleep; promoting slow-wave sleep; enhancing EEG-δ activity during sleep; reducing nighttime awakenings, especially early morning awakenings; improving daytime alertness; reducing daytime sleepiness; treating or reducing excessive daytime sleepiness; improving satisfaction with sleep intensity; enhancing sleep maintenance; idiopathic insomnia; sleep problems; insomnia; night terrors, insomnia associated with depressive mood / mood disorders, Alzheimer's disease, or cognitive impairment, as well as sleepwalking and bedwetting, and those associated with age-related deterioration. Sleep disorders occurring frequently; Alzheimer's sunset syndrome; disorders related to circadian rhythms, and mental and physical anxieties associated with cross-time zone travel and shift work arrangements; disorders caused by medications that reduce REM sleep; fibromyalgia; syndromes characterized by non-recovery sleep and muscle pain or sleep apnea associated with breathing disturbances during sleep; conditions caused by decreased sleep quality; enhancing learning; enhancing memory; enhancing memory retention; eating disorders related to overeating and their associated complications, compulsive eating disorders, obesity (for any reason, whether genetic or environmental), obesity-related disorders. Overeating, anorexia, bulimia, cachexia, appetite control disorder, hypertension, diabetes, elevated plasma insulin concentration and insulin resistance, dyslipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, lung disease, abnormal heart rhythms and arrhythmias, myocardial infarction, congestive heart failure, coronary heart disease, acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; ischemic or hemorrhagic stroke; subarachnoid hemorrhage; ulcers; allergies; benign prostatic hyperplasia; chronic renal failure; kidney disease; impaired glucose tolerance;Sudden death, polycystic ovary syndrome, craniopharyngioma, Prid-Willi syndrome, Flehrich syndrome, GH-deficient individuals, normal-variant short stature, Turner syndrome, and other pathological conditions exhibiting reduced metabolic activity or a decreased percentage of total lean body mass at rest, such as children with acute lymphoblastic leukemia, metabolic syndrome (also known as syndrome X), insulin resistance syndrome, reproductive hormone abnormalities, sexual and reproductive dysfunctions such as impaired fertility, infertility, male hypogonadism and female hirsutism, and maternal-female infertility. Obesity-related fetal defects, gastrointestinal motility disorders, intestinal motility disorders, obesity-related gastroesophageal reflux, hypothalamic diseases, pituitary diseases, respiratory diseases such as obesity-hypopnea syndrome (Pickwick syndrome), dyspnea, cardiovascular diseases, inflammation such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricemia, back pain, gallbladder disease, gout, kidney cancer, increased risk of anesthesia, reducing the risk of secondary obesity outcomes such as reducing the risk of left ventricular hypertrophy; diseases or disorders involving abnormal oscillatory activity in the brain, including depression and migraine. Pain, neuropathic pain, Parkinson's disease, psychosis, and schizophrenia, and diseases or disorders, particularly those involving abnormal thalamic activity; enhancing cognitive function, including cognitive impairments, which include all types of deficits in attention, learning, and memory that occur transiently or persistently in normal, healthy, young, adult, or elderly populations, as well as cognitive impairments that occur transiently or persistently in mental, neurological, cardiovascular, and immune diseases; treating or controlling Guillain-Barré syndrome; treating or controlling Levin's syndrome; treating or controlling psychosis; treating or controlling depression, mood disorders, mental disorders, and anxiety disorders; treating anesthetic complications; enhancing memory; improving memory; enhancing immune response; enhancing immune function; hot flashes; night sweats; extending lifespan; schizophrenia; muscle-related disorders controlled by excitation / relaxation rhythms imposed by the nervous system, such as heart rhythms and other cardiovascular disorders; disorders related to cell proliferation, such as vasodilation or vasoconstriction and blood pressure; cancer; arrhythmias; hypertension; congestive heart failure; reproductive / urinary system disorders; sexual and fertility disorders; renal adequacy. (of renal function); responsiveness to anesthetic drugs; mood disorders such as depression or more specifically, depressive disorder, for example, single or recurrent major depressive disorder and psychotic depression, or bipolar disorder, for example, bipolar I, bipolar II and cyclothymic mood disorders, mood disorders caused by general medical conditions, and substance-induced mood disorders; affective neurosis; depressive neurosis; anxiety neurosis; anxiety disorders, including acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and anxiety caused by general medical conditions;Acute neurological and psychiatric disorders, such as brain defects after coronary artery bypass surgery and transplantation, stroke, ischemic stroke, cerebral ischemia, spinal cord injury, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage; Huntington's disease; Huntington's disease and Tourette syndrome; Cushing's syndrome / disease; basophilic adenoma; prolactinoma; hyperprolactinemia; pituitary tumor / adenoma; hypothalamic diseases; inflammatory bowel disease; gastric diskinesia; gastric ulcer; Freulich's syndrome; adrenohypophysis. Diseases; pituitary diseases; hypopituitarism; hyperpituitarism; hypogonadism; Kallmann syndrome (loss of smell, hyposmegma); functional or psychogenic amenorrhea; hypopituitarism; hypothyroidism; hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disease due to growth hormone deficiency; idiopathic growth defects; dwarfism; gigantism; acromegaly; amyotrophic lateral sclerosis; multiple sclerosis; eye damage; retinopathy; cognitive impairment Idiopathic and drug-induced Parkinson's disease; muscle spasms and related disorders, including tremor, epilepsy, convulsions, seizure disorders, absence seizures, complex focal and generalized seizures; Lennox-Gastaut syndrome; cognitive impairment, including dementia (associated with Alzheimer's disease, ischemia, trauma, vascular problems or stroke, HIV / AIDS, Parkinson's disease, Huntington's disease, Pick's disease, Croutfellow-Jacob's disease, perinatal hypoxia, other general medical conditions or substance abuse); delirium, amnesia, or age-related cognitive decline; schizophrenia or psychosis, including schizophrenia (paranoid, disorganized, catatonic, or undifferentiated), schizophrenia-like disorders, schizoaffective disorders, delusional disorders, transient psychotic disorders, co-occurring psychotic disorders, psychotic disorders caused by general medical conditions, and substance-induced psychotic disorders; dissociative disorders, including multiple personality syndrome and psychogenic amnesia; substance-related disorders, substance use, substance abuse. Use, substance seeking, substance recovery, all types of psychological and physical addictions and addictive behaviors, reward-related behaviors (including substance-induced delirium, persistent dementia, persistent amnesia, mental disorders or anxiety disorders); tolerance, addictive eating, addictive eating behaviors, binge eating / clearing eating behaviors, dependence, withdrawal or relapse of substances such as alcohol, amphetamines, marijuana, cocaine, hallucinogens, inhalants, morphine, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics; appetite, taste or eating disorders;Movement disorders, including akinesia and akinesia-rigid syndrome (including Parkinson's disease, drug-induced Parkinson's disease, post-encephalitis Parkinson's disease, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, Parkinson-ALS dementia complex, and basal ganglia calcification), chronic fatigue syndrome, fatigue, including Parkinson's disease fatigue, multiple sclerosis fatigue, fatigue caused by sleep disorders or circadian rhythm disorders; drug-induced Parkinson's disease (such as antipsychotic-induced Parkinson's disease, antipsychotic malignant syndrome, antipsychotic-induced acute dystonia, antipsychotic-induced acute akathisia, antipsychotic-induced tardive dyskinesia, and drug-induced postural tremor), Tourette syndrome, epilepsy, and movement disorders [including tremor]. (e.g., resting tremor, essential tremor, postural tremor, and intention tremor), chorea (e.g., Sidham chorea, Huntington's disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea, and hemiparesis), myoclonus (including generalized myoclonus and focal myoclonus), tics (including simple tics, complex tics, and symptomatic tics), restless legs syndrome, and dystonia (including generalized dystonia, such as iodine-induced dystonia, drug-induced dystonia, symptomatic dystonia, and paroxysmal dystonia, as well as focal dystonia, such as blepharospasm, oromandibular dystonia, spastic dystonia, spastic phonation disorder, spastic torticollis, and axial dystonia). dystonia, spastic dystonia and hemiplegic dystonia; neurodegenerative diseases, including disease entities such as desaturation-dementia-Parkinsonian-amyotrophic complex; globus pallidus-pontine-substantia nigra degeneration; epilepsy; epilepsy; attention deficit / hyperactivity disorder (ADHD); conduct disorder; migraine (including migraine headache); headache; hyperalgesia; pain; increased or exaggerated sensitivity to pain such as hyperalgesia, burning pain, and tenderness to touch; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndromes I and II; arthritis pain; sports injury pain; pain associated with infection such as HIV, post-chemotherapy pain; post-stroke pain; postoperative pain; neuralgia; emesis, nausea, vomiting; gastric motility disorders; gastric ulcers; Kallmann syndrome (loss of smell) Asthma; cancer; diseases associated with visceral pain such as irritable bowel syndrome and angina; eating disorders; urinary incontinence; drug tolerance and withdrawal (including opioids, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.); psychosis; schizophrenia; anxiety (including generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder); mood disorders (including depression, mania, and bipolar disorder); trigeminal neuralgia; hearing loss; tinnitus; neuronal damage, including eye damage; retinopathy; macular degeneration.Vomiting; cerebral edema; pain, including acute and chronic pain states, severe pain, intractable pain, inflammatory pain, neuropathic pain, post-traumatic pain, bone and joint pain (osteoarthritis), repetitive motion pain, toothache, cancer pain, myofascial pain (muscle injury, fibromyalgia), perioperative pain (general surgery, gynecological surgery), chronic pain, neuropathic pain, post-traumatic pain, trigeminal neuralgia, migraine and migraine headache, and other conditions associated with general orexin system dysfunction.

[0547] The compounds of this invention may also be used in methods for preventing, treating, controlling, alleviating, or reducing the risk of the diseases, disorders, and conditions described herein. The dosage of the active ingredient in the compositions of this invention can vary; however, the amount of the active ingredient must be sufficient to obtain a suitable dosage form. The active ingredient can be administered to the individual (animal and human) requiring such treatment at a dosage that provides optimal pharmaceutical efficacy. The selected dosage depends on the desired therapeutic effect, route of administration, and duration of treatment. The dosage will vary between individuals based on the nature and severity of the disease, the individual's weight, any specific diet subsequently followed by the individual, concurrent medication, and other factors that will be recognized by those skilled in the art.

[0548] Generally, dose levels of 0.0001 to 100 mg / kg body weight are administered daily to individuals such as humans, adolescents, and the elderly to achieve an effective agonistic effect on orexin receptors. The dosage range is generally about 0.5 mg to 10.0 g per individual per day, administered via a single or multiple dose. In one embodiment, the dosage range will be about 0.5 mg to 500 mg per individual per day; in another embodiment, about 0.5 mg to 200 mg per individual per day; and in yet another embodiment, about 5 mg to 50 mg per individual per day. The pharmaceutical compositions of the present invention can be provided in solid dosage forms, for example, containing about 0.5 mg to 500 mg of the active ingredient, or about 1 mg to 250 mg of the active ingredient. The pharmaceutical compositions can be provided in solid dosage forms containing about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 200 mg, or 250 mg of the active ingredient. For oral administration, the composition may be provided in tablet form containing 1.0 to 1000 mg of active ingredient (e.g., 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 mg of active ingredient) for symptomatic adjustment of the dose to be administered to the individual being treated. The compound may be administered in a regimen of 1 to 4 times daily, for example, once or twice daily. The compound may be administered once or more throughout the day. The compound may be administered upon waking or otherwise in the morning or during the waking period. For example, the compound may be administered approximately 1 hour after waking, approximately 30 minutes after waking, or immediately after waking.

[0549] The compounds of the present invention can be used in combination with one or more other drugs for treating, preventing, controlling, alleviating, or reducing the risk of a disease in which the compounds of the present invention or the other drugs are effective, wherein the combination of drugs is safer or more effective than the use of any one drug alone. These other drugs can be administered simultaneously or sequentially with the compounds of the present invention via their usual route of use and dosage. When the compounds of the present invention are used simultaneously with one or more other drugs, a pharmaceutical composition comprising a unit dosage form of such other drugs and the compounds of the present invention is envisioned. However, combination therapy may also include therapy in which the compounds of the present invention and one or more other drugs are administered at different, overlapping schedules. It is also envisioned that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients can be used at lower doses than when used alone. Therefore, pharmaceutical compositions of the present invention include compositions containing one or more other active ingredients in addition to the compounds of the present invention. The above combinations include not only combinations of the compounds of the present invention with one other active compound, but also combinations of the compounds of the present invention with two or more other active compounds.

[0550] The weight ratio of the compound of the present invention to the second active ingredient can vary and depends on the effective dose of each ingredient. Generally, an effective dose of each ingredient should be used. Thus, for example, when the compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent is generally from about 1000:1 to about 1:1000, for example from about 200:1 to about 1:200. The combination of the compound of the present invention and other active ingredients will generally also be within the above range, but in each case, an effective dose of each active ingredient should be used. In such combinations, the compound of the present invention and other active agents can be administered alone or together. Furthermore, the administration of one agent can be carried out before, simultaneously with, or after the administration of other agents.

[0551] The compounds of the present invention may be administered in combination with compounds known in the art for the treatment or control of narcolepsy, including, for example, methylphenidate, amphetamine, pimox, phenelzine, protriptyline, gamma-hydroxybutyric acid, sodium hydroxybutyrate or other oxybate salts, modafinil, armodafinil, caffeine, and their salts and combinations thereof.

[0552] The compounds of the present invention can be used in combination with compounds known in the art for the prevention and treatment of sleep disorders and sleep disturbances, including, for example, sedatives, hypnotics, anxiolytics, antipsychotics, antihistamines, benzodiazepines, barbiturates, cyclopyrrolones, GABA agonists, 5HT-2 antagonists (including 5HT-2A antagonists and 5HT-2A / 2C antagonists), histamine antagonists (including histamine H3 antagonists), histamine H3 inverse agonists, imidazopyridines, weak sedatives, melatonin agonists and antagonists, melatoninogens, orexin antagonists, and other orexin agonists. Actions, prodynein agonists and antagonists, pyrazolopyrimidines, T-type calcium channel antagonists, triazolopyrimidines, etc., such as: adidazolam, allobarbital, allomidone, alprazolam, amitriptyline, amoxapine, armodafinil, APD-125, benzodiazepam, benzozalamine, bromotezolam, bupropion, buspirone, sec-butylbarbital, butabarbital, caprepinephrine, caprepinephrine, carbochlor, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, clonazepam, chloroperaldehyde, clorazepam, chlorpromazine, clozapine, conazepam, ciprozepam, diazepam, cycloheptapyrrolizol, diazepam. Chlorpyrimethamine, Divalproic acid, Diphenhydramine, Doxepin, EMD-281014, Eliserin, Estazolam, Eszopiclone, Ethchlorynol, Etomidate, Fenofan, Flunitrazepam, Flurazepam, Fluvoxamine, Fluoxetine, Phosphatidylcholine, Gabosadol, Glucimetamide, Halazepam, Hydroxyzine, Ibuprofen, Imipramine, Indiplon, Lithium, Lorazepam, Chlormethazine, LY-156735, Maprotiline, MDL-100907, Methoxyquinone, Melatonin, Phenobarbital, Meprobamate, Formaldehyde Ketone, Methoxyphenidone, Midaflutole, Midazolam, Modafinil, Nefazodone, NGD-2-73, Nissodium, Nitrazepam, Nortriptyline, o The compounds of the present invention include rnortriptyline, oxisapam, paroxetine, pentobarbital, piperapine, perphenazine, phenelzine, phenobarbital, plarazepam, promethazine, propofol, protriptyline, quazepam, rameltein, reclozepam, glimepiride, secobarbital, sertraline, suprofen, TAK-375, temazepam, thioridazine, tiagabin, tracarzolate, cycloamphetamine, trazodone, triazolam, trazepam, trimetazidine, triclophosphamide, trifluoperazine, trimetazidine, trimethoprim, udazepam, venlafaxine, zaleplon, zoprazepam, zopiclone, zolpidem, and their salts and combinations thereof, or compounds of the present invention may be administered in combination with physical methods such as phototherapy or electrostimulation.

[0553] In another embodiment, the compounds of the present invention may be used in combination with other compounds known in the art, either alone or in the same pharmaceutical composition, including but not limited to: insulin sensitizers, including (i) PPARγ antagonists such as glitazones (e.g., cycloglitazone; dapaglitazone; empaglitazone; isaglitazone (MCC-555); pioglitazone; rosiglitazone; troglitazone; tularik; BRL49653; CLX-0921; 5-BTZD), GW-0207, LG-100641, and LY-300512, etc.); (iii) biguanides such as metformin and phenformin; and (b) insulin or insulin mimics such as biota, LP-100, NovoRapid, and detemirna islet. (c) Sulfonylureas, such as hexamethylenetetramine acetate; chlorpropamide; terbinafine; glibenclamide; glipizide; glibenclamide; glimepiride; gliclazide; glibenclamide; glimepiride; gliclazide; glibenclamide; gliclazide; gliclazide; gliclazide; gliclazide; gliclazide; gliclazide; gliclazide; gliclazide; gliclazide; gliclazide; gliclazide; gliclazide; gliclazide; gliclazide; gliclazide; gliclazide; gliclazide; gliclazide; gliclazide; gliclazide; gliclazide; gliclazide; gliclazide; gliclazide; gliclazide; gliclazide; gliclazide; gliclazide; pradimicin-q; salbostatin; CKD-711; MDL-25,637; MDL-73,945; and MOR 14; (e) cholesterol-lowering agents, such as (i) HMG-CoA reductase inhibitors (atorvastatin, ivastatin, fluvastatin, lovastatin, pravastatin, rivastatin, rosuvastatin, simvastatin and other statins), (ii) bile acid absorbers / chelators, such as cholestyramine, colestipol, and dialkylamine alkyl derivatives of croscarmellose; (ii) Nicotinic acid, nicotinic acid, or their salts; (iii) proliferator-activated receptor α agonists, such as fenofibrate derivatives (gemfibrozil, clofibrate, fenofibrate, and bezafibrate); (iv) cholesterol absorption inhibitors, such as sterol esters, β-sitosterol, sterol glycosides, such as tequila; and azacyclines, such as ezetimibe, and (acyl-CoA: cholesterol acyltransferase (ACAT)) inhibitors such as avamidimide and methyllinoleamide; (v) antioxidants, such as probucol; (vi) vitamin E; (vii) thyroid hormone analogs; (f) PPARα agonists, such as benzylclofibrate, bezafibrate, ciprofibrate, clofibrate, etopofibrate, fenofibrate, and gemfibrozil; and other fibric acid derivatives, such as and(g) PPARα agonists as described in WO 97 / 36579; (h) PPARδ agonists, such as those disclosed in WO 97 / 28149; (i) PPARα / δ agonists, such as mogtazine, and compounds disclosed in US 6,414,002; (ii) anti-obesity agents, such as (1) growth hormone secretagogue, growth hormone secretagogue receptor agonists / antagonists, such as NN703, haisarelin, MK-0677, SM-130686, CP-424,391, L-692,429 and L-163,255, and US Patent Nos. 5,536,716 and 6,358,951, US Patent Application Nos. 2002 / 049196 and 2002 / 022637 and PCT Application Nos. WO 01 / 56592 and WO Those disclosed in 02 / 32888; (2) protein tyrosine phosphatase-1B (PTP-1B) inhibitors; (3) cannabinoid receptor ligands, such as cannabinoid CB1 receptor antagonists or inverse agonists, such as rimonaban, taranabant, AMT-251, and SR-14778 and SR 141716A (Sanofi Synthelabo), SLV-319 (Solvay), BAY 65-2520 (Bayer), and U.S. Patents 5,532,237, 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736, 5,624,941, 6,028,084, PCT Application No. WO96 / 33159, WO 98 / 33765、WO98 / 43636、WO98 / 43635、WO 01 / 09120、WO98 / 31227、WO98 / 41519、WO98 / 37061、WO00 / 10967、WO00 / 10968、WO97 / 29079、WO99 / 02499、WO 01 / 58869, WO 01 / 64632, WO 01 / 64633, WO 01 / 64634, WO02 / 076949, WO 03 / 007887, WO 04 / 048317 and WO 05 / 000809.(4) Anti-obesity serotonergic agents, such as fenfluramine, dexfenfluramine, phentermine and sibutramine; (5) β3-adrenergic receptor agonists, AD9677 / TAK677 (Dainippon / Takeda), CL-316,243, SB418790, BRL-37344, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, Trecadrine, Zeneca D7114, SR 59119A; (6) Pancreatic lipase inhibitors, such as orlistat. Triton WR1339, RHC80267, lipristatin, tetrahydrolipristatin, tea saponins, diethylumbelliferone phosphate, and those disclosed in PCT application No. 01 / 77094; (7) neuropeptide Y1 antagonists, such as BIBP3226, J-115814, BIBO3304, LY-357897, CP-671906, GI-264879A, and U.S. Patent No. 6,001,836 and PCT Patent Publication Nos. WO 96 / 14307, WO 01 / 23387, WO 99 / 51600, WO 01 / 85690, WO 01 / 85098, WO 01 / 85173 and WO Those disclosed in 01 / 89528; (8) neuropeptide Y5 antagonists, such as GW-569180A, GW-594884A, GW-587081X, GW-548118X, FR226928, FR 240662, FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104, and U.S. Patent Nos. 6,057,335; 6,043,246; 6,140,354; 6,166,038; 6,180,653; 6,191,160; 6,313,298; 6,335,345; 6,337,332; 6,326,375; 6,329,395; 6,340,683; 6,388,077; 6,462,053; 6,649,624 and 6,723,847, European Patent Nos. EP-01010691 and EP-01044970; and PCT International Patent Publication No.WO97 / 19682, WO97 / 20820, WO97 / 20821, WO97 / 20822, WO97 / 20823, WO98 / 24768; WO98 / 25907; WO98 / 25908; WO98 / 27063; WO98 / 47505; WO9 WO01 / 85714; WO01 / 85730; WO01 / 07 409; WO01 / 02379; WO01 / 02379; WO01 / 23388; WO01 / 23389; WO01 / 44201; WO01 / 62737; WO01 / 62738; WO01 / 09120; WO02 / 22592; WO0248152 and WO02 / 49648; WO02 / 094825; WO03 / 014083; WO03 / 10191; WO03 / 092889; WO04 / 002986; and those published in WO04 / 031175; (9) melanin-aggregating hormone (MCH) receptor antagonists, such as WO Those disclosed in WO 01 / 21577 and WO 01 / 21169; (10) melanin-aggregating hormone 1 receptor (MCH1R) antagonists, such as T-226296 (Takeda), and PCT patent applications No. WO 01 / 82925, WO 01 / 87834, WO 02 / 051809, WO 02 / 06245, WO 02 / 076929, WO 02 / 076947, WO 02 / 04433, WO 02 / 51809, WO 02 / 083134, WO 02 / 094799, WO Those disclosed in 03 / 004027; (11) melanin-aggregating hormone 2 receptor (MCH2R) agonists / antagonists; (12) orexin receptor antagonists, such as SB-334867-A, and those disclosed in this patent publication; (13) serotonin reuptake inhibitors, such as fluoxetine, paroxetine, and sertraline; (14) melanocortin agonists, such as melanostatin II; (15) Mc4r (melanocortin 4 receptor) agonists, such as CHIR 86036 (Chiron), ME-10142 and ME-10145 (Melacure), CHIR86036 (Chiron); PT-141 and PT-14 (Palatin); (16) 5HT-2 agonists; (17) 5HT2C (serotonin receptor 2C) agonists, such as BVT933, DPCA37215, WAY161503, R-1065, and U.S. Patent No.Those disclosed in 3,914,250 and PCT applications No. WO 02 / 36596, WO 02 / 48124, WO 02 / 10169, WO 01 / 66548, WO 02 / 44152, WO 02 / 51844, WO 02 / 40456 and WO 02 / 40457; (18) glycopyridine antagonists; (19) CCK agonists; (20) CCK-A (cholecystokinin-A) agonists, such as AR-R 15849, GI 181771, JMV-180, A-71378, A-71623, and SR14613, and those described in U.S. Patent No. 5,739,106; (21) GLP-1 agonists; (22) corticotropin-releasing hormone agonists; (23) histamine receptor-3 (H3) modulators; (24) histamine receptor-3 (H3) antagonists / inverse agonists, such as hioperamide, 3-(1H-imidazol-4-yl)propyl N-(4-pentyl)carbamate, clobenpropit, iodop Henpropit, imoproxifan, GT2394 (Gliatech), and O-[3-(1H-imidazol-4-yl)propanol]carbamate; (25) β-hydroxysteroid dehydrogenase-1 inhibitors (β-HSD-1); (26) PDE (phosphodiesterase) inhibitors, such as theophylline, pentoxifylline, toprast, sildenafil, amrinone, milrinone, ciloxamide, cyclophosphamide, and silositol; (27) phosphodiesterase 3B (PDE3B) inhibitors; (28) NE (norepinephrine) transport inhibitors, such as GW 320659, despiramine, tasupram, and nomiphenecin; (29) ghrelin receptor antagonists, such as those disclosed in PCT applications No. WO 01 / 87335 and WO 02 / 08250; (30) leptin, including recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionine-based human leptin (Amgen); (31) leptin derivatives; (32) BRS3 (frog dermal receptor subtype 3) agonists, such as [D-Phe6,beta-Ala11,Phe13,Nle14]Bn(6-14) and [D-Phe6,Phe13]Bn(6-13) propionamide, and Pept. Sci.Those disclosed in 2002 Aug; 8(8):461-75); (33) CNTFs (ciliary neurotrophic factors), such as GI-181771 (Glaxo-SmithKline), SR146131 (Sanofi Synthelabo), butabindide, PD170,292 and PD 149164 (Pfizer); CNTF derivatives, such as axokine (Regeneron); monoamine reuptake inhibitors, such as sibutramine; (36) UCP-1 (uncoupling protein-1) activators, UCP-2 activators or UCP-3 activators, such as phytanoic acid, 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propenyl]benzoic acid (TTNPB), retinoic acid; (3 7) Thyroid hormone β agonists, such as KB-2611 (KaroBioBMS); (38) Fatty acid synthase (FAS) inhibitors, such as physcion and C75; (39) DGAT1 (diacylglycerol acyltransferase 1) inhibitors; (40) DGAT2 (diacylglycerol acyltransferase 2) inhibitors; (41) ACC2 (acetyl-CoA carboxylase-2) inhibitors; (42) Glucocorticoid antagonists; (43) Acyl estrogens, such as delta-lactone (DEL) Oleidylestradiol disclosed in Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001); (44) dipeptidyl peptidase IV (DP-IV) inhibitors, such as isoleucine thiazolidide, valine pyrolidide, NVP-DPP728, LAF237, P93 / 01, TSL 225, TMC-2A / 2B / 2C, FE999011, P9310 / K364, VIP 0177, SDZ 274-444, sitagliptin; and in US 6,699,871, WO 03 / 004498; WO 03 / 004496; EP 1 258 476; WO 02 / 083128; WO Compounds disclosed in WO 02 / 062764; WO 03 / 000250; WO 03 / 002530; WO 03 / 002531; WO 03 / 002553; WO 03 / 002593; WO 03 / 000180; and WO 03 / 000181; (46) dicarboxylic acid transporter inhibitors; (47) glucose transporter inhibitors; (48) phosphate transporter inhibitors; (49) metformin. (50) Topiramate (50) YY peptide, PYY3-36, YY peptide analogs, derivatives and fragments such as BIM-43073D, BIM-43004C (Olitvak, D.A et al., Dig. Dis. Sci. 44(3):643-48(1999)); (51) Neuropeptide Y2 (NPY2) receptor agonists such as NPY3-36, N-acetyl[Leu(28,31)]NPY 24-36, TASP-V, cyclo-(28 / 32)-Ac-[Lys28-Glu32]-(25-36)-pNPY; (52) neuropeptide Y4 (NPY4) agonists, such as trypsin (PP) and other Y4 agonists, such as 1229U91; (54) cyclooxygenase-2 inhibitors, such as etoricoxib, celecoxib, vardicoxib, parecoxib, romecoxib, BMS347070, tiracoxib, or JTE522, ABT963, CS502 and GW406381; (55) neuropeptide Y1 (NPY1) antagonists, such as BIBP3226, J-115814, BIBO3304, LY-357897, CP-671906, GI-264879A; (56) opioid antagonists, such as nalmefene. 3-Methoxynaltrexone, naloxone, naltrexone; (57) 11βHSD-1 (11β-hydroxysteroid dehydrogenase type 1) inhibitors, such as BVT3498, BVT 2733 and in WO 01 / 90091, WO 01 / 90090, WO 01 / 90092, US 6,730,690 and US The following are disclosed in 2004-0133011: (58) amirex; (59) amplechloral; (60) amphetamine; (61) benzylphenamine; (62) p-chlorophenbutamine; (63) chlorobenzylex; (64) chlorophorex; (65) chloramphenicol; (66) chlortetramine; (67) cyclexedrine; (68) dexfenfluramine; (69) ethylamphenicol; (70) N-ethylamphenicol; (71) fenbuprofen; (72) phenoxymethylamine. orex); (73) Fentolax; (74) Fluorolax; (75) Fluorolax; (76) Furfurylmethylamphetamine; (77) L-phenylephrine; (78) Levofloxacin; (79) Mefenex; (80) Methamphetamine; (81) Methamphetamine; (82) Norpyrene; (83) Pentorex; (84) Benzotriazine; (85) Benzomorpholine; (86) Pycillax; (87) Phytopharm 57; (88) zonisamide, and (89) neuroregulatory peptide U and its analogues or derivatives, (90) gastrin and its analogues or derivatives, and (91) neurokinin-1 receptor antagonists (NK-1 antagonists), such as the compounds disclosed in U.S. Patent Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, and 5,637,699.

[0554] In another embodiment, the compounds of the present invention can be used in combination with antidepressants or anxiolytics, including norepinephrine reuptake inhibitors (including tertiary and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible monoamine oxidase inhibitors (RIMAs), serotonin and norepinephrine reuptake inhibitors (SNRIs), corticotropin-releasing factor (CRF) antagonists, alpha-adrenergic receptor antagonists, neurokinin-1 receptor antagonists, atypical antidepressants, benzodiazepines, and 5-HT. 1A Agonists or antagonists, especially 5-HT 1APartial agonists, and corticotropin-releasing factor (CRF) antagonists. Specific drugs include: amitriptyline, clomipramine, doxepin, imipramine, and trimethoprim; amoxapine, disipramine, maprotiline, nortriptyline, and protriptyline; citalopram, duloxetine, fluoxetine, fluvoxamine, paroxetine, and sertraline; iscarbohydrazine, phenelzine, tranylcypromine, and selegiline; moclobemide; venlafaxine; aprepitant; bupropion, lithium, nefazodone, trazodone, and veloxacin; alprazolam, chlordiazepoxide, clonazepam, benzalkonium chloride, diazepam, halazepam, lorazepam, oxazepam, and plasazepam; buspirone, flesinoxan, piperazine, and ixaprone, and their pharmaceutically acceptable salts.

[0555] In another embodiment, the compounds of the present invention may be used in combination with the following drugs: anti-Alzheimer's drugs; β-secretase inhibitors, such as velostatin; γ-secretase inhibitors; growth hormone secretagogues; recombinant growth hormone; HMG-CoA reductase inhibitors; NSAIDs, including ibuprofen; vitamin E; anti-amyloid antibodies; CB-1 receptor antagonists or CB-1 receptor inverse agonists; antibiotics, such as doxycycline and rifampin; N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine; cholinesterase inhibitors, such as galantamine, rivastigmine, donepezil, and tacrine; growth hormone secretagogues, such as ibuprofen, ibuprofen mesylate, and carmonesin; histamine H3 antagonists; AMPA receptor agonists; PDEIV inhibitors; GABAA inverse agonists; or neuronal nicotine agonists.

[0556] In another embodiment, the compounds of the present invention can be used with pharmaceutical compositions of: sedatives, hypnotics, anxiolytics, antipsychotics, anxiolytics, cyclopyrrolidones, imidazopyridines, pyrazolopyrimidines, weak sedatives, melatonin agonists and antagonists, melatoninogens, benzodiazepines, barbiturates, 5HT-2 antagonists, etc., such as adidazolam, allobarbital, allomidone, alprazolam, amitriptyline, amoxicillin, and amoxa. Benzodiazepam, benzodiazepine, bromhexol, bupropion, buspirone, butylbarbital, butabarbital, caprulide, carbochlor, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, clonazepam, chloroperaldehyde, chloramphenicol, chlorpromazine, clozapine, ciprozepam, diazepam, cycloheptapyrrol, diazepam, chloral pyrine, divalproic acid, diphenhydramine, doxepin, estazolam, eszopiclone, ethclovinol, etomidate, fenofibrate, flunitrazepam Flurazepam, fluvoxamine, fluoxetine, phosphatase, glutethimide, halazepam, hydroxyzine, imipramine, lithium, lorazepam, chlormethazine, maprotiline, methylchloroquine, melatonin, phenobarbital, meprobamate, formaldehyde ketone, midazolam, nefazodone, nisoxamide, nitrazepam, nortriptyline, oxisapam, paroxetine, pentobarbital, piperapine, perphenazine, phenelzine, phenobarbital, prarazepam, promethazine, propofol, protriptyline The compounds of the present invention may be used in combination with quazepam, reclozepam, glimepiride, secobarbital, sertraline, suprofen, temazepam, thioridazine, tracarzolate, cycloamphetamine, trazodone, triazolam, trazepam, trimetazine, triclofos, trifluoperazine, trimetazine, trimethoprim, udazepam, venlafaxine, zaleplon, zolazepam, zolpidem, and their salts and combinations thereof, or may be administered in conjunction with physical methods such as phototherapy or electrostimulation.

[0557] In another embodiment, the compounds of the present invention may be used in combination with the following drugs: acetaminophen, alentemoxol, trihexyphenidyl, bromocriptine, biperiden, chlorpromazine, cloprothioxan, clozapine, diazepam, fenodopam, flufenazine, fluphenazine, levodopa, levodopa with benzylazine, levodopa with carbidopa, ergotamine, loxapine, mesoridazine, molindolone, nagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, risperidone, sulpiride, tetrabenzylquinazine, trihexyphenidyl, thioridazine, tevothioxan, or trifluoperazine.

[0558] In another embodiment, the compounds of the present invention can be used in combination with compounds from antipsychotic drugs derived from phenothiazines, thioxanthates, heterocyclic dibenzodiazepines, phenobutanones, diphenylbutylpiperidines, and indoleones. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetaminophen, fluphenazine, perphenazine, and trifluoperazine. Suitable examples of thioxanthates include cloprothiophene and tevothiophene. One example of a heterocyclic dibenzodiazepine is clozapine. One example of a phenobutanone is fluphenazine. One example of a diphenylbutylpiperidine is pimozide. One example of an indoleone is molindolone. Other antipsychotic drugs include loxapine, sulpiride, and risperidone.

[0559] In another embodiment, the compounds of the present invention may be used in combination with nicotine agonists or nicotine receptor partial agonists, such as varenicline, opioid antagonists (such as naltrexone (including naltrexone depot), antabux, and nalmefene), dopaminergic agents (such as apomorphine), and ADD / ADHD agents (such as methylphenidate hydrochloride). and ), atomoxetine (e.g.) Monoamine oxidase inhibitors (MAOIs), amphetamines (such as...) And anti-obesity agents, such as apo-B / MTP inhibitors, 11β-hydroxysteroid dehydrogenase-1 (11β-HSD type 1) inhibitors, peptide YY3-36 or its analogues, MCR-4 agonists, CCK-A agonists, monoamine reuptake inhibitors, sympathomimetic agents, β3-adrenergic receptor agonists, dopamine receptor agonists, melanocyte-stimulating hormone receptor analogues, 5-HT2c receptor agonists, melanin aggregation hormone receptor antagonists, leptin, leptin analogues, leptin receptor agonists, and glycopeptide receptor antagonists. Drugs, lipase inhibitors, dermal receptor agonists, neuropeptide-Y receptor antagonists (e.g., NPY-Y5 receptor antagonists), thyroid-stimulating agents, dehydroepiandrosterone or analogues thereof, glucocorticoid receptor antagonists, orexin receptor antagonists (e.g., suvorexant), other orexin agonists, glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factor, human guinea pig-associated protein antagonists, ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, and neuron U receptor agonists, and pharmaceutically acceptable salts thereof.

[0560] In another embodiment, the compounds of the present invention may be used in combination with the following pharmaceutical agents: amiralex, amphetamine, amphetamine, chlorpheniramine, chlorpheniramine, chlorpheniramine, chlorpheniramine, chlorpheniramine, chlorpheniramine, chlorpheniramine, cyclexedrine, dexfenfluramine, dextroamphetamine, diethylamine benzophenone, ethylamphetamine, N-ethylamphetamine, fenbuprofen, fluoroamphetamine, fenisorex, fiproxetine, fludroxetine, fluoroamphetamine, furfurylamide. ylmethylamphetamine), levoflavone, levoflavone, maindo, mefenexyx, methylamphetamine, methamphetamine, norpseudoephedrine, pentorexate, benzotriazine, benzylmorpholine, phenylbutanolamine, phenylpropanolamine, pixylexyx, and sibutramine; selective serotonin reuptake inhibitors (SSRIs); halogenated amphetamine derivatives, including p-chloroamphetamine, clofraxetine, clofraxetine, chlortetramine, dexfenfluramine, fluoroamphetamine, pixylexyx, and sibutramine; and their pharmaceutically acceptable salts.

[0561] In another embodiment, the compounds of the present invention may be used in combination with the following agents: opioid agonists, lipoxygenase inhibitors (such as 5-lipoxygenase inhibitors), cyclooxygenase inhibitors (such as cyclooxygenase-2 inhibitors), interleukin inhibitors (such as interleukin-1 inhibitors), NMDA antagonists, nitric oxide inhibitors or nitric oxide synthesis inhibitors, nonsteroidal anti-inflammatory agents or cytokine-suppressing anti-inflammatory agents, for example, in combination with compounds such as acetaminophen, aspirin, codeine, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, steroidal analgesics, sufentanil, sunlindac, tenidap. Similarly, the compounds of the present invention can be administered in combination with: analgesics; enhancers such as caffeine, H2-antagonists, simethicone, aluminum, or magnesium hydroxide; decongestants such as phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, buprofen, propoxur, or levodophedrine; antitussives such as codeine, hydrocodone, caramex, pentoxyverine, or dextramethorphan; diuretics; and sedative or non-sedative antihistamines.

[0562] The compounds of this invention can be administered orally, parenterally (e.g., intramuscular, intraperitoneal, intravenous, ICV, cisternal injection or infusion, subcutaneous injection or implantation), by inhalation spray, nasal, vaginal, rectal, sublingual, or local administration routes, and can be formulated alone or together in suitable dosage unit formulations comprising conventionally non-toxic, pharmaceutically acceptable carriers, adjuvants, and vehicles suitable for each route of administration. In addition to treatment in warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, and monkeys, the compounds of this invention can also be effectively used in humans.

[0563] Pharmaceutical compositions for administering the compounds of the present invention can be readily available in dosage units and can be prepared by any method known in the pharmaceutical field. All methods involve the step of combining the active ingredient with a carrier constituting one or more excipients. Typically, pharmaceutical compositions are prepared by uniformly and tightly combining the active ingredient with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired dosage form. In a pharmaceutical composition, the active target compound is contained in an amount sufficient to produce the desired effect on the course of a disease or symptom. As used herein, the term "composition" is intended to include products containing a specified amount of the specified ingredient, and any product composed directly or indirectly of a specified amount of the specified ingredient.

[0564] Pharmaceutical compositions for oral administration can be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and these compositions may contain one or more formulations selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically elegant and palatable formulation. Tablets contain an active ingredient mixed with a non-toxic, pharmaceutically acceptable excipient suitable for tablet manufacturing. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated using known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period. Orally administered compositions may also be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or in the form of soft gelatin capsules in which the active ingredient is mixed with water or an oily medium such as peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain active ingredients mixed with excipients suitable for making aqueous suspensions. Oily suspensions can be formulated by suspending the active ingredient in a suitable oil. Oil-in-water emulsions can also be used. Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide active ingredients mixed with dispersants or wetting agents, suspending agents, and one or more preservatives. Pharmaceutical compositions of the compounds of the present invention can be in the form of sterile, injectable aqueous or oily suspensions. The compounds of the present invention can also be used for rectal administration in the form of suppositories. For topical use, emulsions, ointments, gels, solutions, or suspensions containing the compounds of the present invention can be used. The compounds of the present invention can also be formulated for inhalation administration. The compounds of the present invention can also be administered via transdermal patches by methods known in the art.

[0565] Several methods for preparing the compounds of the present invention are illustrated in the following schemes and examples. The starting materials were prepared according to procedures known in the art or shown herein. The following abbreviations are used herein or are known in the art: Me: methyl; Et: ethyl; t-Bu: tert-butyl; Ar: aryl; Ph: phenyl; BINAP: 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl; Bn: benzyl; Ac: acetyl; AcCl: acetyl chloride; AcOH: acetic acid; ACN: acetonitrile; B2Pin2: bis(pinacol)diboron; BPinn: pinacolboron; BAST: bis(2-methoxyethyl)aminosulfur trifluoride; Bn: benzyl; BnOH: benzyl alcohol; Boc: tert-butyloxycarbonyl; Boc2O Boc anhydride: di-tert-butyldecarbonate; BSA: bovine serum albumin; CbzCl: benzyl chloroformate; CDI: carbonyl diimidazole; DAST: (diethylamine) sulfur trifluoride; DCM (CH2Cl2): dichloromethane; DCE: dichloroethane; DDQ: 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; DEAD: diethylazodicarboxylate; DIBAL-H: diisobutylaluminum hydride; DIPEA: N,N-diisopropylethylamine; DMA, DMAc: dimethylacetamide; DMAP: 4- Dimethylaminopyridine; DMF: N,N-dimethylformamide; DMP: Dess-Martin high-valent iodine compound; DMSO: dimethyl sulfoxide; DPPA: diphenylphosphine azide; dppf: 1,1′-ferrocene di-bis(diphenylphosphine); DMSO: dimethyl sulfoxide; GrubbsII: benzenemethylene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidine-2-yl]-ruthenium dichloride, tricyclohexylphosphine; EDC: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide; Et3N: triethylamine; EtOAc: ethyl acetate; EtOH: Ethanol; HCl: hydrochloric acid; Hoveyda-GrubbsII: [1,3-bis(2,4,6-trimethylphenyl)imidazolidine-2-ylidene]-dichloro-[(2-prop-2-yloxyphenyl)methylene]ruthenium; HOAt: 1-hydroxy-7-aza-benzotriazole; HOBT: hydroxybenzotriazole hydrate; HPLC: high performance liquid chromatography; Hunig'sbase, DIEA: N,N-diisopropylethylamine; GrubbsII catalyst: (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidineylidene)dichloro-(phenylmethylene)(tricyclohexylphosphine)ruthenium;HATU: 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethylamine hexafluorophosphate N-oxide; Hoveyda Grubbs II catalyst: (1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinedimethyl)dichloro(o-isopropoxyphenylmethylene)ruthenium, dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinedimethyl](2-isopropoxyphenylmethylene)ruthenium(II); IBX: 2-iodobenzoic acid; IPA, iPrOH : Isopropyl alcohol; LC-MS: Liquid chromatography-mass spectrometry; LDA: Diisopropyl lithium amide; LiHMDS: Lithium hexamethyldisilazide; mCPBA: m-chloroperoxybenzoic acid; MeOH: Methanol; MgSO4: Magnesium sulfate; Ms: Methanesulfonyl; MTBE: Methyl tert-butyl ether; NaHCO3: Sodium bicarbonate; NaOH: Sodium hydroxide; nBu3SnCl: Tributyltin chloride; n-BuLi: n-Butyllithium; NMM: N-methylmorpholine; NMR: Nuclear magnetic resonance; Oxone: Potassium peroxymonosulfate; PCy3PdG2: Chloro[(tricyclohexylphosphine)-2-(2′-aminobiphenyl)]-palladium(II); Pd(dppf)Cl2: [1,1′-bis(diphenylphosphine)di... [Ferrocene]-Palladium(II) dichloride; Pd(PPh3)2Cl2: Bis(triphenylphosphine)-Palladium(II) dichloride; Pd(PPh3)4: Tetra(triphenylphosphine)palladium(O); Pd2dba3: Tris(diphenylmethyleneacetone)dipalladium(O); PPTS: Pyridine p-toluenesulfonate; PtO2: Platinum oxide; PyClu: 1-(chloro-1-pyrrolylmethylene)-pyrrolidineonium hexafluorophosphate; rt: Room temperature; SOCl2: Thionyl chloride; T3P: 2,4,6-tripropyl-1,3,5,2,4,6-trioxotriphosphate-2,4,6-trioxide; TBAF: Tetrabutylammonium fluoride; TBDPSCl: tert-butyl(chloro)diphenyl-silane; TBSCl: tert-butyldimethyl... 2,2,6,6-Tetramethyl-1-piperidinyloxy; t-Bu: tert-butyl; TEA, Et3N: triethylamine; TEMPO: 2,2,6,6-tetramethyl-1-piperidinyloxy; THF: tetrahydrofuran; TFA: trifluoroacetic acid; TLC: thin-layer chromatography; TMSCl: trimethylchlorosilane; TsCl: p-toluenesulfonyl chloride; XPhosPdG2: chloro(2-dicyclohexylphosphine-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]-palladium(II); XPhosPdG3: (2-dicyclohexylphosphine-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate;X-Phos: 2-(dicyclohexylphosphine)-2',4',6'-triisopropylbiphenyl.

[0566] The compounds of this invention can be prepared in a variety of ways. In some cases, the final product can be further modified, for example by controlling the substituents. These controls can include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions known to those skilled in the art. In some cases, the order of the above reaction schemes can be changed to promote the reaction or avoid unwanted reaction products. The following examples are provided to better understand the invention. These examples are merely illustrative and should not be construed as limiting the invention in any way.

[0567] The starting materials are manufactured according to procedures known in the art or shown herein.

[0568] Intermediate A5

[0569] (S)-7,7,7-trifluorohept-1-en-4-amine (A5)

[0570] Option A1

[0571]

[0572] Step 1: 4,4,4-Trifluorobutyraldehyde (A2)

[0573] A solution of 4,4,4-trifluorobutane-1-ol (A1, 10 g, 78 mmol) in DCM (77 mL) was cooled to 0 °C. TEMPO (0.183 g, 1.171 mmol) and KBr (1.394 g, 11.71 mmol) (1.394 g in 30 mL of water) were added to this solution, and the temperature was maintained at 0 °C. Sodium hypochlorite (10%, 100 mL, 78 mmol) was added dropwise to the reaction mixture at 0 °C, and the mixture was buffered to pH 8.5 with a saturated NaHCO3 aqueous solution. The reaction mixture was stirred at 0 °C for 3 h, followed by stirring at 10 °C for 10 h. The organic phase was separated, and the aqueous layer was extracted with DCE (200 mL). The combined organic layers were dried (Na2SO4) and filtered to obtain a solution of 4,4,4-trifluorobutanal (A2) in DCM (77 mL) and DCE (200 mL), without further purification.

[0574] 1 H NMR (400MHz, CDCl3) δ9.73 (s, 1H), 2.72 (t, J = 7.6Hz, 2H), 2.49-2.33 (m, 2H).

[0575] Step 2: (S,E)-2-methyl-N-(4,4,4-trifluorobutylene)propane-2-sulfinamide (A3)

[0576] To a solution of 4,4,4-trifluorobutyraldehyde (A2, 9.8 g, 78 mmol) in DCM (77 mL) and DCE (200 mL), (S)-2-methylpropane-2-sulfinamide (12.25 g, 101 mmol), PPTS (1.563 g, 6.22 mmol), and MgSO4 (24.33 g, 202 mmol) were added. The reaction mixture was stirred at 80 °C for 14 h. LC-MS showed the formation of the desired product. The reaction mixture was filtered. The filtrate was concentrated and purified by rapid silica gel chromatography (7.7% ethyl acetate in petroleum ether) to give (S,E)-2-methyl-N-(4,4,4-trifluorobutylene)propane-2-sulfinamide (A3). 1 H NMR (400MHz, CDCl3) δ8.10 (br d, J=2.9Hz, 1H), 2.85-2.71 (m, 2H), 2.58-2.38 (m, 2H), 1.18 (s, 9H).

[0577] Step 3: (S)-2-methyl-N-((S)-7,7,7-trifluorohept-1-en-4-yl)propane-2-sulfinamide (A4)

[0578] At 0 °C, a solution of (S,E)-2-methyl-N-(4,4,4-trifluorobutyl)propane-2-sulfinamide (A3, 5 g, 21.81 mmol) in DCM (100 mL) was added to allyl magnesium bromide (109 mL, 109 mmol) (1.0 M, in Et2O). The reaction mixture was stirred at 0 °C for 3 h, and LC-MS showed complete conversion. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (150 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (0–19% ethyl acetate gradient in petroleum ether) to (S)-2-methyl-N-((S)-7,7,7-trifluorohept-1-en-4-yl)propane-2-sulfinamide (A4). 1 H NMR (400MHz, CDCl3) δ5.75 (tdd, J=7.2, 10.2, 17.0Hz, 1H), 5.23-5.10 (m, 2H), 3.36 (qd, J=6.3, 12.5Hz, 1H), 3.21 (br d, J=6.4Hz, 1H), 2.42-2.33 (m, 2H), 2.27-2.03 (m, 2H), 1.90-1.75 (m, 1H), 1.73-1.57 (m, 1H), 1.21-1.15 (m, 9H).

[0579] Step 4: (S)-7,7,7-trifluorohept-1-en-4-amine (A5)

[0580] Acetyl chloride (2.89 g, 36.9 mmol) was added to a solution of (S)-2-methyl-N-((S)-7,7,7-trifluorohept-1-en-4-yl)propane-2-sulfinamide (A4, 5 g, 18.43 mmol) in MeOH (100 mL). The reaction mixture was stirred at 20 °C for 2 hours, and LC-MS showed complete conversion. The reaction mixture was concentrated to give a crude product. Water (100 mL) was added to the crude product, and the aqueous layer was extracted with ethyl acetate (3 × 30 mL) to remove impurities. The aqueous layer was freeze-dried to give (S)-7,7,7-trifluorohept-1-en-4-amine (A5) as an HCl salt.

[0581] 1 H NMR (400MHz, CD3OD) δ5.82 (tdd, J=7.3, 10.0, 17.2Hz, 1H), 5.35-5.23 (m, 2H), 3.37 (quin, J=6.5Hz, 1H), 2.57-2.28 (m, 4H), 1.99-1.82 (m, 2H).

[0582] Intermediate A8

[0583] Option A2

[0584]

[0585] Step 1: (S)-2-methyl-N-((S)-6,6,6-trifluorohex-1-en-3-yl)propane-2-sulfinamide (A6)

[0586] At 0 °C, a solution of (S,E)-2-methyl-N-(4,4,4-trifluorobutylene)propane-2-sulfinamide (A3, 4 g, 17.45 mmol) in DCM (80 mL) was added to a solution of vinyl magnesium bromide (34.9 mL, 34.9 mmol). The reaction mixture was stirred at 0–15 °C for 5 hours, and TLC showed complete conversion. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (100 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (25% ethyl acetate in petroleum ether) and separated from its diastereomers to give (S)-2-methyl-N-((S)-6,6,6-trifluorohex-1-en-3-yl)propane-2-sulfinamide (A6, the more polar diastereomer on TLC). A6: 1 H NMR (400MHz, CDCl3) δ5.85-5.73 (m, 1H), 5.33-5.17 (m, 2H), 3.80 (quin, J=6.4Hz, 1H), 3.20-3.10(m, 1H), 2.20-2.03(m, 2H), 1.92-1.76(m, 2H), 1.22-1.09(m, 9H).

[0587] Step 2: (S)-6,6,6-trifluorohex-1-en-3-amine (A8)

[0588] (S)-6,6,6-trifluorohex-1-en-3-amine (A8)HCl salt was prepared from a suitable sulfinamide in a manner similar to that described in step 4 of intermediate A5 scheme A1.

[0589] A8: 1 H NMR (400MHz, CD3OD) δ 5.88-5.77 (m, 1H), 5.55-5.46 (m, 2H), 3.86-3.76 (m, 1H), 2.35-2.18 (m, 2H), 2.10-1.99 (m, 1H), 1.95-1.81 (m, 1H).

[0590] Intermediate A14-A17

[0591] Intermediates A14-A17 were prepared from suitable sulfinamides (A10-A13) as described below, in a manner similar to that described in intermediate A5 scheme A1.

[0592]

[0593] (S)-2-methyl-N-((R)-1,1,1-trifluorohex-5-en-3-yl)propane-2-sulfinamide (A10)

[0594] (S)-2-methyl-N-((S)-7,7,7-trifluorohept-1-en-4-yl)propane-2-sulfinamide (A4) scheme A1 was used to obtain (S)-2-methyl-N-((R)-1,1,1-trifluorohex-5-en-3-yl)propane-2-sulfinamide (A10) by starting with 3,3,3-trifluoropropanal instead of 4,4,4-trifluorobutanal (A2). 1 H NMR: (500MHz, CDCl3δ5.71 (ddt, J=17.4, 10.3, 7.2Hz, 1H), 5.30-4.97 (m, 2H), 3.63 (p, J=6. 6Hz, 1H), 3.42 (d, J=7.4Hz, 1H), 2.45 (t, J=6.6Hz, 2H), 2.25 (tdd, J=10.7, 6.0, 4.7Hz, 2H).

[0595]

[0596] (S)-2-methyl-N-((R)-1,1,1-trifluorooct-7-en-4-yl)propane-2-sulfinamide (1A11)

[0597] (S)-2-methyl-N-((S)-7,7,7-trifluorohept-1-en-4-yl)propane-2-sulfinamide (A4) was prepared by replacing allyl magnesium bromide with but-3-en-1-yl magnesium bromide in a manner similar to that described in scheme A1. LC-MS: 286.3 (M+1). 1 HNMR: (500MHz, CDCl3) δ5.69 (ddt, J=16.9, 10.2, 6.6Hz, 1H), 5.02-4.92 (m, 1H), 4.89 (d, J=10.2Hz, 1H), 3.19 (d, J =8.9Hz, 2H), 2.16-1.96 (m, 4H), 1.84-1.69 (m, 1H), 1.65 (dt, J = 13.8, 7.0Hz, 1H), 1.61-1.48 (m, 2H), 1.11 (s, 9H).

[0598]

[0599] (R)-2-methyl-N-((R)-1,1,1-trifluoropent-4-en-2-yl)propane-2-sulfinamide (A12)

[0600] By using a similar manner to that described in scheme A1 for (S)-2-methyl-N-((S)-7,7,7-trifluorohept-1-en-4-yl)propane-2-sulfinamide (A4), (R,E)-2-methyl-N-(2,2,2-trifluoroethylene)propane-2-sulfinamide was substituted for (S,E)-2-methyl-N-(4,4,4-trifluorobutylene)propane-2-sulfinamide (A3) to obtain (R)-2-methyl-N-((R)-1,1,1-trifluoropent-4-en-2-yl)propane-2-sulfinamide (A12). LC-MS: 244.2 (M+1).

[0601]

[0602] (S)-2-methyl-N-((R)-1,1,1-trifluoropent-4-en-2-yl)propane-2-sulfinamide (A13)

[0603] By using a similar manner to that described in scheme A1 for (S)-2-methyl-N-((S)-7,7,7-trifluorohept-1-en-4-yl)propane-2-sulfinamide (A4), (S,E)-2-methyl-N-(2,2,2-trifluoroethylene)propane-2-sulfinamide was substituted for (S,E)-2-methyl-N-(4,4,4-trifluorobutylene)propane-2-sulfinamide (A3) to obtain (S)-2-methyl-N-((R)-1,1,1-trifluoropent-4-en-2-yl)propane-2-sulfinamide (A13). LC-MS: 244.2 (M+1).

[0604] Option A3

[0605]

[0606] Step 1: (R)-1,1,1-trifluorohex-5-en-3-amine (A14)

[0607] (S)-2-methyl-N-((R)-1,1,1-trifluorohex-5-en-3-yl)propane-2-sulfinamide (A10, 272 mg, 1.057 mmol) was dissolved in MeOH (5.3 mL), and HCl (264 μL, 1.057 mmol) (4 M, in dioxane) was added. The reaction mixture was stirred at room temperature for 45 min. LC-MS analysis showed complete conversion. The reaction mixture was concentrated, dissolved in dichloromethane, and concentrated twice to give (R)-1,1,1-trifluorohex-5-en-3-amine (A14) as an HCl salt, which was used directly in the next step without purification. LC-MS: 154.1 (M+1).

[0608] The following intermediates (HCl salt form) from Table A1 are obtained by deprotection of the corresponding sulfinamides in a manner similar to that described in scheme A3 for intermediate A14.

[0609] Table A1

[0610]

[0611]

[0612] Intermediate A21

[0613] (S)-7,7-Difluorooct-1-en-4-amine (A21)

[0614] Option A4

[0615]

[0616] Step 1: Ethyl 4-oxovalerate (A19)

[0617] BAST (38.4 mL, 208 mmol) was added to a solution of ethyl 4-oxovalerate (A18, 10 g, 69.4 mmol) in DCM (75 mL), and the reaction mixture was heated at 50 °C for 48 h. TLC showed the consumption of the starting material and the formation of new spots. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (150 mL), dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (0–20% ethyl acetate gradient in petroleum ether) to give ethyl 4,4-difluorovalerate (A19). 1H NMR: (400MHz, CDCl3) δ4.23-4.07(m, 2H), 2.59-2.48(m, 2H), 2.28-2.15(m, 2H), 1.69-1.56(m, 3H), 1.33-1.17(m, 3H).

[0618] Step 2: 4,4-Difluoropentanal (1.20)

[0619] A solution of ethyl 4,4-difluoropentanoate (A19, 3.6 g, 21.67 mmol) in DCM (36 mL) was added to DIBAL-H (26.0 mL, 26.0 mmol) (1 M, in toluene) at 78 °C. The resulting mixture was stirred at -78 °C for 30 min under nitrogen. TLC showed the consumption of the starting material and the formation of a new spot. The reaction mixture was poured into water (30 mL) and extracted with DCE (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), and filtered to give a solution of 4,4-difluoropentanal (A20), which was used for the next step without purification.

[0620] Steps 3 and 4: (S)-7,7-difluorooct-1-en-4-amine (A21)

[0621] In a manner similar to that described in scheme A1 of (S)-7,7,7-trifluorohept-1-en-4-amine (A5), intermediate A21 in the form of an HCl salt is obtained, starting with 4,4-difluoropentanal (A20) instead of 4,4,4-trifluorobutanal (A2).

[0622] 1 H NMR: (400MHz, CDCl3) δ5.90-5.74 (m, 1H), 5.33-5.18 (m, 2H), 3.33 (br d, J=4.7Hz, 1H), 2.60-2.45 (m, 2H), 2.18-1.89 (m, 4H), 1.61 (t, J=18.4Hz, 3H).

[0623] Intermediate A24

[0624] 7,7,7-Trifluoro-3-methylhept-1-en-4-amine (A24)

[0625] Solution A5

[0626]

[0627] Step 1: (E)-2-methyl-N-(4,4,4-trifluorobutylene)propane-2-sulfinamide (A22)

[0628] To a solution of 4,4,4-trifluorobutyraldehyde (A2, 4.92 g, 39.0 mmol) in DCM (65 mL), DCE (60 mL), 2-methylpropane-2-sulfinamide (5.68 g, 46.8 mmol), PPTS (0.785 g, 3.12 mmol), and MgSO4 (11.74 g, 98 mmol) were added. The reaction mixture was stirred at 80 °C for 12 h. LC-MS showed the formation of the desired product. The reactants were filtered, concentrated, and purified by rapid silica gel chromatography (25% EtOAc in petroleum ether) to give (E)-2-methyl-N-(4,4,4-trifluorobutylene)propane-2-sulfinamide (A22). LC-MS: 230.0 (M+1). 1 H NMR: (400MHz, CDCl3δ8.10 (br s, 1H), 2.77 (td, J=3.8, 7.6Hz, 2H), 2.58-2.30 (m, 2H), 1.33-1.16 (m, 9H).

[0629] Step 2: 2-Methyl-N-(7,7,7-trifluoro-3-methylhept-1-en-4-yl)propane-2-sulfinamide (A23)

[0630] (E)-1-bromobut-2-ene (1.531 g, 11.34 mmol) was added to a solution of (E)-2-methyl-N-(4,4,4-trifluorobutylene)propane-2-sulfinamide (A22, 2 g, 8.72 mmol) in DMF (20 mL). The solution was cooled at 0 °C, and then indium (1.302 g, 11.34 mmol) and TMS-Cl (0.112 mL, 0.872 mmol) were added. The reaction mixture was slowly heated at 20 °C for 5 hours. LC-MS showed the formation of the desired product. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (10% EtOAc in petroleum ether) to give 2-methyl-N-(7,7,7-trifluoro-3-methylhept-1-en-4-yl)propane-2-sulfinamide (A23). LC-MS: 286.1 (M+1).

[0631] 1H NMR: (400MHz, CDCl3) δ5.78-5.60 (m, 1H), 5.30-5.04 (m, 2H), 3.44-3.34 (m, 1H), 3.23-3.11 (m, 1H), 2.69 (qd, J=6.9, 13.4Hz, 1H), 2. 28-2.21 (m, 1H), 2.19-1.99 (m, 1H), 1.94-1.80 (m, 1H), 1.74-1.59 (m, 1H), 1.55-1.37 (m, 1H), 1.30-1.19 (m, 9H), 1.12-1.04 (m, 3H).

[0632] Step 3: 7,7,7-Trifluoro-3-methylhept-1-en-4-amine (A24)

[0633] Acetyl chloride (0.972 mL, 13.67 mmol) was added to a solution of 2-methyl-N-(7,7,7-trifluoro-3-methylhept-1-en-4-yl)propane-2-sulfinamide (A23, 1.3 g, 4.56 mmol) in MeOH (10 mL), and the reaction mixture was stirred at 25 °C for 2 h. LC-MS showed the formation of the desired product. The reaction mixture was concentrated to give 7,7,7-trifluoro-3-methylhept-1-en-4-amine in the form of an HCl salt (A24), which was used for the next step without purification. LC-MS: 182.2 (M+1).

[0634] Intermediate A31

[0635] 2-Methyl-N-(1,1,1-trifluoro-8-hydroxy-6-methyloct-4-yl)propane-2-sulfinamide (A31)

[0636] Option A6

[0637]

[0638] Step 1: 5-((tert-butyldimethylsilyl)oxy)-3-methylpentane-1-ol (A26)

[0639] TBSCl (10.20 g, 67.7 mmol) was added to a solution of 3-methylpentane-1,5-diol (A25, 10 g, 85 mmol) and imidazole (11.52 g, 169 mmol) in anhydrous DCM (100 mL) at 0 °C. The reaction mixture was heated from 0 °C to 20 °C over 15 hours. TLC showed the formation of new spots. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (15% EtOAc gradient in petroleum ether) to give 5-((tert-butyldimethylsilyl)oxy)-3-methylpentane-1-ol (A26).

[0640] Step 2: 5-((tert-butyldimethylsilyl)oxy)-3-methylpentanal (A27)

[0641] DMP (8.76 g, 20.65 mmol) was added to a solution of 5-((tert-butyldimethylsilyl)oxy)-3-methylpentan-1-ol (A26, 4 g, 17.21 mmol) in anhydrous DCM (40 mL) at 0 °C, and the reaction mixture was stirred at 10 °C for 5 h. TLC showed the formation of new spots. The reaction mixture was filtered and concentrated. The crude product was purified by rapid silica gel chromatography (11% EtOAc in petroleum ether) to give 5-((tert-butyldimethylsilyl)oxy)-3-methylpentanal (A27).

[0642] Step 3: (E)-N-(5-((tert-butyldimethylsilyl)oxy)-3-methylpentyl)-2-methylpropane- 2-Sulfanamide (A28)

[0643] To a solution of 5-((tert-butyldimethylsilyl)oxy)-3-methylpentanal (A27, 3 g, 13.02 mmol) in DCE (30 mL), 2-methylpropane-2-sulfinamide (1.894 g, 15.62 mmol), pyridine-4-methylbenzenesulfonate (0.327 g, 1.302 mmol), and magnesium sulfate (3.92 g, 32.5 mmol) were added. The reaction mixture was stirred at 10 °C for 14 h. LC-MS showed the formation of the desired product. The reaction mixture was filtered. The crude product was purified by rapid silica gel chromatography (12% EtOAc, in petroleum ether) to give (E)-N-(5-((tert-butyldimethylsilyl)oxy)-3-methylpentyl)-2-methylpropane-2-sulfinamide (A28). LC-MS: 334.3 (M+1).

[0644] Step 4: N-(8-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluoro-6-methyloct-2-yne-4- 2-Methylpropane-2-sulfinamide (A29)

[0645] Diisopropylamine (1.820 g, 17.99 mmol) in THF (20 mL) was added to butyllithium (7.19 mL, 17.99 mmol) (2.5 M, in hexane) at -78 °C. The reaction mixture was stirred at -78 °C for 30 min. 2-Bromo-3,3,3-trifluoroprop-1-ene (1.573 g, 8.99 mmol) was slowly added at -78 °C. The reaction mixture was stirred at -78 °C for 30 min. (E)-N-(5-((tert-butyldimethylsilyl)oxy)-3-methylpentyl)-2-methylpropane-2-sulfinamide (A28, 2 g, 6.00 mmol) was added to the solution, and the reaction mixture was heated from -78 °C to 0 °C over 3 hours. LC-MS showed the formation of the desired product. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (15% EtOAc in petroleum ether) to give N-(8-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluoro-6-methyloct-2-yn-4-yl)-2-methylpropane-2-sulfinamide (A29). LC-MS: 428.2 (M+1).

[0646] Step 5: N-(8-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluoro-6-methyloct-4-yl)-2- Methylpropane-2-sulfinamide (A30)

[0647] A solution of N-(8-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluoro-6-methyloct-2-yn-4-yl)-2-methylpropane-2-sulfinamide (A29, 1.4 g, 3.27 mmol) in MeOH (20 mL) was mixed with Pd-C (300 mg, 0.282 mmol) (10% carbon-loaded), and the reaction mixture was stirred at 30 °C for 3 h under H2 (40 psi). LC-MS showed complete conversion. The reaction mixture was filtered and concentrated to give N-(8-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluoro-6-methyloct-4-yl)-2-methylpropane-2-sulfinamide (A30). LC-MS: 432.3 (M+1).

[0648] Step 6: 2-Methyl-N-(1,1,1-trifluoro-8-hydroxy-6-methyloct-4-yl)propane-2-sulfinamide (A31)

[0649] A solution of N-(8-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluoro-6-methyloct-4-yl)-2-methylpropane-2-sulfinamide (A30, 900 mg, 2.085 mmol) in THF (10 mL) was added to TBAF (4.17 mL, 4.17 mmol) (1 M, in THF), and the reaction mixture was stirred at 10 °C for 2 h. LC-MS showed the formation of the desired product. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (100 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (100% EtOAc) to give 2-methyl-N-(1,1,1-trifluoro-8-hydroxy-6-methyloct-4-yl)propane-2-sulfinamide (A31). LC-MS: 318.2 (M+1).

[0650] Intermediate A39

[0651] 1-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6,6,6-trifluorohexyl-3-amine (A39)

[0652] Solution A7

[0653]

[0654] Step 1: Ethyl 3-(2-(benzyloxy)ethoxy)propionate (A33)

[0655] Sodium (0.151 g, 6.57 mmol) was added to a solution of 2-(benzyloxy)ethoxy-1-ol (A32, 10 g, 65.7 mmol) and ethyl acrylate (5.92 g, 59.1 mmol) in THF (200 mL) at 20 °C, and the reaction mixture was stirred at 20 °C for 16 h. TLC showed the consumption of starting materials and the formation of new spots. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (40% EtOAc in petroleum ether) to give ethyl 3-(2-(benzyloxy)ethoxy)propionate (A33). 1 H NMR: (500MHz, CDCl3) δ7.29-7.14(m, 5H), 4.55-4.40(m, 2H), 4.10-3.93(m, 2H), 3.6 9 (t, J=6.5Hz, 2H), 3.59-3.48 (m, 4H), 2.52 (t, J=6.5Hz, 2H), 1.17 (t, J=7.1Hz, 3H).

[0656] Step 2: 3-(2-(benzyloxy)ethoxy)propionaldehyde (A34)

[0657] A solution of 3-(2-(benzyloxy)ethoxy)propionate (A33, 4.3 g, 17.04 mmol) cooled to -78 °C in DCM (60 mL) was slowly added to DIBAL-H (20.45 mL, 20.45 mmol) (1.0 M, in toluene). The reaction mixture was stirred at -78 °C for 1 h. TLC was used to show the consumption of the starting material. The solution was quenched with saturated NH4Cl aqueous solution (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (40% EtOAc in petroleum ether) to give 3-(2-(benzyloxy)ethoxy)propionaldehyde (A34).

[0658] Step 3: (Z)-N-(3-(2-(benzyloxy)ethoxy)propylidene)-2-methylpropane-2-sulfinamide (A35)

[0659] To a solution of 3-(2-(benzyloxy)ethoxy)propanal (A34, 2.4 g, 11.52 mmol) in DCE (40 mL), 2-methylpropane-2-sulfinamide (1.816 g, 14.98 mmol), PPTS (0.290 g, 1.152 mmol), and MgSO4 (4.16 g, 34.6 mmol) were added. The reaction mixture was stirred at 80 °C for 8 hours. TLC showed the consumption of the starting material and the formation of a new spot. The reaction mixture was poured into water (30 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (50% EtOAc in petroleum ether) to give (Z)-N-(3-(2-(benzyloxy)ethoxy)propylidene)-2-methylpropane-2-sulfinamide (A35).

[0660] Step 4: N-(1-(2-(benzyloxy)ethoxy)-6,6,6-trifluorohex-4-yn-3-yl)-2-methylpropane-2-imide Sulfonamide (A36)

[0661] Butyllithium (10.02 mL, 25.04 mmol) was added to a solution of diisopropylamine (3.64 mL, 25.9 mmol) in THF (40 mL) at -78 °C. The mixture was stirred at -78 °C for 30 min. 2-Bromo-3,3,3-trifluoroprop-1-ene (2.191 g, 12.52 mmol) was slowly added at -78 °C. The mixture was stirred at -78 °C for 30 min. (Z)-N-(3-(2-(benzyloxy)ethoxy)propylidene)-2-methylpropane-2-sulfinamide (A35, 2.6 g, 8.35 mmol) was added to the above solution, and the reaction mixture was stirred at -78 °C for 1 h, then heated to 20 °C and stirred for 15 min. TLC showed the consumption of the starting material and the formation of new spots. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (50% EtOAc in petroleum ether) to give N-(1-(2-(benzyloxy)ethoxy)-6,6,6-trifluorohex-4-yn-3-yl)-2-methylpropane-2-sulfinamide (A36).

[0662] Step 5: N-(1-(2-(benzyloxy)ethoxy)-6,6,6-trifluorohex-3-yl)-2-methylpropane-2-sulfinyl Amine (A37)

[0663] A solution of N-(1-(2-(benzyloxy)ethoxy)-6,6,6-trifluorohexyl-4-yn-3-yl)-2-methylpropane-2-sulfinamide (A36, 1.7 g, 4.19 mmol) in MeOH (40 mL) was mixed with Pd(OH)₂ (1.178 g, 8.39 mmol) (10% carbon-loaded), and the reaction mixture was stirred at 30 °C for 16 h under H₂ (50 psi). LC-MS showed the formation of the desired product. The reaction mixture was filtered and concentrated to give N-(1-(2-(benzyloxy)ethoxy)-6,6,6-trifluorohexyl-3-yl)-2-methylpropane-2-sulfinamide (A37).

[0664] Step 6: 2-((3-amino-6,6,6-trifluorohexyl)oxy)ethanol-1-ol (A38)

[0665] A solution of N-(1-(2-(benzyloxy)ethoxy)-6,6,6-trifluorohexyl-3-yl)-2-methylpropane-2-sulfinamide (A37, 900 mg, 2.198 mmol) in DCM (20 mL) was added with boron trichloride (2.116 mL, 13.19 mmol), and the solution was stirred at 20 °C for 3 h. LC-MS showed the formation of the desired product. The reactants were quenched with MeOH (5 mL). HCl (10 mL) (4 M, in MeOH) was added, and the reactants were stirred at 20 °C for 2 h. The mixture was concentrated to give 2-((3-amino-6,6,6-trifluorohexyl)oxy)ethanol-1-ol (A38) in the form of an HCl salt.

[0666] Step 7: 1-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6,6,6-trifluorohexyl-3-amine (A39)

[0667] Imidazole (329 mg, 4.83 mmol) and TBS-Cl (364 mg, 2.416 mmol) were added to a solution of 2-((3-amino-6,6,6-trifluorohexyl)oxy)eth-1-ol (A38, 260 mg, 1.208 mmol) in DCM (15 mL) at 20 °C. The reaction mixture was stirred at 20 °C for 10 h. The mixture was poured into water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by preparative TLC (100% EtOAc) to give 1-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6,6,6-trifluorohexyl-3-amine (A39).

[0668] 1 H NMR (400MHz, CDCl3) δ3.72-3.70(m, 2H), 3.58-3.50(m, 2H), 3.48-3.40(m, 2H), 2.90(brs , 1H), 2.30-2.03(m, 2H), 1.72-1.63(m, 2H), 1.62-1.45(m, 2H), 0.83(s, 9H), 0.00(s, 6H).

[0669] Intermediate A49

[0670] 6-Amino-6-(isoxazol-3-yl)hex-1-ol (A49)

[0671] Solution A8

[0672]

[0673]

[0674] Step 1: (E)-N-(isoxazo-3-ylmethylene)-2-methylpropane-2-sulfinamide (A47)

[0675] Isoxazol-3-carboxaldehyde (A46, 0.250 g, 2.58 mmol) was dissolved in DCM (5.15 mL) and treated with 2-methylpropane-2-sulfonamide (0.389 g, 2.83 mmol) and copper(II) sulfate (0.904 g, 5.67 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered and concentrated on a Celite bed. The crude product (0-50% EtOAc:EtOH 3:1 mixture in hexane) was purified by rapid silica gel chromatography to give (E)-N-(isoxazo-3-ylmethylene)-2-methylpropane-2-sulfinamide (A47). LC-MS: 201.1 (M+1).

[0676] Step 2: N-(6-((tert-butyldimethylsilyl)oxy)-1-(isoxazo-3-yl)hexyl)-2-methylpropane Alkyl-2-sulfinamide (A48)

[0677] (E)-N-(isoxazo-3-ylmethylene)-2-methylpropane-2-sulfinamide (A47, 0.361 g, 1.803 mmol) was dissolved in THF (9 mL) and cooled to 0 °C. The solution was treated with 5-(tert-butyldimethylsiloxy)pentylmagnesium chloride (0.5 M, in THF) (6.49 mL, 3.24 mmol) and stirred for 90 min. The reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc. The combined organic layers were washed with water, dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (0–60% EtOAc gradient in hexane) to give N-(6-((tert-butyldimethylsilyl)oxy)-1-(isoxazo-3-yl)hexyl)-2-methylpropane-2-sulfinamide (A48). LC-MS: 403.4 (M+1).

[0678] Step 3: 6-Amino-6-(isoxazol-3-yl)hex-1-ol (A49)

[0679] N-(6-((tert-butyldimethylsilyl)oxy)-1-(isoxazo-3-yl)hexyl)-2-methylpropane-2-sulfinamide (A48, 130 mg, 0.323 mmol) was dissolved in MeOH (3.3 mL) and treated with HCl (4.0 M in dioxane) (161 μL, 0.646 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give 6-amino-6-(isoxazo-3-yl)hex-1-ol in the form of an HCl salt (A49), which was used for the next step without purification. LC-MS: 185.2 (M+1).

[0680] Intermediate A51

[0681] The following intermediates from Table A2 are obtained from a suitable aldehyde in a manner similar to that used in Scheme A8 to obtain intermediate A49.

[0682] Table A2

[0683]

[0684] Intermediate A53

[0685] Ethyl 2-(2-((((4-nitrophenoxy)carbonyl)amino)methyl)thiazolyl-4-yl)acetate (A53)

[0686] Solution A9

[0687]

[0688] Ethyl 2-[2-(aminomethyl)-1,3-thiazol-4-yl]acetate dihydrochloride (A52, 100 mg, 0.366 mmol) was dissolved in DCM (1830 μL), treated with a saturated aqueous solution of NaHCO3 (1830 μL), and then treated with 4-nitrophenyl chloroformate (89 mg, 0.439 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM, washed with a saturated aqueous solution of NaHCO3, dried by filtration (through a hydrophobic Frit filter), and concentrated to give ethyl 2-(2-(((((4-nitrophenoxy)carbonyl)amino)methyl)thiazol-4-yl)acetate (A53), which was used directly in the next step without purification. LC-MS: 366.2 (M+1).

[0689] Intermediates A55 and A57

[0690] In a manner similar to that described in Scheme A9 for the synthesis of intermediate A53, the intermediates in Table A3 below are synthesized using appropriate amines.

[0691] Table A3

[0692]

[0693] Intermediate A60

[0694] (2-Aminoethyl)(3-((tert-butyldimethylsilyl)oxy)propyl)tert-butyl carbamate (A60)

[0695] Plan A10

[0696]

[0697] Step 1: N1-(3-((tert-butyldimethylsilyl)oxy)propyl)ethane-1,2-diamine (A58)

[0698] N-(3-hydroxypropyl)ethylenediamine (A57, 150 mg, 1.269 mmol) was dissolved in DCM (6 mL). Imidazole (104 mg, 1.523 mmol) was added, and the reaction mixture was stirred at room temperature for 10 minutes. TBSCl (230 mg, 1.523 mmol) was added, and the reaction mixture was stirred for 16 hours. The reaction mixture was quenched with water (5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated to give N1-(3-((tert-butyldimethylsilyl)oxy)propyl)ethane-1,2-diamine (A58), which was used directly in the next step without purification.

[0699] Step 2: tert-butyl(3-((tert-butyldimethylsilyl)oxy)propyl)(2-(2,2,2-trifluoroacetamide) (A59) ethyl carbamate

[0700] N1-(3-((tert-butyldimethylsilyl)oxy)propyl)ethane-1,2-diamine (A58, 228 mg, 0.981 mmol) was dissolved in DCM (5 mL) and cooled to 0 °C. Ethyl trifluoroacetate (129 μL, 1.079 mmol) was slowly added to the reaction mixture. The mixture was stirred at 0 °C for 15 min, then stirred at room temperature for 1 h. Boc anhydride (273 μL, 1.177 mmol) was added to the mixture, followed by triethylamine (273 μL, 1.962 mmol), and the mixture was stirred for another 1 h. The mixture was washed with water (5 mL), the organic layer was dried (Na2SO4), filtered, and concentrated to give tert-butyl(3-((tert-butyldimethylsilyl)oxy)propyl)(2-(2,2,2-trifluoroacetamido)ethyl)carbamate (A59), which was used directly in the next step without purification. LC-MS: 429.2 (M+1).

[0701] Step 3: tert-butyl(2-aminoethyl)(3-((tert-butyldimethylsilyl)oxy)propyl)carbamic acid Ester (A60)

[0702] tert-Butyl(3-((tert-Butyldimethylsilyl)oxy)propyl)(2-(2,2,2-trifluoroacetamido)ethyl)carbamate (A59, 413 mg, 0.964 mmol) was dissolved in MeOH (3.2 mL) and water (1.6 mL) and treated with sodium hydroxide (281 mg, 7.03 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated. The crude product was dissolved in water (5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated to give tert-Butyl(2-aminoethyl)(3-((tert-Butyldimethylsilyl)oxy)propyl)carbamate (A60), which was used directly for the next step without purification. LC-MS: 333.2 (M+1).

[0703] Intermediate A62

[0704] In a manner similar to that described in scheme A10 for the synthesis of intermediate A60, the intermediates in Table A4 below are synthesized using appropriate amino alcohols.

[0705] Table A4

[0706]

[0707] Intermediate A64

[0708] 2-(3-((tert-butyldimethylsilyl)oxy)cyclopentyl)ethyl-1-amine (A64)

[0709] Option A11

[0710]

[0711] 3-(2-aminoethyl)cyclopentan-1-ol (A63, 200 mg, 1.548 mmol) was dissolved in DCM (6 mL). Imidazole (126 mg, 1.858 mmol) was added, and the reaction mixture was stirred at room temperature for 10 min. TBSCl (280 mg, 1.858 mmol) was added, and the reaction mixture was stirred for 16 h. The reaction mixture was quenched with water (5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated to give 2-(3-((tert-butyldimethylsilyl)oxy)cyclopentyl)ethyl-1-amine (A64), which was used directly in the next step without purification. LC-MS: 244.2 (M+1).

[0712] Intermediates A66, A68, A70 and A72

[0713] In a manner similar to that described in scheme A11 for the synthesis of intermediate A64, the intermediates in Table A5 below are synthesized using appropriate amino alcohols.

[0714] Table A5

[0715]

[0716]

[0717] Intermediate A79

[0718] tert-butyl (1,1,1,7,7-pentafluoro-9-hydroxynon-4-yl)carbamate (A79)

[0719] Option A12

[0720]

[0721] Step 1: 3-(benzyloxy)propionaldehyde (A74)

[0722] IBX (2.53 g, 9.02 mmol) was added to a solution of 3-(benzyloxy)propan-1-ol (A73, 1 g, 6.02 mmol) in DMSO (10 mL). The reaction mixture was stirred at 20 °C for 12 h. TLC showed the consumption of the starting material and the formation of a new spot. The reaction mixture was poured into water (50 mL), filtered, and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated to give 3-(benzyloxy)propanal (A74), which was used directly in the next step without purification.

[0723] Step 2: 5-(benzyloxy)pent-1-yn-3-one (A75)

[0724] A solution of 3-(benzyloxy)propionaldehyde (A74, 4.5 g, 27.4 mmol) in THF (50 mL) was added to magnesium acetylenide (82 mL, 41.1 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 12 hours. The mixture was poured into water (250 mL), filtered, and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (0–11% EtOAc gradient in petroleum ether) to give 5-(benzyloxy)pentan-1-yn-3-ol.

[0725] DMP (9.36 g, 22.08 mmol) was added to a solution of 5-(benzyloxy)pentan-1-yn-3-ol (2.8 g, 14.72 mmol) in anhydrous DCM (45 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h. LC-MS showed the formation of the desired product. The reaction mixture was quenched with saturated aqueous NaHCO3 solution (25 mL) and saturated aqueous Na2SO3 solution (25 mL), and extracted with DCM (3 × 20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (0-60% EtOAc in petroleum ether) to give 5-(benzyloxy)pentan-1-yn-3-one (A75). LC-MS: 189.3 (M+H).

[0726] Step 3: (((3,3-difluoropent-4-yn-1-yl)oxy)methyl)benzene (A76)

[0727] DAST (26 mL, 197 mmol) was added to a solution of 5-(benzyloxy)pentan-1-yn-3-one (A75, 2.55 g, 13.55 mmol) in DCM cooled to 0 °C. The reaction mixture was heated to 40 °C and held for 6 hours. TLC showed the formation of a new spot. The reaction mixture was poured into water (100 mL) and extracted with DCM (3 × 25 mL). The combined organic layers were washed with brine (30 mL), dried (Na₂SO₄), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (0–40% EtOAc gradient in petroleum ether) to give (((3,3-difluoropentan-4-yn-1-yl)oxy)methyl)benzene (A76). 1 H NMR (400MHz, CDCl3) δ7.38-7.24 (m, 5H), 4.55-4.48 (m, 2H), 3.72 (t, J=6.97Hz, 2H), 2.77 (t, J=5.14Hz, 1H), 2.48-2.22 (m, 2H).

[0728] Step 4: N-(9-(benzyloxy)-1,1,1,7,7-pentafluoronon-5-yn-4-yl)-2-methylpropane-2-sulfinamide (A77)

[0729] A solution of (((3,3-difluoropent-4-yn-1-yl)oxy)methyl)benzene (A76, 1.3 g, 6.18 mmol) in THF (20 mL) was added to nBuLi (2.474 mL, 6.18 mmol) (2.5 M, in hexane) at -78 °C, and the reaction mixture was stirred for 30 min. A solution of (Z)-2-methyl-N-(4,4,4-trifluorobutylene)propane-2-sulfinamide (A22, 1.418 g, 6.18 mmol) in THF (12 mL) was added, and the reaction mixture was stirred at -78 °C for 4 h. LC-MS showed the formation of the desired product. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (30 mL), dried (Na₂SO₄), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (0-30% EtOAc gradient in petroleum ether) to give N-(9-(benzyloxy)-1,1,1,7,7-pentafluoronon-5-yn-4-yl)-2-methylpropane-2-sulfinamide (A77). LC-MS: 440.2 (M+1).

[0730] Step 5: Tert-butyl (9-(benzyloxy)-1,1,1,7,7-pentafluoronon-5-yn-4-yl)carbamate (A78)

[0731] Acetyl chloride (89 mg, 1.138 mmol) was added to a solution of N-(9-(benzyloxy)-1,1,1,7,7-pentafluoronon-5-yn-4-yl)-2-methylpropane-2-sulfinamide (A77, 100 mg, 0.228 mmol) in MeOH (2 mL), and the reaction mixture was stirred at 0 °C for 30 min. LC-MS showed the formation of the desired product. The reaction mixture was concentrated to give 9-(benzyloxy)-1,1,1,7,7-pentafluoronon-5-yn-4-amine in HCl salt form, which was used directly in the next step without purification. LC-MS: 336.2 (M+1).

[0732] Triethylamine (0.087 mL, 0.626 mmol) and Boc anhydride (0.058 mL, 0.251 mmol) were added to a solution of 9-(benzyloxy)-1,1,1,7,7-pentafluoronon-5-yn-4-yl)amine (70 mg, 0.209 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 5 hours. LC-MS showed the formation of the desired product. The reaction mixture was poured into water (10 mL) and extracted with DCM (3 × 15 mL). The combined organic layers were washed with brine (10 mL), dried (Na₂SO₄), filtered, and concentrated. The crude product was concentrated and purified by preparative TLC (1:3 EtOAc, in petroleum ether) to give tert-butyl(9-(benzyloxy)-1,1,1,7,7-pentafluoronon-5-yn-4-yl)carbamate (A78). LC-MS: 336.2 (M+1-Boc).

[0733] Step 6: Tert-butyl (1,1,1,7,7-pentafluoro-9-hydroxynon-4-yl)carbamate (A79)

[0734] Pd(OH)₂ (97 mg, 0.069 mmol) (10% carbon loading) and Pd (73.3 mg, 0.069 mmol) (10% carbon loading) were added to a solution of tert-butyl(9-(benzyloxy)-1,1,1,7,7-pentafluoro-9-hydroxynon-4-yl)carbamate (A79). The reaction mixture was stirred at 30 °C for 12 h under H₂ (50 psi). LC-MS showed the formation of the desired product. The reaction mixture was filtered and concentrated to give tert-butyl(1,1,1,7,7-pentafluoro-9-hydroxynon-4-yl)carbamate (A79). LC-MS: 250.3 (M+1-Boc).

[0735] Intermediate A86

[0736] 3-((2-amino-5,5,5-trifluoropentyl)oxy)prop-1-ol (A86)

[0737] Plan A13

[0738]

[0739]

[0740] Step 1: 2-(3-((tert-butyldimethylsilyl)oxy)propoxy)ethanol-1-ol (A81)

[0741] Sodium hydride (4.74 g, 118 mmol) (60% in mineral oil) was added to a solution of ethylene glycol (22.01 mL, 395 mmol) in DMF (100 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 30 min. Then (3-bromopropoxy)(tert-butyl)dimethylsilane (A80, 10 g, 39.5 mmol) was added to the reaction mixture. TLC showed the formation of new spots. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried (Na₂SO₄), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (20% EtOAc in petroleum ether) to give 2-(3-((tert-butyldimethylsilyl)oxy)propoxy)ethanol-1-ol (A81).

[0742] Step 2: 2-(3-((tert-butyldimethylsilyl)oxy)propoxy)acetaldehyde (A82)

[0743] DMP (2.71 g, 6.40 mmol) was added to a solution of 2-(3-((tert-butyldimethylsilyl)oxy)propoxy)acetaldehyde (A81, 1 g, 4.27 mmol) in DCM (20 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. TLC showed the formation of a new spot. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (100 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with saturated Na2SO3 aqueous solution (100 mL) and brine (50 mL), dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (20% EtOAc in petroleum ether) to give 2-(3-((tert-butyldimethylsilyl)oxy)propoxy)acetaldehyde (A82).

[0744] Step 3: (E)-N-(2-(3-((tert-butyldimethylsilyl)oxy)propoxy)ethylene)-2-methylpropane Alkyl-2-sulfinamide (A83)

[0745] To a solution of 2-(3-((tert-butyldimethylsilyl)oxy)propoxy)acetaldehyde (A82, 470 mg, 2.022 mmol) in DCE (10 mL), 2-methylpropane-2-sulfinamide (368 mg, 3.03 mmol), PPTS (25.4 mg, 0.101 mmol), and MgSO4 (974 mg, 8.09 mmol) were added. The reaction mixture was stirred at 80 °C for 16 h. TLC showed the formation of a new spot. The reaction mixture was filtered and concentrated. The crude product was purified by rapid silica gel chromatography (30% EtOAc in petroleum ether) to give (E)-N-(2-(3-((tert-butyldimethylsilyl)oxy)propoxy)ethylene)-2-methylpropane-2-sulfinamide (A83).

[0746] Step 4: N-(1-(3-((tert-butyldimethylsilyl)oxy)propoxy)-5,5,5-trifluoropent-3-yne- 2-yl)-2-methylpropane-2-sulfinamide (A84)

[0747] A solution of LDA (1.430 mL, 2.86 mmol) (2 M, in hexane) in THF (2 mL) was added to 2-bromo-3,3,3-trifluoroprop-1-ene (375 mg, 2.146 mmol) in THF (2 mL). The reaction mixture was stirred at -78 °C for 30 min. (E)-N-(2-(3-((tert-butyldimethylsilyl)oxy)propoxy)-ethylidene)-2-methylpropane-2-sulfinamide (A83, 480 mg, 1.430 mmol) was slowly added at -78 °C. The reaction mixture was stirred at -78 °C for 30 min, then heated to 20 °C and stirred for 30 min. TLC showed the formation of new spots. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (2 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (20% EtOAc in petroleum ether) to give N-(1-(3-((tert-butyldimethylsilyl)oxy)propoxy)-5,5,5-trifluoropent-3-yn-2-yl)-2-methylpropane-2-sulfinamide (A84). LC-MS: 430.2 (M+1).

[0748] Step 5: N-(1-(3-((tert-butyldimethylsilyl)oxy)propoxy)-5,5,5-trifluoropent-2-yl)- 2-Methylpropane-2-sulfinamide (A85)

[0749] Pd(OH)₂ (100 mg, 0.071 mmol) (carbon-loaded 10%) was added to a solution of N-(1-(3-((tert-butyldimethylsilyl)oxy)propoxy)-5,5,5-trifluoropent-3-yn-2-yl)-2-methylpropane-2-sulfinamide (A84, 240 mg, 0.559 mmol) in MeOH (5 mL). The reaction mixture was stirred at room temperature for 16 h under H₂ (15 psi). TLC showed the formation of a new spot. The reaction mixture was filtered and concentrated. The crude product was purified by preparative TLC (1:3 EtOAc, in petroleum ether) to give N-(1-(3-((tert-butyldimethylsilyl)oxy)propoxy)-5,5,5-trifluoropent-2-yl)-2-methylpropane-2-sulfinamide (A85).

[0750] Step 6: 3-((2-amino-5,5,5-trifluoropentyl)oxy)prop-1-ol (A86)

[0751] Acetyl chloride (43.4 mg, 0.553 mmol) was added to a solution of N-(1-(3-((tert-butyldimethylsilyl)oxy)propoxy)-5,5,5-trifluoropent-2-yl)-2-methylpropane-2-sulfinamide (A85, 120 mg, 0.277 mmol) in MeOH (2 mL). The reaction mixture was stirred at 0 °C for 30 min. LC-MS showed the formation of the desired product. The mixture was concentrated to give 3-((2-amino-5,5,5-trifluoropentyl)oxy)prop-1-ol (A86) in the form of an HCl salt, which was used directly for the next step without purification. LC-MS: 216.1 (M+1).

[0752] Intermediate A91

[0753] N 2 -(2-((tert-butyldiphenylsilyl)oxy)ethyl)-3,3,3-trifluoro-N 2 -Methylpropane-1,2-dimethylpropane Amine (A91)

[0754] Option A14

[0755]

[0756] Step 1: Ethyl N-(3-((tert-butoxycarbonyl)amino)-1,1,1-trifluoroprop-2-yl)-N-methylglycine Ester (A88)

[0757] Dissolved in DMF (6.19 mL), and subsequently treated with ethyl bromoethyl (0.411 mL, 3.72 mmol) and then with DIEA (0.865 mL, 4.95 mmol), tert-butyl (3,3,3-trifluoro-2-(methylamino)-propyl)carbamate (A87, 0.3 g, 1.238 mmol) was placed in a sealable vial. The vial was capped, and the reaction mixture was heated to 50 °C and maintained for 18 hours. The mixture was then diluted with EtOAc, washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (a 0–20% EtOAc:EtOH 3:1 mixture gradient in hexane) to give ethyl N-(3-((tert-butoxycarbonyl)amino)-1,1,1-trifluoropropyl-2-yl)-N-methylglycine ester (A88). LC-MS: 329.3 (M+1).

[0758] Step 2: tert-butyl (3,3,3-trifluoro-2-((2-hydroxyethyl)(methyl)amino)propyl)carbamate (A89)

[0759] Ethyl N-(3-((tert-butoxycarbonyl)amino)-1,1,1-trifluoropropyl-2-yl)-N-methylglycine ester (A88, 276 mg, 0.841 mmol) was dissolved in THF (5604 μL) and treated with lithium boron hydride (841 μL, 1.681 mmol) (2.0 M, in THF). The reaction mixture was stirred at room temperature for 90 min. The mixture was then diluted with DCM, washed with saturated NH4Cl aqueous solution, dried (Na2SO4), filtered, and concentrated to give tert-butyl(3,3,3-trifluoro-2-((2-hydroxyethyl)(methyl)amino)propyl)carbamate (A89), which was used directly in the next step without purification. LC-MS: 287.2 (M+1).

[0760] Step 3: tert-butyl(2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)(methyl)amino)-3,3, 3-Trifluoropropyl)carbamate (A90)

[0761] tert-Butyl(3,3,3-trifluoro-2-((2-hydroxyethyl)(methyl)amino)propyl)carbamate (A89, 159 mg, 0.555 mmol) was dissolved in DMF (617 μL) and treated with tert-butyldiphenylchlorosilane (173 μL, 0.666 mmol) and imidazole (76 mg, 1.111 mmol). The reaction mixture was stirred at room temperature for 18 hours. The mixture was then diluted with EtOAc, washed with water and then with saturated brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (0-10% EtOAc, in a hexane gradient) to give tert-butyl(2-((2-((tert-butyldiphenylsilyl)oxy)ethyl)(methyl)amino)-3,3,3-trifluoropropyl)carbamate (A90). LC-MS: 525.4 (M+1).

[0762] Step 4: N 2 -(2-((tert-butyldiphenylsilyl)oxy)ethyl)-3,3,3-trifluoro-N 2 -Methylpropane- 1,2-Diamine (A91)

[0763] tert-butyl(2-((2-((tert-butyldiphenylsilyl)oxy)-ethyl)(methyl)amino)-3,3,3-trifluoropropyl)carbamate (A90, 204 mg, 0.389 mmol) was placed in a flask, and HCl (972 μL, 3.89 mmol) (4 M, in dioxane) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give N in the form of HCl salt. 2 -(2-((tert-butyldiphenylsilyl)oxy)ethyl)-3,3,3-trifluoro-N 2 1,2-Methylpropane-1,2-diamine (A91) was used directly in the next step without purification. LC-MS: 425.3 (M+1).

[0764] Intermediate A97

[0765] 4-Nitrophenyl(2-((3-((tert-butyldiphenylsilyl)oxy)propyl)(methyl)amino)-3,3,3- Trifluoropropyl carbamate (A97)

[0766] Option A15

[0767]

[0768] Step 1: 3-((tert-butyldiphenylsilyl)oxy)propionyl chloride (A93)

[0769] 3-((tert-butyldiphenylsilyl)oxy)propionic acid (A92, 0.5 g, 1.522 mmol) was dissolved in DCM (7.61 mL), and the solution was cooled to 0 °C. The solution was treated with oxalyl chloride (1.522 mL, 3.04 mmol) (2.0 M, in DCM) and DMF (0.012 mL, 0.152 mmol), and stirred at 0 °C for 90 min. The reaction mixture was concentrated to give 3-((tert-butyldiphenylsilyl)oxy)propionyl chloride (A93), which was used directly in the next step without purification.

[0770] Step 2: tert-butyl(2-(3-((tert-butyldiphenylsilyl)oxy)-N-methylpropionamidyl)-3,3,3- Trifluoropropyl carbamate (A94)

[0771] tert-butyl N-[3,3,3-trifluoro-2-(methylamino)propyl]carbamate (A87, 250 mg, 1.032 mmol) was dissolved in DMF (5160 μL) and treated with 3-((tert-butyldiphenylsilyl)-oxy)propionyl chloride (A93) (526 mg, 1.517 mmol) and DIEA (541 μL, 3.10 mmol). The reaction mixture was heated to 50 °C and stirred for 18 hours. The reaction mixture was diluted with DCM, washed with a saturated aqueous solution of NaHCO3, dried by filtration (through a hydrophobic Frit filter), and concentrated. The crude product was purified by rapid silica gel chromatography (0-50% EtOAc:EtOH 3:1 mixture in hexane) to give tert-butyl(2-(3-((tert-butyldiphenylsilyl)oxy)-N-methylpropionamido)-3,3,3-trifluoropropyl)carbamate (A94).

[0772] LC-MS: 553.2 (M+1).

[0773] Step 3: tert-butyl(2-((3-((tert-butyldiphenylsilyl)oxy)propyl)(methyl)amino)-3,3, 3-Trifluoropropyl)carbamate (A95)

[0774] tert-butyl(2-(3-((tert-butyldiphenylsilyl)oxy)-N-methylpropamido)-3,3,3-trifluoropropyl)carbamate (A94, 570 mg, 1.031 mmol) was dissolved in THF (5 mL) and treated with a borane-tetrahydrofuran complex (3094 μL, 3.09 mmol) (1.0 M, in THF). The reaction mixture was heated to 70 °C and held for 18 hours. The reaction mixture was diluted with DCM, washed with 2 M NaOH, dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (a 0-50% EtOAc:EtOH 3:1 mixture gradient in hexane) to give tert-butyl(2-((3-((tert-butyldiphenylsilyl)oxy)propyl)(methyl)amino)-3,3,3-trifluoropropyl)carbamate (A95).

[0775] LC-MS: 539.5 (M+1).

[0776] Step 4: N 2 -(3-((tert-butyldiphenylsilyl)oxy)propyl)-3,3,3-trifluoro-N 2 -Methylpropane- 1,2-Diamine (A96)

[0777] Tert-butyl(2-((3-((tert-butyldiphenylsilyl)oxy)propyl)(methyl)amino)-3,3,3-trifluoropropyl)carbamate (A95) (50 mg, 0.093 mmol) was treated with HCl (232 μL, 0.928 mmol) (4 M, in dioxane) and the reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was concentrated under vacuum to give N in the form of HCl salt. 2 -(3-((tert-butyldiphenylsilyl)oxy)propyl)-3,3,3-trifluoro-N 2 1,2-Methylpropane-1,2-diamine (A96) was used directly in the next step without purification. LC-MS: 439.4 (M+1).

[0778] Step 5: 4-Nitrophenyl(2-((3-((tert-butyldiphenylsilyl)oxy)propyl)(methyl)amino)- 3,3,3-Trifluoropropyl)carbamate (A97)

[0779] N 2 -(3-((tert-butyldiphenylsilyl)oxy)propyl)-3,3,3-trifluoro-N 2 1,2-Methylpropane-1,2-diamine (A96) (47.5 mg, 0.093 mmol) was dissolved in DCM (464 μL) and treated with 4-nitrophenyl chlorocarbamate (23 mg, 0.111 mmol) and saturated NaHCO3 aqueous solution (464 μL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was then diluted with DCM, washed with water, dried by filtration (through a hydrophobic Frit filter), and concentrated to give 4-nitrophenyl (2-((3-((tert-butyldiphenylsilyl)oxy)propyl)(methyl)amino)-3,3,3-trifluoropropyl)carbamate (A97), which was used directly in the next step without purification. LC-MS: 604.5 (M+1).

[0780] Intermediate A100

[0781] 1-((R)-1-(4-(8-(but-3-en-1-yloxy)imidazo[1,2-a]pyrazin-6-yl)-5-methoxypyrazine (A100)-Pyridin-2-yl)ethyl)-1-ethyl-3-(6-methylhept-1-en-4-yl)urea

[0782] Option A16

[0783]

[0784] Step 1: 4-Isocyano-6-methylhept-1-ene (A99)

[0785] Under nitrogen atmosphere, 2-isobutylpent-4-enoic acid (A98, 200 mg, 1.28 mmol) was dissolved in ACN (4.3 mL), and triethylamine (357 μL, 2.56 mmol) was added. DPPA (303 μL, 1.41 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and filtered through a silica stopper using 10% EtOAc in hexane. The filtrate was concentrated, dissolved in ACN (5 mL), and heated to 85 °C and maintained for 4 hours. The resulting solution of 4-isocyano-6-methylhept-1-ene (A99) was used for the next step without purification.

[0786] Step 2: 1-((R)-1-(4-(8-(but-3-en-1-yloxy)imidazo[1,2-a]pyrazin-6-yl)-5-methoxy (A100) pyridin-2-yl)ethyl)-1-ethyl-3-(6-methylhept-1-en-4-yl)urea

[0787] Add (R)-1-(4-(8-(but-3-en-1-yloxy)imidazo[1,2-a]pyrazin-6-yl)-5-methoxypyridin-2-yl)-N-ethylethyl-1-amine (C74, 60 mg, 0.163 mmol) to a solution of crude 4-isocyano-6-methylhept-1-ene (A99, 120 mg, 0.78 mmol) in ACN (4 mL), and stir the reaction mixture at room temperature for 15 minutes. The reactants were then concentrated and the crude product was purified by rapid silica gel chromatography (50-100% EtOAc gradient in hexane) to give 1-((R)-1-(4-(8-(but-3-en-1-yloxy)imidazo[1,2-a]pyrazin-6-yl)-5-methoxypyridin-2-yl)ethyl)-1-ethyl-3-(6-methylhept-1-en-4-yl)urea (A100). LC-MS: 521.3 (M+1).

[0788] Intermediate A101-A103

[0789] The intermediates in Table A5 below are synthesized using appropriate commercially available acids in a manner similar to that described in General Scheme A16 for the synthesis of intermediate A100.

[0790] Table A6

[0791]

[0792] Intermediate A106-A108

[0793] Plan A17

[0794]

[0795] 2-Cyclopropylpent-4-enoic acid (A105)

[0796] 2-Cyclopropylacetic acid (A104, 0.45 mL, 4.63 mmol) was dissolved in THF (14 mL) under nitrogen atmosphere, and the solution was cooled to 0 °C. LDA (4.86 mL, 9.72 mmol) (2 M, in THF) was added dropwise, and the reaction mixture was stirred at 0 °C for 1 hour. Allyl bromide (0.4 mL, 4.63 mmol) was added dropwise, and the reaction mixture was stirred for 1 hour. The reaction mixture was quenched with 1 N HCl aqueous solution (20 mL) and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated to give 2-cyclopropylpent-4-enoic acid (A105), which was used directly in the next step without purification.

[0797] The intermediates in Table A7 below are synthesized by allylation of a suitable commercially available acid and subsequent formation of an isocyanate and urea of ​​the listed intermediate C, as described in scheme A16 for intermediate A100, in a manner similar to that described in scheme A17 for acid A105.

[0798] Table A7

[0799]

[0800]

[0801]

[0802] Intermediate A111-A125

[0803] Option A18

[0804]

[0805] 2-((1-(trifluoromethyl)cyclopropyl)methyl)pent-4-enoic acid (A110)

[0806] Pentyl-4-enoic acid (A109, 0.3 mL, 2.94 mmol) was dissolved in THF (10 mL) under nitrogen atmosphere, and the solution was cooled to 0 °C. LDA (3.09 mL, 6.17 mmol) (2 M) was added dropwise, and the reaction mixture was stirred for 1 hour. 1-(bromomethyl)-1-(trifluoromethyl)cyclopropane (0.597 g, 2.94 mmol) was added, and the reaction mixture was heated to room temperature overnight. The reaction mixture was quenched with 1 N HCl aqueous solution (15 mL) and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated to give 2-((1-(trifluoromethyl)cyclopropyl)methyl)pentyl-4-enoic acid (A110), which was used directly in the next step without purification.

[0807] The intermediates in Table A8 below are synthesized by alkylating pent-4-enoic acid with a suitable alkyl chloride or alkyl bromide and then forming an isocyanate and urea of ​​the listed intermediate C as described in scheme A16 of intermediate A100, in a manner similar to that described in scheme A18 of acid A110.

[0808] Table A8

[0809]

[0810]

[0811]

[0812]

[0813]

[0814] Intermediate A126

[0815] (S)-7,7,7-trifluoro-4-isocyanohepten-1-ene (A126)

[0816] Option A19

[0817]

[0818] Triphosgene (240 mg, 0.810 mmol) was added to a solution of (S)-7,7,7-trifluoroheptane-1-en-4-amine (A5, 500 mg, 2.455 mmol) in DCM (5 mL) and saturated NaHCO3 aqueous solution (5 mL) at 0 °C, and the reaction mixture was stirred for 1 hour. The reaction mixture was poured into water (20 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated to give (S)-7,7,7-trifluoro-4-isocyanohepten-1-ene (A126), which was used directly in the next step without purification.

[0819] 1 H NMR (400MHz, CDCl3) δ 5.87-5.72 (m, 1H), 5.27-5.16 (m, 2H), 3.60 (tt, J=4.5, 8.6Hz, 1H), 2.46-2.06 (m, 4H), 1.88-1.61 (m, 2H).

[0820] Intermediate A133

[0821] tert-Butyl (6,6-difluoro-1-(2-hydroxyethoxy)hex-3-yl)carbamate (A133)

[0822]

[0823] LDA (10.86 mL, 21.72 mmol) (2 M, in THF) was added to a solution of 5,5-difluorovaleric acid (1 g, 7.24 mmol) in THF (25 mL) at 0 °C, and the mixture was stirred for 30 minutes. Hexamethylphosphoramide (1.298 g, 7.24 mmol) and ((2-(2-iodoethoxy)ethoxy)methyl)benzene (2.66 g, 8.69 mmol) were added, and the mixture was stirred at 25 °C for 12 hours. The reaction mixture was poured into water (50 mL), adjusted to pH 4 with 1 N HCl, and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine (50 mL), dried on Na₂SO₄, and filtered. The filtrate was concentrated and analyzed by rapid silica gel chromatography (…). 12g Silica Flash Column, eluent: [0-60]% ethyl acetate / petroleum ether gradient) to 2-(2-(2-(benzyloxy)ethoxy)ethyl)-5,5-difluorovalerate.

[0824] Diphenylphosphoazide (940 mg, 3.41 mmol) was added to a solution of 2-(2-(2-(benzyloxy)ethoxy)ethyl)-5,5-difluoropentanoic acid (900 mg, 2.84 mmol) and TEA (0.793 mL, 5.69 mmol) in toluene (10 mL). The mixture was stirred at 100 °C for 1 hour. Then benzyl alcohol (923 mg, 8.53 mmol) was added, and the mixture was stirred at 100 °C for 16 hours. LC-MS showed the formation of the desired product. The mixture was quenched with H₂O (20 mL), extracted with EtOAc (15 mL × 3), washed with brine (20 mL), dried on Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was analyzed by rapid silica gel chromatography (…). 4g Silica Flash Column, eluent: 0–20% EtOAc / petroleum ether gradient) purification yielded benzyl (1-(2-(benzyloxy)ethoxy)-6,6-difluorohexyl-3-yl)carbamate. LCMS m / z (M+H): expected value 422.2, measured value 422.1.

[0825] Add BOC anhydride (0.606 mL, 2.61 mmol), Pd(OH)₂ (0.167 g, 0.237 mmol), and Pd-C (0.252 g, 0.237 mmol) to a solution of benzyl (1-(2-(benzyloxy)ethoxy)-6,6-difluorohexyl-3-yl)carbamate (1 g, 2.373 mmol) in EtOAc (20 mL). In H 2(The mixture was stirred at 25°C for 12 hours under 50 psi (50 psi). The reaction mixture was filtered, concentrated, and analyzed by rapid silica gel chromatography (50 psi). 12g Purification using Silica Flash Column (elution buffer: [0-50]% ethyl acetate / petroleum ether gradient) yielded tert-butyl (6,6-difluoro-1-(2-hydroxyethoxy)hex-3-yl)carbamate. LCMS m / z (M+H): Expected value 520.6, Measured value 520.6.

[0826] Intermediate A134

[0827] 7,7-Difluoro-4-isocyano-hept-1-ene (A134)

[0828]

[0829] LDA (32.6 mL, 65.2 mmol) (2 M, in THF) was added to a solution of 5,5-difluorovaleric acid (3 g, 21.72 mmol) in THF (75 mL) at 0 °C, and the mixture was stirred at 0 °C for 1 hour. 3-Bromoprop-1-ene (5.26 g, 43.4 mmol) was added, and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (50 mL × 3). The organic layer was washed with brine (50 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated and analyzed by rapid silica gel chromatography (…). 4g Silica Flash Column, eluent: [0-20]% ethyl acetate / petroleum ether gradient) was used to purify 2-(3,3-difluoropropyl)pent-4-enoic acid. 1 H NMR (500MHz, CDCl3) δ5.97-5.65(m, 2H), 5.17-5.06(m, 2H), 2.57-2.37(m, 2H), 2.35-2.24(m, 1H), 1.97-1.68(m, 4H)

[0830] Add Et3N (0.728 mL, 5.22 mmol) and diphenylphosphoazide (790 mg, 2.87 mmol) to a solution of 2-(3,3-difluoropropyl)pent-4-enoic acid (465 mg, 2.61 mmol) in MeCN (9 mL). Stir the mixture at 25 °C for 30 minutes. Concentrate the reaction mixture to a minimum amount of MeCN and pour it into a silica stopper, which is then washed with 100 mL of 10% ethyl acetate / petroleum ether. Concentrate the filtrate and dissolve it in 9 mL of anhydrous acetonitrile under N2, heating to 85 °C and maintaining the solution for 1 hour. A mixture of 7,7-difluoro-4-isocyanatohept-1-ene A134 is used directly as a crude product.

[0831] Intermediate A135

[0832] 2-((3-amino-6,6-difluoroheptyl)oxy)ethanol-1-ol (A135)

[0833]

[0834] 2-((3-amino-6,6-difluoroheptyl)oxy)ethanol-1-ol was prepared according to the method described for A133, starting with ethyl 5,5-difluorohexanoate, and without Boc2O in the final step. LCMS m / z (M+H): Expected value 212.2, Found value 212.2.

[0835] To a solution of ethyl 4-acetylbutyrate (15 g, 95 mmol) in DCM (350 mL), bis(2-methoxyethyl)aminosulfur trifluoride (43.7 mL, 237 mmol) was added. The mixture was stirred at 50 °C for 12 hours. The mixture was quenched with H₂O (500 mL), extracted with DCM (300 mL × 3), washed with brine (300 mL), dried on Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was analyzed by rapid silica gel chromatography (…). 120g Ethyl 5,5-difluorohexanoate was obtained by purification using a Silica Flash Column (elution buffer: 10% EtOAc / petroleum ether gradient). 1 H NMR (400MHz, CDCl3) δ = 4.16-4.06 (m, 2H), 2.33 (br t, J = 7.1Hz, 2H), 1.92-1.52 (m, 7H), 1.27-1.20 (m, 3H)

[0836] Intermediate A136

[0837] tert-butyl (6,6,6-trifluoro-1-(2-hydroxyethoxy)hex-3-yl)carbamate (A136)

[0838]

[0839] A solution of tert-butyl 3-(2-(benzyloxy)ethoxy)propionate (15 g, 53.5 mmol) in DCM (300 mL) was added to DIBAL-H (80 mL, 80 mmol) (1 M, in toluene). The mixture was stirred at -78 °C for 1 hour. The reaction mixture was poured into water (600 mL) and extracted with EtOAc (300 mL × 3). The organic phase was dried over Na₂SO₄ and filtered. The filtrate was concentrated to give 3-(2-(benzyloxy)ethoxy)propionaldehyde, which was used directly in the next step without purification. LCMS m / z (M+H): Expected value 209.2, Found value 209.2.

[0840] To a solution of 3-(2-(benzyloxy)ethoxy)propionaldehyde (13 g, 62.4 mmol) in DCE (300 mL), MgSO4 (45.1 g, 375 mmol), 2-methylpropane-2-sulfinamide (9.08 g, 74.9 mmol), and PPTS (1.569 g, 6.24 mmol) were added. The resulting mixture was stirred at 80 °C for 12 hours under N2 protection. The reaction mixture was concentrated and analyzed by rapid silica gel chromatography (…). 120g (E)-N-(3-(2-(benzyloxy)ethoxy)propene)-2-methylpropane-2-sulfinamide was obtained by purification using Silica Flash Column (elution buffer: 60% ethyl acetate / petroleum ether gradient). LCMS m / z (M+H): expected value 312.1, measured value 312.1.

[0841] LDA (34.7 mL, 69.4 mmol) (2 M, in THF) was added to a solution of 2-bromo-3,3,3-trifluoroprop-1-ene (6.07 g, 34.7 mmol) in THF (200 mL) at -78 °C. The reaction mixture was stirred at -78 °C for 30 min, then (E)-N-(3-(2-(benzyloxy)ethoxy)propylidene)-2-methylpropane-2-sulfinamide (9 g, 28.9 mmol) was added, and the reaction mixture was stirred at -78 °C for 2 h. The reaction mixture was poured into NH4Cl (600 mL) and extracted with EtOAc (300 mL × 3). The organic layer was dried on Na2SO4 and filtered. The filtrate was concentrated and analyzed by rapid silica gel chromatography (…). 120g Purification using a Silica Flash Column (elution buffer: 60% ethyl acetate / petroleum ether gradient) yielded N-(1-(2-(benzyloxy)ethoxy)-6,6,6-trifluorohexyl-4-yn-3-yl)-2-methylpropane-2-sulfinamide. LCMS m / z (M+H): Expected value 406.1, Measured value 406.1.

[0842] Pd-C (1.575 g, 1.480 mmol) (10 wt%) and palladium hydroxide (1.039 g, 1.480 mmol) (20 wt%) were added to a solution of N-(1-(2-(benzyloxy)ethoxy)-6,6,6-trifluorohex-4-en-3-yl)-2-methylpropane-2-sulfinamide (6 g, 14.80 mmol) in MeOH (100 mL). The solution was stirred at 25 °C for 10 h under 15 psi hydrogen (excess). The mixture was filtered and concentrated to give (E)-N-(1-(2-(benzyloxy)ethoxy)-6,6,6-trifluorohex-4-en-3-yl)-2-methylpropane-2-sulfinamide, which was used directly for the next step without purification. LCMS m / z (M+H): Expected value 408.1, Found value 408.1.

[0843] Nickel (3.96 g, 67.5 mmol) was added to a solution of (E)-N-(1-(2-(benzyloxy)ethoxy)-6,6,6-trifluorohex-4-en-3-yl)-2-methylpropane-2-sulfinamide (5.5 g, 13.50 mmol) in MeOH (80 mL). The solution was stirred at 25 °C for 12 h under 15 psi hydrogen (excess). The mixture was filtered and concentrated to give N-(1-(2-(benzyloxy)ethoxy)-6,6,6-trifluorohex-3-yl)-2-methylpropane-2-sulfinamide, which was used directly in the next step without purification. LCMS m / z (M+H): Expected value 410.1, Found value 410.1.

[0844] An AcCl solution (1.910 mL, 26.9 mmol) was added to a solution of N-(1-(2-(benzyloxy)ethoxy)-6,6,6-trifluorohexyl-3-yl)-2-methylpropane-2-sulfinamide (5.5 g, 13.43 mmol) in MeOH (80 mL). The reaction mixture was stirred at 20 °C for 2 hours. The mixture was concentrated under reduced pressure and freeze-dried to give 1-(2-(benzyloxy)ethoxy)-6,6,6-trifluorohexyl-3-amine, which was used directly in the next step without purification. LCMS m / z (M+H): Expected value 306.1, Found value 306.1.

[0845] Et3N (5.48 mL, 39.3 mmol) and BOC anhydride (4.56 mL, 19.65 mmol) were added to a solution of 1-(2-(benzyloxy)ethoxy)-6,6,6-trifluorohexyl-3-amine (4 g, 13.10 mmol) in DCM (80 mL) at 0 °C. The reaction mixture was stirred at 0–25 °C for 12 hours. The mixture was quenched with H2O (150 mL), extracted with DCM (100 mL * 3), washed with brine (50 mL), dried on Na2SO4, filtered, and concentrated under reduced pressure. The crude product was analyzed by rapid silica gel chromatography (…). 40g Purification using Silica Flash Column (elution buffer: 20% EtOAc / petroleum ether gradient) yielded tert-butyl(1-(2-(benzyloxy)ethoxy)-6,6,6-trifluorohexyl-3-yl)carbamate. LCMS m / z (M-100+H): Expected value 306.1, Measured value 306.1.

[0846] Raney nickel (1.448 g, 24.66 mmol) was added to a solution of tert-butyl(1-(2-(benzyloxy)ethoxy)-6,6,6-trifluorohexyl-3-yl)carbamate (2 g, 4.93 mmol) in MeOH (50 mL). The solution was stirred at 25 °C for 24 hours under 50 psi H2. The mixture was filtered and concentrated, and the crude product was subjected to rapid silica gel chromatography (…). 40g Purification using Silica Flash Column (elution buffer: 85% ethyl acetate / petroleum ether gradient) yielded tert-butyl (6,6,6-trifluoro-1-(2-hydroxyethoxy)hex-3-yl)carbamate A136. LCMS m / z (M-Boc+H): Expected value 216.2, measured value 216.1. ¹H NMR (400MHz, chloroform-d) δ=4.45(br d, J=9.4Hz, 1H), 3.89-3.72(m, 1H), 3.68-3.50(m, 3H), 3.50-3.36(m, 3H), 2.74(br s, 1H), 2.21-1.97(m, 3H), 1.87-1.61(m, 3H), 1.57-1.35(m, 12H), 1.32-1.16(m, 1H)

[0847] Intermediate A137

[0848] tert-Butyl (6,6-difluoro-1-(2-hydroxyethoxy)hept-3-yl)carbamate (A137)

[0849]

[0850] tert-butyl(6,6-difluoro-1-(2-hydroxyethoxy)hept-3-yl)carbamate was prepared from ethyl 5,5-difluorohexanoate according to the method described for A133. LCMS m / z (M-100+H): Expected value 212.2, Measured value 212.2.

[0851] Intermediate A138

[0852] 2-Methyl-N-(6,6,6-trifluoro-1-(2-hydroxyethoxy)hex-3-yl)propane-2-sulfinamide (A138)

[0853]

[0854] A solution of N-(1-(2-(benzyloxy)ethoxy)-6,6,6-trifluorohexyl-3-yl)-2-methylpropane-2-sulfinamide (100 mg, 0.244 mmol) in DCM (1 mL) was added to BCl3 (0.118 mL, 0.733 mmol), and the solution was stirred at 20 °C for 3 hours. The mixture was quenched with MeOH (1 mL) and concentrated to give 2-methyl-N-(6,6,6-trifluoro-1-(2-hydroxyethoxy)hexyl-3-yl)propane-2-sulfinamide A138. LCMS m / z (M+H): Expected value 320.0, Measured value 320.0.

[0855] Intermediate A139

[0856] (S)-1-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6,6,6-trifluorohexyl-3-amine (A139)

[0857]

[0858] Step 1: (R,E)-N-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)propylidene)-2-methyl Propane-2-sulfinamide

[0859] (R)-2-methylpropane-2-sulfinamide (4.81 g, 39.7 mmol) and copper(II) sulfate (12.7 g, 79.0 mmol) were added to a solution of 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)propionaldehyde (6.15 g, 26.5 mmol) in dichloromethane (60 mL). The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was diluted with dichloromethane, filtered through a Celite pan, and concentrated. The crude product was purified by rapid silica gel chromatography (0-25% EtOAc gradient in heptane) to give (R,E)-N-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)propylidene)-2-methylpropane-2-sulfinamide.

[0860] Step 2: (R)-N-((S)-1-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6,6,6-trifluoro (hexyl)-2-methylpropane-2-sulfinamide

[0861] A solution of (R,E)-N-(3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)propylidene)-2-methylpropane-2-sulfinamide (6.45 g, 19.2 mmol) in dichloromethane (100 mL) was slowly added to a 0.5 M solution of (3,3,3-trifluoropropyl)magnesium bromide in diethyl ether (148 mL, 74.0 mmol). The mixture was stirred at 0 °C for 4 hours, then quenched with a saturated aqueous solution of ammonium chloride (300 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (0-50% EtOAc gradient in heptane) to give (R)-N-((S)-1-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6,6,6-trifluorohex-3-yl)-2-methylpropane-2-sulfinamide.

[0862] Step 3: (S)-1-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6,6,6-trifluorohexyl-3-amine (A139)

[0863] Sodium carbonate (2.57 g, 24.2 mmol) and DMAP (0.197 g, 1.61 mmol) were added to a solution of (R)-N-((S)-1-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6,6,6-trifluorohex-3-yl)-2-methylpropane-2-sulfinamide (3.50 g, 8.07 mmol) in tetrahydrofuran (80 mL) and water (80 mL). The reaction mixture was stirred until the solid dissolved, and then iodine (5.12 g, 20.2 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched by adding a saturated aqueous solution of sodium thiosulfate (25 mL). The mixture was poured into water (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (0-100% EtOAc / EtOH 3:1 mixture gradient in heptane) to give (S)-1-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6,6,6-trifluorohexyl-3-amine. LC-MS: 330.3 (M+1)

[0864] Intermediate A140

[0865] 6,6-Difluorohept-1-en-4-amine (A140)

[0866]

[0867] Ethyl 4,4-difluoropentanoate (5 g, 30.1 mmol) was added to a solution of LDA (22.57 mL, 45.1 mmol) (2 M, in THF) in 50 mL of THF at -78 °C, and the mixture was stirred at -78 °C for 30 min. 3-Bromoprop-1-ene (23.64 mL, 33.1 mmol) was added to the mixture, and the mixture was stirred at -78 °C to -20 °C for 12 h. The mixture was quenched with NH4Cl (200 mL), extracted with EtOAc, washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative-TLC (silica, petroleum ether / EtOAc = 5:1) to give ethyl 2-(2,2-difluoropropyl)pent-4-enoate. LCMS m / z (M+H): Expected value 207.1, 2 Found value 07.1.

[0868] Sodium hydroxide (1.524 g, 38.1 mmol) was added to a solution of ethyl 2-(2,2-difluoropropyl)pent-4-enoic acid ester (2.62 g, 12.70 mmol) in EtOH (50 mL) and water (20.00 mL). The reaction mixture was stirred at 20 °C for 12 h. The mixture was quenched with 1 M HCl to adjust the pH to 3, extracted with EtOAc, washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give 2-(2,2-difluoropropyl)pent-4-enoic acid. LCMS m / z (M+H): Expected value 179.1, Measured value 179.1.

[0869] Diphenylphosphohydrin (3.52 g, 12.80 mmol) was added to a solution of 2-(2,2-difluoropropyl)pent-4-enoic acid (1.9 g, 10.66 mmol) and triethylamine (2.97 mL, 21.33 mmol) in toluene (50 mL). The mixture was stirred at 100 °C for 1 hour. Then benzyl alcohol (3.46 g, 32.0 mmol) was added, and the mixture was stirred at 100 °C for 12 hours. The mixture was quenched with H₂O (30 mL), extracted with EtOAc (20 mL x 3), washed with brine (30 mL), dried on Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was analyzed by rapid silica gel chromatography (…). 4g Silica Flash Column, eluent: 20% EtOAc / petroleum ether gradient) purification yielded benzyl (6,6-difluorohept-1-en-4-yl) carbamate. LCMS m / z (M+H): expected value 284.1, measured value 325.2 [+MeCN]

[0870] A mixture of benzyl (6,6-difluorohept-1-en-4-yl) carbamate (500 mg, 1.765 mmol) and hydrochloric acid (10 mL, 60.0 mmol) (6 M, in water) was stirred at 100 °C for 16 hours. The mixture was concentrated to give 6,6-difluorohept-1-en-4-amine, which was used without purification. LCMS m / z (M+H): Expected value 150.1, Found value 150.2.

[0871] Intermediate A141

[0872] 2-((3-amino-6,6,6-trifluorohexyl)oxy)ethanol-1-ol (A141)

[0873]

[0874] TFA (2 ml) was added to a solution of tert-butyl(6,6,6-trifluoro-1-(2-hydroxyethoxy)hex-3-yl)carbamate A136 (500 mg, 1.586 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure and freeze-dried to give 2-((3-amino-6,6,6-trifluorohexyl)oxy)ethanol-1-ol. LCMS m / z (M+H): expected value 216.2, measured value 216.1.

[0875] Intermediate A142

[0876] (S)-1-(3-((tert-butyldimethylsilyl)oxy)propoxy)-5,5,5-trifluoropentane-2- Amine (A142)

[0877]

[0878] Step 1: 2-(3-((tert-butyldimethylsilyl)oxy)propoxy)ethanol-1-ol

[0879] Potassium tert-butoxide (266 g, 2.34 mol) was added to a solution of ethylene glycol (490 g, 7.90 mol) in DMF (2000 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h, and then (3-bromopropoxy)(tert-butyl)dimethylsilane (200 g, 790 mmol) was added. The reaction mixture was stirred at 20 °C for 12 h, then poured into water (1000 mL) and extracted with MTBE (3 × 500 mL). The combined organic layers were washed with brine (2 × 500 mL), dried (Na₂SO₄), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (2-50% EtOAc gradient in petroleum ether). The crude product was purified by rapid silica gel chromatography (0-25% EtOAc gradient in heptane) to give 2-(3-((tert-butyldimethylsilyl)oxy)propoxy)ethanol-1-ol. 1HNMR: (400MHz, CDCl3) δ3.69-3.73(m, 4H), 3.53-3.59(m, 4H), 2.00(s, 1H), 1.75-1.82(m, 2H), 0.891(s, 9H), 0.049(s, 6H).

[0880] Step 2: 2-(3-((tert-butyldimethylsilyl)oxy)propoxy)acetaldehyde

[0881] Oxaloyl chloride (133 g, 1.05 mol) was added to a solution of DMSO (164 g, 2.10 mol) in dichloromethane (1120 mL) at -78 °C. The reaction mixture was stirred at -78 °C for 1 hour, and then 2-(3-((tert-butyldimethylsilyl)oxy)propoxy)ethanol-1-ol (112 g, 480 mmol) was added. The reaction mixture was stirred at -78 °C for 2 hours. Triethylamine (242 g, 2.39 mol) was added at -78 °C, and the reaction mixture was heated to 20 °C and held for 1 hour. The reaction mixture was poured into ice water (400 mL) and extracted with PE (3 × 400 mL). The combined organic layers were washed with brine (2 × 400 mL), dried (Na₂SO₄), filtered, and concentrated to give 2-(3-((tert-butyldimethylsilyl)oxy)propoxy)acetaldehyde, which was used without purification.

[0882] Step 3: (S,E)-N-(2-(3-((tert-butyldimethylsilyl)oxy)propoxy)ethylene)-2-methyl Propane-2-sulfinamide

[0883] A solution of 2-(3-((tert-butyldimethylsilyl)oxy)propoxy)acetaldehyde (81.0 g, 348 mmol) in dichloroethane (1620 mL) was added to (S)-2-methylpropane-2-sulfinamide (63.4 g, 523 mmol), PPTS (4.38 g, 17.4 mmol), and magnesium sulfate (168 g, 1390 mmol). The reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was filtered and concentrated. The crude product was purified by rapid silica gel chromatography (2-50% EtOAc gradient in petroleum ether) to give (S,E)-N-(2-(3-((tert-butyldimethylsilyl)oxy)propoxy)ethylidene)-2-methylpropane-2-sulfinamide. 1 H NMR (400MHz, CDCl3) δ8.09 (t, J=3.6Hz, 1H), 4.34-4.36 (m, 2H), 3.69-3.73 (m, 2H ), 3.60-3.64(m, 2H), 1.79-1.85(m, 2H), 1.21(s, 9H), 0.89(s, 9H), 0.04(s, 6H).

[0884] Step 4: (R)-N-((S)-1-(3-((tert-butyldimethylsilyl)oxy)propoxy)-5,5,5-trifluoro Pentyl-3-yn-2-yl)-2-methylpropane-2-sulfinamide

[0885] A solution of 2-bromo-3,3,3-trifluoroprop-1-ene (10.9 g, 62.6 mmol) in tetrahydrofuran (60 mL) at -78 °C was slowly added. The mixture was stirred at -78 °C for 0.5 h, followed by the addition of (S,E)-N-(2-(3-((tert-butyldimethylsilyl)oxy)propoxy)ethylidene)-2-methylpropane-2-sulfinamide over 0.5 h. The reaction mixture was heated to 20 °C and held for 0.5 h, then poured into ice water (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (2-50% EtOAc gradient in petroleum ether) to give (R)-N-((S)-1-(3-((tert-butyldimethylsilyl)oxy)propoxy)-5,5,5-trifluoropent-3-yn-2-yl)-2-methylpropane-2-sulfinamide. 1 HNMR (400MHz, CDCl3) δ4.41 (s, 1H), 3.70-3.87 (m, 1H), 3.58-3.70 (m, 6H), 1.74-1.81 (m, 2H), 1.24 (s, 9H), 0.88 (s, 9H), 0.04 (s, 6H).

[0886] Step 5: (R)-N-((S)-1-(3-((tert-butyldimethylsilyl)oxy)propoxy)-5,5,5-trifluoro pentyl-2-yl)-2-methylpropane-2-sulfinamide

[0887] Add (R)-N-((S)-1-(3-((tert-butyldimethylsilyl)oxy)propoxy)-5,5,5-trifluoropent-3-yn-2-yl)-2-methylpropane-2-sulfinamide (7.00 g, 16.0 mmol) to a suspension of 20% palladium hydroxide (6.86 g, 48.9 mmol) in methanol (140 mL). Stir the mixture at 30 psi for 12 hours. Filter and concentrate the reaction mixture to give (R)-N-((S)-1-(3-((tert-butyldimethylsilyl)oxy)propoxy)-5,5,5-trifluoropent-2-yl)-2-methylpropane-2-sulfinamide. 1 H NMR (400MHz, CDCl3) δ3.65-3.69(m, 3H), 3.53-3.57(m, 4H), 3.39-3.51(m, 1H) , 1.81-1.83(m, 2H), 1.75-1.80(m, 4H), 1.22(s, 9H), 0.88(s, 9H), 0.04(s, 6H).

[0888] Step 6: (S)-1-(3-((tert-butyldimethylsilyl)oxy)propoxy)-5,5,5-trifluoropent-2-amine(A142)

[0889] Sodium carbonate (3.78 g, 35.6 mmol) and DMAP (0.290 g, 2.38 mmol) were added to a solution of (R)-N-((S)-1-(3-((tert-butyldimethylsilyl)oxy)propoxy)-5,5,5-trifluoropent-2-yl)-2-methylpropane-2-sulfinamide (5.15 g, 11.9 mmol) in tetrahydrofuran (60 mL) and water (60 mL). The reaction mixture was stirred until the solid dissolved, and then iodine (7.54 g, 29.7 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into a saturated aqueous solution of sodium sulfite (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (0-100% EtOAc / EtOH 3:1 mixture gradient in hexane) to give (S)-1-(3-((tert-butyldimethylsilyl)oxy)propoxy)-5,5,5-trifluoropentane-2-amine. LC-MS: 330.3 (M+1).

[0890] Intermediate A143

[0891] 1-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6,6-difluorohept-3-amine (A143)

[0892]

[0893] Triethylamine (1.68 mL, 12.1 mmol), DMAP (246 mg, 2.01 mmol), and TBS-Cl (1030 mg, 6.84 mmol) were added to a solution of 2-((3-amino-6,6-difluoroheptyl)oxy)ethanol-1-ol (850 mg, 4.02 mmol) in 20 mL of DCM. The reaction mixture was stirred at 35 °C for 48 hours. The mixture was quenched with 20 mL of H₂O, extracted with 3 mL of DCM, washed with 10 mL of brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was analyzed by rapid silica gel chromatography (…). 12g Purification using a Silica Flash Column (elution buffer: 100% EtOAc gradient in petroleum ether) yielded 1-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6,6-difluoroheptane-3-amine (A143). LCMS m / z (M+H): Expected value 326.2, Measured value 326.3. 1H NMR (400MHz, CD3OD) δ3.79-3.74(m, 2H), 3.66-3.48(m, 4H), 2.93-2.86(m, 1H), 2. 04-1.80 (m, 2H), 1.76-1.68 (m, 1H), 1.66-1.45 (m, 6H), 0.91 (s, 9H), 0.08 (s, 6H).

[0894] Intermediate A144

[0895] (S)-1-(3-((tert-butyldimethylsilyl)oxy)propoxy)-5,5-difluorohexyl-2-amine (A144)

[0896]

[0897] A mixture of ethyl (S)-2-((tert-butoxycarbonyl)amino)-5-oxohexanoate (2.00 g, 7.32 mmol) and DAST (10.0 mL, 76.0 mmol) was stirred at 15 °C for 16 hours. The reaction mixture was then poured into a saturated aqueous solution of NaHCO3. ( Extracted with DCM (3 × 50 mL) for 200 mL, followed by washing with (50 mL) brine. The organic layer was dried on Na₂SO₄, filtered, and the filtrate was concentrated. The residue was subjected to rapid silica gel chromatography (…). 20g Ethyl(S)-2-((tert-butoxycarbonyl)amino)-5,5-difluorohexanoate was obtained by purification using a Silica Flash Column (elution buffer: 30% ethyl acetate / petroleum ether gradient). LCMS m / z (M+H-Boc): expected value 196.1, measured value 196.1. 1 H NMR (400MHz, CDCl3) δ8.92 (br s, 1H), 4.46-4.02 (m, 3H), 3.23-2.91 (m, 1H), 2.07-1.80 (m, 3H), 1.60 (br t, J=18.3Hz, 3H), 1.49-1.44 (s, 9H), 1.30 (br t, J=7.1Hz, 3H).

[0898] Ethyl(S)-2-((tert-butoxycarbonyl)amino)-5,5-difluorohexanoate (7.00 g, 23.7 mmol) in THF (20 mL) was added to a stirred solution of LiAlH4 (1.00 g, 26.3 mmol) in THF (80 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was diluted with H2O (1 mL), NaOH (15%, 1 mL), and H2O (3 mL), dried over MgSO4, filtered, and concentrated to obtain tert-butyl(S)-(5,5-difluoro-1-hydroxyhexyl-2-yl)carbamate, which was used directly in the next step. LCMS m / z (M+H): Expected value 254.1, Measured value 254.1. 1 H NMR(400MHz, CDCl3)δ4.74(br s, 1H), 3.72-3.54 (m, 3H), 2.35-2.20 (m, 1H), 1.93 (dtd, J=6.6, 9.9, 16.1Hz, 2H), 1.81-1.70 (m, 1H), 1.66-1.55 (m, 3H), 1.45 (s, 9H).

[0899] Ethyl acrylate (11.8 mL, 109 mmol) was added to a mixture of tert-butyl (S)-(5,5-difluoro-1-hydroxyhexyl-2-yl)carbamate (5.50 g, 21.7 mmol) and Cs₂CO₃ (14.2 g, 43.4 mmol) in MeCN (60 mL). The mixture was stirred at 15 °C for 5 hours. H₂O (50 mL) was added to the mixture, and extraction was performed using EtOAc (50 mL × 3). The organic layer was washed with brine (50 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated and analyzed by rapid silica gel chromatography (…). 80g Silica Flash Column, eluent: (0-20% ethyl acetate / petroleum ether gradient) purification yielded ethyl(S)-3-((2-((tert-butoxycarbonyl)amino)-5,5-difluorohexyl)oxy)propionate. LCMS m / z (M+H-Boc): expected value 254.1, measured value 254.1. 1 H NMR(400MHz, CDCl3)δ4.77(br s, 1H), 4.21-4.12 (m, 2H), 3.73 (t, J=6.1Hz, 2H), 3.52-3.39 (m, 2H), 2.57 (t, J=6.2Hz, 2H) , 1.97-1.84(m, 2H), 1.77-1.63(m, 2H), 1.60-1.55(m, 3H), 1.45(s, 9H), 1.31-1.26(m, 3H).

[0900] Ethyl(S)-3-((2-((tert-butoxycarbonyl)amino)-5,5-difluorohexyl)oxy)propionate (3.50 g, 9.90 mmol) in THF (10 mL) was added to a stirred solution of LiAlH4 (500 mg, 13.2 mmol) in THF (30 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was diluted with H2O (0.5 mL), NaOH (15%, 0.5 mL), and H2O (1.5 mL) and dried over MgSO4. The filtrate was filtered and concentrated to give tert-butyl(S)-(5,5-difluoro-1-(3-hydroxypropoxy)hex-2-yl)carbamate, which was used directly in the next step.

[0901] TFA (5.00 mL, 8.03 mmol) was added to a stirred solution of tert-butyl (S)-(5,5-difluoro-1-(3-hydroxypropoxy)hex-2-yl)carbamate (2.50 g, 8.03 mmol) in DCM (20 mL). The reaction mixture was stirred at 15 °C for 1 hour. The mixture was concentrated to give (S)-3-((2-amino-5,5-difluorohexyl)oxy)prop-1-ol, which was used directly in the next step. LCMS m / z (M+H): Expected value 212.1, Found value 212.1.

[0902] TEA (3.30 mL, 23.7 mmol), DMAP (0.145 g, 1.18 mmol), and TBS-Cl (1.07 g, 7.10 mmol) were added to a solution of (S)-3-((2-amino-5,5-difluorohexyl)oxy)prop-1-ol (1.00 g, 4.73 mmol) in DCM (5 mL). The reaction mixture was stirred at 20 °C for 16 hours. The mixture was quenched with H2O (4 mL), extracted with DCM (20 mL × 3), washed with brine (5 mL), dried on Na2SO4, filtered, and concentrated under reduced pressure. The crude product was analyzed by rapid silica gel chromatography (…). 20g Silica Flash Column, eluent: 10% EtOAc / MeOH gradient) purification yielded (S)-1-(3-((tert-butyldimethylsilyl)oxy)propoxy)-5,5-difluorohexyl-2-amine (A144). LCMS m / z (M+H): expected value 326.2, measured value 326.3. 1H NMR (400MHz, CD3OD) δ3.74 (t, J=6.1Hz, 2H), 3.61-3.52 (m, 2H), 3.46 (dd, J=4.3, 9.7Hz, 1H), 3.37-3.32 (m, 1H), 3 .06-2.97 (m, 1H), 2.02-1.88 (m, 2H), 1.83-1.76 (m, 2H), 1.75-1.67 (m, 1H), 1.59 (t, J=18.5Hz, 4H), 0.91 (s, 9H).

[0903] Intermediate A145

[0904] ((S)-2-methyl-N-((R)-1,1,1-trifluoro-9-hydroxynon-4-yl)propane-2-sulfinamide (A145)

[0905]

[0906] Imidazole (16.19 g, 238 mmol) and tert-butyldimethylchlorosilane (26.9 g, 178 mmol) were added to a solution of pentyl-4-yn-1-ol (10.0 g, 119 mmol) in DCM (200 mL). The mixture was stirred at 20 °C for 2 hours. The reaction mixture was poured into water (300 mL) and extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated and analyzed by rapid silica gel chromatography (…). 80g Silica Flash Column, eluent: (0-10% ethyl acetate / petroleum ether gradient) to tert-butyldimethyl(pent-4-yn-1-yloxy)silane. 1 H NMR (400MHz, CDCl3) δ3.64 (t, J=6.0Hz, 2H), 2.22 (dt, J=2.7, 7.1Hz, 2H), 1.87 (t, J=2.7Hz, 1H), 1.72-1.61 (m, 2H), 0.84 (s, 9H), 0.00 (s, 6H)

[0907] To a solution of LiHMDS (52.3 mL, 52.3 mmol) in hexane (160 mL) at -78 °C, tert-butyldimethyl(pentan-4-yn-1-yloxy)silane (10.4 g, 52.3 mmol) was added. The mixture was stirred at 25 °C for 10 min, and then (S,E)-2-methyl-N-(4,4,4-trifluorobutylene)propane-2-sulfinamide (A3, 6.00 g, 26.2 mmol) in hexane (6 mL) was added at -78 °C. The mixture was stirred at 25 °C for 6 h. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (200 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated and analyzed by rapid silica gel chromatography (…). 40g Silica FlashColumn, eluent: (0-23% ethyl acetate / petroleum ether gradient) purification yielded (S)-N-((S)-9-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluoronon-5-yn-4-yl)-2-methylpropane-2-sulfinamide.

[0908] A solution of (S)-N-((S,E)-9-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluoronon-5-en-4-yl)-2-methylpropane-2-sulfinamide (6.00 g, 14.03 mmol) in MeOH (60 mL) was added to Pd(OH)₂ (1.97 g, 2.81 mmol) and stirred at 30 °C for 24 hours under a H₂ (50 psi) atmosphere. The reaction mixture was filtered and concentrated to give (S)-N-((S,E)-9-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluoronon-5-en-4-yl)-2-methylpropane-2-sulfinamide, which was used for the next step without purification.

[0909] Pd(OH)₂ (6.86 g, 9.78 mmol) was added to a solution of (S)-N-((S,E)-9-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluoronon-5-en-4-yl)-2-methylpropane-2-sulfinamide (6.00 g, 14.0 mmol) in MeOH (60 mL), and the mixture was stirred at 30 °C for 24 hours under a H₂ (50 psi) atmosphere. The reaction mixture was filtered, concentrated, and analyzed by rapid silica gel chromatography (…). 12g Silica Flash Column, eluent: (25-30% ethyl acetate / petroleum ether gradient) purification yielded (S)-N-((R)-9-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluoronon-4-yl)-2-methylpropane-2-sulfinamide. 1 H NMR (400MHz, CDCl3) δ3.59 (t, J=6.5Hz, 2H), 3.37-3.22 (m, 1H), 2.95 (br d, J=6.7Hz, 1H), 2.29-2.03(m, 2H), 1.92-1.78(m, 1H), 1.70-1.61(m, 2H), 1.52(q d, J=6.7, 13.3Hz, 3H), 1.43-1.29 (m, 4H), 1.22 (s, 10H), 0.88 (s, 9H), 0.04 (s, 6H)

[0910] Add TBAF (11.6 mL, 11.6 mmol) (1 M, in THF) to a solution of (S)-N-((R)-9-((tert-butyldimethylsilyl)oxy)-1,1,1-trifluoronon-4-yl)-2-methylpropane-2-sulfinamide (2.50 g, 5.79 mmol) in THF (40 mL). Stir the mixture at 25 °C for 12 hours. Pour the reaction mixture into water (50 mL) and extract with EtOAc (30 mL × 3). Wash the organic layer with brine (30 mL), dry on Na2SO4 and filter. Concentrate the filtrate and extract by rapid silica gel chromatography (…). 25g Silica Flash Column, eluent: (80-90% ethyl acetate / petroleum ether gradient) purification yielded (S)-2-methyl-N-((R)-1,1,1-trifluoro-9-hydroxynon-4-yl)propane-2-sulfinamide (A145). 1 HNMR (500MHz, CDCl3) δ3.63 (br d, J=4.6Hz, 2H), 3.35-3.22 (m, 1H), 2.98 (br d, J=6.9Hz, 1H), 2.28-2.02(m, 3H), 1.89-1.72(m, 1H), 1.67-1.54(m, 4H), 1.50-1.31(m, 4H), 1.25-1.18(m, 9H)

[0911] Intermediate A146

[0912] (R)-10-((tert-butyldimethylsilyl)oxy)-2,2-difluorodecyl-5-amine (A146)

[0913]

[0914] BAST (38.4 mL, 208 mmol) was added to a solution of ethyl 4-oxovalerate (20.0 g, 139 mmol) in DCM (250 mL) at 20 °C. The mixture was stirred at 50 °C for 24 hours under N2. The mixture was quenched with saturated Na2CO3 aqueous solution (100 mL), extracted with DCM (50 mL × 3), washed with brine (50 mL), dried on Na2SO4, filtered, and concentrated under reduced pressure. The crude product was analyzed by rapid silica gel chromatography (…). 80g Ethyl 4,4-difluorovalerate was obtained by purification using a Silica Flash Column (elution buffer: 20% EtOAc / petroleum ether gradient).

[0915] A solution of ethyl 4,4-difluoropentanol (5.00 g, 30.1 mmol) in DCM (100 mL) was added to DIBAL-H (36.1 mL, 36.1 mmol) at -78 °C. The resulting mixture was stirred at -78 °C for 0.5 h under N2 protection. The reaction mixture was stirred, water (3 mL) was added, followed by 15% NaOH (3 mL), water (8 mL), and MgSO4. The mixture was then filtered. The filtrate was concentrated to give crude 4,4-difluoropentanol, which was used directly in the next step.

[0916] (S)-2-methylpropane-2-sulfinamide (4.01 g, 33.1 mmol), PPTS (0.755 g, 3.01 mmol), and MgSO4 (10.8 g, 90.0 mmol) were added to a solution of 4,4-difluoropentanal (3.67 g, 30.1 mmol) in DCE (50 mL) and DCM (200 mL) at 20 °C. The reaction mixture was stirred at 80 °C for 4 hours. The mixture was filtered and concentrated to give the crude product. The crude product was analyzed by rapid silica gel chromatography (…). 40g (S,E)-N-(4,4-difluoropentylene)-2-methylpropane-2-sulfinamide was obtained by purification using a Silica Flash Column (elution buffer: 20% EtOAc / petroleum ether gradient). LCMS m / z (M+H): expected value 226.1, measured value 225.7.

[0917] (S,E)-N-(4,4-difluoropentyl)-2-methylpropane-2-sulfinamide (8.81 g, 44.4 mmol) was added to a solution of bis(trimethylsilyl)aminolithium (44.4 mL, 44.4 mmol) (1 M, in THF) in hexane (100 mL) at -78 °C. The resulting mixture was stirred at 20 °C for 20 min under N2 protection, and then (S,E)-N-(4,4-difluoropentyl)-2-methylpropane-2-sulfinamide (5.00 g, 22.2 mmol) in hexane (5 mL) was added. The reaction mixture was stirred at 20 °C for 3 h. The reaction mixture was poured into a saturated aqueous solution of NaHCO3 (15 mL) and extracted with EtOAc (150 mL × 3). The organic layer was washed with brine (10 mL), dried over Na2SO4, and filtered. The filtrate was concentrated and analyzed by rapid silica gel chromatography (…). 80g Silica Flash Column, eluent: (0-20% ethyl acetate / petroleum ether gradient) (SiO2, petroleum ether: EtOAc = 5:1) purification yielded N-((S)-10-((tert-butyldimethylsilyl)oxy)-2,2-difluorodec-6-yn-5-yl)-2-methylpropane-2-sulfinamide. LCMS m / z (M+H): expected value 424.2, measured value 424.2.

[0918] A solution of N-((S)-10-((tert-butyldimethylsilyl)oxy)-2,2-difluorodecyl-6-yn-5-yl)-2-methylpropane-2-sulfinamide (3.60 g, 8.50 mmol) in ethanol (10 mL) was added to a solution of Pd(OH)₂ (0.119 g, 0.850 mmol) and 10% Pd-C (0.090 g, 0.850 mmol) in ethanol. The resulting mixture was stirred at 20 °C for 24 hours under a H₂ atmosphere. The reaction mixture was filtered and concentrated to give N-((R)-10-((tert-butyldimethylsilyl)oxy)-2,2-difluorodecyl-5-yl)-2-methylpropane-2-sulfinamide. LCMS m / z (M+H): Expected value 427.9, Found value 428.3.

[0919] A solution of N-((R)-10-((tert-butyldimethylsilyl)oxy)-2,2-difluorodecyl-5-yl)-2-methylpropane-2-sulfinamide (2.70 g, 6.31 mmol) in THF (32 mL and water (8 mL) was mixed with DMAP (0.154 g, 1.263 mmol) and Na₂CO₃ (2.007 g, 18.94 mmol). The resulting mixture was stirred at 20 °C for 5 min, and then I₂ (4.01 g, 15.78 mmol) was added. The mixture was stirred at 20 °C for 24 h under N₂ protection. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (20 mL × 3). The organic layer was washed with brine (10 mL), dried on Na₂SO₄, and filtered. The filtrate was concentrated and analyzed by rapid silica gel chromatography (…). 24g Silica Flash Column, eluent: (0-30% ethyl acetate / petroleum ether gradient) (SiO2, EtOAc) purification yielded (R)-6-amino-9,9-difluorodecyl-1-ol. LCMS m / z (M+H): expected value 324.3, measured value 210.1.

[0920] A solution of (R)-6-amino-9,9-difluorodecyl-1-ol (2.80 g, 9.37 mmol) in DCM (60 mL) was mixed with TBS-Cl (2.54 g, 16.9 mmol), DMAP (0.286 g, 2.34 mmol), and TEA (3.92 mL, 28.1 mmol). The resulting mixture was stirred at 37 °C for 16 hours under N2 protection. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (20 mL × 3). The organic layer was washed with brine (10 mL), dried over Na2SO4, and filtered. The filtrate was concentrated and analyzed by rapid silica gel chromatography (…). 40g Silica Flash Column, eluent: (0-100% ethyl acetate / petroleum ether gradient) (SiO2, EtOAc) purification yielded (R)-10-((tert-butyldimethylsilyl)oxy)-2,2-difluorodecyl-5-amine (A146). LCMS m / z (M+H): expected value 324.3, measured value 324.3. 1 H NMR (400MHz, CDCl3) δ3.61 (t, J=6.5Hz, 2H), 2.72 (br d, J=4.7Hz, 1H), 2.06-1.78 (m, 2H), 1.66-1.23 (m, 13H), 0.90 (s, 9H), 0.07-0.02 (m, 6H)

[0921] Intermediate A175

[0922] N-(6-((tert-butyldimethylsilyl)oxy)-1-(2-methylthiazolyl-4-yl)hexyl)-2-methylpropane-2-sulfinamide (A175)

[0923]

[0924] The title compound was prepared from 2-methylthiazol-4-carboxaldehyde in a manner similar to that listed in steps 1 and 2 of scheme A8. LC-MS: 433.4 (M+1).

[0925] Intermediate A176

[0926] 4-Nitrophenyl (S)-but-3-en-2-ylcarbamate (A176)

[0927]

[0928] Step 1: 4-Nitrophenyl (S)-but-3-en-2-ylcarbamate (A176)

[0929] (S)-But-3-en-2-amine hydrochloride (30 mg, 0.279 mmol) was dissolved in DCM (697 μl) and treated with saturated NaHCO3 (697 μl) and 4-nitrophenyl chlorocarbamate (84 mg, 0.418 mmol) under stirring at room temperature for 18 hours. The work-up consisted of dilution with CH2Cl2, washing with saturated NaHCO3, drying by filtration (through a hydrophobic frit filter), and evaporation to obtain an oil. This oil was purified by rapid silica gel chromatography (0-30% 3:1 EtOAc:EtOH / hexane) to give 4-nitrophenyl (S)-but-3-en-2-ylcarbamate (A176). LC-MS: 237.9 (M+1).

[0930] Intermediate B5

[0931] (R)-1-(4-bromo-5-methoxypyridin-2-yl)-N-ethylethyl-1-amine (B5)

[0932] Option B1

[0933]

[0934] Step 1: (R,E)-N-((4-bromo-5-methoxypyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (B2)

[0935] Tetraethoxytitanium (1056 mg, 4.63 mmol) was added to a solution of 4-bromo-5-methoxypicolinaldehyde (B1, 200 mg, 0.926 mmol) and (R)-2-methylpropane-2-sulfinamide (135 mg, 1.111 mmol) in THF (3 mL). The reaction mixture was stirred at 80 °C for 2 h. LC-MS showed the formation of the desired product. The reaction mixture was extracted with EtOAc (3 × 5 mL) in brine (3 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (50% EtOAc in petroleum ether) to give (R,E)-N-((4-bromo-5-methoxypyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (B2). LC-MS: 319.1, 321.1 (M+1).

[0936] Step 2: (R,E)-N-((4-bromo-5-methoxypyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (B3)

[0937] A solution of (R,E)-N-((4-bromo-5-methoxypyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (B2, 260 mg, 0.774 mmol) in THF (3 mL) was added to a solution of (R,E)-N-((4-bromo-5-methoxypyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (B3) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h under nitrogen. LC-MS showed the formation of the desired product. The reaction mixture was quenched with saturated aqueous NH4Cl solution (2 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The purified crude (R,E)-N-((4-bromo-5-methoxypyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (B3) was obtained by rapid silica gel chromatography (50% EtOAc in petroleum ether). LC-MS: 335.1, 337.1 (M+1).

[0938] Step 3: (R)-N-((R)-1-(4-bromo-5-methoxypyridin-2-yl)ethyl)-N-ethyl-2-methylpropane-2- Sulfaniline (B4)

[0939] Under nitrogen atmosphere, sodium hydride (39.1 mg, 0.978 mmol) (60% in mineral oil) was added to a solution of (R,E)-N-((4-bromo-5-methoxypyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (B3, mg, 0.652 mmol) in DMF (3 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Iodethane (203 mg, 1.303 mmol) was added, and the reaction mixture was stirred at 0 °C for 1 h. LC-MS showed the formation of the desired product. The reaction mixture was poured into water (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (70% EtOAc in petroleum ether) to give (R)-N-((R)-1-(4-bromo-5-methoxypyridin-2-yl)ethyl)-N-ethyl-2-methylpropane-2-sulfinamide (B4).

[0940] LC-MS: 363.1, 365.1 (M+1).

[0941] Step 4: (R)-1-(4-bromo-5-methoxypyridin-2-yl)-N-ethylethyl-1-amine (B5)

[0942] (R)-N-((R)-1-(4-bromo-5-methoxypyridin-2-yl)ethyl)-N-ethyl-2-methylpropane-2-sulfinamide (B4, 466 mg, 1.283 mmol) was dissolved in MeOH (6413 μL), and HCl (321 μL, 1.283 mmol) (4 M, in dioxane) was added. The reaction mixture was stirred at room temperature for 20 min. LC-MS showed the formation of the desired product. The reaction mixture was concentrated and rotary evaporated twice with DCM to give (R)-1-(4-bromo-5-methoxypyridin-2-yl)-N-ethylethyl-1-amine (B5) in the form of an HCl salt. LC-MS: 259.2, 261.2 (M+1)

[0943] Intermediate B10

[0944] (R)-1-(4-bromopyridin-2-yl)-N-ethylethyl-1-amine (B10)

[0945] Option B2

[0946]

[0947] Step 1: (R,E)-N-((4-bromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (B7)

[0948] Copper(II) sulfate (19.56 g, 123 mmol) was added to a solution of 4-bromopicolinaldehyde (B6, 5.18 g, 27.8 mmol) and (R)-2-methylpropane-2-sulfinamide (6.75 g, 55.7 mmol) in DCM (111 mL) at room temperature, and the solution was stirred for 68 hours. The mixture was filtered through a Celite filter, washed with DCM (3 × 20 mL), and concentrated. The crude product was purified by rapid silica gel chromatography (0-60% EtOAc gradient in hexane) to give (R,E)-N-((4-bromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (B7).

[0949] LC-MS: 289.1, 291.1 (M+1).

[0950] Step 2: (R)-N-((R)-1-(4-bromopyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (B8)

[0951] Methyl magnesium bromide (19.18 mL, 57.6 mmol) (3 M, in THF) was added dropwise to a solution of (R,E)-N-((4-bromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (B7, 7.43 g, 25.7 mmol) in THF (184 mL) at -78 °C over 20 minutes, and the reaction mixture was stirred at -78 °C for 1.5 hours. The reaction mixture was quenched by slow addition of a saturated aqueous solution of NH4Cl (50 mL) at -78 °C, then poured into water (100 mL) and extracted with EtOAc (3 × 60 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (0-100% EtOAc gradient in hexane) to give (R)-N-((R)-1-(4-bromopyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (B8). LC-MS: 305.1, 307.1 (M+1).

[0952] Step 3: (R)-N-((R)-1-(4-bromopyridin-2-yl)ethyl)-N-ethyl-2-methylpropane-2-sulfinamide (B9)

[0953] Sodium hydride (60%, in mineral oil, 1.390 g, 34.7 mmol) was added to a solution of (R)-N-((R)-1-(4-bromopyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (B8, 7.07 g, 23.16 mmol) in DMF (93 mL) at 0 °C, and the solution was stirred for 30 min. Then iodoethane (2.226 mL, 27.8 mmol) was added, and stirring continued for 3 h. The reaction mixture was quenched by adding water (50 mL) dropwise, then poured into water (300 mL), and extracted with Et2O (3 × 100 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (0-60% EtOAc gradient in hexane) to give (R)-N-((R)-1-(4-bromopyridin-2-yl)ethyl)-N-ethyl-2-methylpropane-2-sulfinamide (B9). LC-MS: 333.0, 335.0 (M+1).

[0954] Step 4: (R)-1-(4-bromopyridin-2-yl)-N-ethylethyl-1-amine (B10)

[0955] A solution of (R)-N-((R)-1-(4-bromopyridin-2-yl)ethyl)-N-ethyl-2-methylpropane-2-sulfinamide (B9, 4.37 g, 13.11 mmol) in MeOH (26.2 mL) was added to HCl (3.28 mL, 13.11 mmol) (4 M, in dioxane), and the reaction mixture was stirred for 30 min. The reaction mixture was concentrated and dried under high vacuum to give (R)-1-(4-bromopyridin-2-yl)-N-ethylethyl-1-amine (B10) in the form of an HCl salt. LC-MS: 229.0, 231.0 (M+1).

[0956] Intermediates B12, B14 and B16

[0957] Using a suitable aldehyde, synthesize the intermediates listed in Table B1 below in a manner similar to that described in Scheme B1 for the synthesis of intermediate B5.

[0958] Table B1

[0959]

[0960]

[0961] *In the synthesis of (S)-N-((R)-1-(5-bromo-6-methoxypyridin-3-yl)ethyl)-N-ethyl-2-methylpropane-2-sulfinamide (B14) and (R)-N-((R)-1-(6-bromopyridin-2-yl)ethyl)-N-ethyl-2-methylpropane-2-sulfinamide (B89), (S)-2-methylpropane-2-sulfinamide is used instead of (R)-2-methylpropane-2-sulfinamide. In the synthesis of N-(1-(4-chloro-3-fluoropyridin-2-yl)ethyl)-N-ethyl-2-methylpropane-2-sulfinamide (B93), (RS)-2-methylpropane-2-sulfinamide is used instead of (R)-2-methylpropane-2-sulfinamide.

[0962] Intermediate B17

[0963] (2-((R)-1-(((R)-tert-butylsulfinyl)(ethyl)amino)ethyl)-5-methoxypyridin-4-yl)boron Acid (B17)

[0964] Option B3

[0965]

[0966] XPhos Pd G2 (0.123 g, 0.157 mmol) was added to a mixture of (R)-N-((R)-1-(4-chloro-5-methoxypyridin-2-yl)ethyl)-N-ethyl-2-methylpropane-2-sulfinamide (B12, 1 g, 3.14 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxane-2,2'-dioxane) (1.593 g, 6.27 mmol) and potassium acetate (0.923 g, 9.41 mmol) in dioxane (10 mL). The reaction mixture was stirred at 80 °C for 16 h under nitrogen. LC-MS showed the formation of the desired product. The reaction mixture was filtered and concentrated to give borate ester B17, which was used directly for the next step without purification. LC-MS: 329.2 (M+H).

[0967] Option B4

[0968]

[0969] Pd(dppf)Cl2 (40.3 mg, 0.055 mmol) was added to a mixture of (R)-N-((R)-1-(4-bromo-5-methoxypyridin-2-yl)ethyl)-N-ethyl-2-methylpropane-2-sulfinamide (B4, 200 mg, 0.550 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxane) (280 mg, 1.101 mmol), and potassium acetate (162 mg, 1.651 mmol) in 1,4-dioxane (3 mL). The reaction mixture was stirred at 80 °C for 4 hours under nitrogen. LC-MS showed the formation of the desired product. The reaction mixture was filtered and concentrated to give borate ester B17, which was used directly for the next step without purification. LC-MS: 329.2 (M+1).

[0970] Intermediate B18

[0971] tert-Butyl(R)-(1-(4-bromo-5-methoxypyridin-2-yl)ethyl)(ethyl)carbamate (B18)

[0972] Option B5

[0973]

[0974] (R)-1-(4-bromo-5-methoxypyridin-2-yl)-N-ethylethyl-1-amine (B5, 172 mg, 0.664 mmol) was dissolved in DCM (6637 μL) and Boc anhydride (185 μL, 0.796 mmol), and triethylamine (111 μL, 0.796 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. LC-MS analysis showed complete conversion. The reaction mixture was quenched with MeOH (3 mL) and concentrated. The crude product was purified by ISCO column chromatography (0-100% EtOAc:EtOH 3:1 gradient in hexane) to give tert-butyl(R)-(1-(4-bromo-5-methoxypyridin-2-yl)ethyl)(ethyl)carbamate (B18). LC-MS: 359.2, 361.2 (M+1).

[0975] Intermediates B19 and B20

[0976]

[0977] (R)-1-(5-bromo-6-methoxypyridin-3-yl)-N-ethylethyl-1-amine (B19)

[0978] Intermediate B19 was prepared from intermediate B14 in a manner similar to that described in step 4 of scheme B2 for the synthesis of intermediate B10. LC-MS: 258.9, 260.9 (M+1). 1H NMR: (400MHz, CD3OD) δ8.24 (d, J=2.3Hz, 1H), 8.12 (d, J=2.3Hz, 1H), 4.42 (q, J=6.7Hz, 1H), 4. 01 (s, 3H), 3.11-3.00 (m, 1H), 2.98-2.81 (m, 1H), 1.67 (d, J=7.0Hz, 3H), 1.29 (t, J=7.4Hz, 3H).

[0979] In a manner similar to that described for intermediate B19, intermediates as shown in Table B19-1 are prepared starting from a suitable halide.

[0980]

[0981]

[0982] (5-((R)-1-(((S)-tert-butylsulfinyl)(ethyl)amino)ethyl)-2-methoxypyridin-3-yl)boron Acid (B20)

[0983] Intermediate B20 is prepared from intermediate B14 in a manner similar to that described in scheme B4 for synthesizing intermediate B17.

[0984] LC-MS: 329.3 (M+1).

[0985] Intermediate B27

[0986] (R)-1-(2-chloropyridin-4-yl)-N-ethylethyl-1-amine (B27)

[0987] Option B6

[0988]

[0989]

[0990] Step 1: (S,E)-N-((2-chloropyridin-4-yl)methylene)-2-methylpropane-2-sulfinyl Amine (B22)

[0991] 2-Chloroisocyanate (B21, 160 g, 1.13 mol, 1.0 eq) was dissolved in THF (1.5 L). (S)-2-methylpropane-2-sulfinamide (205 g, 1.70 mol, 1.5 eq) and Ti(OEt)4 (773 g, 3.39 mol, 703 mL, 3.0 eq) were added to the solution. The reactants were degassed by purging with nitrogen and then heated to 70–80 °C and held for 1 hour. TLC showed the formation of a more polar spot. The reactants were quenched with water (2.0 L) and diluted with EtOAc (2.0 L). The two-phase mixture was extracted with ethyl acetate (3 × 2.0 L). The organic layers were combined, washed with brine (2.0 L), dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (in a petroleum ether gradient of 1:20 to 1:3 EtOAc) to give (S,E)-N-((2-chloropyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (B22). 1 H NMR: (400MHz, CDCl3) δ: 8.56-8.54 (m, 1H), 7.75-7.70 (m, 1H), 7.61-7.59 (m, 1H), 1.62 (s, 9H).

[0992] Step 2: (S)-N-((R)-1-(2-chloropyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (B23) and (S)-N-((S)-1-(2-chloropyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (B24)

[0993] (S,E)-N-((2-chloropyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (B22, 220 g, 899 mmol) was dissolved in THF (2.2 L), the solution was purged with nitrogen to degas, and then cooled to -60°C to -70°C. MeMgBr (900 mL, 2.7 mol) (3.0 M, in THF) was added dropwise to the reaction mixture at -60°C to -70°C. The reaction mixture was stirred at -60°C to -70°C for 1 h. TLC showed the formation of a more polar spot. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl (2 L), diluted with EtOAc (2 L), and extracted with EtAOc (3 × 2 L). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (in petroleum ether at a gradient of 1:20 to 1:3 EtOAc) to give a mixture of (S)-N-((R)-1-(2-chloropyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (B23) and (S)-N-((S)-1-(2-chloropyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (B24). 1H NMR: (400MHz, CDCl3) δ: 8.37-8.35 (m, 1H), 7.32-7.30 (m, 1H), 7.23-7.21 (m, 1H) ), 4.53-4.50 (m, 1H), 3.51-3.38, (m, 1H), 1.53-1.51 (m, 3H), 1.25-1.23 (m, 9H).

[0994] Step 3: (S)-N-((R)-1-(2-chloropyridin-4-yl)ethyl)-N-ethyl-2-methylpropane-2-sulfinamide (B25) and (S)-N-((S)-1-(2-chloropyridin-4-yl)ethyl)-N-ethyl-2-methylpropane-2-sulfinamide (B26)

[0995] A mixture of (S)-N-((R)-1-(2-chloropyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (B24) was dissolved in THF (800 mL) and DMF (80 mL). The solution was degassed by purging with nitrogen and then cooled to 0–5 °C. Sodium hydride (24.5 g, 613 mmol) (60% in mineral oil) was added in 10 portions, and the reaction mixture was stirred at 0–5 °C for 30 min. Iodoethane (95.7 g, 613 mmol) was added, and the reaction mixture was stirred at 15 °C to room temperature for 2 h. TLC showed the formation of a new spot. The reaction mixture was quenched with water (2 L), diluted with EtOAc (2 L), and extracted with EtOAc (3 × 2 L). The combined organic layers were washed with brine (2 L), dried (Na2SO4), filtered, and concentrated. The crude product was purified by reversed-phase HPLC (35%-55% ACN in water, containing 0.1% TFA as a modifier) ​​to obtain isolated (S)-N-((R)-1-(2-chloropyridin-4-yl)ethyl)-N-ethyl-2-methylpropane-2-sulfinamide (B25) and (S)-N-((S)-1-(2-chloropyridin-4-yl)ethyl)-N-ethyl-2-methylpropane-2-sulfinamide (B26). B25: 1 H NMR (400MHz, CDCl3) δ: 8.32-8.31 (m, 1H), 7.28-7.27 (m, 1H), 7.21-7.19 (m, 1H), 4.58-4.52 (m, 1H), 3.20-3.14 (m, 1H), 2.91-2.85 (m, 1H), 1.60 (d, J=3.2Hz, 3H), 1.24 (t, J=7.2Hz, 3H). 1.21(s,9H). B26: 1H NMR (400MHz, CDCl3) δ: 8.35-8.33 (m, 1H), 7.43-7.40 (m, 2H), 4.63-4.58 (m, 1H), 3.20-3. 13 (m, 1H), 2.63-2.59 (m, 1H), 1.60 (d, J=3.2Hz, 3H), 1.26 (s, 9H), 1.08 (t, J=7.2Hz, 3H).

[0996] Step 4: (R)-1-(2-chloropyridin-4-yl)-N-ethylethyl-1-amine (B27)

[0997] (S)-N-((R)-1-(2-chloropyridin-4-yl)ethyl)-N-ethyl-2-methylpropane-2-sulfinamide (B25, 15.0 g, 0.05 mmol) was dissolved in MeOH (50 mL), and the solution was cooled to 0–5 °C. HCl (200 mL, 800 mmol) (4 M, in EtOAc) was added, and the reaction mixture was stirred at 0–5 °C for 2 hours. TLC showed the formation of a more polar spot. The reaction mixture was concentrated. The crude product was slurried with EtOAc (30 mL) at room temperature for 2 hours. The slurry was filtered to give (R)-1-(2-chloropyridin-4-yl)-N-ethylethyl-1-amine (B27) in the form of an HCl salt. 1 H NMR: (400MHz, DMSO-d6) δ: 10.03 (s, 1H), 9.60 (s, 1H), 8.50-8.48 (m, 1H), 7.85-7.83 (m, 1H), 7.72-7.70 (m, 1H), 4.45-4.40 (m, 1H), 2.90-2.86 (m, 1H), 2.72-2.69 (m, 1H), 1.57 (d, J=6.8Hz, 3H), 1.20 (t, J=7.2Hz, 3H).

[0998] Intermediate B31

[0999] (R)-N-((R)-1-(4-chloro-5-methylpyridin-2-yl)ethyl)-N-ethyl-2-methylpropane-2-sulfinamide

[1000] Option B7

[1001]

[1002] Step 1: 4-Chloro-5-methylpicolinaldehyde (B30)

[1003] A solution of ethyl 4-chloro-5-methylpicolinate (B29, 1.2 g, 6.01 mmol) in anhydrous DCM (20 mL) was slowly added to DIBAL-H (9.02 mL, 9.02 mmol) (1.0 M, in toluene) at -78 °C, and the reaction mixture was stirred at -78 °C for 1 h under nitrogen. LC-MS showed the formation of the desired product. The reaction mixture was poured into water (50 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried (Na₂SO₄), filtered, and concentrated to give 4-chloro-5-methylpicolinaldehyde (B30), which was used directly in the next step without purification. LC-MS: 156.2 (M+1).

[1004]

[1005] (R)-N-((R)-1-(4-chloro-5-methylpyridin-2-yl)ethyl)-N-ethyl-2-methylpropane-2-sulfinamide (B31)

[1006] Intermediate B31 was prepared in a manner similar to that described in Scheme B1 for the synthesis of intermediate B4. LC-MS: 303.2 (M+1). 1 H NMR δ8.37 (s, 1H), 7.35 (s, 1H), 4.64 (q, J=6.8Hz, 1H), 3.29-3.17 (m, 1H), 2.93 ( qd, J=6.9, 14.3Hz, 1H), 2.32 (s, 3H), 1.64 (d, J=6.8Hz, 3H), 1.18-1.09 (m, 12H)

[1007] Intermediate B33

[1008] 1-(6-Chloropremine-4-yl)-N-ethylethyl-1-amine (B33)

[1009] Plan B8

[1010]

[1011] Magnesium sulfate (707 mg, 5.88 mmol), ethylamine (2.0 M, in THF, 7.35 mL, 14.69 mmol), and acetic acid (0.673 mL, 11.75 mmol) were added to a solution of 1-(6-chloropyrimidin-4-yl)ethyl-1-one (B32, 460 mg, 2.94 mmol) in EtOH (10 mL). The reaction mixture was heated to 90 °C and held for 1 hour, then cooled to room temperature. Sodium cyanoborohydride (369 mg, 5.88 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was cooled and poured into 0.5 N NaOH aqueous solution (60 mL), and extracted with DCM (3 × 30 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (a gradient of 0-100% EtOAc / EtOH 3:1 mixture in hexane) to give 1-(6-chloropyrimidin-4-yl)-N-ethylethyl-1-amine (B33). LC-MS: 186.1 (M+1).

[1012] Intermediate B35

[1013] 1-(2-chloropyridin-4-yl)-N-ethylethyl-1-amine (B35)

[1014] Option B9

[1015]

[1016] Step 1: 1-(2-chloropyridin-4-yl)-N-ethylethyl-1-amine (B35)

[1017] A solution of 1-(2-chloropyridin-4-yl)ethyl-1-one (B34, 530 mg, 3.41 mmol) dissolved in EtOH (20 mL), treated with magnesium sulfate (820 mg, 6.81 mmol) and ethylamine (8.52 mL, 17.03 mmol) (2.0 M, in THF) was placed in a sealable vial. Acetic acid (0.780 mL, 13.63 mmol) was added, and the reaction mixture was heated to 50 °C and maintained for 1 hour. The reaction mixture was cooled to room temperature, and sodium cyanoborohydride (428 mg, 6.81 mmol) was added, followed by stirring for 20 hours. The reaction mixture was filtered through a Celite pan, washed with EtOAc (3 × 20 mL), and concentrated. The crude product was purified by rapid silica gel chromatography (0–15% NH4OH / MeOH 100:1 mixture in DCM) to give 1-(2-chloropyridin-4-yl)-N-ethylethyl-1-amine (B35). LC-MS: 185.1 (M+1).

[1018] Intermediate B43

[1019] (R)-1-(5-chloro-6-methoxypyridazin-3-yl)-N-ethylethyl-1-amine (B43)

[1020] Plan B10

[1021]

[1022] Step 1: Methyl 5-bromo-6-hydroxypyridazine-3-carboxylate (B37)

[1023] Potassium acetate (80 g, 811 mmol) and bromine (104 g, 649 mmol) were slowly added to a solution of methyl 6-hydroxypyridazine-3-carboxylate (B36, 5 g, 162 mmol) in AcOH (250 mL), and the reaction mixture was stirred at 80 °C for 3 h. LC-MS showed the formation of the desired product. The reaction mixture was adjusted to pH 8 with saturated NaHCO3 aqueous solution and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated to give methyl 5-bromo-6-hydroxypyridazine-3-carboxylate (B37), which was used directly in the next step without purification. 1 H NMR: (400MHz, CD3OD) δ8.33 (s, 1H), 3.91 (s, 3H).

[1024] Step 2: Methyl 5,6-dichloropyridazine-3-carboxylate (B38)

[1025] A solution of 5-bromo-6-hydroxypyridazine-3-carboxylate (B37, 15 g, 64.4 mmol) in POCl3 (150 mL) was stirred at 110 °C for 3 hours. LC-MS showed complete conversion. The reaction mixture was concentrated to give methyl 5,6-dichloropyridazine-3-carboxylate (B38), which was used directly in the next step without purification.

[1026] Step 3: Methyl 5-chloro-6-methoxypyridazine-3-carboxylate (B39)

[1027] A solution of methyl 5,6-dichloropyridazine-3-carboxylate (B38, 30 g, 145 mmol) in MeOH (300 mL) was stirred at 20 °C for 3 h. LC-MS showed complete conversion. The reaction mixture was concentrated and dissolved in water (500 mL). The pH was adjusted to 8 with saturated NaHCO3 aqueous solution, and the mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (0–20% ethyl acetate gradient in petroleum ether) to give methyl 5-chloro-6-methoxypyridazine-3-carboxylate (B39).

[1028] 1 H NMR: (400MHz, CDCl3) δ8.16 (s, 1H), 4.30 (s, 3H), 4.04 (s, 3H).

[1029] Step 4: 1-(5-chloro-6-methoxypyridazin-3-yl)ethyl-1-one (B40)

[1030] A solution of methyl 5-chloro-6-methoxypyridazine-3-carboxylate (B39, 4 g, 19.74 mmol) in THF (40 mL) was added to methyl magnesium bromide (13.16 mL, 39.5 mmol), and the reaction mixture was stirred at -78 °C for 4 h. LC-MS showed the formation of the desired product. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with (30 mL) brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (0–16% EtOAc gradient in petroleum ether) to give 1-(5-chloro-6-methoxypyridazine-3-yl)ethyl-1-one (B40).

[1031] 1-(5-Chloro-6-methoxypyridazin-3-yl)-N-ethylethyl-1-amine (B41)

[1032] Intermediate B41 was prepared in a manner similar to that described in Scheme B8 for the synthesis of intermediate B33. 1 HNMR: (500MHz, CDCl3) δ7.58 (s, 1H), 4.25-4.15 (m, 3H), 4.14-4.04 (m, 1H), 2.60 (qd, J=7. 1, 11.4Hz, 1H), 2.46 (qd, J=7.2, 11.3Hz, 1H), 1.40 (d, J=6.7Hz, 3H), 1.08 (t, J=7.1Hz, 3H)

[1033] (R)-1-(5-chloro-6-methoxypyridazin-3-yl)-N-ethylethyl-1-amine (B43)

[1034] Two enantiomers of 1-(5-chloro-6-methoxypyridazin-3-yl)-N-ethylethyl-1-amine (B41) were separated by chiral SFC separation (Daicel Chiralpack AY-H column, 20% EtOH, 80% CO2, 0.1% NH3H2O ​​as additive) to (R)-1-(5-chloro-6-methoxypyridazin-3-yl)-N-ethylethyl-1-amine (B43) and its enantiomers. 1 H NMR (400MHz, CD3OD) δ7.83 (s, 1H), 4.14 (s, 3H), 4.03 (q, J=6.8Hz, 1H), 2.51 (qd, J=7.2, 11.5Hz, 1H), 2.38 (qd, J=7.2, 11.4Hz, 1H), 1.38 (d, J=6.8Hz, 3H), 1.07 (t, J=7.1Hz, 3H).

[1035] Intermediate B48

[1036] 1-(4-Chloro-5-methoxypyrimidin-2-yl)-N-ethylethyl-1-amine (B48)

[1037] Option B11

[1038]

[1039] Step 1: 5-Methoxy-2-(prop-1-en-2-yl)-4-(2-(trimethylsilyl)ethoxy)pyrimidine (B45)

[1040] A solution of 2-chloro-5-methoxy-4-(2-(trimethylsilyl)ethoxy)pyrimidine (B44, 1.7 g, 6.52 mmol), potassium isopropenyltrifluoroborate (1.061 g, 7.17 mmol), and Na2CO3 (1.382 g, 13.04 mmol) in 1,4-dioxane (30 mL) and water (10 mL) was purged with nitrogen at room temperature, and Pd(dppf)Cl was added. 2( 0.266 g, 0.326 mmol). The reactants were heated at 90 °C for 10 h under nitrogen. TLC showed almost complete conversion to the desired product. The reactants were cooled, diluted with water, and extracted with EtOAc (5 × 10 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (10% EtOAc in petroleum ether) to give 5-methoxy-2-(prop-1-en-2-yl)-4-(2-(trimethylsilyl)ethoxy)pyrimidine (B45). LC-MS: m / z (M+H): 267.1, 267.1.

[1041] Step 2: 1-(5-methoxy-4-(2-(trimethylsilyl)ethoxy)pyrimidin-2-yl)ethyl-1-one (B46)

[1042] Osmium oxide (VIII) (0.15 g, 0.601 mmol) (1% aqueous solution) was added to a solution of 5-methoxy-2-(prop-1-en-2-yl)-4-(2-(trimethylsilyl)ethoxy)-pyrimidine (B45, 3.2 g, 12.01 mmol) in THF (50 mL) at 0 °C, and the reaction mixture was stirred for 30 min. Sodium periodate (10.28 g, 48.0 mmol) was then added, and the reaction mixture was stirred at 20 °C for 12 h. LCMS analysis showed the formation of the desired product. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with saturated Na₂SO₃ aqueous solution (20 mL) and brine (20 mL), dried (Na₂SO₄), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (30% EtOAc in petroleum ether) to give 1-(5-methoxy-4-(2-(trimethylsilyl)ethoxy)pyrimidin-2-yl)ethyl-1-one.

[1043] Step 3: 1-(4-chloro-5-methoxypyrimidin-2-yl)ethyl-1-one (B47)

[1044] Phosphorus oxychloride (12.57 g, 82 mmol) was added to 1-(5-methoxy-4-(2-(trimethylsilyl)ethoxy)pyrimidin-2-yl)ethyl-1-one (B46, 2 g, 7.45 mmol) under nitrogen atmosphere. The reaction mixture was stirred and refluxed at 80 °C for 3 h. TLC showed the consumption of the starting material and the formation of a new spot. The reaction mixture was concentrated. The residue was poured into water (150 mL). Neutralized with Na₂CO₃ and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (55% EtOAc in petroleum ether) to give 1-(4-chloro-5-methoxypyrimidin-2-yl)ethyl-1-one (B47). LC-MS: 186.9 (M+1).

[1045] 1-(4-Chloro-5-methoxypyrimidin-2-yl)-N-ethylethyl-1-amine (B48)

[1046] Intermediate B48 was prepared in a manner similar to that described in scheme B8 for the synthesis of intermediate B33. LC-MS: 216.1 (M+1).

[1047] Intermediate B51

[1048] 1-(6-Chloro-2-methylpyrimidin-4-yl)-N-ethylethyl-1-amine (B51)

[1049] Option B12

[1050]

[1051] Step 1: 1-(6-chloro-2-methylpyrimidin-4-yl)acet-1-one (B50)

[1052] A solution of 4,6-dichloro-2-methylpyrimidine (B49, 606 mg, 3.72 mmol) in dioxane (33 mL) was degassed with nitrogen. Tributyl(1-ethoxyethylene)tin (1.884 mL, 5.58 mmol) and tetrakis(triphenylphosphine)palladium (0) (430 mg, 0.372 mmol) were added, and the reaction mixture was heated at 100 °C for 3 hours. The reaction mixture was cooled to room temperature, and 10% HCl aqueous solution (1 mL) was added, with stirring continued for 1 hour. The reaction mixture was poured into a saturated NaHCO3 aqueous solution (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (a gradient of 0-100% EtOAc / EtOH 3:1 mixture in hexane). The desired products were combined to give 1-(6-chloro-2-methylpyrimidin-4-yl)ethyl-1-one (B50). LC-MS: 171.0 (M+1).

[1053]

[1054] 1-(6-Chloro-2-methylpyrimidin-4-yl)-N-ethylethyl-1-amine (B51)

[1055] Intermediate B51 was prepared in a manner similar to that described in Scheme B8 for the synthesis of intermediate B33. LC-MS: 200.1 (M+1).

[1056] intermediate B53

[1057] Starting with a suitable halide, the intermediates in Table B2 below are prepared in a manner similar to that described in schemes B12 and B8 for the synthesis of intermediate B51.

[1058] Table B2

[1059]

[1060] Intermediate B58

[1061] (R)-N-((R)-1-(6-bromo-5-methoxypyridin-2-yl)ethyl)-N-ethyl-2-methylpropane-2-sulfinyl Amine (B58)

[1062] Option B13

[1063]

[1064] Step 1: 1-(6-bromo-5-methoxypyridin-2-yl)ethyl-1-one (B55)

[1065] N-methoxy-N-methylacetamide (1.084 g, 10.51 mmol) was added to a solution of 2-bromo-6-iodo-3-methoxypyridine (B54, 3 g, 9.56 mmol) in THF (30 mL) cooled to 0 °C, followed by the addition of isopropyl magnesium chloride (7.17 mL, 14.33 mmol). The solution was stirred at 0 °C to 20 °C for 3 hours. TLC showed complete conversion. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dried (Na₂SO₄), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (0–25% EtOAc gradient in petroleum ether) to give 1-(6-bromo-5-methoxypyridin-2-yl)ethyl-1-one (B55).

[1066] Step 2: (R,E)-N-(1-(6-bromo-5-methoxypyridin-2-yl)ethylene)-2-methylpropane-2-sulfinyl amine

[1067] (R)-2-methylpropane-2-sulfinamide (1.580 g, 13.04 mmol) and tetraisopropoxytitanium (11.12 g, 39.1 mmol) were added to a solution of 1-(6-bromo-5-methoxypyridin-2-yl)ethyl-1-one (B55, 1.5 g, 6.52 mmol) in THF (30 mL). The reaction mixture was stirred at 75 °C for 5 h. TLC showed complete conversion. The reaction mixture was poured into brine (100 mL), and the layers were separated after filtering the solids formed. The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (20-50% EtOAc gradient in petroleum ether) to give (R,E)-N-(1-(6-bromo-5-methoxypyridin-2-yl)ethylene)-2-methylpropane-2-sulfinamide (B56).

[1068] Step 3: (R)-N-((R)-1-(6-bromo-5-methoxypyridin-2-yl)ethyl)-2-methylpropane-2-sulfinyl amine

[1069] A solution of (R,E)-N-(1-(6-bromo-5-methoxypyridin-2-yl)ethylene)-2-methylpropane-2-sulfinamide (B56, 1.3 g, 3.90 mmol) in THF (20 mL) was added to NaBH4 (0.443 g, 11.70 mmol) at -10 °C. The reaction mixture was stirred at -10 °C for 5 hours under nitrogen. LC-MS showed complete conversion. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (0-30% EtOAc gradient in petroleum ether) to give (R)-N-((R)-1-(6-bromo-5-methoxypyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (B57). LC-MS: 335.3, 337.3 (M+1).

[1070] Step 4: (R)-N-((R)-1-(6-bromo-5-methoxypyridin-2-yl)ethyl)-N-ethyl-2-methylpropane-2- sulfinamide

[1071] Sodium hydride (260 mg, 6.50 mmol) was added to a solution of (R)-N-((R)-1-(6-bromo-5-methoxypyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (B57, 0.8 g, 2.386 mmol) in DMF (50 mL) under nitrogen atmosphere and at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Iodoethane (744 mg, 4.77 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. LC-MS showed the formation of the desired product. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (50 mL), dried (Na₂SO₄), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (30-70% EtOAc gradient in petroleum ether) to give (R)-N-((R)-1-(6-bromo-5-methoxypyridin-2-yl)ethyl)-N-ethyl-2-methylpropane-2-sulfinamide (B58). LC-MS: 364.5, 366.5 (M+1).

[1072] Intermediate B61

[1073] (R)-N-((R)-1-(5-bromo-6-methylpyridin-3-yl)ethyl)-N-ethyl-2-methylpropane-2-sulfinamide

[1074] Option B14

[1075]

[1076] Step 1: 1-(5-bromo-6-methylpyridin-3-yl)ethyl-1-one (B60)

[1077] A solution of 3,5-dibromo-2-methylpyridine (B59, 20 g, 80 mmol) in dioxane (200 mL) was added to tributyl(1-ethoxyethylene)stanane (25.9 g, 71.7 mmol) and bis(triphenylphosphine)-palladium(II) dichloride (2.80 g, 3.99 mmol). The reaction mixture was stirred at 100 °C for 10 h. LCMS showed complete conversion. The reaction mixture was cooled to 20 °C, and HCl (100 mL) (4 M, in dioxane) was added. The mixture was stirred for 1 h. LCMS showed the formation of the desired product. The reaction mixture was extracted with EtOAc (3 × 200 mL) in a 10% KF aqueous solution (300 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (54% EtOAc in petroleum ether) to give 1-(5-bromo-6-methylpyridin-3-yl)ethyl-1-one (B60). LC-MS: 214.1, 216.1 (M+1). 1H NMR: (400MHz, CDCl3) δ8.92 (d, J=1.7Hz, 1H), 8.31 (d, J=2.0Hz, 1H), 2.87-2.64 (m, 3H), 2.60-2.53 (m, 3H)

[1078]

[1079] (R)-N-((R)-1-(5-bromo-6-methylpyridin-3-yl)ethyl)-N-ethyl-2-methylpropane-2-sulfinamide

[1080] Intermediate B61 was prepared in a manner similar to that described in the last three steps of Scheme B13 for the synthesis of intermediate B58. In step 3, DIBAL-H was used instead of NaHB4. LC-MS: 347.1, 349.1 (M+1). 1 H NMR: (400MHz, CDCl3) δ8.41 (d, J=1.7Hz, 1H), 7.77 (d, J=1.7Hz, 1H), 4.53 (br d, J=6.4Hz, 1H), 3.23 (qd, J=7.3, 14.7Hz, 1H), 2.93-2.74 (m, 1H), 2.63 (s, 3H), 1.68-1.56 (m, 3H), 1.33-1.13 (m, 3H), 1.09-1.01 (m, 9H)

[1081] Intermediate B65

[1082] tert-Butylethyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzyl)carbamic acid Ester (B65)

[1083] Option B15

[1084]

[1085] Step 1: N-(3-bromobenzyl)ethylamine (B63)

[1086] Ethylamine (18.04 g, 400 mmol) was added to a solution of 1-bromo-3-(bromomethyl)benzene (B62, 10 g, 40.0 mmol) in MeOH (100 mL), and the reaction mixture was stirred at room temperature for 4 hours. TLC showed the formation of a new spot. The reaction mixture was concentrated to give N-(3-bromobenzyl)ethylamine (B63), which was used directly in the next step without purification.

[1087] Step 2: tert-butyl(3-bromobenzyl)(ethyl)carbamate (B64)

[1088] TEA (16.74 mL, 120 mmol) and Boc anhydride (17.5 g, 80 mmol) were added to a solution of N-(3-bromobenzyl)ethylamine (B63, 8.57 g, 40.0 mmol) in DCM (100 mL). The reaction mixture was stirred at room temperature for 16 hours. LC-MS showed the formation of the desired product. The reaction mixture was poured into water (200 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried (Na₂SO₄), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (0–10% EtOAc gradient in petroleum ether) to give tert-butyl(3-bromobenzyl)(ethyl)carbamate (B64).

[1089] LC-MS: 258.1, 260.1 (M+1-tBu). 1 H NMR: (400MHz, CDCl3) δ7.37-7.10 (m, 4H), 4.37 (br s, 2H), 3.38-3.06 (m, 2H), 1.49-1.40 (m, 9H), 1.14-1.00 (m, 3H).

[1090] Step 3: tert-butylethyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzyl)amino B65 (B65)

[1091] A solution of tert-butyl(3-bromobenzyl)(ethyl)carbamate (B64, 2 g, 6.37 mmol) in dioxane (35 mL) was added to a solution of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxacyclopentaborane) (2.10 g, 8.27 mmol), KOAc (1.25 g, 12.74 mmol), and PdCl2 (dppf) (0.466 g, 0.637 mmol). The reaction mixture was stirred at 80 °C for 5 h under nitrogen. LC-MS showed the formation of the desired product. The resulting solution of tert-butylethyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzyl)carbamate (B65) was used for the next step without purification.

[1092] LC-MS: Measured value 306.2 (M+1-tBu).

[1093] Intermediates B69-B71 and B73

[1094] Option B16

[1095]

[1096] Step 1: N-((4-bromo-5-methoxypyridin-2-yl)methyl)ethylamine (B67)

[1097] A solution of 4-bromo-5-methoxypicolinaldehyde (B66, 100 mg, 0.463 mmol) in ethylamine (209 mg, 4.63 mmol) was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved in MeOH (1 mL) and sodium borohydride (35.0 mg, 0.926 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C and then heated to 20 °C and held for 1 hour. LC-MS showed the formation of the desired product. The reaction mixture was quenched with HCl (4 M, in dioxane) to adjust the pH to 7. The resulting solution of N-((4-bromo-5-methoxypyridin-2-yl)methyl)ethylamine (B67) was used for the next step without purification.

[1098] Starting with a suitable halide, the intermediates in Table B3 below are synthesized in a manner similar to that described in Scheme B15 for the synthesis of intermediate B65.

[1099] Table B3

[1100]

[1101] *Between Boc protection and borylation, the conversion of (R)-1-(3-bromophenyl)ethyl-1-amine (B72) to borate B73 includes N-alkylation with iodoethane as described in step 4 of scheme B13 for the conversion of intermediate B57 to intermediate B58.

[1102] Intermediate B76

[1103] 1-(4-Chloro-5-methoxypyridin-2-yl)-N-ethyl-2,2,2-trifluoroethyl-1-amine (B76)

[1104] Plan B17

[1105]

[1106] Step 1: 1-(4-chloro-5-methoxypyridin-2-yl)-2,2,2-trifluoroethane-1-ol (B74)

[1107] 4-Chloro-5-methoxypicolinaldehyde (B11, 140 g, 816 mmol), CF3SiMe3 (232 g, 1.63 mol), and K2CO3 (45.1 g, 326 mmol) were combined in DMF (1.00 L) at 15 °C. The reaction mixture was stirred at 15 °C for 12 h. TLC showed complete conversion. The reaction mixture was then dissolved in 1 M HCl aqueous solution (1 L) and stirred at 15 °C for another 15 min. The pH was then adjusted to 7–8 using solid NaHCO3. The reaction mixture was extracted with EtOAc (3 × 500 mL). The combined organic layers were dried (Na2SO4) and concentrated to give 1-(4-chloro-5-methoxypyridin-2-yl)-2,2,2-trifluoroethane-1-ol (B74), which was used directly in the next step without purification. 1H-NMR: (400MHz, CDCl3) δ8.27 (s, 1H), 7.45 (s, 1H), 5.08 (s, 1H), 4.95 (s, 1H), 4.04 (s, 3H)

[1108] Step 2: 1-(4-chloro-5-methoxypyridin-2-yl)-2,2,2-trifluoroethyl-1-one (B75)

[1109] 1-(4-chloro-5-methoxypyridin-2-yl)-2,2,2-trifluoroethane-1-ol (B74, 179 g, 741 mmol) and MnO2 (258 g, 2.96 mol) were combined in dioxane (1.1 L) at 15 °C. The reaction mixture was heated to 100 °C and held for 12 h. LC-MS showed complete conversion. The reaction mixture was filtered through a Celite filter and washed with EtOAc (3 L). The filtrate was concentrated to give 1-(4-chloro-5-methoxypyridin-2-yl)-2,2,2-trifluoroethane-1-one (B75), which was used directly in the next step without purification. 1 H-NMR: (400MHz, CDCl3) δ8.43 (s, 1H), 8.20 (s, 1H), 4.12 (s, 3H)

[1110] Step 3: 1-(4-chloro-5-methoxypyridin-2-yl)-N-ethyl-2,2,2-trifluoroethyl-1-amine (B76)

[1111] 1-(4-chloro-5-methoxypyridin-2-yl)-2,2,2-trifluoroethyl-1-one (B75, 126 g, 526 mmol), EtNH2 (119 g, 2.63 mol, 172 mL, 5.00 eq) and TiCl were added at 15 °C. 4 (200 g, 1.05 mol, 2.00 eq) were combined in DCM (760 mL). The reaction mixture was stirred at 15 °C for 12 h. NaBH3CN (99.2 g, 1.58 mol) was added to the reaction mixture in portions, and the mixture was stirred at 15 °C for another 2 h. TLC showed complete conversion. The reaction mixture was added to MeOH (550 mL) and stirred at 15 °C for 30 min. The pH was then adjusted to 10 with 5 M NaOH aqueous solution. The reaction mixture was then filtered through Celite, washed with DCM (2 L), and concentrated. The crude product was purified by rapid silica gel chromatography (3-100% EtOAc in petroleum ether) to give 1-(4-chloro-5-methoxypyridin-2-yl)-N-ethyl-2,2,2-trifluoroethyl-1-amine (B76).

[1112] 1 H NMR: (400MHz, CDCl3) δ8.29 (s, 1H), 7.44 (s, 1H), 4.18 (q, J=14.4Hz, 1H), 4.03 (s, 3H), 2.61-2.65 (m, 2H), 1.12 (t, J=7.2Hz, 3H)

[1113] Intermediate B80

[1114] 1-(2-chlorothiazo-5-yl)-N-ethylethyl-1-amine (B80)

[1115] Option B18

[1116]

[1117] Step 1: (E)-N-((2-chlorothiazol-5-yl)methylene)-2-methylpropane-2-sulfinamide (B78)

[1118] 2-Chlorothiazol-5-carboxaldehyde (B77, 250 mg, 1.694 mmol), 2-methylpropane-2-sulfinamide (411 mg, 3.39 mmol), and CuSO4 (1190 mg, 7.45 mmol) were combined in DCM (8 mL) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted with DCM and filtered through a Celite pan (washed with DCM). The filtrate was concentrated. The crude product was purified by rapid silica gel chromatography (0–25% EtOAc gradient in heptane) to give (E)-N-((2-chlorothiazol-5-yl)methylene)-2-methylpropane-2-sulfinamide (B78). LC-MS: 250.9 (M+1). 1 H-NMR: (500MHz, CDCl3) δ8.65 (s, 1H), 7.93 (s, 1H), 1.24 (s, 9H).

[1119] Step 2: N-(1-(2-chlorothiazol-5-yl)ethyl)-N-ethyl-2-methylpropane-2-sulfinyl Amine (B79)

[1120] A solution of (E)-N-((2-chlorothiazol-5-yl)methylene)-2-methylpropane-2-sulfinamide (B78, 103 mg, 0.411 mmol) in THF (2 mL) was cooled to 0 °C. MeMgBr (0.21 mL, 0.630 mmol) (3 M, in Et2O) was slowly added to this solution, and the reaction mixture was stirred at 0 °C for hours. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and then heated to room temperature. The resulting mixture was diluted with H2O and then extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated to give N-(1-(2-chlorothiazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide, which was used directly for the next step without purification.

[1121] Crude N-(1-(2-chlorothiazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide (110 mg, 0.411 mmol) was dissolved in THF (2 mL). NaH (32.9 mg, 0.822 mmol) (60% mineral oil) was added to the solution at room temperature. After gas escaping ceased, iodoethane (0.13 mL, 1.609 mmol) was added, and stirring continued overnight at room temperature. The reaction mixture was quenched with saturated NH4Cl aqueous solution, diluted with H2O, and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (0–100% EtOAc gradient in heptane) to give N-(1-(2-chlorothiazol-5-yl)ethyl)-N-ethyl-2-methylpropane-2-sulfinamide (B79). LC-MS: 295.0 (M+1).

[1122] Step 3: 1-(2-chlorothiazo-5-yl)-N-ethylethyl-1-amine (B80)

[1123] N-(1-(2-chlorothiazol-5-yl)ethyl)-N-ethyl-2-methylpropane-2-sulfinamide (B79, 61 mg, 0.207 mmol) was dissolved in HCl (1.5 mL) (4 M, in dioxane), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give 1-(2-chlorothiazol-5-yl)-N-ethylethyl-1-amine (B80), which was used directly in the next step without purification. LC-MS: 191.0 (M+1).

[1124] Intermediate B84

[1125] 1-(5-chlorothiazol-2-yl)-N-ethylethyl-1-amine (B84)

[1126] Plan B19

[1127]

[1128] Step 1: 1-(5-chlorothiazo-2-yl)ethanol-1-ol (B82)

[1129] MeMgBr (0.85 mL, 2.55 mmol) (3 M, in Et2O) was slowly added to a solution of 5-chlorothiazol-2-carboxaldehyde (B81, 250 mg, 1.694 mmol) in THF (8 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched with a saturated aqueous NH4Cl solution, then heated to room temperature, diluted with H2O, and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated to give 1-(5-chlorothiazol-2-yl)ethanol-1-ol (B82), which was used directly in the next step without purification. LC-MS: 163.9 (M+1).

[1130] Step 2: 1-(5-chlorothiazol-2-yl)ethyl-1-one (B83)

[1131] 1-(5-chlorothiazol-2-yl)ethyl-1-ol (B82, 0.277 g, 1.694 mmol) was dissolved in CHCl3 (8 mL), and MnO2 (0.74 g, 8.51 mmol) was added. The reaction mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature, diluted with CHCl3, and filtered through a Celite filter, followed by washing with CHCl3. The filtrate was concentrated to give 1-(5-chlorothiazol-2-yl)ethyl-1-one (B83), which was used directly in the next step without purification.

[1132] Step 3: 1-(5-chlorothiazol-2-yl)-N-ethylethyl-1-amine (B84)

[1133] To a solution of 1-(5-chlorothiazol-2-yl)ethyl-1-one (B83, 218 mg, 1.349 mmol) in EtOH (7 mL) in a microwave-safe vial, 2M ethylamine (3.4 mL, 6.80 mmol), AcOH (0.39 mL, 6.81 mmol), and MgSO4 (325 mg, 2.70 mmol) in THF were added, followed by the addition of NaBH3CN (170 mg, 2.70 mmol). The vial was sealed and heated to 80 °C overnight using conventional heating. The reaction mixture was cooled to room temperature, diluted with EtOH, and filtered through a Celite filter (washed with EtOH). The filtrate was concentrated. The crude product was dissolved in 20 mL of 1:1 DCM:TEA and then concentrated. The crude product was then purified by rapid silica gel chromatography (a gradient of 0–100% EtOAc:EtOH in a 3:1 mixture in heptane) to obtain mixed fractions. The fractions containing the product were combined and then concentrated. The crude product was purified by reversed-phase HPLC (5-50% ACN in water, containing 0.1% TFA as a modifier) ​​to give 1-(5-chlorothiazol-2-yl)-N-ethylethyl-1-amine (B84). LC-MS: 191.0 (M+1). 1 H-NMR: (500MHz, CDCl3) δ7.62 (s, 1H), 4.65 (q, J=6.9Hz, 1H), 3.10 (qt, J=7.4, 3.8Hz, 2H), 1.78 (d, J=6.9Hz, 3H), 1.34 (t, J=7.3Hz, 3H).

[1134] Intermediate B87

[1135] 1-(6-Chloropremine-4-yl)ethyl-1-one (B87)

[1136] Plan B20

[1137]

[1138] Step 1: 4-Chloro-6-(1-ethoxyvinyl)pyrimidine (B86)

[1139] A solution of 4,6-dichloropyrimidine (B85, 10 g, 67.1 mmol) in DMF (100 mL) was mixed with tributyl(1-ethoxyvinyl)stanane (24.24 g, 67.1 mmol) and Pd(Ph3P)4 (7.76 g, 6.71 mmol). The mixture was stirred at 120 °C for 12 h. TLC showed the formation of new spots. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated. The crude product was purified by rapid silica gel chromatography (0–4% EtOAc gradient in petroleum ether) to give 4-chloro-6-(1-ethoxyvinyl)pyrimidine (B86).

[1140] 1 H NMR: (400MHz, CDCl3) δ8.88 (s, 1H), 7.65 (s, 1H), 5.70 (d, J=2.3Hz, 1H), 4.56 (d, J=2.0Hz, 1H), 3.96 (q, J=7.0Hz, 2H), 1.44 (t, J=7.0Hz, 3H).

[1141] Step 2: 1-(6-chloropyrimidin-4-yl)ethyl-1-one (B87)

[1142] A solution of 4-chloro-6-(1-ethoxyvinyl)pyrimidine (B86, 3.5 g, 18.96 mmol) in acetone (40 mL) was added to HCl (56.9 mL, 114 mmol) (2 M, in HCl), and the reaction mixture was stirred at 20 °C for 3 h. TLC showed complete conversion. The reaction mixture was poured into a saturated aqueous solution of NaHCO3 (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated. The filtrate was concentrated and purified by rapid silica gel chromatography (0–3% EtOAc gradient in petroleum ether) to give 1-(6-chloropyrimidin-4-yl)ethyl-1-one (B87). 1 H NMR (400MHz, CDCl3) δ9.18 (d, J=0.8Hz, 1H), 7.92 (d, J=0.8Hz, 1H), 2.72 (s, 3H).

[1143] intermediate B88

[1144] (R)-(2-(1-((tert-butoxycarbonyl)(ethyl)amino)ethyl)-5-fluoropyridin-4-yl)boronic acid (B88)

[1145]

[1146] Dess-Martin high-valent iodide (5.78 g, 13.62 mmol) was added to a solution of (4-chloro-5-fluoropyridin-2-yl)methanol (2 g, 12.38 mmol) in DCM (50 mL) at 0 °C. The mixture was stirred at 0 °C to 20 °C for 3 hours. The mixture was quenched with NaHCO3 (30 mL) and H2O (50 mL) and filtered, then extracted with DCM (50 mL × 3), washed with brine (50 mL), dried on Na2SO4, filtered, and concentrated under reduced pressure. The crude product was subjected to rapid silica gel chromatography (…). 20g 4-Chloro-5-fluoropicolinaldehyde was obtained by purification using a Silica Flash Column (elution buffer: 5% EtOAc / petroleum ether gradient). LCMS m / z (M+H): expected value 160.0, measured value 160.1.

[1147] To a solution of 4-chloro-5-fluoropicolinaldehyde (1.7 g, 10.66 mmol) in DCE (50 mL), MgSO4 (7.69 g, 63.9 mmol), (R)-2-methylpropane-2-sulfinamide (1.550 g, 12.79 mmol), and PPTS (0.268 g, 1.066 mmol) were added. The resulting mixture was stirred at 80 °C for 12 hours under N2 protection. The reaction mixture was concentrated and analyzed by rapid silica gel chromatography (…). 20g (R,E)-N-((4-chloro-5-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide was obtained by purification using a Silica Flash Column (elution buffer: 50% ethyl acetate / petroleum ether gradient). LCMS m / z (M+H): expected value 263.0, measured value 263.0. 1 H NMR 5044576-0127-1 (400MHz, CDCl3) δ8.55 (d, J=15.9Hz, 2H), 8.05 (d, J=6.0Hz, 1H), 1.28-1.16 (m, 9H)

[1148] Add methyl magnesium bromide (9.90 mL, 29.7 mmol) (3 M, in Et₂O) to a solution of (R,E)-N-((4-chloro-5-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (1.95 g, 7.42 mmol) in THF (50 mL). Stir the mixture at 0 °C for 2 hours under N₂ protection. Pour the reaction mixture into NH₄Cl (100 mL), extract with EtOAc (50 mL × 3), dry on Na₂SO₄, and filter. Concentrate the filtrate and analyze by rapid silica gel chromatography (…). 40g Silica Flash Column, eluent: 60% EtOAc / petroleum ether gradient) purification yielded (R)-N-((R)-1-(4-chloro-5-fluoropyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide. LCMS m / z (M+H): expected value 279.1, measured value 279.1.

[1149] NaH (0.488 g, 12.20 mmol) (60 wt%) was added to a solution of (R)-N-((R)-1-(4-chloro-5-fluoropyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (1.7 g, 6.10 mmol) in DMF (50 mL) at 0 °C and N2. The mixture was stirred at 0 °C for 30 min, and iodoethane (0.976 mL, 12.20 mmol) was added and stirred at 0 °C for 2 h. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried on Na2SO4, and filtered. The filtrate was concentrated and analyzed by rapid silica gel chromatography (…). 40g Silica Flash Column, eluent: 60% EtOAc / petroleum ether gradient) purification yielded (R)-N-((R)-1-(4-chloro-5-fluoropyridin-2-yl)ethyl)-N-ethyl-2-methylpropane-2-sulfinamide. LCMS m / z (M+H): expected value 307.1, measured value 307.0.

[1150] An AcCl solution (0.742 mL, 10.43 mmol) of (R)-N-((R)-1-(4-chloro-5-fluoropyridin-2-yl)ethyl)-N-ethyl-2-methylpropane-2-sulfinamide (1.6 g, 5.21 mmol) in MeOH (40 mL) was added at 0 °C. The reaction mixture was stirred at 0 °C to 25 °C for 2 hours. Et3N was added to adjust the pH to 7-8, and the reaction mixture was then concentrated under reduced pressure to give (R)-1-(4-chloro-5-fluoropyridin-2-yl)-N-ethylethyl-1-amine, which was used directly in the next step without purification. LCMS m / z (M+H): Expected value 203.1, Found value 203.0.

[1151] Et3N (2.063 mL, 14.80 mmol) and Boc-anhydride (1.719 mL, 7.40 mmol) were added to a solution of (R)-1-(4-chloro-5-fluoropyridin-2-yl)-N-ethylethyl-1-amine (1 g, 4.93 mmol) in DCM (40 mL) at 0 °C. The reaction mixture was stirred at 0 °C to 25 °C for 14 hours. The mixture was quenched with H2O (100 mL), extracted with DCM (50 mL × 3), washed with brine (30 mL), dried on Na2SO4, filtered, and concentrated under reduced pressure. The filtrate was concentrated and analyzed by rapid silica gel chromatography (…). 20g Purification using Silica Flash Column (elution buffer: 10% ethyl acetate / petroleum ether gradient) yielded tert-butyl(R)-(1-(4-chloro-5-fluoropyridin-2-yl)ethyl)(ethyl)carbamate. LCMS m / z (M+H): expected value 303.1, measured value 303.0.

[1152] A solution of tert-butyl(R)-(1-(4-chloro-5-fluoropyridin-2-yl)ethyl)(ethyl)carbamate (300 mg, 0.991 mmol) in dioxane (5 mL) was added to 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxane)borane (327 mg, 1.288 mmol), potassium acetate (292 mg, 2.97 mmol), and chloro(2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(ii) (78 mg, 0.099 mmol). The resulting mixture was stirred at 80 °C for 12 hours under N2 protection. The crude mixture of (R)-(2-(1-((tert-butoxycarbonyl)(ethyl)amino)ethyl)-5-fluoropyridin-4-yl)boronic acid (B88) in dioxane was used without purification. LCMS m / z (M+H): Expected value 313.2, Found value 313.1.

[1153] Intermediate B89

[1154] (R)-(2-(1-((tert-butoxycarbonyl)(ethyl)amino)ethyl)pyridin-4-yl)boronic acid (B89)

[1155]

[1156] Et3N (6.28 mL, 45.0 mmol) and Boc-anhydride (5.23 mL, 22.52 mmol) were added to a solution of (R)-1-(4-bromopyridin-2-yl)-N-ethylethyl-1-amine B10 (3.44 g, 15.01 mmol) in DCM (50 mL) at 0 °C. The reaction mixture was stirred at 0 °C to 25 °C for 12 hours. The mixture was quenched with H2O (50 mL), extracted with DCM (50 mL × 3), washed with brine (50 mL), dried on Na2SO4, filtered, and concentrated under reduced pressure. The crude product was analyzed by rapid silica gel chromatography (…). 40g Purification using a Silica Flash Column (elution buffer: 6% EtOAc / petroleum ether gradient) yielded tert-butyl(R)-(1-(4-bromopyridin-2-yl)ethyl)(ethyl)carbamate. LCMS m / z (M-100+H): expected value 329.1, measured value 329.0.

[1157] A solution of tert-butyl(R)-(1-(4-bromopyridin-2-yl)ethyl)(ethyl)carbamate (3 g, 9.11 mmol) in dioxane (60 mL) was added to 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxane)borane (3.47 g, 13.67 mmol), potassium acetate (2.68 g, 27.3 mmol), and chloro(2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(ii) (0.358 g, 0.456 mmol). The resulting mixture was stirred at 80 °C for 12 hours under N2 protection. The mixture was filtered and concentrated under reduced pressure to obtain (R)-(2-(1-((tert-butoxycarbonyl)(ethyl)amino)ethyl)pyridin-4-yl)boronic acid B89, which was used without purification. LCMS m / z (M+H): Expected value 295.2, measured value 295.1.

[1158] Intermediate B91

[1159] tert-Butyl(1-(2-bromopyridin-4-yl)ethyl)(ethyl)carbamate (B91)

[1160]

[1161] Under N2 protection, DMAP (0.213 g, 1.746 mmol) was added to a solution of 1-(2-bromopyridin-4-yl)ethyl-1-amine (4 g, 0.00 mmol), TEA (4.87 mL, 34.9 mmol), and BOC anhydride (8.11 mL, 34.9 mmol) in MeCN (100 mL). The resulting mixture was stirred at 25 °C for 10 hours. The reaction mixture was concentrated, quenched with water (10 mL), and extracted with EtOAc (10 mL × 3), washed with brine (10 mL). The organic layer was dried on Na2SO4, filtered, and the filtrate was concentrated. The residue was analyzed by rapid silica gel chromatography (…). 25g Silica Flash Column, eluent: 15% EtOAc / petroleum ether) purification yielded tert-butyl (1-(2-bromopyridin-4-yl)ethyl)carbamate. LRMS m / z (M+H): expected value 329.2, measured value 329.2.

[1162] NaH (2.422 g, 60.6 mmol) was added to a solution of tert-butyl (1-(2-bromopyridin-4-yl)ethyl)carbamate (9.12 g, 30.3 mmol) in DMF (150 mL) at 0 °C, and the mixture was stirred at 0 °C for 30 min under N2. Iodoethane (9.45 g, 60.6 mmol) was then added to the mixture, and the mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (200 mL × 3). The organic layer was washed with brine (100 mL), dried on Na2SO4, and filtered. The filtrate was concentrated and analyzed by rapid silica gel chromatography (…). 120g Purification using a SilicaFlash Column (elution buffer: 15-30% EtOAc / petroleum ether gradient) yielded tert-butyl (1-(2-bromopyridin-4-yl)ethyl)(ethyl)carbamate (B91). LCMS m / z (M+H+2): expected value 331.0, measured value 330.7.

[1163] Intermediate B92

[1164] 2-Chloro-3-fluoro-4-iodo-5-methoxypyridine (B92)

[1165]

[1166] 2.5 M butyllithium (7.22 mL, 18.0 mmol) was added dropwise to a solution of 2-chloro-3-fluoro-5-methoxypyridine (2.65 g, 16.4 mmol) in tetrahydrofuran (50 mL) at -78 °C, and the solution was stirred at -78 °C for 1 hour. Iodine (4.62 g, 18.2 mmol) was added in portions, and the solution was heated to room temperature over 2 hours. The mixture was quenched by slow addition of a saturated aqueous solution of sodium bisulfite (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated to give 2-chloro-3-fluoro-4-iodo-5-methoxypyridine (B92). LC-MS: 288.0 (M+1).

[1167] Intermediate B95

[1168] tert-butyl(1-(4-chloro-5-fluoropyridin-2-yl)ethyl)(ethyl)carbamate

[1169]

[1170] Step 1: 1-(4-chloro-5-fluoropyridin-2-yl)ethyl-1-one

[1171] 1-(4-chloro-5-fluoropyridin-2-yl)ethyl-1-one was prepared using 2-bromo-4-chloro-5-fluoropyridine and tributyl(1-ethoxyvinyl)stannane in a manner similar to C152. LC-MS: 174.0

[1172] Step 2: 1-(4-chloro-5-fluoropyridin-2-yl)-N-ethylethyl-1-amine

[1173] 1-(4-chloro-5-fluoropyridin-2-yl)-N-ethyl-1-amine was prepared using 1-(4-chloro-5-fluoropyridin-2-yl)ethyl-1-one and ethylamine in a manner similar to C153. LC-MS: 203.0

[1174] Step 3: tert-butyl (1-(4-chloro-5-fluoropyridin-2-yl)ethyl)(ethyl)carbamate (B95)

[1175] A solution of 1-(4-chloro-5-fluoropyridin-2-yl)-N-ethylethyl-1-amine (2.20 g, 10.89 mmol) and triethylamine (3.0 mL, 21.78 mmol) in THF (27 mL) was mixed with BOC-anhydride (2.61 g, 11.98 mmol) and stirred at room temperature. Additional BOC-anhydride was added if necessary until the reaction was complete as determined by LC-MS. The mixture was diluted with water and extracted several times with ethyl acetate. The combined organic layers were concentrated. The crude product was purified by rapid silica gel chromatography (0–20% EtOAc in hexane) to give tert-butyl(1-(4-chloro-5-fluoropyridin-2-yl)ethyl)(ethyl)carbamate (B95). LC-MS: 303.1

[1176] 4-Chloro-5-fluoropicolinaldehyde (B96)

[1177]

[1178] A solution of (4-chloro-5-fluoropyridin-2-yl)methanol (B5, 1.00 g, 6.19 mmol) in dichloromethane (20 mL) at room temperature was added fractionally to Dess-Martin high-valent iodide (2.63 g, 6.19 mmol), and the reaction mixture was stirred for 20 min. Saturated sodium thiosulfate and sodium bicarbonate solutions were added, and the mixture was stirred for 10 min. The reaction mixture was extracted several times with DCM, and the combined organic layers were concentrated. The crude product was purified by rapid silica gel chromatography (0–20% EtOAc in hexane) to give 4-chloro-5-fluoropicolinaldehyde (B96). LC-MS: 178.1 (M+1+18).

[1179] Intermediate B98

[1180] tert-butyl (1-(4-chloro-5-fluoropyridin-2-yl)ethyl)(cyclopropyl)carbamate)

[1181]

[1182] Step 1: N-(1-(4-chloro-5-fluoropyridin-2-yl)ethyl)cyclopropylamine

[1183] N-(1-(4-chloro-5-fluoropyridin-2-yl)ethyl-1-one and cyclopropylamine were prepared in a manner similar to C153 using 1-(4-chloro-5-fluoropyridin-2-yl)ethyl-1-one and cyclopropylamine. LC-MS: 215.0

[1184] Step 2: tert-butyl (1-(4-chloro-5-fluoropyridin-2-yl)ethyl)(cyclopropyl)carbamate (B98)

[1185] tert-butyl(1-(4-chloro-5-fluoropyridin-2-yl)ethyl)(cyclopropyl)carbamate (B98) was prepared using N-(1-(4-chloro-5-fluoropyridin-2-yl)ethyl)cyclopropylamine and Boc-anhydride, similar to B95. LC-MS: 315.1

[1186] intermediate C6

[1187] (R)-1-(5-(8-(but-3-en-1-yloxy)-5-methylimidazo[1,2-a]pyrazin-6-yl)-6-methoxy Pyridin-3-yl)-N-ethylethyl-1-amine (C6)

[1188] Option C1

[1189]

[1190] Step 1: 3,5-Dibromo-6-methylpyrazine-2-amine (C2)

[1191] Br2 (1.180 mL, 22.91 mmol) was added dropwise to a solution of 6-methylpyrazine-2-amine (C1, 1 g, 9.16 mmol) and pyridine (1.853 mL, 22.91 mmol) in DCM (20 mL). The reaction mixture was stirred at room temperature for 15 hours. LC-MS showed the formation of the desired product. The reaction mixture was poured into a saturated aqueous solution of NaHCO3 to pH 7 and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated to give 3,5-dibromo-6-methylpyrazine-2-amine (C2), which was used directly for the next step without purification. LC-MS: 268.0 (M+1).

[1192] Step 2: 6,8-Dibromo-5-methylimidazo[1,2-a]pyrazine (C3)

[1193] To a solution of 3,5-dibromo-6-methylpyrazine-2-amine (C2, 4 g, 14.99 mmol) in water (40 mL) and IPA (8 mL), 2-chloroacetaldehyde (5.88 g, 30.0 mmol) was added, and the reaction mixture was stirred at 110 °C for 3 h. LC-MS showed the formation of the desired product. The reaction mixture was poured into water (10 mL) and the pH was adjusted to 8 with Na2CO3. The mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated to give 6,8-dibromo-5-methylimidazo[1,2-a]pyrazine (C3), which was used directly for the next step without purification. LC-MS: 292.1 (M+1). 1 H-NMR (400MHz, CDCl3) δppm 8.31 (dd, J=4.70, 1.57Hz, 1H), 7.93 (dd, J=8.41, 1.37Hz, 1H), 3.06 (s, 3H).

[1194] Step 3: 6-Bromo-8-(but-3-en-1-yloxy)-5-methylimidazo[1,2-a]pyrazine (C4)

[1195] Butyllithium (3.30 mL, 8.25 mmol) (2.5 M, in hexane) was added to a solution of but-3-en-1-ol (0.595 g, 8.25 mmol) in THF (10 mL) at -78 °C, and the reaction mixture was stirred at -78 °C for 30 min. 6,8-Dibromo-5-methylimidazo[1,2-a]pyrazine (C3, 1.5 g, 4.12 mmol) was added to THF (10 mL), and the reaction mixture was stirred at 80 °C for 12 h. LC-MS showed the formation of the desired product. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl (10 mL) and extracted with EtOAc (3 × 10 mL)...

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof: I in: Selected from: ； Y is unsubstituted or selected from 1 to 3 elements of R. 4 The following groups are substituted by the following groups: phenyl, pyridinyl, pyridinyl, pyridofuranyl, oxazolyl, thiazolyl; Z is ; R is independently selected from H or C. 1-6 alkyl; 1)R 1 Selected from: 2) Hydrogen, 3)-CH2OCH2CF3-, 4)-CH2OCH2CHCF2-, 5)C 1-6 Alkyl groups, which are unsubstituted or substituted by one to three independent substituents selected from the following. aC 1-6 alkyl, b. Halogens, c. Hydroxyl group, d. Unsubstituted or substituted with 1 to 3 substituents selected from halogens -OC 1-6 Alkyl, or unsubstituted or halogenated, C 1-6 Alkyl or fluorinated C 1-6 Alkyl-substituted C 3-6 cycloalkyl, eC 3-6 Cycloalkyl groups, which are unsubstituted or have one to three R groups. 4 replace, f. Heteroaryl, unsubstituted or with 1 to 3 R groups 4 replace, g. Heterocyclic group, unsubstituted or surrounded by 1 to 3 R groups 4 replace, h.CN, and iS(O)2R; R 2 Selected from 1) Straight chain or branched chain C 1-10 Alkyl or C 4-8 alkenyl, 2)-(CR2) 1-6 -O-(CR2) 1-6 -; 3)-(CR2) 1-6 -N(R 9 )-(CR2) 1-6 -, where R 9 It is hydrogen or -C 1-6 Alkyl, wherein the -C 1-6 The alkyl group is either unsubstituted or substituted with a halogen. 4)-(CR2) 1-6 C 3-6 Cycloalkyl-(CR2) 1-6 -, where -C 3-6 The cycloalkyl group is unsubstituted or converted to -C. 1-6 Alkyl or halogen substitution, and 5) Unsubstituted or -C 1-6 The following groups, alkyl or halogen-substituted, are piperidinyl, pyrrolyl, oxazolyl, oxadiazolyl, or thiazolyl rings; R 3 Selected from direct key, -S-, -NR-, -OC 1-6 Alkyl-,-SC 1-6 Alkyl- and -S(O)2-C 1-6 alkyl-; R 4 Selected from: (1) Hydrogen, (2) Hydroxyl group, (3) Halogen, (4)-C 1-6 Alkyl groups, which are unsubstituted or substituted with 1 to 6 fluorine atoms, (5)-OC 1-6 Alkyl groups, which are unsubstituted or substituted with 1 to 6 fluorine atoms, and (6)C 3-6 cycloalkyl; R 5 and R 6 Selected independently from: (1) Hydrogen, and (2)-C 1-6 Alkyl group, wherein the alkyl group is unsubstituted or substituted by one to six substituents independently selected from halogens; R 7 Selected from: (1) Hydrogen, (2)-C 1-6 Alkyl groups, wherein the alkyl group is unsubstituted or substituted by 1 to 6 substituents independently selected from halogens, and (3)-C 3-6 cycloalkyl, wherein the -C 3-6 The cycloalkyl group is unsubstituted or converted to -C. 1-6 Alkyl or halogen substitution.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the group: for: 。 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Y is phenyl, pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Z is... and R 1 Selected from hydrogen, -C(O)NR2, CH2OCH2CF3, CH2OCH2CHCF2 and -C 1-6 Alkyl group, wherein the alkyl group is unsubstituted or substituted by one to three substituents independently selected from the following: C 1-6 Alkyl, halogen, hydroxyl, CN, unsubstituted or with 1 to 3 R 4 Replacement C 3-6 Cycloalkyl, unsubstituted or substituted with 1 to 3 substituents selected from halogens -OC 1-6 Alkyl, or unsubstituted or halogenated, C 1-6 Alkyl or fluorinated C 1-6 Alkyl-substituted C 3-6 cycloalkyl; R 2 Selected from 1) Straight chain or branched chain C 1-10 Alkyl or C 4-8 alkenyl, 2)(CR2) 1-6 -O-(CR2) 1-6 -; 3)(CR2) 1-6 -N(R 9 )-(CR2) 1-6 -, where R 9 It is hydrogen or -C 1-6 Alkyl, wherein the -C 1-6 The alkyl group is either unsubstituted or substituted with a halogen. 4)-(CR2) 1-6 C 3-6 Cycloalkyl-(CR2) 1-6 Wherein -C 3-6 The cycloalkyl group is unsubstituted or converted to -C. 1-6 Alkyl or halogen substitution, and 5) Unsubstituted or -C 1-6 The following groups, alkyl or halogen-substituted, are piperidinyl, pyrrolyl, oxazolyl, oxadiazolyl, or thiazolyl rings; and R 3 Selected from direct key, -S-, -NR-, -OC 1-6 Alkyl, -SC 1-6 Alkyl groups and -S(O)2-C 1-6 alkyl.

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from: (1)C 1-6 Alkyl groups, and (2)-OC 1-6 alkyl.

6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 Selected independently from: (1) Hydrogen, and (2)-C 1-6 Alkyl group, wherein the alkyl group is unsubstituted or substituted by one to six substituents independently selected from fluorine.

7. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 7 Selected from: (1) Hydrogen, and (2)-C 1-6 alkyl.

8. A compound selected from: (10R,E)-9-ethyl-10-methyl-3-oxa-7,9-diaza-2(6,8)-imidazo[1,2-a]pyrazin-1(1,3)-benzo-4(1,3)-cyclopentacyclodeca-8-one; (12R)-13-ethyl-12-methyl-12,13,16,17,19,20-hexahydro-6,22-(azaene)-11,7-(methylene)imidazo[1,2-o][1,18,4,6,15]dioxatriazacycloeicosene-14(15H)-one; (12R)-13-ethyl-12-methyl-18-(propyl-2-yl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[1,2-r][1,4,7,9,18]oxatetraazacycloeicosene-14-one; (12R)-13-ethyl-12-methyl-12,13,15,16,17,18,21,22,22a,23-decahydro-14H,20H-6,25-(azaene)-11,7-(methylene)imidazo[1,2-s]pyrrolo[2,1-c][1,4,8,10,19]oxatetraazacyclotetradecene-14-one; (7R)-8-ethyl-7-methyl-18-oxa-8,10,13,21,24,26-hexaazapentacyclo-[17.6.1.1~2,6~.1~13,17~.0~20,24~]octadec-1(25),2(28),3,5,19(26),20,22-heptaen-9-one; (12R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,20,21-octahydro-14H-6,23-(azaene)-11,7-(methylene)imidazo[2,1-f][1,4,7,13,16,18]dioxatetraazacyclotetradecene-14-one; (12R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,20,21-octahydro-14H-6,23-(azaene)-11,7-(methylene)imidazo[2,1-f][1,4,7,13,16,18]dioxatetraazacyclotetradecene-14-one; (12R)-13-ethyl-8-methoxy-12-methyl-12,13,15,16,17,18,20,21-octahydro-14H-6,23-(azaene)-11,7-(methylene)imidazo[2,1-f][1,4,7,13,16,18]dioxatetraazacyclotetradecene-14-one; (12R)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,20,21-hexahydro-19H-6,23-(azaene)-11,7-(methylene)imidazo[1,2-o][1,18,4,6,9,15]dioxatetraazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-8-methoxy-12,16-dimethyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-8-methoxy-12,16-dimethyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (R,E)-4-ethyl-3-methyl-13-oxa-4,6,9-triaza-1(6,8)-imidazo[1,2-a]pyrazin-2(1,3)benzerocyclodeca-5-one; (12R)-13-ethyl-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[1,2-s][1,4,8,10,19]oxatetraazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclic icosenoen-14(15H)-one; (12R)-13-ethyl-12,19,19-trimethyl-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclic eicosene-14-one; (12R)-13-ethyl-12-methyl-12,13,15,16,17,18,20,21-octahydro-14H-6,23-(azaene)-11,7-(methylene)imidazo[2,1-f][1,4,7,16,18]dioxatriazacyclotetradecene-14-one; (12R)-13,18-diethyl-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15,18]oxatetraazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-12,18,21-trimethyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15,18]oxatetraazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-12-methyl-12,13,16,17,20,21-hexahydro-19H-6,23-(azaben)-11,7-(methylene)imidazo[1,2-o][1,18,4,6,15]dioxatriazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-12,16-dimethyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclic icosenoen-14(15H)-one; (12R)-13-ethyl-12-methyl-16-(1,3-thiazolyl-4-yl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-12-methyl-16-(1,3-thiazolyl-4-yl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-12-methyl-16-(1,2-oxazol-3-yl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,20,21-hexahydro-19H-6,23-(azaene)-11,7-(methylene)imidazo[1,2-o][1,18,4,6,9,15]dioxatetraazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,20,21-hexahydro-19H-6,23-(azaene)-11,7-(methylene)imidazo[1,2-o][1,18,4,6,9,15]dioxatetraazacyclotetradecene-14(15H)-one; (R,27E,62Z)-10-ethyl-11-methyl-3-oxa-8,10-diaza-6(4,2)-thiazoza-2(6,8)-imidazo[1,2-a]pyrazin-1(1,3)benzacycloundecanone-9-one; (R,27E,62Z)-10-ethyl-11-methyl-3-oxa-8,10-diaza-6(4,2)-thiazoza-2(6,8)-imidazo[1,2-a]pyrazin-1(1,3)benzacycloundecanone-9-one; (R,27E,54Z)-10-ethyl-11-methyl-3-oxa-8,10-diaza-5(3,5)-oxadiaza-2(6,8)-imidazo[1,2-a]pyrazin-1(1,3)benzacycloundecanone-9-one; (3R,E)-4-ethyl-3,9-dimethyl-8-(trifluoromethyl)-12-oxa-4,6,9-triaza-1(6,8)-imidazo[1,2-a]pyrazin-2(1,3)benzerocyclododecano-5-one; (3R,E)-4-ethyl-3,9-dimethyl-8-(trifluoromethyl)-13-oxa-4,6,9-triaza-1(6,8)-imidazo[1,2-a]pyrazin-2(1,3)benzerocyclodeca-5-one; (3R,7R,E)-4-ethyl-22-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-12-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(3,5-pyridazine-cyclododecano-5-one; (3R,7R,E)-4-ethyl-22-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(3,5)pyridinium ring tridecanone; (12S,16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacycloeicosene-14-one; (12R,16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacycloeicosene-14-one; (12S,16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (17E,3R,7S,9Z)-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-12-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(1,3-benzylcyclododecano-9-en-5-one; (3R,7R,E)-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-12-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(1,3-benzylcyclododecano-5-one; (16S,18Z)-13-ethyl-8-methoxy-12-(trifluoromethyl)-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,20-hexahydro-14H-6,22-(azaene)-11,7-(methylene)[1,2,4]triazolo[5,1-c][1,4,10,13,15]oxatetraazacycloeicosene-14-one; (16R)-13-ethyl-8-methoxy-12-(trifluoromethyl)-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)[1,2,4]triazolo[5,1-c][1,4,10,13,15]oxatetraazacycloeicosene-14-one; (16R)-13-ethyl-8-methoxy-12-(trifluoromethyl)-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)[1,2,4]triazolo[5,1-c][1,4,10,13,15]oxatetraazacycloeicosene-14-one; 13-Ethyl-8-methoxy-12-(trifluoromethyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)[1,2,4]triazolo[5,1-c][1,4,10,13,15]oxatetraazacycloeicosene-14-one; (16R)-13-ethyl-8-methoxy-12,16-bis(trifluoromethyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)[1,2,4]triazolo[5,1-c][1,4,10,13,15]oxatetraazacycloeicosene-14-one; (16R)-13-ethyl-8-methoxy-16-(2,2,2-trifluoroethyl)-12-(trifluoromethyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)[1,2,4]triazolo[5,1-c][1,4,10,13,15]oxatetraazacycloeicosene-14-one; (16R)-13-ethyl-8-methoxy-12,16-bis(trifluoromethyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacycloeicosene-14-one; (16R)-13-ethyl-8-methoxy-12,16-bis(trifluoromethyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacycloeicosene-14-one; (12S,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacycloeicosene-14-one; (12R,18Z)-13-ethyl-12,17-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,20-hexahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclic eicosene-14-one; (12R,18Z)-13-ethyl-12,17-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,20-hexahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclic eicosene-14-one; (12R,18Z)-13-ethyl-12,17-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,20-hexahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclic eicosene-14-one; (12R)-13-ethyl-12,17-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclic eicosene-14-one; (12R)-13-ethyl-12,17-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclic eicosene-14-one; (12R)-13-ethyl-12,17-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclic eicosene-14-one; (12R)-13-ethyl-12,17-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclic eicosene-14-one; (16R)-13-ethyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclic eicosene-14-one; (16R)-13-ethyl-8-methoxy-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclic eicosene-14-one; (16R)-13-ethyl-8-methoxy-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacycloeicosene-14-one; (3R,7R,E)-4-ethyl-22-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-12-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(3,5-pyridazinecyclododecano-5-one; (3R,7R,E)-4-ethyl-22-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(3,5-pyridone-cyclotridefan-5-one; (3R,E)-4-ethyl-3,9-dimethyl-7-(3,3,3-trifluoropropyl)-12-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(1,3-benzylcyclododecano-5-one; (12R)-13-ethyl-12-methyl-12,13,15,16,17,18,19,20-octahydro-14H-6,22-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,13,15]oxatriazacyclic eicosene-14-one; (7R)-8-ethyl-14,14-difluoro-3-methoxy-7-methyl-11-(3,3,3-trifluoropropyl)-17-oxa-5,8,10,20,23,25-hexaazatetracyclo[16.6.1.12,6.019,23]hexacarbon-1(24),2(26),3,5,18(25),19,21-heptaen-9-one; (7R)-8-ethyl-14,14-difluoro-3-methoxy-7-methyl-11-(3,3,3-trifluoropropyl)-17-oxa-5,8,10,20,23,25-hexaazatetracyclo[16.6.1.12,6.019,23]hexacarbon-1(24),2(26),3,5,18(25),19,21-heptaen-9-one; (7R)-8-ethyl-14,14-difluoro-3-methoxy-7-methyl-11-(3,3,3-trifluoropropyl)-17-oxa-5,8,10,20,23,25-hexaazatetracyclo[16.6.1.12,6.019,23]hexacarbon-1(24),2(26),3,5,18(25),19,21-heptaen-9-one; (3R,7R,E)-4-ethyl-23-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyridazine-2(2,6)pyridazine-cyclotridefan-5-one; (16R)-13-ethyl-8-methoxy-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,9,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-13,16-diethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-13,16-diethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-8-methoxy-12-methyl-16-(2-methylpropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetraenocene-14(15H)-one; (12R)-13-ethyl-8-methoxy-12-methyl-16-(2-methylpropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetraenocene-14(15H)-one; (12R)-13-ethyl-8-methoxy-12-methyl-16-propyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-8-methoxy-12-methyl-16-propyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-16-(cyclopropylmethyl)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-16-(cyclopropylmethyl)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-8-methoxy-16-(2-methoxyethyl)-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-8-methoxy-16-(2-methoxyethyl)-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-16-cyclopropyl-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-16-cyclopropyl-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-8-methoxy-16-(methoxymethyl)-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-8-methoxy-16-(methoxymethyl)-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-16-[(2,2-difluorocyclopropyl)methyl]-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19, 20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-16-[(2,2-difluorocyclopropyl)methyl]-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-16-[(2,2-difluorocyclopropyl)methyl]-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-16-[(2,2-difluorocyclopropyl)methyl]-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-8-methoxy-16-(3-methoxypropyl)-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-8-methoxy-16-(3-methoxypropyl)-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-16-(cyclobutylmethyl)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-16-(cyclobutylmethyl)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-16-(ethoxymethyl)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-16-(ethoxymethyl)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-16-tert-butyl-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-16-tert-butyl-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-16-(2-ethylbutyl)-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-16-(2-ethylbutyl)-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-16-(cyclopentylmethyl)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-16-(cyclopentylmethyl)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-8-methoxy-12-methyl-16-{[1-(trifluoromethyl)cyclopropyl]methyl}-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-8-methoxy-12-methyl-16-{[1-(trifluoromethyl)cyclopropyl]methyl}-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-8-methoxy-12-methyl-16-[(tetrahydrofuran-3-yl)methyl]-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-8-methoxy-12-methyl-16-[(tetrahydrofuran-3-yl)methyl]-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-8-methoxy-12-methyl-16-(tetrahydropyran-4-yl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacycloteicosene-14(15H)-one; (12R)-13-ethyl-8-methoxy-12-methyl-16-(tetrahydropyran-4-yl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacycloteicosene-14(15H)-one; (12R)-16-[(3,3-difluorocyclobutyl)methyl]-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-16-[(3,3-difluorocyclobutyl)methyl]-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-16-{[1-(difluoromethyl)cyclopropyl]methyl}-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-16-{[1-(difluoromethyl)cyclopropyl]methyl}-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-16-(3-fluoro-3-methylbutyl)-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetraenocene-14(15H)-one; (12R)-13-ethyl-16-(3-fluoro-3-methylbutyl)-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetraenocene-14(15H)-one; (12R)-13-ethyl-16-(3-fluorobutyl)-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetraenocene-14(15H)-one; (12R)-13-ethyl-16-(3-fluorobutyl)-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetraenocene-14(15H)-one; (12R)-13-ethyl-8-methoxy-12-methyl-16-[2-(trifluoromethoxy)ethyl]-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-8-methoxy-12-methyl-16-[2-(trifluoromethoxy)ethyl]-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (9R,E)-12-ethyl-13-methyl-9-(3,3,3-trifluoropropyl)-3-oxa-10,12-diaza-1(7,5)-furano[3,2-b]pyridazo-2(6,8-imidazo[1,2-a]pyrazine-11-one; (12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(trifluoromethyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R,16R)-13-ethyl-8,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,9,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R,16R)-13-ethyl-8,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (15R)-12-ethyl-7-methoxy-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-10,6-(azaene)-5,22-(methylene)pyrazolo[1,5-c][1,3,9,13,15]oxatetraazacyclotetraenocene-13(14H)-one; (15R)-12-ethyl-7-methoxy-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-10,6-(azaene)-5,22-(methylene)pyrazolo[1,5-c][1,3,9,13,15]oxatetraazacyclotetraenocene-13(14H)-one; (12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20,21,22-decahydro-14H-6,23-(azaene)-11,7-(methylene)imidazo[1,2-l][1,3,6,12]tetraazacyclotetradecene-14-one; (12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)[1,2,4]triazolo[5,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R,16R)-16-(3,3-difluorobutyl)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,9,13,15]oxatetraazacyclotetraenocene-14(15H)-one; (12R,16R)-16-(3,3-difluorobutyl)-13-ethyl-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R)-13-ethyl-8-methoxy-12-methyl-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R,16R)-13-ethyl-8-methoxy-5,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,9,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R,16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,5,13,15]oxatetraazacyclotetradecene-14(15H)-one; (15R)-12-ethyl-7-methoxy-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-5,22-(azaene)-10,6-(methylene)pyrazolo[1,5-c][1,3,10,13,15]oxatetraazacyclotetraenocene-13(14H)-one; (15R)-12-ethyl-7-methoxy-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-5,22-(azaene)-10,6-(methylene)pyrazolo[1,5-c][1,3,10,13,15]oxatetraazacyclotetraenocene-13(14H)-one; (12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(methylene)imidazo[2,1-c][1,4,5,9,13,15]oxapentazone-14(15H)-one; (16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(azaben)imidazo[2,1-c][1,4,13,15]oxatriazacyclotetradecene-14(15H)-one; (12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(methylene)imidazo[2,1-c][1,4,9,13,15]oxatetraazacyclotetradecene-14(15H)-one; (16R)-13-ethyl-10,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,8,13,15]oxatetraazacyclotetradecene-14(15H)-one; (16R)-13-ethyl-10,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,8,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12S,16R)-13-ethyl-8,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(azaene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R,16R)-13-ethyl-8,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(azaene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (15R)-12-ethyl-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-6,22-(azaene)-7,10-cyclothionidazo[2,1-c][1,4,8,12,14]oxatetraazacycloeicosene-13(14H)-one; (15R)-12-ethyl-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-6,22-(azaene)-7,10-cyclothionidazo[2,1-c][1,4,8,12,14]oxatetraazacycloeicosene-13(14H)-one; (15R)-12-ethyl-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-6,22-(azaene)-7,10-cyclothionidazo[2,1-c][1,4,9,12,14]oxatetraazacycloeicosene-13(14H)-one; (16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(methylene)imidazo[2,1-c][1,4,8,10,13,15]oxapentazone-14(15H)-one; (16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(methylene)imidazo[2,1-c][1,4,8,10,13,15]oxapentazone-14(15H)-one; (12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(azaben)imidazo[2,1-c][1,4,13,15]oxatriazacyclotetradecene-14(15H)-one; (11R,15R)-12-ethyl-7-methoxy-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-5,22-(azaene)-10,6-(methylene)pyrazolo[1,5-c][1,3,5,10,13,15]oxapentazone-13(14H)-one; (12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(2,2,2-trifluoroethyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,5,9,13,15]oxapentazone-14(15H)-one; (11R,15R)-12-ethyl-7-methoxy-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-5,22:10,6-di(methylene)pyrazolo[1,5-c][1,3,5,10,13,15]oxapentazone-13(14H)-one; (12R,16R)-13-ethyl-12-methyl-16-(2,2,2-trifluoroethyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,5,10,13,15]oxapentazone-14(15H)-one; (12R,16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,5,10,13,15]oxapentazone-14(15H)-one; (12R,16R)-13-ethyl-12-methyl-16-(2,2,2-trifluoroethyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (15R)-12-ethyl-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-6,22-(azaene)-7,10-epoxyimidazo[2,1-c][1,4,8,12,14]oxatetraazacycloeicosene-13(14H)-one; (15R)-12-ethyl-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-6,22-(azaene)-7,10-epoxyimidazo[2,1-c][1,4,8,12,14]oxatetraazacycloeicosene-13(14H)-one; (15R)-12-ethyl-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-6,22:10,7-di(azaben)imidazo[2,1-c][1,8,4,12,14]dioxatriazacycloeicosene-13(14H)-one; (15R)-12-ethyl-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-6,22:10,7-di(azaben)imidazo[2,1-c][1,8,4,12,14]dioxatriazacycloeicosene-13(14H)-one; (12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,15,16,17,18,19,20,21,22-decahydro-14H-11,7-(azaene)-6,23-(methylene)imidazo[1,2-l][1,3,12]triazacyclic icosenoen-14-one; (12S,16R)-13-ethyl-9,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R,16R)-13-ethyl-9,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (15R)-12-ethyl-11-methyl-15-(3,3,3-trifluoropropyl)-11,12,15,16,17,18,19,20-octahydro-6,22-(azaene)-7,10-epoxyimidazo[2,1-c][1,4,9,12,14]oxatetraazacycloeicosene-13(14H)-one; (3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-14-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridazine-14-adenosine-5-one; (3R,7R,E)-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridone-decaproic acid-5-one; (3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone; (12R,16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,8,10,13,15]oxapentazone-14(15H)-one; (16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,8,10,13,15]oxapentazone-14(15H)-one; (12S,16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,8,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R,16R)-13-ethyl-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,8,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(2,2,2-trifluoroethyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R,16S)-13-ethyl-8-methoxy-12-methyl-16-(trifluoromethyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,9,10,13,15]oxapentazone-14(15H)-one; (12S,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(azaene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R,16R)-13-ethyl-8-methoxy-12-methyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23:11,7-di(azaben)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12S,16R)-13-ethyl-9,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,8,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12R,16R)-13-ethyl-9,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,8,13,15]oxatetraazacyclotetradecene-14(15H)-one; (12S,16R)-13-ethyl-9,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,8,10,13,15]oxapentazone-14(15H)-one; (12R,16R)-13-ethyl-9,12-dimethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,8,10,13,15]oxapentazone-14(15H)-one; (16R)-13-ethyl-16-(3,3,3-trifluoropropyl)-12,13,16,17,18,19,20,21-octahydro-6,23-(azaene)-11,7-(methylene)imidazo[2,1-c][1,4,10,13,15]oxatetraazacyclotetradecene-14(15H)-one; (3R,E)-7-(2,2-difluorobutyl)-4-ethyl-25,3-dimethyl-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridone-decaproic acid-5-one; (R,E)-7-(3,3-difluorobutyl)-4-ethyl-22-methoxy-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(3,5)pyridone-2-triazin-5-one; (3R,7R,E)-4-ethyl-7-(fluoromethyl)-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone; (3R,7S,E)-7-(3,3-difluoropropyl)-4-ethyl-25-fluoro-3-methyl-10,13-dioxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(4,2)pyridone-2-pyridone-5-one; (3R,7R,E)-25-chloro-7-(3,3-difluoropropyl)-4-ethyl-3-methyl-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone; (3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-25,3-dimethyl-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridone-decaproic acid-5-one; (3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-((R)-3,3,3-trifluoro-2-hydroxypropyl)-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone; (3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-((S)-3,3,3-trifluoro-2-hydroxypropyl)-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone; (3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-((R)-3,3,3-trifluoro-1-hydroxypropyl)-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone; (3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-((S)-3,3,3-trifluoro-1-hydroxypropyl)-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone; (3R,7S,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-10-thia-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone; (3R,7S,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-10-thia-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone 10,10-dioxide; (3R,7S,E)-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridone-decaproic acid-5-one; (3R,7R,E)-4-ethyl-10-hydroxy-22,3-dimethyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(3,5)pyridinium ring tridecanone; (3R,7R,Z)-4-ethyl-23-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-4,6-diaza-1(6,8)-imidazo[1,2-a]pyridazine-2(2,6-pyridazine-cyclododecano-5-one; (3R,7R,E)-4-ethyl-23-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(2,6)pyrazin-cyclotridefan-5-one; (3R,7R,E)-4-ethyl-26-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(5,7)-pyrazolo[1,5-a]pyridazine-2(5,3)-pyridazine heterocyclic tridecanone; (3R,7S,E)-4-ethyl-8,8-difluoro-25-methoxy-3,7-dimethyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone; (3R,7R,E)-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone; (R,E)-4-ethyl-3,3-dimethyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone; (3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-12-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone; (3R,E)-4-ethyl-25-methoxy-3-methyl-12-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridazin-7(1,2)-cyclopropanecyclododecano-5-one; (3R,7R,E)-7-(3,3-difluorobutyl)-4-ethyl-22,3-dimethyl-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(3,5)pyridone-1,3-dicyclodeca-5-one; (3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyrimidine heterocyclic tridecanone; (3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-22-methoxy-3-methyl-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(3,5)pyridinium ring tridecanone; (3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-b]pyridazinza-2(4,2)-pyridinium ring tridecanone; (3R,7S,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyridaz-2(4,2)pyridazine-1-tetrazan-5-one; (3R,7R,E)-7-(2,2-difluoropropyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone; (3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-(3-methylpyrazin-2-yl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone; (3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-25,3-dimethyl-9,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridone-decaproic acid-5-one; (3R,7R,E)-4-ethyl-25-methoxy-3-methyl-7-(2-(methanesulfonyl)ethyl)-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone; (3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-25-methoxy-3-methyl-10,13-dioxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(4,2)pyridone-2-pyridone-5-one; (3R,7R,E)-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(5,7)-pyrazolo[1,5-a]pyridazine-2(4,2)pyridazine-13-adenosine-5-one; (3R,7R)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-quinolina-2(4,2)-pyridinium ring tridecanone; (3R,7R,E)-3,4-dimethyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone; (3R,7R,E)-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(5,3-pyridazin-hexacyclic tridecanone; (3R,7R,E)-7-(3,3-difluorobutyl)-4-ethyl-15,3-dimethyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(2,4)pyridinium ring tridecanone; (3R,7S,E)-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-10,13-dioxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(2,4-pyridinium ring tridecanone; (3R,7R)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-naphthidia-2(4,2)-pyridazine-13-adenosine-5-one; (3R,7S,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-naphthia-2(4,2)-pyridylidene-13-adenosine-9-en-5-one; (3R,7S,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone; (3R,7S,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-10,13-dioxa-4,6-diaza-1(5,7)-pyrazolo[1,5-c]pyrimidinazole-2(4,2)pyridone-decaproic acid-5-one; (3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-25-methoxy-3-methyl-10,13-dioxa-4,6-diaza-1(5,7)-pyrazolo[1,5-c]pyrimidinazole-2(4,2)pyridone-decaproic acid-5-one; (3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-25-methoxy-3-methyl-9,13-dioxa-4,6-diaza-1(5,7)-pyrazolo[1,5-c]pyrimidinazole-2(4,2)pyridone-decaproic acid-5-one; (3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-25-methoxy-3-methyl-9,13-dioxa-4,6-diaza-1(5,7)-pyrazolo[1,5-c]pyrimidinazole-2(4,2)pyridone-decaproic acid-5-one; (3R,7R,E)-7-(3,3-difluorobutyl)-4-ethyl-25-methoxy-15,3-dimethyl-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone; (3R,7S,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-9,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[4,3-a]pyrazin-2(4,2)pyridinium ring tridecanone; (3R,7S,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-9,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone; (3R,7S,E)-4-ethyl-23-fluoro-3-methyl-7-(3,3,3-trifluoropropyl)-9,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone; (3R,7R,E)-7-(3,3-difluorobutyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(7,5)-[1,2,4]triazolo[1,5-c]pyrimidinazole-2(4,2)-pyridazine-1-tetrazon-5-one; (R,E)-4-ethyl-25-methoxy-3-methyl-14-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridazine-1,4-diazon-5-one; (R,E)-4-ethyl-25-methoxy-3-methyl-11-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridazine-1 / undecano-5-one; (7S,E)-4-ethyl-23-fluoro-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium ring tridecanone; (3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-3-methyl-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridone-decaproic acid-5-one; (3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-3-methyl-10,13-dioxa-4,6-diaza-1(5,7)-pyrazolo[1,5-c]pyrimidinazole-2(4,2)pyridone-decaproic acid-5-one; (3R,E)-7-(2-(difluoromethoxy)ethyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone; (3R,E)-4-ethyl-7-((1-fluorocyclopropyl)methyl)-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone; (3R,E)-7-(4,4-difluorobutyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone; (3R,E)-4-ethyl-7-(isopropoxymethyl)-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone; (3R,E)-7-(2,2-difluoroethyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone; (3R,E)-4-ethyl-25-methoxy-3-methyl-7-(2,2,3,3-tetrafluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone; (3R,E)-4-ethyl-25-methoxy-3-methyl-7-((2,2,2-trifluoroethoxy)methyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone; (3R,E)-4-ethyl-25-methoxy-3-methyl-7-(tetrahydrofuran-3-yl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone; (3R,E)-7-((2,2-difluoroethoxy)methyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone; (3R,E)-4-ethyl-25-methoxy-7-(1-methoxyethyl)-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone; (3R,E)-7-(2,2-difluorocyclopropyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)pyridinium ring tridecanone; (3R,E)-4-ethyl-25-methoxy-3-methyl-7-(tetrahydrofuran-2-yl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)pyridinium ring tridecanone; 2-((3R,E)-4-ethyl-25-methoxy-3-methyl-5-oxo-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridonecyclodeca-7-yl)acetonitrile; (3R,E)-7-(3,3-difluorocyclobutyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone; 3-((3R,E)-4-ethyl-25-methoxy-3-methyl-5-oxo-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium trideca-7-yl)propionitrile; (3R,E)-25-cyclopropyl-7-(3,3-difluoropropyl)-4-ethyl-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridazine-1,3-dicyclodeca-5-one; (3R,E)-25-chloro-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone; (3R,E)-4-ethyl-25-fluoro-7-(methoxymethyl)-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone; (3R,E)-7-(3,3-difluorobutyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(4,2)pyridone-2-pyridone-5-one; (3R,E)-7-(3,3-difluoropropyl)-4-ethyl-25,3-dimethyl-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridone-13-adenosine-5-one; (3R,E)-7-(3,3-difluoropropyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(4,2)pyridone-2-pyridone-5-one; (3R,E)-7-(bicyclo[1.1.1]pent-1-ylmethyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(4,2)-pyridone-decaproic acid-5-one; (3R,E)-7-(3,3-difluoropropyl)-4-ethyl-25-fluoro-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-b]pyridazinza-2(4,2)-pyridinium ring tridecanone; (3R,E)-4-cyclopropyl-7-(3,3-difluoropropyl)-25-fluoro-3-methyl-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(4,2)pyridazine-13-adenosine-5-one; (3R,E)-4-ethyl-25-methoxy-3-methyl-7-((1-methylcyclopropyl)methyl)-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(4,2)pyridone-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(4,2)-pyridone-13-adenosine-5-one; (3R,E)-7-(2,2-difluoropropyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(4,2)pyridone-2-pyridone-5-one; (3S,E)-7-(3,3-difluoropropyl)-4-ethyl-25-methoxy-3-(trifluoromethyl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone; (9 R ,13 R , E )-14-Cyclopropyl-12-ethyl-13-methyl-9-(3,3,3-trifluoropropyl)-3-oxa-10,12-diaza-1(5,2)-thiazoza-2(6,8)-imidazo[1,2- a ]Pyrazine heterocyclic tridecafen-11-one; (16 E ,twenty two E 7 R )-25-Cyclopropyl-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-21 H -13-oxa-4,6-diaza-1(5,7)-pyrazolo[1,5- a ]Pyridazon-2(1,3)-pyrazolocyclic tridecaneno-5-one; (9 R ,13 R , E )-14-cyclopropyl-12-ethyl-13-methyl-9-(3,3,3-trifluoropropyl)-3-oxa-10,12-diaza-1(5,2)-oxazola-2(6,8)-imidazo[1,2- a ]Pyrazine heterocyclic tridecafen-11-one; (3R,E)-4-ethyl-2 5 -Methoxy-3-methyl-7 4 -(trifluoromethyl)-11-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridazin-7(3,1)-pyrrolidone-1,1,2-a-cycloundecan-5-one; (3R,E)-4-ethyl-7 4 7 4 -Difluoro-3-methyl-11-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-7(3,1)-pyrrolidone-2(1,3)benzacycloundecanone-5-one; (3R,E)-4-ethyl-25-methoxy-3-methyl-7 4 -(trifluoromethyl)-12-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridazin-7(3,1)-pyrrolidone-1,2-a-cyclododecano-5-one; (3R,E)-4-ethyl-2 2 -Methoxy-3-methyl-7-(2-methylthiazo-4-yl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(3,5)pyridone-decaproic acid-5-one; (3R,E)-4-ethyl-2 5 -Methoxy-3-methyl-7-(2-methylthiazo-5-yl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)pyridinium ring tridecanone; (3R,E)-4-ethyl-2 5 -Methoxy-3-methyl-7-(1-methyl-1H-tetrazol-5-yl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)pyridinium ring tridecanone; (3R,E)-4-ethyl-2 5 -Methoxy-3-methyl-7-(4-methylthiazo-2-yl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)pyridinium ring tridecanone; (3R,E)-4-ethyl-2 5 -Methoxy-3-methyl-7-(1-methyl-1H-1,2,4-triazol-5-yl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)pyridinium ring tridecanone; (1 7 E,3R,8E)-4-ethyl-11,11-difluoro-2 5 -Methoxy-3,7-dimethyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium-hexacyclic tridecane-8-en-5-one; (3R,7S,E)-4-ethyl-11,11-difluoro-2 5 -Methoxy-3,7-dimethyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinium ring tridecanone; (3'R,7'S,7'E,8'E)-4'-ethyl-5'-methoxy-3',7'-dimethyl-2,3,5,6-tetrahydrospiro[pyran-4,11'-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2-pyridinium tridecaneno]-8'-en-5'-one; (3'R,7'S,E)-4'-ethyl-5'-methoxy-3',7'-dimethyl-2,3,5,6-tetrahydrospiro[pyran-4,11'-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2-pyridinium tridecanone]-5'-one; (3R,E)-4-ethyl-2 5 -Methoxy-3-methyl-5-oxo-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazinaza-2(4,2)-pyridinium heterocyclic tridecanenoic acid-7-carboxynitrile; and (3R,E)-4-ethyl-2 5 -Fluoro-3-methyl-5-oxo-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)-pyridinehexacyclic tridecanedio-7-carboxamide; Or its pharmaceutically acceptable salt.

9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from: (3R,7R,E)-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium heterocyclic tridecanone-5-one ; (3R,7S,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium heterocyclic tridecanone ; (3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-25-methoxy-3-methyl-10,13-dioxa-4,6-diaza-1(5,7)-pyrazolo[1,5-c]pyrimidinazole-2(4,2)pyridinazole-1,3-decaproic acid-5-one ; (3R,7S,E)-4-ethyl-23-fluoro-3-methyl-7-(3,3,3-trifluoropropyl)-9,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium heterocyclic tridecanone-5-one ; (3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-3-methyl-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium heterocyclic tridecanone-5-one ; (3R,E)-7-(2,2-difluorocyclopropyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2-pyridinium heterocyclic tridecanone-5-one ; (3R,E)-7-(3,3-difluorobutyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(4,2-pyridinium heterocyclic tridecafen-5-one ; (3R,E)-7-(3,3-difluoropropyl)-4-ethyl-25-fluoro-3-methyl-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-b]pyridazinazin-2(4,2)-pyridinium heterocyclic tridecanone-5-one ; (3R,E)-4-cyclopropyl-7-(3,3-difluoropropyl)-25-fluoro-3-methyl-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(4,2-pyridinium heterocyclic tridecafen-5-one ; and (3R,E)-4-ethyl-2 5 -Methoxy-3-methyl-7-(1-methyl-1H-tetrazol-5-yl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2)pyridinium heterocyclic tridecanone 。 10. The compound according to claim 9, or a pharmaceutically acceptable salt thereof: (3R,7R,E)-4-ethyl-3-methyl-7-(3,3,3-trifluoropropyl)-13-oxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium heterocyclic tridecanone-5-one 。 11. The compound according to claim 9, or a pharmaceutically acceptable salt thereof: (3R,7S,E)-4-ethyl-25-methoxy-3-methyl-7-(3,3,3-trifluoropropyl)-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium heterocyclic tridecanone 。 12. The compound according to claim 9, or a pharmaceutically acceptable salt thereof: (3R,7S,E)-4-ethyl-23-fluoro-3-methyl-7-(3,3,3-trifluoropropyl)-9,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium heterocyclic tridecanone-5-one 。 13. The compound according to claim 9, or a pharmaceutically acceptable salt thereof: (3R,7S,E)-7-(3,3-difluorobutyl)-4-ethyl-3-methyl-10,13-dioxa-4,6-diaza-1(6,8)-[1,2,4]triazolo[1,5-a]pyrazin-2(4,2)pyridinium heterocyclic tridecanone-5-one 。 14. The compound according to claim 9, or a pharmaceutically acceptable salt thereof: (3R,E)-7-(3,3-difluorobutyl)-4-ethyl-25-methoxy-3-methyl-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(4,2-pyridinium heterocyclic tridecafen-5-one 。 15. The compound according to claim 9, or a pharmaceutically acceptable salt thereof: (3R,E)-4-cyclopropyl-7-(3,3-difluoropropyl)-25-fluoro-3-methyl-13-oxa-4,6-diaza-1(2,4)-imidazo[2,1-f][1,2,4]triazinza-2(4,2-pyridinium heterocyclic tridecafen-5-one 。 16. The compound according to claim 9, or a pharmaceutically acceptable salt thereof: (3R,E)-4-ethyl-25-methoxy-3-methyl-7-(1-methyl-1H-tetrazol-5-yl)-13-oxa-4,6-diaza-1(6,8)-imidazo[1,2-a]pyrazin-2(4,2-pyridinium heterocyclic tridecanone-5-one 。 17. A pharmaceutical composition comprising an inert carrier and a compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-16.

18. Use of the compound of any one of claims 1-16 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing sleep disorders.

19. Use of any compound of claims 1-16 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating narcolepsy in mammalian individuals.

20. Use of any compound of claims 1-16 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating drowsiness in mammalian individuals.

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