Fused tricyclic heterocycles having activity against HIV infection

Abstract

The present disclosure relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof. The present disclosure also relates to pharmaceutical compositions comprising such compounds and methods of using such compounds in prevention and treatment of HIV infection in a human.

Description

[0001] 70504W001

[0002] FUSED TRICYCLIC HETEROCYCLES HAVING ACTIVITY AGAINST HIV INFECTION BACKGROUND OF THE INVENTION

[0003] Human immunodeficiency virus type 1 (HIV-1) infection leads to the contraction of acquired immune deficiency disease (AIDS). According to the Joint United Nations Programme on HIV / AIDS (UNAIDS), the number of cases of HIV continues to rise, and an estimated over thirty-nine million individuals worldwide suffer from HIV infection at the end of 2023.

[0004] Presently, long-term suppression of viral replication with antiretroviral drugs is the only option for treating HIV-1 infection. Almost all HIV positive patients are treated with therapeutic regimens of antiretroviral drug combinations termed, highly active antiretroviral therapy (" HAART"). The therapeutic medication period is quite long because people living with HIV have an average life expectancy closer to that of healthy people. These therapies must be administered often (daily) and regimented to prevent the emergence of drug resistant HIV-1 variants.

[0005] Another way to potentially address preventing formation of mutations is to increase patient adherence to a drug regimen. One manner that may be employed to accomplish this is by reducing the dosing frequency. For parenteral administration, it is believed to be advantageous to have drug substances with high lipophilicity or crystallinity in order to reduce solubility and limit the release rate within interstitial fluid. The development of therapeutic drugs with longer dosing intervals (e.g., Long-acting injections in which treatments can be dosed every 1, 2, 3, 6, or 12 months) is desired to reduce medication fatigue and improve patient quality of life.

[0006] SUMMARY OF THE INVENTION

[0007] In a first aspect, the present invention provides a compound of Formula (!) or a pharmaceutically acceptable salt thereof:

[0008]

[0009] wherein

[0010] ring A is a substituted or unsubstituted 3- to 10-membered heterocycloalkyl; 70504W001

[0011] ring C is a benzene ring, a pyridine ring, or a 5-membered heteroaryl;

[0012] L is a bond, -C(O)-, -C(O)R5-, -CH2-O-C(O)-, or -CH2-O-C(O)R5-;

[0013] Y is selected from the group consisting of (Ci.24)alkyl, (C2.24)alkenyl, (Ci-io)alkoxy, 5- to 10- membered heteroaryl, (C1-8)alkylene-R8, (C2.s)alkenylene-R8, (C3-i4)cycloalkyl, (Ce-ujaryl, (C6- i4)bicycloalkyl, bridged (C8-14)tricycloalkyl, and 3- to 10-membered heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, wherein (Cs-ujcycloalkyl, (Ce-ujaryl, (Cs-ujbicycloalkyl, bridged (Cs-i4)tricycloalkyl or the 3- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -O-C(O)-(Ci. sjalkyl, (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -C(O)R7, oxo, and halogen;

[0014] or

[0015] Y is (Y-2),

[0016] ZR11

[0017] a — R1°

[0018] *

[0019]

[0020] * R12(Y-2);

[0021] or

[0022] Y is (Y-3)

[0023] , H2CH3

[0024] C R13

[0025] CH3 (Y-3);

[0026] R1is independently selected from the group consisting of halogen, alkyl, haloalkyl, alkyloxy, cyano, and haloalkoxy;

[0027] R2aand R2bare each independently hydrogen, alkyl, or haloalkyl; or

[0028] R2aand R2b, together with the carbon atom to which they are both adjacent, form a 3- to 8- membered cycloalkyl, a 6- to 10-membered bicycloalkyl, or a 3- to 10-membered heterocycloalkyl;

[0029] R3is substituted or unsubstituted alkyl, substituted or unsubstituted 3- to 8-membered cycloalkyl, substituted or unsubstituted 6- to 10-membered bicycloalkyl, or substituted or unsubstituted 3- to 10-membered heterocycloalkyl;

[0030] R4is hydrogen, or substituted or unsubstituted alkyl; or

[0031] R3and R4, or R3and a substituent on ring A may be taken together with the adjacent atoms to form a substituted or unsubstituted heterocycloalkyl;

[0032] R5is -O- or -NR6-;

[0033] R6is hydrogen or (Ci-sjalkyl;

[0034] R7is (Ci-io)alkyl, (Ci-io)alkoxy, or -NH-(Ci-io)alkyl; 70504W001

[0035] R8is selected from the group consisting of (Ci.24)alkoxy, (C2-24)alkenyloxy, -NH-C(O)-(Ci-i4)alkyl, - C(O)-(C! -24)alkoxy, -O-(CH2CH2O)n-(Ci-i4)alkyl, (Cs-wjcycloalkyl, (Cs ujbicycloalkyl, bridged (Cs- ujtricycloalkyl, (Cs-ujaryl, 3- to 10-membered heterocycloalkyl, -O-(Ci-8)alkylene-(C6-i4)aryl, and -OP(O)(OR9)2, wherein (C3-i4)cycloalkyl, (Ce-ujbicycloalkyl, bridged (Cs-ultricycloalkyl, (C6- i4)aryl, 3- to 10-membered heterocycloalkyl, or -O-(Ci-8)alkylene-(C6-i4)aryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -0-C(0)-(Ci-io)alkyl, (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -C(0)-(Ci-io)alkoxy, -C(O)- NH-(Ci-io)alkyl, oxo, and halogen;

[0036] R9is independently selected from hydrogen and (C1-8)alkyl;

[0037] R10is -CH- or -N-;

[0038] R11and R12are independently selected from the group consisting of (Ci-io)alkyl, -C(0)-0-(Ci-io)alkyl, (Ci-6)alkylene-(C6-i4)aryl, -C(0)-NH-(Ci-io)alkyl, (Ci-s)alkylene-S-(Ci-6)alkyl, -O-C(O)-(Ci- io)alkoxy, -O-C(O)-(Ci-8)alkyl, (Ci-8)alkylene-C(0)-(Ci-io)alkoxy, (Ci-8)alkylene-C(O)-NH-(Ci. io)alkyl, -NH-(Ci-io)alkyl, (Ci-8)alkylene-C(O)OH, and -C(O)OH, wherein (Ci-6)alkylene-(C6-i4)aryl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of (Ci-sjalkyl and halogen;

[0039] R13is (C6-i4)aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of:

[0040] (Ci-io)alkyl,

[0041] -0-C(0)-(Ci-io)alkyl,

[0042] -(Ci.6)alkylene-O-C(O)-(Ci-8)alkyl,

[0043] -O-C(O)-(C6-i4)aryl optionally substituted by (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -0-(Ci-6)alkylene-(C6-io)aryl optionally substituted by -0-C(0)-(Ci-io)alkyl, -O-C(O)-(C3-i4)cycloalkyl, and

[0044] -OP(O)(OR9)2;

[0045] m is an integer selected from 1-3; and

[0046] n is an integer selected from 1-10.

[0047] In a second aspect, the present invention provides a compound selected from the group consisting of Formulae (l-a), (l-b), (l-c), (l-d), (l-e), and (l-f, 70504W001

[0048]

[0049] or a pharmaceutically acceptable salt thereof,

[0050] wherein:

[0051] L is a bond, -C(O)-, -C(O)R5-, -CH2-O-C(O)-, or -CH2-O-C(O)R5-;

[0052] Y is selected from the group consisting of (Ci.24)alkyl, (C2.24)alkenyl, (Ci-io)alkoxy, 5- to 10- membered heteroaryl, (C1-8)alkylene-R8, (C2.s)alkenylene-R8, (C3.i4)cycloalkyl, bridged (C8- i4)tricycloalky I, (Ce-ujaryl, (C6-i4)bicycloalkyl, and 3- to 10-membered heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, wherein (C3.i4)cycloalkyl, bridged (C8-14)tricycloalkyl, (Ce-ujaryl, (Ce-ujbicycloalkyl, or the 3- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -O-C(O)-(Ci. sjalkyl, (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -C(O)R7, oxo, and halogen;

[0053] or

[0054] Y is (Y-2),

[0055]

[0056] R12(Y-2); 70504W001

[0057] or

[0058] Y is (Y-3)

[0059] H2CH3

[0060] §-C R13

[0061]

[0062] CH3 (Y-3);

[0063] R5is -O- or -NR6-;

[0064] R6is hydrogen or (Ci-6)alkyl;

[0065] R7is (Ci-io)alkyl, (Ci-io)alkoxy, or -NH-(Ci-io)alkyl;

[0066] R8is selected from the group consisting of (Ci.24)alkoxy, (C2-24)alkenyloxy, -NH-C(O)-(Ci-i4)alkyl, - C(O)-(C! -24)alkoxy, -O-(CH2CH2O)n-(C1-14)alkyl, (C3-14)cycloalkyl, (C6-14)bicycloalkyl, bridged (C8-14)tricycloalkyl, (C6-14)aryl, 3- to 10-membered heterocycloalkyl, -O-(Ci.8)alkylene-(C6-i4)aryl, and -OP(O)(OR9)2, wherein (C3-i4)cycloalkyl, (Ce-ujbicycloalkyl, bridged (Cs-ultricycloalkyl, (C6- i4)aryl, 3- to 10-membered heterocycloalkyl, or -O-(Ci-8)alkylene-(C6-i4)aryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -0-C(0)-(Ci-io)alkyl, (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -C(0)-(Ci-io)alkoxy, -C(O)- NH-(Ci-io)alkyl, oxo, and halogen;

[0067] R9is independently selected from hydrogen and (C1-8)alkyl;

[0068] R10is -CH- or -N-;

[0069] R11and R12are independently selected from the group consisting of (Ci-io)alkyl, -C(0)-0-(Ci-io)alkyl, (Ci-6)alkylene-(C6-i4)aryl, -C(0)-NH-(Ci-io)alkyl, (Ci-8)alkylene-S-(Ci.6)alkyl, -O-C(O)-(Ci. io)alkoxy, -O-C(O)-(Ci-8)alkyl, (Ci-8)alkylene-C(0)-(Ci-io)alkoxy, (Ci-8)alkylene-C(O)-NH-(Ci. io)alkyl, -NH-(Ci-io)alkyl, (Ci-8)alkylene-C(O)OH, and -C(O)OH, wherein (Ci-6)alkylene-(C6-i4)aryl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of (Ci.6)alkyl and halogen;

[0070] R13is (C6-i4)aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of:

[0071] (Ci-io)alkyl

[0072] -0-C(0)-(Ci.io)alkyl,

[0073] (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl,

[0074] -O-C(O)-(C6-i4)aryl optionally substituted by (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -0-(Ci-6)alkylene-(C6-io)aryl optionally substituted by -0-C(0)-(Ci-io)alkyl, -O-C(O)-(C3-i4)cycloalkyl, and

[0075] -OP(O)(OR9)2; and

[0076] n is an integer selected from 1-10. 70504W001

[0077] In a third aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0078] In a fourth aspect, the present invention provides a method of treating an HIV infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.

[0079] In a fifth aspect, the present invention provides a method of preventing an HIV infection in a subject at risk of developing an HIV infection, comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof. In a sixth aspect, there is provided a compound of the invention or a pharmaceutically acceptable salt thereof for use in therapy.

[0080] In a seventh aspect, there is provided a compound of the invention or a pharmaceutically acceptable salt thereof for use in treating an HIV infection.

[0081] in an eighth aspect, there is provided a compound of the invention or a pharmaceutically acceptable salt thereof for use in preventing an HIV infection.

[0082] In a ninth aspect, there is provided the use of a compound of the invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating an HIV infection.

[0083] In a tenth aspect, there is provided the use of a compound of the invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing an HIV infection.

[0084] These and other aspects are encompassed by the invention as set forth herein.

[0085] DESCRIPTION OF DRAWINGS / FIGURES

[0086] FIG. 1 depicts X-Ray Powder Diffraction (XRPD) of the crystalline form of Compound 5 (15,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl icosanoate.

[0087] FIG. 2 depicts XRPD of the crystalline form of Compound 14 (15,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl heptanoate.

[0088] FIG. 3 depicts XRPD of the crystalline form of Compound 35 (15,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl isopropyl carbonate. 70504W001

[0089] FIG. 4 depicts XRPD of the crystalline form of Compound 80 (15,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 2-cyclopentylacetate.

[0090] FIG. 5 depicts XRPD of the crystalline form of Compound 86 (15,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 3-methylbutanoate.

[0091] FIG. 6 depicts XRPD of the crystalline form of Compound 230 (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H- pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6-yl 3- cyclopentylpropanoate.

[0092] FIG. 7 depicts XRPD of the crystalline form of Compound 231 (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l- / ]pyrrolo[l,2-b][l,2,4]triazin-6-yl 3,5-dimethylbenzoate.

[0093] FIG. 8 depicts XRPD of the crystalline form of Compound 232 (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H- pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6-yl 2,2,3,3-tetramethylcyclopropane-1-carboxylate. FIG. 9 depicts XRPD of the crystalline form of Compound 233 (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H- pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6-yl 3- cyclopropyl-3-methylbutanoate.

[0094] FIG. 10 depicts XRPD of the crystalline form of Compound 234 (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H- pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6-yl 2- cycloheptylacetate.

[0095] FIG. 11 depicts XRPD of the crystalline form of Compound 235 (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H- pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6-yl 2- cyclobutylacetate.

[0096] FIG. 12 depicts XRPD of the crystalline form of Compound 236 (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H- pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6-yl 2- cyclopropylacetate.

[0097] FIG. 13 depicts XRPD of the crystalline form of Compound 237 (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H- pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6-yl 2- ((3S,5S,7S)-adamantan-1-yl)acetate. 70504W001

[0098] DETAILED DESCRIPTION

[0099] Definitions

[0100] The term "alkyl" refers to a saturated hydrocarbon radical, straight or branched, having the specified number of carbon atoms. For example, the term " Ci-6alkyl" refers to an alkyl group having 1 to 6 carbon atoms. Exemplary groups include, but are not limited to, methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, sec-butyl, isobutyl and tert-butyl), pentyl, and hexyl.

[0101] When the term "alkyl" is used in combination with other substituent groups, such as "haloalkyl", the term "alkyl" is intended to encompass a divalent straight or branched chain hydrocarbon radical, wherein the point of attachment is through the alkyl moiety.

[0102] The term "alkenyl" refers to a straight or branched hydrocarbon radical containing the specified number of carbon atoms and at least 1 double bond. For example, "(C2.24)alkenyl" has 2 to 24 carbon atoms. Exemplary groups include, but are not limited to, ethenyl and propenyl.

[0103] The term "alkylene" refers to a divalent radical derived from a straight or branched, saturated hydrocarbon group of, for example, 1 to 6 carbon atoms (Ci-6alkylene). Exemplary groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2CH2-.

[0104] The term "alkenylene" refers to a divalent radical derived from a straight or branched, unsaturated hydrocarbon group containing at least 1 (e.g., 1, 2, or 3) double bond and, for example, 2 to 24 carbon atoms ((C2.24)alkenylene). Exemplary groups include, but are not limited to, -CH=CH-, -CH=CHCH2-, and -CH2CH=CH-.

[0105] The term "cycloalkyl" refers to a non-aromatic, monocyclic, hydrocarbon ring containing the specified number of carbon atoms. For example, "cycloalkyl" may contain 3 to 14 carbon atoms, i.e., (C3. i4)cycloalkyl. In another example, "cycloalkyl" may contain 3 to 8 carbon atoms, i.e., (C3-8)cycloalkyl. Exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecanyl, cyclododecanyl, cyclotridecanyl, and cyclotetradecanyl.

[0106] The term "bicycloalkyl" refers to a saturated, bridged, fused, or spiro, bicyclic hydrocarbon ring system containing the specified number of carbon atoms. For example, "bicycloalkyl" may contain 6 to 10 carbon atoms, i.e., C6-io bicycloalkyl. Exemplary groups include, but are not limited to bicyclo[2.1.1]hexyl, bicyclo[2.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, bicyclo[4.3.1]decyl, bicyclo[2.2.0]hexyl, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.1.0]heptyl, octahydropentalenyl, bicyclo[4.2.0]octyl, 70504W001

[0107] decahydronaphthalenyl, spiro[3.3]heptyl, spiro[2.4]heptyl, spiro[3.4]octyl, spiro[2.5]octyl, spiro[4.4]nonyl, spiro[3.5]nonyl, and spiro[4.5]decyl.

[0108] The term "bridged (C8-i4)tricycloalkyl" refers to: 1) a bridged bicycloalkyl ring where two non-adjacent carbon atoms of the bridged bicycloalkyl ring are linked by an alkylene bridge of one to three additional carbon atoms (i.e., a bridging group of the form -(CH2)q-, where q is 1, 2, or 3), or 2) a fused bicycloalkyl ring where two unshared ring atoms on each ring are linked by an alkylene bridged of 1 to 3 additional carbon atoms (i.e., a bridging group of the form -(CH2)q-, where q is 1, 2, 3), wherein the described "a fused bicycloalkyl ring" refers to a mono-cycloalkyl ring fused to a mono-cycloalkyl ring. Exemplary

[0109] groups include, but are not limited to,

[0110]

[0111] The term "alkenyloxy" means an oxy attached to the above "alkenyl," such as vinyloxy, 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 1,3-butadienyloxy, 3-methyl-2-butenyloxy, and the like. For example, "(C2.24)alkenyloxy" has 2 to 24 carbon atoms with an oxy group attached. The term "alkoxy" refers to an -O-alkyl group, i.e., an alkyl group which is attached through an oxygen linking atom, wherein "alkyl" is defined above. For example, the term "(Ci.24)alkoxy" refers to an alkoxy group having 1 to 24 carbon atoms, and the term "(Ci-io)alkoxy" refers to an alkoxy group having 1 to 10 carbon atoms. Exemplary groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, isobutoxy, and t-butoxy.

[0112] The term "haloalkoxy" refers to a straight or branched chain hydrocarbon radical, having at least one carbon atom with one or more halogen atoms, which may be the same or different, attached to one or more carbon atoms, which radical is attached through an oxygen linking atom. Exemplary groups include, but are not limited to, -OCHF2(difluoromethoxy), -OCF3(trifluoromethoxy), and -OCH(CF3)2(hexafluoroisopropoxy).

[0113] The term "alkoxyalkyl" refers to a linear monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 6 carbons substituted with 1 alkoxy group, as defined above. Examples include, but are not limited to, 2-methoxyethyl, 1-, 2- or 3-methoxypropyl, 2-ethoxyethyl, and the like.

[0114] The term "heterocycloalkyl" refers to a saturated or unsaturated, non-aromatic 3- to 10-membered monocyclic or bicyclic ring, which must contain at least one (e.g., 1, 2, 3, or 4) heteroatom, which is selected from nitrogen, oxygen, and sulfur. Heterocycloalkyl groups may contain one or more C(O), S(O) or SO2groups. Bicyclic heterocycloalkyl groups may be bridged, fused or spiro bicyclic groups. However, heterocycloalkyl groups are not aromatic. Heterocycloalkyl groups containing more than one 70504W001

[0115] heteroatom may contain different heteroatoms. "5- or 6- membered heterocycloalkyl" refers to a saturated or unsaturated 5- or 6-membered monocyclic ring, which must contain 1 or 2 non-carbon atoms, which are selected from nitrogen, oxygen, and sulfur. Exemplary groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, di hydrofuranyl, 1,3-dioxolanyl, tetrahydro-2H-pyranyl, dihydropyranyl, morpholinyl, morpholinyl-3-one, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, 1,4-oxathiolanyl, 1,4-oxathianyl, 1,4-dithianyl, piperidyl-2-one, pyrimidinyl-2, 4(11-1, 3H)-dione, thiomorpholinyl, and thiomorpholinyl 1,1-dioxide.

[0116] The term "aryl" refers to a monocyclic or bicyclic, hydrocarbon, aromatic radical. Aryl includes, for example, phenyl, naphthyl, indenyl, and dihydroindenyl. An aryl group may contain 6 to 14 carbon atoms.

[0117] The term "heteroaryl" refers to a group or moiety comprising an aromatic monovalent monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including at least one (e.g., one, two, three, or four) heteroatom independently selected from nitrogen, oxygen and sulfur. This term also encompasses bicyclic heterocyclic-aryl compounds containing an aryl ring moiety fused to a heterocycloalkyl ring moiety, containing 5 to 10 ring atoms, including at least one heteroatom independently selected from nitrogen, oxygen and sulfur. Exemplary groups include, but are not limited to furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuryl, 2,3-dihydrobenzofuryl, 1,3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indolizinyl, indolyl, isoindolyl, dihydroindolyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzthiazolyl, benzoisothiazolyl, dihydrobenzoisothiazolyl, indazolyl, imidazopyridinyl, pyrazolopyridyl, benzotriazolyl, triazolopyridyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, and pteridinyl. Examples of 5-membered "heteroaryl" groups include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, and isothiazolyl. Examples of 6-membered "heteroaryl" groups include oxo-pyridyl, pyridyl, pyridazinyl, pyrazinyl, and pyrimidinyl. Examples of 6,6-fused "heteroaryl" groups include quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, and pteridinyl. Examples of 6,5-fused "heteroaryl" groups include benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, indolizinyl, indolyl, isoindolyl, and indazolyl.

[0118] For the avoidance of doubt, all bicyclic ring systems may be attached at any suitable position on either ring. 70504W001

[0119] The terms "halogen" and "halo" represent chloro, fluoro, bromo, or iodo substituents.

[0120] The term "oxo" represents a double-bonded oxygen moiety; for example, if attached directly to a carbon atom forms a carbonyl moiety (C = O).

[0121] The term "optionally substituted" indicates that a group may be unsubstituted or substituted with one or more substituents as defined herein. The term "substituted" in reference to a group indicates that a hydrogen atom attached to a member atom within a group is replaced by one of the defined substituents. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different.

[0122] The term "independently selected" means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different. Thus, each substituent is separately selected from the entire group of recited possible substituents.

[0123] The term "member atoms" refers to the atom or atoms that form a chain or ring. Where more than one member atom is present in a chain and within a ring, each member atom is covalently bound to an adjacent member atom in the chain or ring. Atoms that make up a substituent group attached to a chain or ring are not member atoms in the chain or ring.

[0124] The term "pharmaceutically acceptable excipient" refers to an excipient for administration of a pharmaceutical agent, such as the compounds described herein. The term refers to any pharmaceutical excipient that may be administered without undue toxicity.

[0125] The term "pharmaceutically acceptable salts" refers to those compounds, materials, compositions, and dosage forms, which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, or other problem or complication. The skilled artisan will appreciate that pharmaceutically acceptable salts of compounds according to the invention may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.

[0126] Compounds

[0127] In a first aspect, the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof: 70504W001

[0128] Y

[0129] i

[0130]

[0131] wherein

[0132] ring A is a substituted or unsubstituted 3- to 10-membered heterocycloalkyl;

[0133] ring C is a benzene ring, a pyridine ring, or a 5-membered heteroaryl;

[0134] L is a bond, -C(O)-, -C(O)R5-, -CH2-O-C(O)-, or -CH2-O-C(O)R5-;

[0135] Y is selected from the group consisting of (Ci.24)alkyl, (C2.24)alkenyl, (Ci-io)alkoxy, 5- to 10- membered heteroaryl, (Ci.8)alkylene-R8, (C2.8)alkenylene-R8, (C3-i4)cycloalkyl, bridged (C8. i4)tricycloalky I, (C6-i4)aryl, (C6-i4)bicycloalkyl, and 3- to 10-membered heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, wherein (C3-i4)cycloalkyl, bridged (C8-i4)tricycloalkyl (C6-i4)aryl, (C6-i4)bicycloalkyl, or the 3- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -O-C(O)-(Ci.

[0136] 8)alkyl, (Ci-6)alkylene-O-C(O)-(Ci.8)alkyl, -C(O)R7, oxo, and halogen;

[0137] or

[0138] Y is (Y-2),

[0139] ZR11

[0140] < -R\

[0141]

[0142] ’ R12(Y-2);

[0143] or

[0144] Y is (Y-3)

[0145] > H2CH3

[0146] C R13

[0147]

[0148] CH3 (Y-3);

[0149] R1is each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, cyano, and haloalkoxy;

[0150] R2aand R2bare each independently hydrogen, alkyl, or haloalkyl; or 70504W001

[0151] R2aand R2b, together with the carbon atom to which they are both adjacent, form a 3- to 8- membered cycloalkyl, a 6- to 10-membered bicycloalkyl, or a 3- to 10-membered heterocycloalkyl;

[0152] R3is substituted or unsubstituted alkyl, substituted or unsubstituted 3-to 8-membered cycloalkyl, substituted or unsubstituted 6- to 10-membered bicycloalkyl, or substituted or unsubstituted 3- to 10-membered heterocycloalkyl;

[0153] R4is hydrogen, or substituted or unsubstituted alkyl; or

[0154] R3and R4, or R3and a substituent on ring A may be taken together with the adjacent atoms to form a substituted or unsubstituted heterocycloalkyl;

[0155] R5is -O- or -NR6-;

[0156] R6is hydrogen or (C1-6)alkyl;

[0157] R7is (Ci-io)alkyl, (Ci-io)alkoxy, or -NH-(Ci-io)alkyl;

[0158] R8is selected from the group consisting of (C1-24)alkoxy, (C2-24)alkenyloxy, -NH-C(O)-(C1-14)alkyl, -C(O)-(C1-24)alkoxy, -O-(CH2CH2O)n-(C1-14)alkyl, (C3-14)cycloalkyl, (C6-14)bicycloalkyl, bridged (C8-14)tricycloalkyl, (C6-14)aryl, 3- to 10-membered heterocycloalkyl, -O-(C1-8)alkylene-(C6-14)aryl, and -OP(O)(OR9)2, wherein (C3-14)cycloalkyl, (C6-14)bicycloalkyl, bridged (C8-14)tricycloalkyl, (C6-14)aryl, 3- to 10-membered heterocycloalkyl, or -O-(C1-8)alkylene-(C6-14)aryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (C1-10)alkyl, -O-C(O)-(C1-10)alkyl, (C1-6)alkylene-O-C(O)-(C1-8)alkyl, -C(O)-(C1-10)alkoxy, -C(O)-NH-(C1-10)alkyl, oxo, and halogen;

[0159] R9is independently selected from hydrogen and (C1-8)alkyl;

[0160] R10is -CH- or -N-;

[0161] R11and R12are independently selected from the group consisting of (C1-10)alkyl, -C(O)-O-(C1-10)alkyl, (C1-6)alkylene-(C6-14)aryl, -C(O)-NH-(C1-10)alkyl, (C1-8)alkylene-S-(C1-6)alkyl, -O-C(O)-(C1-10)alkoxy, -O-C(O)-(C1-8)alkyl, (C1-8)alkylene-C(O)-(C1-10)alkoxy, (C1-8)alkylene-C(O)-NH-(C1-10)alkyl, -NH-(C1-10)alkyl, (C1-8)alkylene-C(O)OH, and -C(O)OH, wherein (C1-6)alkylene-(C6-14)aryl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of (C1-6)alkyl and halogen;

[0162] R13is (C6-14)aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of:

[0163] (Ci-io)alkyl,

[0164] -0-C(0)-(Ci-io)alkyl,

[0165] (Ci-6)alkylene-O-C(O)-(Ci-s)alkyl,

[0166] -O-C(O)-(C6-i4)aryl optionally substituted by (Ci-6)alkylene-O-C(O)-(Ci-8)alkyl, 70504W001

[0167] -O-(C1-6)alkylene-(C6-10)aryl optionally substituted by -O-C(O)-(C1-10)alkyl,

[0168] -O-C(O)-(C3-i4)cycloalkyl, and

[0169] -OP(O)(OR9)2;

[0170] m is an integer selected from 1-3; and

[0171] n is an integer selected from 1-10.

[0172] In an embodiment, R3is unsubstituted or substituted alkyl (wherein examples of the substituents include halogen, alkyloxy, haloalkyloxy, cycioalkyl, bicycioalkyl, or heterocycloalkyi), unsubstituted or substituted cycloalkyl (wherein examples of the substituents include halogen), unsubstituted or substituted bicycloalkyi (wherein examples of substituents include halogen), or unsubstituted or substituted heterocycloalkyi (wherein examples of the substituent include halogen). In an embodiment, R3Is alkyl or haloalkyl. In an embodiment, R3is alkyl.

[0173] In an embodiment, ring A of the compound of Formula (I), or pharmaceutically acceptable salt thereof, is any of the following rings:

[0174]

[0175] wherein

[0176] R4is hydrogen, or substituted or unsubstituted alkyl;

[0177]

[0178] for the avoidance of doubt, the broken line represents the presence or absence of a double bond between Z’-Z3, Zl-Z':, or Zl-Z:!as appropriate, for example, 70504W001

[0179] s / VW'

[0180]

[0181] Z1, Z2, Z3, Z4and Z5are each independently CR5aR5b, CR5a, O, N, NR5c, or S, wherein the number of heteroatoms constituting the ring structure of ring A in Z1, Z2, Z3, Z4and Z5is 0 or 1;

[0182] Z1and Z3, Z1and Z4, Z1and Z5, Z2and Z4, Z2and Z5, Z3and Z5, R4and Z2, R4and Z3, R4and Z4, or R4and Z5may be taken together to form a substituted or unsubstituted C1-C4cross-link optionally interrupted by a heteroatom selected from NR5c, O and S;

[0183] R5aand R5bare each independently hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy;

[0184] R5aand R5bon the same carbon atom may be taken together to form a substituted or unsubstituted 3- to 8-membered cycloalkyl, a 6- to 10-membered bicycloalkyl, or a substituted or unsubstituted 3- to 10-membered heterocycloalkyl;

[0185] R5cis each Independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyi, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroaryl;

[0186] R3and R4may be taken together with the adjacent atoms to form a substituted or unsubstituted heterocycloalkyl. For the avoidance of doubt,

[0187]

[0188] indicates a point of attachment to the remainder of the compound.

[0189] In an embodiment, ring A of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is any of the following rings: 70504W001

[0190] (al) (bl) (cl) (dl) (el) (fl)

[0191]

[0192] 70504W001

[0193] wherein

[0194] R is hydrogen, or substituted or unsubstituted alkyl;

[0195]

[0196] for the avoidance of doubt, the broken line

[0197]

[0198] represents the presence or absence of a double bond between Zl-Z4or Z:-Z3as appropriate;

[0199] ring B is a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted bicycloalkyl, or a substituted or unsubstituted heterocycloalkyl;

[0200] Z1, Z2, Z3, Z4and Z5are each independently CR5aR5b, CR5a, C, O, N, NR5c, or S (provided that at least one atom constituting ring B is CR5a, C, or N);

[0201] Z1and Z3, Z1and Z4, Z1and Z5, Z2and Z4, Z2and Z5, Z3and Z5, R4and Z2, R4and Z3, R4and Z4or R4and Z5may be taken together to form a substituted or unsubstituted C1-C4cross-link optionally interrupted by a heteroatom selected from NR5c, O and

[0202]

[0203] R5aand R5bare each independently hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy;

[0204] R5aand R5bon the same carbon atom may be taken together to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted bicycloalkyl, or a substituted or unsubstituted heterocycloalkyl;

[0205] R5cis hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl;

[0206] R3and R4may be taken together with the adjacent atoms to form a substituted or unsubstituted heterocycloalkyl. For the avoidance of doubt,

[0207]

[0208] indicates a point of attachment to the remainder of the compound.

[0209] In an embodiment, ring A is any of the following rings: 70504W001

[0210]

[0211] X1is CRA9aRA9bor O;

[0212] RA5a, RA5b, RA6a, RA6b, RA7aand RA7bare each independently hydrogen, alkyl, alkoxy, or alkoxyalkyl; RA5aand RA6a, or RA6aand RA7amay be taken together with the adjacent atoms to form a 6- to 14-membered aryl optionally substituted by halogen, a 3- to 8-membered cycloalkyl optionally substituted by halogen, a 6- to 10-membered bicycloalkyl optionally substituted by halogen, or a 4- to 6-membered heterocycloalkyl optionally substituted by halogen (provided that, when forming a 6- to 14-membered aryl, RA5band RA6b, or RA6band RA7bare taken together to form a bond);

[0213] RA5band RA6bmay be taken together to form a bond; RA8a, RA8b, RA9a, RA9b, RA10a, RA10b, RA11aand RA11bare each independently hydrogen, alkyl, alkoxy, or alkoxyalkyl;

[0214] RA8aand RA10amay be taken together to form a C1-C3cross-link;

[0215]

[0216] RA10aand RA11amay be taken together with the adjacent atoms to form a 5-membered cycloalkyl; RA9aand RA9bmay be taken together with the adjacent atom to form a 4-membered cycloalkyl or a 5-membered heterocycloalkyl;

[0217] RA8aand RA9amay be taken together to form a bond;

[0218] ring C is a benzene ring or a pyridine ring;

[0219] R1is each independently halogen, alkyl, haloalkyl, alkoxy, cyano, or haloalkoxy;

[0220] R2aand R2bare each independently hydrogen, alkyl, or haloalkyl;

[0221] R3is alkyl or haloalkyl;

[0222] R4is hydrogen or alkyl;

[0223] m is an integer of 1 to 3. 70504W001

[0224] In an embodiment, R3is alkyl or haloalkyl. in another embodiment, R3is alkyl, in another embodiment, R3is haloalkyl. in another embodiment, R3is methyl or ethyl, in another embodiment, R3is methyl, in another embodiment, R3is ethyl.

[0225] In an embodiment, R4is hydrogen or alkyl, in another embodiment, R4is hydrogen, In another embodiment, R4is alkyl.

[0226] In an embodiment, R1is each independently halogen, alkyl, or haloalkyl. in another embodiment, R1is each independently halogen.

[0227] In an embodiment, R2ais hydrogen and R2bis hydrogen or alkyl, or R2aand R2bare taken together with the adjacent carbon atom to form a C3-C4cycloalkyl. In another embodiment, R2ais hydrogen and R2bis hydrogen or alkyl.

[0228] In an embodiment, ring A is any of the following rings:

[0229]

[0230] In an embodiment, ring C is a benzene ring or a pyridine ring. In another embodiment, ring C is a benzene ring, in another embodiment, ring C is a pyridine ring, in another embodiment, ring C is any of the following rings:

[0231]

[0232] In an embodiment, m is 1. In another embodiment, m is 2. In another embodiment, m is 3, In an embodiment, n is 1. In another embodiment, n Is 2, In another embodiment, n Is 3. in another embodiment, n is 4. in another embodiment, n is 5. In another embodiment, n is 6, In another embodiment, n is 7. In another embodiment, n is 8. In another embodiment, n is 9. In another embodiment, n is 10.

[0233] In an embodiment, the present invention provides a compound selected from the group consisting of Formula (II- a), (ll-b), (II -c), and (ll-d), 70504W001

[0234]

[0235] or a pharmaceutically acceptable salt thereof,

[0236] wherein:

[0237] RASa, RASB, RA6a, RA',h, RA / aand RA'“are each independently hydrogen, alkyl, alkoxy, or alkoxyalkyl; RA5'3and RAb'3, or RA6aand RA7amay be taken together with the adjacent atoms to form a 6- to 14- membered aryl optionally substituted by halogen, a 3- to 8-membered cycloalkyl optionally substituted by halogen, a 6- to 10-membered blcycloalkyl optionally substituted by halogen, or a 4-to 6-membered heterocycloalkyl optionally substituted by halogen (provided that, when forming a 6- to 14-membered aryl, R^and RAbh, or RA£, Band RA / bare taken together to form a bond);

[0238] RA5band RA6bmay be taken together to form a bond;

[0239] RA8a, RA8b, RA9a, RA9b, RA10a, RA10b, RA11aand RA11bare each independently hydrogen, alkyl, alkoxy, or alkoxyalkyl;

[0240] RA8aand RA10amay be taken together to form a C1-C3cross-link; 70504W001

[0241] RA10aand RA11amay be taken together with the adjacent atoms to form a 5-membered cycioaikyi; RA9'3and RA9brnay be taken together with the adjacent atom to form a 4-membered cycloalkyl or a 5- m e m b e re d h et e ro eye I o a I ky I;

[0242] RA8aand RA9amay be taken together to form a bond;

[0243] R1is each independently halogen, alkyl, haloaikyi, alkoxy, cyano, or haioalkoxy;

[0244] R4is hydrogen or alkyl;

[0245] m is an integer of 1 to 3;

[0246] L is a bond, -C(O)-, -C(O)R5-, -CH2-O-C(O)-, or -CH2-O-C(O)R5-;

[0247] Y is selected from the group consisting of (Ci.24)alkyl, (C2.24)alkenyl, (Ci-io)alkoxy, 5- to 10- membered heteroaryl, (Ci-sjalkylene-R8, (C2.s)alkenylene-R8, (C3-i4)cycloalkyl, (C6-i4)aryl, (C6- i4)bicycloalkyl, bridged (C8-i4)tricycloa Iky I, and 3- to 10-membered heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, wherein (C3-i4)cycloalkyl, (C6-i4)aryl, (C6-i4)bicycloa Ikyl, bridged (C8-i4)tricycloalkyl, or the 3- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -O-C(O)-(Ci. s)alkyl, (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -C(O)R7, oxo, and halogen;

[0248] or

[0249] Y is (Y-2),

[0250] / R11

[0251] | -R\

[0252]

[0253] ’ R12(y-2);

[0254] or

[0255] Y is (Y-3)

[0256] H2CH3

[0257] §-C R13

[0258]

[0259] CH3 (Y-3);

[0260] R5is -O- or -NR6-;

[0261] R6is hydrogen or (Ci-6)alkyl;

[0262] R7is (Ci-io)alkyl, (Ci-io)alkoxy, or -NH-(Ci-io)alkyl;

[0263] R8is selected from the group consisting of (Ci.24)alkoxy, (C2.24)alkenyloxy, -NH-C(O)-(Ci-i4)alkyl, - C(O)-(C1-24)alkoxy, -O-(CH2CH2O)n-(C1-14)alkyl, (C3-14)cycloalkyl, (C6-14)bicycloalkyl, bridged (C8-14)tricycloalkyl, (C6-i4)aryl, 3- to 10-membered heterocycloalkyl, -O-(Ci-8)alkylene-(C6-i4)aryl, 70504W001

[0264] and -OP(O)(OR9)2, wherein (C3-i4)cycloalkyl, (Ce-ujbicycloalkyl, bridged (Cs-ultricycloalkyl, (C6- i4)aryl, 3- to 10-membered heterocycloalkyl, or -O-(Ci-8)alkylene-(C6-i4)aryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -0-C(0)-(Ci-io)alkyl, (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -C(0)-(Ci-io)alkoxy, -C(O)- NH-(Ci-io)alkyl, oxo, and halogen;

[0265] R9is independently selected from hydrogen and (C1-8)alkyl;

[0266] R10is -CH- or -N-;

[0267] R11and R12are independently selected from the group consisting of (Ci-io)alkyl, -C(0)-0-(Ci-io)alkyl, (Ci-6)alkylene-(C6-i4)aryl, -C(0)-NH-(Ci-io)alkyl, (Ci-8)alkylene-S-(Ci.6)alkyl, -O-C(O)-(Ci. io)alkoxy, -O-C(O)-(Ci-8)alkyl, (Ci-8)alkylene-C(0)-(Ci-io)alkoxy, (Ci-8)alkylene-C(O)-NH-(Ci. io)alkyl, -NH-(Ci-io)alkyl, (Ci-8)alkylene-C(O)OH, and -C(O)OH, wherein (Ci-6)alkylene-(C6-i4)aryl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of (Ci.6)alkyl and halogen;

[0268] R13is (C6-i4)aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of:

[0269] (Ci-io)alkyl,

[0270] -0-C(0)-(Ci.io)alkyl,

[0271] (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl,

[0272] -O-C(O)-(C6-i4)aryl optionally substituted by (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -0-(Ci-6)alkylene-(C6-io)aryl optionally substituted by -0-C(0)-(Ci-io)alkyl, -O-C(O)-(C3-i4)cycloalkyl, and

[0273] -OP(O)(OR9)2; and

[0274] n is an integer selected from 1-10.

[0275] In an embodiment, the present invention provides a compound selected from the group consisting of Formulae (l-g), (l-h), (l-i), (l-j), and (l-k), 70504W001

[0276] (l-j), and

[0277]

[0278] or a pharmaceutically acceptable salt thereof,

[0279] wherein:

[0280] R1is each independently halogen, alkyl, haioalkyl, alkoxy, cyano, or haloalkoxy;

[0281] m is an integer of 1 to 3;

[0282] L is a bond, -C(O)-, -C(O)R5-, -CH2-O-C(O)-, or -CH2-O-C(O)R5-;

[0283] Y is selected from the group consisting of (Ci-24)alkyl, (C2.24)alkenyl, (Ci-io)alkoxy, 5- to 10- membered heteroaryl, (C1-8)alkylene-R8, (C2.s)alkenylene-R8, (C3-i4)cycloalkyl, (C6-i4)aryl, (C6- i4)bicycloalkyl, bridged (C8-i4)tricycloa Iky I, and 3- to 10-membered heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, wherein (C3-i4)cycloalkyl, (C6-i4)aryl, (C6-i4)bicycloa Ikyl, bridged (C8-i4)tricycloalkyl, or the 3- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -O-C(O)-(Ci. sjalkyl, (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -C(O)R7, oxo, and halogen;

[0284] or

[0285] Y is (Y-2), 70504W001

[0286] ZR11

[0287] < - R1°

[0288] R12(Y-2);

[0289] or

[0290] Y is (Y-3)

[0291] H2CH3

[0292] C R13

[0293] CH3 (Y-3);

[0294] R5is -O- or -NR6-;

[0295] R6is hydrogen or (Ci-6)alkyl;

[0296] R7is (Ci-io)alkyl, (Ci-io)alkoxy, or -NH-(Ci-io)alkyl;

[0297] R8is selected from the group consisting of (Ci.24)alkoxy, (C2-24)alkenyloxy, -NH-C(O)-(Ci-i4)alkyl, - C(O)-(C! -24)alkoxy, -O-(CH2CH2O)n-(C1-14)alkyl, (C3-14)cycloalkyl, (C6-14)bicycloalkyl, bridged (C8-14)tricycloalkyl, (C6-14)aryl, 3- to 10-membered heterocycloalkyl, -O-(Ci.8)alkylene-(C6-i4)aryl, and -OP(O)(OR9)2, wherein (C3-i4)cycloalkyl, (Ce-ujbicycloalkyl, bridged (Cs-ultricycloalkyl, (C6- i4)aryl, 3- to 10-membered heterocycloalkyl, or -O-(Ci-8)alkylene-(C6-i4)aryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -0-C(0)-(Ci-io)alkyl, (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -C(0)-(Ci-io)alkoxy, -C(O)- NH-(Ci-io)alkyl, oxo, and halogen;

[0298] R9is independently selected from hydrogen and (C1-8)alkyl;

[0299] R10is -CH- or -N-;

[0300] R11and R12are independently selected from the group consisting of (Ci-io)alkyl, -C(0)-0-(Ci-io)alkyl, (Ci-6)alkylene-(C6-i4)aryl, -C(0)-NH-(Ci-io)alkyl, (Ci-8)alkylene-S-(Ci.6)alkyl, -O-C(O)-(Ci. io)alkoxy, -O-C(O)-(Ci-8)alkyl, (Ci-8)alkylene-C(0)-(Ci-io)alkoxy, (Ci-8)alkylene-C(O)-NH-(Ci. io)alkyl, -NH-(Ci-io)alkyl, (Ci-8)alkylene-C(O)OH, and -C(O)OH, wherein (Ci-6)alkylene-(C6-i4)aryl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of (Ci.6)alkyl and halogen;

[0301] R13is (C6-i4)aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of:

[0302] (Ci-io)alkyl,

[0303] -0-C(0)-(Ci.io)alkyl,

[0304] (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl,

[0305] -O-C(O)-(C6-i4)aryl optionally substituted by (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -0-(Ci-6)alkylene-(C6-io)aryl optionally substituted by -0-C(0)-(Ci-io)alkyl, -O-C(O)-(C3-i4)cycloalkyl, and 70504W001

[0306] -OP(O)(OR9)2; and

[0307] n is an integer selected from 1-10.

[0308] In another embodiment, the present invention provides a compound selected from the group consisting of Formula (l-g), (l-h), (l-i), (l-j), and (l-k),

[0309] (l-j), and

[0310]

[0311] or a pharmaceutically acceptable salt thereof,

[0312] wherein:

[0313] R1is independently halogen;

[0314] m is an integer of 1 to 3;

[0315] L is -C(O)- or -C(O)R5-;

[0316] Y is (C1-24)alkyl or (C1-8)alkylene-R8;

[0317] R5is -O-; and

[0318] R8is (C3-14)cycloalkyl. 70504W001

[0319] In a second aspect, the present invention provides a compound selected from the group consisting of Formulae (l-a), (l-b), (l-c), (l-d), (l-e), and

[0320]

[0321] or a pharmaceutically acceptable salt thereof,

[0322] wherein:

[0323] L is a bond, -C(O)-, -C(O)R5-, -CH2-O-C(O)-, or -CH2-O-C(O)R5-;

[0324] Y is selected from the group consisting of (Ci.24)alkyl, (C2.24)alkenyl, (Ci-io)alkoxy, 5- to 10- membered heteroaryl, (C1-8)alkylene-R8, (C2.s)alkenylene-R8, (C3.i4)cycloalkyl, (Ce-ujaryl, (C6- i4)bicycloalkyl, bridged (C8-14)tricycloalkyl, and 3- to 10-membered heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, wherein (C3.i4)cycloalkyl, (C6-i4)aryl, (C6-i4)bicycloa Ikyl, bridged (C8-14)tricycloalkyl, or the 3- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -O-C(O)-(Ci. sjalkyl, (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -C(O)R7, oxo, and halogen;

[0325] or

[0326] Y is (Y-2), 70504W001

[0327] ZR11

[0328] < - R1°

[0329] R12(Y-2);

[0330] or

[0331] Y is (Y-3)

[0332] H2CH3

[0333] C R13

[0334] CH3 (Y-3);

[0335] R5is -O- or -NR6-;

[0336] R6is hydrogen or (Ci-6)alkyl;

[0337] R7is (Ci-io)alkyl, (Ci-io)alkoxy, or -NH-(Ci-io)alkyl;

[0338] R8is selected from the group consisting of (Ci.24)alkoxy, (C2-24)alkenyloxy, -NH-C(O)-(Ci-i4)alkyl, - C(O)-(C! -24)alkoxy, -O-(CH2CH2O)n-(C1-14)alkyl, (C3-14)cycloalkyl, (C6-14)bicycloalkyl, bridged (C8-14)tricycloalkyl, (C6-14)aryl, 3- to 10-membered heterocycloalkyl, -O-(Ci.8)alkylene-(C6-i4)aryl, and -OP(O)(OR9)2, wherein (C3-i4)cycloalkyl, (Ce-ujbicycloalkyl, bridged (Cs-ultricycloalkyl, (C6- i4)aryl, 3- to 10-membered heterocycloalkyl, or -O-(Ci-8)alkylene-(C6-i4)aryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -0-C(0)-(Ci-io)alkyl, (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -C(0)-(Ci-io)alkoxy, -C(O)- NH-(Ci-io)alkyl, oxo, and halogen;

[0339] R9is independently selected from hydrogen and (C1-8)alkyl;

[0340] R10is -CH- or -N-;

[0341] R11and R12are independently selected from the group consisting of (Ci-io)alkyl, -C(0)-0-(Ci-io)alkyl, (Ci-6)alkylene-(C6-i4)aryl, -C(0)-NH-(Ci-io)alkyl, (Ci-8)alkylene-S-(Ci.6)alkyl, -O-C(O)-(Ci. io)alkoxy, -O-C(O)-(Ci-8)alkyl, (Ci-8)alkylene-C(0)-(Ci-io)alkoxy, (Ci-8)alkylene-C(O)-NH-(Ci. io)alkyl, -NH-(Ci-io)alkyl, (Ci-8)alkylene-C(O)OH, and -C(O)OH, wherein (Ci-6)alkylene-(C6-i4)aryl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of (Ci.6)alkyl and halogen;

[0342] R13is (C6-i4)aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of:

[0343] (Ci-io)alkyl,

[0344] -0-C(0)-(Ci.io)alkyl,

[0345] (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl,

[0346] -O-C(O)-(C6-i4)aryl optionally substituted by (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -0-(Ci-6)alkylene-(C6-io)aryl optionally substituted by -0-C(0)-(Ci-io)alkyl, -O-C(O)-(C3-i4)cycloalkyl, and 70504W001

[0347] -OP(O)(OR9)2; and

[0348] n is an integer selected from 1-10.

[0349] In an embodiment, the compound of the present invention is selected from the group consisting of Formulae (l-a), (l-b), (l-c), and (l-d),

[0350]

[0351] or a pharmaceutically acceptable salt thereof,

[0352] wherein:

[0353] L is a bond, -C(O)-, -C(O)R5-, -CH2-O-C(O)-, or -CH2-O-C(O)R5-;

[0354] Y is selected from the group consisting of (Ci-24)alkyl, (C2.24)alkenyl, (Ci-io)alkoxy, 5- to 10- membered heteroaryl, (C1-8)alkylene-R8, (C2.s)alkenylene-R8, (C3-i4)cycloalkyl, (Ce-ujaryl, (C6- i4)bicycloalkyl, bridged (Cs-ujtricycloa Iky I, and 3- to 10-membered heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, wherein (Cs-ujcycloalkyl, (Ce-ujaryl, (Cs-ujbicycloalkyl, bridged (Cs-ujtricycloalkyl, or the 3- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -O-C(O)-(Ci. sjalkyl, (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -C(O)R7, oxo, and halogen;

[0355] or

[0356] Y is (Y-2),

[0357] ZR11

[0358] < - R1°

[0359] R12(Y-2); 70504W001

[0360] or

[0361] Y is (Y-3)

[0362] H2CH3

[0363] §-C R13

[0364]

[0365] CH3 (Y-3);

[0366] R5is -O- or -NR6-;

[0367] R6is hydrogen or (Ci-6)alkyl;

[0368] R7is (Ci-io)alkyl, (Ci-io)alkoxy, or -NH-(Ci-io)alkyl;

[0369] R8is selected from the group consisting of (Ci.24)alkoxy, (C2-24)alkenyloxy, -NH-C(O)-(Ci-i4)alkyl, - C(O)-(C! -24)alkoxy, -O-(CH2CH2O)n-(C1-14)alkyl, (C3-14)cycloalkyl, (C6-14)bicycloalkyl, bridged (C8-14)tricycloalkyl, (C6-14)aryl, 3- to 10-membered heterocycloalkyl, -O-(Ci.8)alkylene-(C6-i4)aryl, and -OP(O)(OR9)2, wherein (C3-i4)cycloalkyl, (Ce-ujbicycloalkyl, bridged (Cs-ultricycloalkyl, (C6- i4)aryl, 3- to 10-membered heterocycloalkyl, or -O-(Ci-8)alkylene-(C6-i4)aryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -0-C(0)-(Ci-io)alkyl, (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -C(0)-(Ci-io)alkoxy, -C(O)- NH-(Ci-io)alkyl, oxo, and halogen;

[0370] R9is independently selected from hydrogen and (C1-8)alkyl;

[0371] R10is -CH- or -N-;

[0372] R11and R12are independently selected from the group consisting of (Ci-io)alkyl, -C(0)-0-(Ci-io)alkyl, (Ci-6)alkylene-(C6-i4)aryl, -C(0)-NH-(Ci-io)alkyl, (Ci-8)alkylene-S-(Ci.6)alkyl, -O-C(O)-(Ci. io)alkoxy, -O-C(O)-(Ci-8)alkyl, (Ci-8)alkylene-C(0)-(Ci-io)alkoxy, (Ci-8)alkylene-C(O)-NH-(Ci. io)alkyl, -NH-(Ci-io)alkyl, (Ci-8)alkylene-C(O)OH, and -C(O)OH, wherein (Ci-6)alkylene-(C6-i4)aryl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of (Ci.6)alkyl and halogen;

[0373] R13is (C6-i4)aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of:

[0374] (Ci-io)alkyl,

[0375] -0-C(0)-(Ci.io)alkyl,

[0376] (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl,

[0377] -O-C(O)-(C6-i4)aryl optionally substituted by (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -0-(Ci-6)alkylene-(C6-io)aryl optionally substituted by -0-C(0)-(Ci-io)alkyl, -O-C(O)-(C3-i4)cycloalkyl, and

[0378] -OP(O)(OR9)2; and

[0379] n is an integer selected from 1-10. 70504W001

[0380] In another embodiment, the compound of the present invention is selected from the group consisting of Formulae (l-e) and (l-f),

[0381]

[0382] or a pharmaceutically acceptable salt thereof,

[0383] wherein:

[0384] L is a bond, -C(O)-, -C(O)R5-, -CH2-O-C(O)-, or -CH2-O-C(O)R5-;

[0385] Y is selected from the group consisting of (Ci.24)alkyl, (C2.24)alkenyl, (Ci-io)alkoxy, 5- to 10- membered heteroaryl, (C1-8)alkylene-R8, (C2.s)alkenylene-R8, (C3.i4)cycloalkyl, (Ce-ujaryl, (C6- i4)bicycloalkyl, bridged (Cs-ujtricycloa Iky I, and 3- to 10-membered heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, wherein (C3.i4)cycloalkyl, (C6-i4)aryl, (Ce-ujbicycloalkyl, bridged (C8-14)tricycloalkyl, or the 3- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -O-C(O)-(Ci. sjalkyl, (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -C(O)R7, oxo, and halogen;

[0386] or

[0387] Y is (Y-2),

[0388] zR11

[0389] 1 - R1°

[0390] R12(Y-2);

[0391] or

[0392] Y is (Y-3)

[0393] > H2CH3

[0394] §-C R13

[0395]

[0396] CH3 (Y-3);

[0397] R5is -O- or -NR6-;

[0398] R6is hydrogen or (Ci-6)alkyl;

[0399] R7is (Ci-io)alkyl, (Ci-io)alkoxy, or -NH-(Ci-io)alkyl;

[0400] R8is selected from the group consisting of (C1-24)alkoxy, (C2-24)alkenyloxy, -NH-C(O)-(C1-14)alkyl, - C(O)-(C1-24)alkoxy, -O-(CH2CH2O)n-(C1-14)alkyl, (C3-14)cycloalkyl, (C6-14)bicycloalkyl, bridged (C8- 70504W001

[0401] i4)tricycloalky I, (C6-i4)aryl, 3- to 10-membered heterocycloalkyl, -O-(Ci.8)alkylene-(C6-i4)aryl, and -OP(O)(OR9)2, wherein (C3-i4)cycloalkyl, (C6-i4)bicycloalkyl, bridged (Cs-ultricycloalkyl, (C6- i4)aryl, 3- to 10-membered heterocycloalkyl, or -O-(Ci-8)alkylene-(C6-i4)aryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -0-C(0)-(Ci-io)alkyl, (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -C(0)-(Ci-io)alkoxy, -C(O)- NH-(Ci-io)alkyl, oxo, and halogen;

[0402] R9is independently selected from hydrogen and (C1-8)alkyl;

[0403] R10is -CH- or -N-;

[0404] R11and R12are independently selected from the group consisting of (Ci-io)alkyl, -C(0)-0-(Ci-io)alkyl, (Ci-6)alkylene-(C6-i4)aryl, -C(0)-NH-(Ci-io)alkyl, (Ci-8)alkylene-S-(Ci.6)alkyl, -O-C(O)-(Ci. io)alkoxy, -O-C(O)-(Ci-8)alkyl, (Ci-8)alkylene-C(0)-(Ci-io)alkoxy, (Ci-8)alkylene-C(O)-NH-(Ci. io)alkyl, -NH-(Ci-io)alkyl, (Ci-8)alkylene-C(O)OH, and -C(O)OH, wherein (Ci-6)alkylene-(C6-i4)aryl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of (Ci.6)alkyl and halogen;

[0405] R13is (C6-i4)aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of:

[0406] (Ci-io)alkyl,

[0407] -0-C(0)-(Ci.io)alkyl,

[0408] (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl,

[0409] -O-C(O)-(C6-i4)aryl optionally substituted by (Ci-6)alkylene-O-C(O)-(Ci-s)alkyl, -0-(Ci-6)alkylene-(C6-io)aryl optionally substituted by -0-C(0)-(Ci-io)alkyl, -O-C(O)-(C3-i4)cycloalkyl, and

[0410] -OP(O)(OR9)2; and

[0411] n is an integer selected from 1-10.

[0412] In an embodiment, the compound selected from the group consisting of Formulae (l-a), (l-b), (l-c), (I-d), (l-e), and (l-f) is a compound of Formula (l-a),

[0413]

[0414] or a pharmaceutically acceptable salt thereof, 70504W001

[0415] wherein:

[0416] L is a bond, -C(O)-, -C(O)R5-, -CH2-O-C(O)-, or -CH2-O-C(O)R5-;

[0417] Y is selected from the group consisting of (Ci.24)alkyl, (C2.24)alkenyl, (Ci-io)alkoxy, 5- to 10- membered heteroaryl, (C1-8)alkylene-R8, (C2.s)alkenylene-R8, (C3.i4)cycloalkyl, (Ce-ujaryl, (C6- i4)bicycloalkyl, bridged (Cs-ujtricycloalkyl, and 3- to 10-membered heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, wherein (C3.i4)cycloalkyl, (C6-i4)aryl, (Ce-ujbicycloalkyl, bridged (C8-14)tricycloalkyl, or the 3- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -O-C(O)-(Ci. sjalkyl, (Ci-6)alkylene-O-C(O)-(Ci-s)alkyl, -C(O)R7, oxo, and halogen;

[0418] or

[0419] Y is (Y-2),

[0420] zR11

[0421] < -R1\

[0422]

[0423] R12(Y-2);

[0424] or

[0425] Y is (Y-3)

[0426] , H2CH3

[0427] C R13

[0428] CH3 (Y-3);

[0429] R5is -O- or -NR6-;

[0430] R6is hydrogen or (Ci-6)alkyl;

[0431] R7is (Ci-io)alkyl, (Ci-io)alkoxy, or -NH-(Ci-io)alkyl;

[0432] R8is selected from the group consisting of (Ci-24)alkoxy, (C2.24)alkenyloxy, -NH-C(O)-(Ci-i4)alkyl, - C(O)-(C! -24)alkoxy, -O-(CH2CH2O)n-(Ci-i4)alkyl, (C3-i4)cycloalkyl, (Cs-ulbicycloalkyl, bridged (Cs- i4)tricycloalky I, (C6-i4)aryl, 3- to 10-membered heterocycloalkyl, -O-(Ci-8)alkylene-(C6-i4)aryl, and -OP(O)(OR9)2, wherein (C3.i4)cycloalkyl, (C6-i4)bicycloalkyl, bridged (Cs-ultricycloalkyl, (C6- i4)aryl, 3- to 10-membered heterocycloalkyl, or -O-(Ci-8)alkylene-(C6-i4)aryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -0-C(0)-(Ci-io)alkyl, (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -C(0)-(Ci-io)alkoxy, -C(O)- NH-(Ci-io)alkyl, oxo, and halogen;

[0433] R9is independently selected from hydrogen and (C1-8)alkyl;

[0434] R10is -CH- or -N-;

[0435] R11and R12are independently selected from the group consisting of (Ci-io)alkyl, -C(0)-0-(Ci-io)alkyl, (Ci-6)alkylene-(C6-i4)aryl, -C(0)-NH-(Ci-io)alkyl, (Ci-8)alkylene-S-(Ci.6)alkyl, -O-C(O)-(Ci. 70504W001

[0436] io)alkoxy, -O-C(O)-(Ci-8)alkyl, (Ci-8)alkylene-C(0)-(Ci-io)alkoxy, (Ci-8)alkylene-C(O)-NH-(Ci. io)alkyl, -NH-(Ci-io)alkyl, (Ci-8)alkylene-C(O)OH, and -C(O)OH, wherein (Ci-6)alkylene-(C6-i4)aryl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of (Ci.6)alkyl and halogen;

[0437] R13is (C6-i4)aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of:

[0438] (Ci-io)alkyl,

[0439] -0-C(0)-(Ci-io)alkyl,

[0440] (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl,

[0441] -O-C(O)-(C6-i4)aryl optionally substituted by (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -0-(Ci-6)alkylene-(C6-io)aryl optionally substituted by -0-C(0)-(Ci-io)alkyl, -O-C(O)-(C3-i4)cycloalkyl, and

[0442] -OP(O)(OR9)2; and

[0443] n is an integer selected from 1-10.

[0444] In another embodiment, the compound is a compound of Formula (l-a),

[0445]

[0446] or a pharmaceutically acceptable salt thereof, wherein:

[0447] L is -C(O)- or -C(O)R5-;

[0448] Y is (C1-24)alkyl or (C1-8)alkylene-R8;

[0449] R5is -O-; and

[0450] R8is (C3-14)cycloalkyl.

[0451] In an embodiment, the compound selected from the group consisting of Formulae (l-a), (l-b), (l-c), (I-d), (l-e), and (l-f) is a compound of Formula (i-b), 70504W001

[0452]

[0453] or a pharmaceutically acceptable salt thereof,

[0454] wherein

[0455] L is a bond, -C(O)-, -C(O)R5-, -CH2-O-C(O)-, or -CH2-O-C(O)R5-;

[0456] Y is selected from the group consisting of (Ci.24)alkyl, (C2.24)alkenyl, (Ci-io)alkoxy, 5- to 10- membered heteroaryl, (C1-8)alkylene-R8, (C2.s)alkenylene-R8, (C3.i4)cycloalkyl, (Ce-ujaryl, (C6- i4)bicycloalkyl, bridged (Cs-ujtricycloa Iky I, and 3- to 10-membered heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, wherein (C3.i4)cycloalkyl, (C6-i4)aryl, (Ce-ujbicycloalkyl, bridged (C8-14)tricycloalkyl, or the 3- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -O-C(O)-(Ci- sjalkyl, (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -C(O)R7, oxo, and halogen;

[0457] or

[0458] Y is (Y-2),

[0459] zR11

[0460] <

[0461] S-R1\

[0462]

[0463] R12(Y-2);

[0464] or

[0465] Y is (Y-3)

[0466] , H CH3

[0467] C R13

[0468] CH3 (Y-3);

[0469] R5is -O- or -NR6-;

[0470] R6is hydrogen or (Ci-6)alkyl;

[0471] R7is (Ci-io)alkyl, (Ci-io)alkoxy, or -NH-(Ci-io)alkyl;

[0472] R8is selected from the group consisting of (Ci.24)alkoxy, (C2.24)alkenyloxy, -NH-C(O)-(Ci.i4)alkyl, - C(O)-(C!.24)alkoxy, -O-(CH2CH2O)n-(Ci-i4)alkyl, (C3.i4)cycloalkyl, (Cs ulbicycloalkyl, bridged (Cs- i4)tricycloalky I, (C6-i4)aryl, 3- to 10-membered heterocycloalkyl, -O-(Ci-8)alkylene-(C6-i4)aryl, and -OP(O)(OR9)2, wherein (C3.i4)cycloalkyl, (C6-i4)bicycloalkyl, bridged (Cs-ultricycloalkyl, (C6- 70504W001

[0473] i4)aryl, 3- to 10-membered heterocycloalkyl, or -O-(Ci.8)alkylene-(C6-i4)aryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -0-C(0)-(Ci-io)alkyl, (Ci-6)alkylene-O-C(O)-(Ci-s)alkyl, -C(0)-(Ci-io)alkoxy, -C(O)- NH-(Ci-io)alkyl, oxo, and halogen;

[0474] R9is independently selected from hydrogen and (C1-8)alkyl;

[0475] R10is -CH- or -N-;

[0476] R11and R12are independently selected from the group consisting of (Ci-io)alkyl, -C(0)-0-(Ci-io)alkyl, (Ci-6)alkylene-(C6-i4)aryl, -C(0)-NH-(Ci-io)alkyl, (Ci-8)alkylene-S-(Ci-6)alkyl, -O-C(O)-(Ci- io)alkoxy, -O-C(O)-(Ci-8)alkyl, (Ci-8)alkylene-C(0)-(Ci-io)alkoxy, (Ci-8)alkylene-C(O)-NH-(Ci. io)alkyl, -NH-(Ci-io)alkyl, (Ci-8)alkylene-C(O)OH, and -C(O)OH, wherein (Ci.6)alkylene-(C6-i4)aryl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of (Ci-sjalkyl and halogen;

[0477] R13is (C6-i4)aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of:

[0478] (Ci-io)alkyl,

[0479] -0-C(0)-(Ci-io)alkyl,

[0480] (Ci-6)alkylene-O-C(O)-(Ci-8)alkyl,

[0481] -O-C(O)-(C6-i4)aryl optionally substituted by (Ci-6)alkylene-O-C(O)-(Ci-8)alkyl, -0-(Ci.6)alkylene-(C6-io)aryl optionally substituted by -0-C(0)-(Ci-io)alkyl, -O-C(O)-(C3-i4)cycloalkyl, and

[0482] -OP(O)(OR9)2; and

[0483] n is an integer selected from 1-10.

[0484] In another embodiment, the compound is a compound of Formula (l-b),

[0485]

[0486] or a pharmaceutically acceptable salt thereof, wherein:

[0487] L is -C(O)- or -C(O)R5-;

[0488] Y is (C1-24)alkyl or (C1-8)alkylene-R8;

[0489] R5is -O-; and 70504W001

[0490] R8is (C3-14)cycloalkyl.

[0491] In another embodiment, the compound is a compound of Formula (l-b),

[0492]

[0493] or a pharmaceutically acceptable salt thereof, wherein:

[0494] L is-C(O)-; and

[0495] Y is (Ci-24)alkyl.

[0496] In another embodiment., the compound is a compound of Formula (l-b),

[0497]

[0498] or a pharmaceutically acceptable salt thereof, wherein:

[0499] L is-C(O)-; and

[0500] Y is (Ci.6)alkyl.

[0501] In an embodiment, the compound selected from the group consisting of Formulae (l-a), (l-b), (l-c), (I-d), (l-e), and (l-f) is a compound of Formula (i-c).

[0502]

[0503] or a pharmaceutically acceptable salt thereof, 70504W001

[0504] wherein

[0505] L is a bond, -C(O)-, -C(O)R5-, -CH2-O-C(O)-, or -CH2-O-C(O)R5-;

[0506] Y is selected from the group consisting of (Ci.24)alkyl, (C2.24)alkenyl, (Ci-io)alkoxy, 5- to 10- membered heteroaryl, (C1-8)alkylene-R8, (C2.s)alkenylene-R8, (C3.i4)cycloalkyl, (Ce-ujaryl, (C6- i4)bicycloalkyl, bridged (Cs-ujtricycloalkyl, and 3- to 10-membered heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, wherein (C3.i4)cycloalkyl, (C6-i4)aryl, (Ce-ujbicycloalkyl, bridged (C8-14)tricycloalkyl, or the 3- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -O-C(O)-(Ci. sjalkyl, (Ci-6)alkylene-O-C(O)-(Ci-s)alkyl, -C(O)R7, oxo, and halogen;

[0507] or

[0508] Y is (Y-2),

[0509] zR11

[0510] < -R1\

[0511]

[0512] R12(Y-2);

[0513] or

[0514] Y is (Y-3)

[0515] , H2CH3

[0516] C R13

[0517] CH3 (Y-3);

[0518] R5is -O- or -NR6-;

[0519] R6is hydrogen or (Ci-6)alkyl;

[0520] R7is (Ci-io)alkyl, (Ci-io)alkoxy, or -NH-(Ci-io)alkyl;

[0521] R8is selected from the group consisting of (Ci-24)alkoxy, (C2.24)alkenyloxy, -NH-C(O)-(Ci-i4)alkyl, - C(O)-(C! -24)alkoxy, -O-(CH2CH2O)n-(Ci-i4)alkyl, (C3-i4)cycloalkyl, (Cs-ulbicycloalkyl, bridged (Cs- i4)tricycloalky I, (C6-i4)aryl, 3- to 10-membered heterocycloalkyl, -O-(Ci-8)alkylene-(C6-i4)aryl, and -OP(O)(OR9)2, wherein (C3.i4)cycloalkyl, (C6-i4)bicycloalkyl, bridged (Cs-ultricycloalkyl, (C6- i4)aryl, 3- to 10-membered heterocycloalkyl, or -O-(Ci-8)alkylene-(C6-i4)aryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -0-C(0)-(Ci-io)alkyl, (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -C(0)-(Ci-io)alkoxy, -C(O)- NH-(Ci-io)alkyl, oxo, and halogen;

[0522] R9is independently selected from hydrogen and (C1-8)alkyl;

[0523] R10is -CH- or -N-;

[0524] R11and R12are independently selected from the group consisting of (Ci-io)alkyl, -C(0)-0-(Ci-io)alkyl, (Ci-6)alkylene-(C6-i4)aryl, -C(0)-NH-(Ci-io)alkyl, (Ci-8)alkylene-S-(Ci.6)alkyl, -O-C(O)-(Ci. 70504W001

[0525] io)alkoxy, -O-C(O)-(Ci-8)alkyl, (Ci-8)alkylene-C(0)-(Ci-io)alkoxy, (Ci-8)alkylene-C(O)-NH-(Ci. io)alkyl, -NH-(Ci-io)alkyl, (Ci-8)alkylene-C(O)OH, and -C(O)OH, wherein (Ci-6)alkylene-(C6-i4)aryl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of (Ci.6)alkyl and halogen;

[0526] R13is (C6-i4)aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of:

[0527] (Ci-io)alkyl,

[0528] -0-C(0)-(Ci-io)alkyl,

[0529] (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl,

[0530] -O-C(O)-(C6-i4)aryl optionally substituted by (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -0-(Ci-6)alkylene-(C6-io)aryl optionally substituted by -0-C(0)-(Ci-io)alkyl, -O-C(O)-(C3-i4)cycloalkyl, and

[0531] -OP(O)(OR9)2; and

[0532] n is an integer selected from 1-10.

[0533] In another embodiment, the compound is a compound of Formula (l-c),

[0534]

[0535] or a pharmaceutically acceptable salt thereof, wherein:

[0536] L is -C(O)- or -C(O)R5-;

[0537] Y is (Ci-24)alkyl or (Ci-s)alkylene-R8;

[0538] R5is -O-; and

[0539] R8is (C3-14)cycloalkyl.

[0540] In an embodiment, the compound selected from the group consisting of Formulae (l-a), (l-b), (l-c), (I-d), (l-e), and (l-f) is a compound of Formula (i-d). 70504W001

[0541]

[0542] or a pharmaceutically acceptable salt thereof,

[0543] wherein

[0544] L is a bond, -C(O)-, -C(O)R5-, -CH2-O-C(O)-, or -CH2-O-C(O)R5-;

[0545] Y is selected from the group consisting of (Ci.24)alkyl, (C2.24)alkenyl, (Ci-io)alkoxy, 5- to 10- membered heteroaryl, (C1-8)alkylene-R8, (C2.s)alkenylene-R8, (C3.i4)cycloalkyl, (Ce-ujaryl, (C6- i4)bicycloalkyl, bridged (Cs-ujtricycloa Iky I, and 3- to 10-membered heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, wherein (C3.i4)cycloalkyl, (C6-i4)aryl, (Ce-ujbicycloalkyl, bridged (C8-14)tricycloalkyl, or the 3- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -O-C(O)-(Ci. sjalkyl, (Ci-6)alkylene-O-C(O)-(Ci-s)alkyl, -C(O)R7, oxo, and halogen;

[0546] or

[0547] Y is (Y-2),

[0548] zR11

[0549] | - R1^

[0550] *

[0551]

[0552] * R12(Y-2);

[0553] or

[0554] Y is (Y-3)

[0555] > H CM3

[0556] C R13

[0557]

[0558] CH3 (Y-3);

[0559] R5is -O- or -NR6-;

[0560] R6is hydrogen or (Ci-6)alkyl;

[0561] R7is (Ci-io)alkyl, (Ci-io)alkoxy, or -NH-(Ci-io)alkyl;

[0562] R8is selected from the group consisting of (Ci.24)alkoxy, (C2.24)alkenyloxy, -NH-C(O)-(Ci.i4)alkyl, - C(O)-(C! -24)alkoxy, -O-(CH2CH2O)n-(Ci-i4)alkyl, (C3-i4)cycloalkyl, (Cs-ulbicycloalkyl, bridged (Cs- i4)tricycloalky I, (C6-i4)aryl, 3- to 10-membered heterocycloalkyl, -O-(Ci-8)alkylene-(C6-i4)aryl, and -OP(O)(OR9)2, wherein (C3.i4)cycloalkyl, (C6-i4)bicycloalkyl, bridged (Cs-ultricycloalkyl, (C6- 70504W001

[0563] i4)aryl, 3- to 10-membered heterocycloalkyl, or -O-(Ci.8)alkylene-(C6-i4)aryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -0-C(0)-(Ci-io)alkyl, (Ci-6)alkylene-O-C(O)-(Ci-s)alkyl, -C(0)-(Ci-io)alkoxy, -C(O)- NH-(Ci-io)alkyl, oxo, and halogen;

[0564] R9is independently selected from hydrogen and (C1-8)alkyl;

[0565] R10is -CH- or -N-;

[0566] R11and R12are independently selected from the group consisting of (Ci-io)alkyl, -C(0)-0-(Ci-io)alkyl, (Ci-6)alkylene-(C6-i4)aryl, -C(0)-NH-(Ci-io)alkyl, (Ci-8)alkylene-S-(Ci-6)alkyl, -O-C(O)-(Ci- io)alkoxy, -O-C(O)-(Ci-8)alkyl, (Ci-8)alkylene-C(0)-(Ci-io)alkoxy, (Ci-8)alkylene-C(O)-NH-(Ci. io)alkyl, -NH-(Ci-io)alkyl, (Ci-8)alkylene-C(O)OH, and -C(O)OH, wherein (Ci.6)alkylene-(C6-i4)aryl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of (Ci-sjalkyl and halogen;

[0567] R13is (C6-i4)aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of:

[0568] (Ci-io)alkyl,

[0569] -0-C(0)-(Ci-io)alkyl,

[0570] (Ci-6)alkylene-O-C(O)-(Ci-8)alkyl,

[0571] -O-C(O)-(C6-i4)aryl optionally substituted by (Ci-6)alkylene-O-C(O)-(Ci-8)alkyl, -0-(Ci.6)alkylene-(C6-io)aryl optionally substituted by -0-C(0)-(Ci-io)alkyl, -O-C(O)-(C3-i4)cycloalkyl, and

[0572] -OP(O)(OR9)2; and

[0573] n is an integer selected from 1-10.

[0574] In another embodiment, the compound is a compound of Formula (l-d),

[0575]

[0576] or a pharmaceutically acceptable salt thereof, wherein:

[0577] L is -C(O)- or -C(O)R5-;

[0578] Y is (C1-24)alkyl or (C1-8)alkylene-R8;

[0579] R5is -O-; and 70504W001

[0580] R8is (C3. i4)cycloalkyl.

[0581] In an embodiment, the compound selected from the group consisting of Formulae (l-a), (l-b), (l-c), (I-d), (l-e), and (l-f) is a compound of Formula (i-e),

[0582]

[0583] or a pharmaceutically acceptable salt thereof,

[0584] wherein

[0585] L is a bond, -C(O)-, -C(O)R5-, -CH2-O-C(O)-, or -CH2-O-C(O)R5-;

[0586] Y is selected from the group consisting of (Ci.24)alkyl, (C2.24)alkenyl, (Ci-io)alkoxy, 5- to 10- membered heteroaryl, (C1-8)alkylene-R8, (C2.s)alkenylene-R8, (C3.i4)cycloalkyl, (Ce-ujaryl, (C6- i4)bicycloalkyl, bridged (Cs-ujtricycloa Iky I, and 3- to 10-membered heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, wherein (C3.i4)cycloalkyl, (C6-i4)aryl, (Ce-ujbicycloalkyl, bridged (C8-14)tricycloalkyl, or the 3- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -O-C(O)-(Ci. sjalkyl, (Ci-6)alkylene-O-C(O)-(Ci-s)alkyl, -C(O)R7, oxo, and halogen;

[0587] or

[0588] Y is (Y-2),

[0589] / R11

[0590]

[0591] R12(Y-2);

[0592] or

[0593] Y is (Y-3)

[0594] , H₂ CH₃

[0595] C R13

[0596]

[0597] CH3 (Y-3);

[0598] R5is -O- or -NR6-;

[0599] R6is hydrogen or (Ci-6)alkyl;

[0600] R7is (Ci-io)alkyl, (Ci-io)alkoxy, or -NH-(Ci-io)alkyl; 70504W001

[0601] R8is selected from the group consisting of (Ci.24)alkoxy, (C2-24)alkenyloxy, -NH-C(O)-(Ci-i4)alkyl, - C(O)-(C! -24)alkoxy, -O-(CH2CH2O)n-(Ci-i4)alkyl, (Cs-wjcycloalkyl, (Cs ujbicycloalkyl, bridged (Cs- ujtricycloalkyl, (Cs-ujaryl, 3- to 10-membered heterocycloalkyl, -O-(Ci-8)alkylene-(C6-i4)aryl, and -OP(O)(OR9)2, wherein (C3-i4)cycloalkyl, (Ce-ujbicycloalkyl, bridged (Cs-ultricycloalkyl, (C6- i4)aryl, 3- to 10-membered heterocycloalkyl, or -O-(Ci-8)alkylene-(C6-i4)aryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -0-C(0)-(Ci-io)alkyl, (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -C(0)-(Ci-io)alkoxy, -C(O)- NH-(Ci-io)alkyl, oxo, and halogen;

[0602] R9is independently selected from hydrogen and (C1-8)alkyl;

[0603] R10is -CH- or -N-;

[0604] R11and R12are independently selected from the group consisting of (Ci-io)alkyl, -C(0)-0-(Ci-io)alkyl, (Ci-6)alkylene-(C6-i4)aryl, -C(0)-NH-(Ci-io)alkyl, (Ci-s)alkylene-S-(Ci-6)alkyl, -O-C(O)-(Ci- io)alkoxy, -O-C(O)-(Ci-8)alkyl, (Ci-8)alkylene-C(0)-(Ci-io)alkoxy, (Ci-8)alkylene-C(O)-NH-(Ci. io)alkyl, -NH-(Ci-io)alkyl, (Ci-8)alkylene-C(O)OH, and -C(O)OH, wherein (Ci-6)alkylene-(C6-i4)aryl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of (Ci-sjalkyl and halogen;

[0605] R13is (C6-i4)aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of:

[0606] (Ci-io)alkyl,

[0607] -0-C(0)-(Ci-io)alkyl,

[0608] (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl,

[0609] -O-C(O)-(C6-i4)aryl optionally substituted by (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -0-(Ci-6)alkylene-(C6-io)aryl optionally substituted by -0-C(0)-(Ci-io)alkyl, -O-C(O)-(C3-i4)cycloalkyl, and

[0610] -OP(O)(OR9)2; and

[0611] n is an integer selected from 1-10.

[0612] In another embodiment, the compound is a compound of Formula (l-e),

[0613]

[0614] or a pharmaceutically acceptable salt thereof, wherein: 70504W001

[0615] L is -C(O)-; and

[0616] Y is (Ci-24)alkyl.

[0617] In an embodiment, the compound selected from the group consisting of Formulae (l-a), (l-b), (l-c), (I-d), (l-e), and (l-f) is a compound of Formula (i-f),

[0618]

[0619] or a pharmaceutically acceptable salt thereof,

[0620] wherein

[0621] L is a bond, -C(O)-, -C(O)R5-, -CH2-O-C(O)-, or -CH2-O-C(O)R5-;

[0622] Y is selected from the group consisting of (Ci.24)alkyl, (C2.24)alkenyl, (Ci-io)alkoxy, 5- to 10- membered heteroaryl, (C1-8)alkylene-R8, (C2.s)alkenylene-R8, (C3.i4)cycloalkyl, (Ce-ujaryl, (C6- i4)bicycloalkyl, bridged (Cs-ujtricycloa Iky I, and 3- to 10-membered heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, wherein (C3.i4)cycloalkyl, (C6-i4)aryl, (Ce-ujbicycloalkyl, bridged (C8-14)tricycloalkyl, or the 3- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -O-C(O)-(Ci. sjalkyl, (Ci-6)alkylene-O-C(O)-(Ci-s)alkyl, -C(O)R7, oxo, and halogen;

[0623] or

[0624] Y is (Y-2),

[0625] zR11

[0626] | - R1^

[0627]

[0628] R12(Y-2);

[0629] or

[0630] Y is (Y-3)

[0631] , H CH3

[0632] C R13

[0633]

[0634] CH3 (Y-3);

[0635] R5is -O- or -NR6-; 70504W001

[0636] R6is hydrogen or (Ci-6)alkyl;

[0637] R7is (Ci-io)alkyl, (Ci-io)alkoxy, or -NH-(Ci-io)alkyl;

[0638] R8is selected from the group consisting of (Ci-24)alkoxy, (C2-24)alkenyloxy, -NH-C(O)-(Ci-i4)alkyl, - C(O)-(C! -24)alkoxy, -O-(CH2CH2O)n-(Ci-i4)alkyl, (C3-i4)cycloalkyl, (C6-i4)bicycloalkyl, bridged (C8- i4)tricycloalkyl, (C6-i4)aryl, 3- to 10-membered heterocycloalkyl, -O-(Ci-8)alkylene-(C6-i4)aryl, and -OP(O)(OR9)2, wherein (C3-i4)cycloalkyl, (C6-i4)bicycloalkyl, bridged (C8-i4)tricycloalkyl, (C6- i4)aryl, 3- to 10-membered heterocycloalkyl, or -O-(Ci-8)alkylene-(C6-i4)aryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -O-C(O)-(Ci-i0)alkyl, (Ci-6)alkylene-O-C(O)-(Ci-8)alkyl, -C(O)-(Ci-i0)alkoxy, -C(O)- NH-(Ci-io)alkyl, oxo, and halogen;

[0639] R9is independently selected from hydrogen and (C1-8)alkyl;

[0640] R10is -CH- or -N-;

[0641] R11and R12are independently selected from the group consisting of (Ci-io)alkyl, -C(O)-O-(Ci-i0)alkyl, (Ci-6)alkylene-(C6-i4)aryl, -C(O)-NH-(Ci-i0)alkyl, (Ci-8)alkylene-S-(Ci-6)alkyl, -O-C(O)-(Ci- io)alkoxy, -O-C(O)-(Ci-s)alkyl, (Ci-8)alkylene-C(O)-(Ci-i0)alkoxy, (Ci-8)alkylene-C(O)-NH-(Ci- io)alkyl, -NH-(Ci-io)alkyl, (Ci-s)alkylene-C(O)OH, and -C(O)OH, wherein (Ci-6)alkylene-(C6-i4)aryl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of (Ci-6)alkyl and halogen;

[0642] R13is (C6-i4)aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of:

[0643] (Ci-io)alkyl,

[0644] -0-C(0)-(Ci-io)alkyl,

[0645] (Ci-6)alkylene-O-C(O)-(Ci-8)alkyl,

[0646] -O-C(O)-(C6-i4)aryl optionally substituted by (Ci-6)alkylene-O-C(O)-(Ci-8)alkyl, -0-(Ci-6)alkylene-(C6-io)aryl optionally substituted by -0-C(0)-(Ci-io)alkyl, -O-C(O)-(C3-i4)cycloalkyl, and

[0647] -OP(O)(OR9)2; and

[0648] n is an integer selected from 1-10.

[0649] In another embodiment, the compound is a compound of Formula (l-f), 70504W001

[0650]

[0651] or a pharmaceutically acceptable salt thereof, wherein:

[0652] L is -C(O)-; and

[0653] Y is (Ci-24)alkyl.

[0654] In an embodiment, L is -C(O)- or -C(O)R5-. In another embodiment, L is -C(O)-. In another embodiment, L is -C(O)R5-.

[0655] In an embodiment, R5is -O-. In another embodiment, R5is -NR6-.

[0656] In an embodiment, Y is (Ci-24)alkyl, (C2.24)alkenyl, (C1-8)alkylene-R8, or (C2.s)alkenylene-R8. In another embodiment, Y is (Ci.24)alkyl. In another embodiment, Y is (C2.24)alkenyl. In another embodiment, Y is (Ci-s)alkylene-R8. In another embodiment, Y is (C2-s)alkenylene-R8.

[0657] In an embodiment, R8is (Ci.24)alkoxy, (C2.2)alkenyloxy, or (C3.i4)cycloalkyl. In an embodiment, R8is (Ci.24)alkoxy. In an embodiment, R8is (C2.2)alkenyloxy. In an embodiment, R8is (C3-14)cycloalkyl.

[0658] In an embodiment, n is 1. In another embodiment, n is 2, In another embodiment, n is 3. in another embodiment, n is 4. in another embodiment, n is 5. In another embodiment, n is 6. In another embodiment, n is 7. In another embodiment, n is 8. In another embodiment, n is 9. In another embodiment, n is 10.

[0659] In an embodiment, the compound of Formula (I), (l-b), (l-h), or (ll-a), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of Compound Nos. 3, 5, 7, 12, 13, 14, 2.3, 28, 29, 33, 35, 36, 37, 38, 42, 48, 49, 52, 53, 80, 81, 85, 86, 162, 179, and 182, or a pharmaceutically acceptable salt thereof.

[0660] In an embodiment, the compound of Formula (I) or (l-b), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of Compound Nos. 3, 5, 7, 12, 13, 14, 23, 28, 29, 33, 35, 36, 37, 33, 42, 48, 49, 52, 53, 80, 31, 85, 86, 162, 179, and 182: 70504W001

[0661]

[0662] 70504W001

[0663]

[0664] or a pharmaceutically acceptable salt thereof.

[0665] In a further embodiment, the compound of Formula (I), (l-b), (l-h), or (ll-a), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of Compound Nos. 5, 7, 14, 35, 80, and 86, or a pharmaceutically acceptable salt thereof.

[0666] In a further embodiment, the compound of Formula (I) or (l-b), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of Compound Nos. 5, 7, 14, 35, 80, and 86, 70504W001

[0667]

[0668] or a pharmaceutically acceptable salt thereof.

[0669] In a further embodiment, the compound of formula (I), (l-b), (l-h), or (ll-a), or a pharmaceutically acceptable salt thereof, is Compound No. 5,

[0670]

[0671] or a pharmaceutically acceptable salt thereof.

[0672] In a further embodiment, the compound of formula (I), (l-b), (l-h), or (ll-a) is Compound No. 5,

[0673]

[0674] In a further embodiment, the compound of Formula (I) or (l-b), or a pharmaceutically acceptable salt thereof, is Compound No. 5 70504W001

[0675]

[0676] or a pharmaceutically acceptable salt thereof.

[0677] In a further embodiment, the compound of Formula (I), (l-b), (l-h), or (ll-a) is Compound No. 7,

[0678]

[0679] or a pharmaceutically acceptable salt thereof.

[0680] In a further embodiment, the compound of Formula (I), (l-b), (l-h), or (ll-a), or a pharmaceutically acceptable salt thereof, is Compound No. 7,

[0681]

[0682] In a further embodiment, the compound of Formula (I) or (l-b), or a pharmaceutically acceptable salt thereof, is Compound No. 7,

[0683]

[0684] or a pharmaceutically acceptable salt thereof.

[0685] In a further embodiment, the compound of Formula (I), (l-b), (l-h), or (ll-a), or a pharmaceutically acceptable salt thereof, is Compound No. 14, 70504W001

[0686]

[0687] or a pharmaceutically acceptable salt thereof.

[0688] in a further embodiment, the compound of formula (I), (l-b), (l-h), or (ll-a) is Compound No. 14,

[0689]

[0690] In a further embodiment, the compound of Formula (I) or (l-b), or a pharmaceutically acceptable salt thereof, is Compound No. 14,

[0691]

[0692] or a pharmaceutically acceptable salt thereof.

[0693] In a further embodiment, the compound of formula (I), (i-b), (l-h), or (ll-a), or a pharmaceutically acceptable salt thereof, is Compound No. 35,

[0694]

[0695] or a pharmaceutically acceptable salt thereof.

[0696] In a further embodiment, the compound of formula (I), (l-b), (l-h), or (ll-a) is Compound No. 35, 70504W001

[0697]

[0698] In a further embodiment, the compound of formula (I) or (l-b), or a pharmaceutically acceptable salt thereof, is Compound No. 35,

[0699]

[0700] or a pharmaceutically acceptable salt thereof.

[0701] In a further embodiment, the compound of formula (I), (l-b), (l-h), or (ll-a), or a pharmaceutically acceptable salt thereof, is Compound Mo. 80,

[0702]

[0703] or a pharmaceutically acceptable salt thereof.

[0704] In a further embodiment, the compound of Formula (I), (l-b), (l-h), or (ll-a) is Compound No, 80,

[0705]

[0706] In a further embodiment, the compound of Formula (I) or (l-b), or a pharmaceutically acceptable salt thereof, is Compound No, 80, 70504W001

[0707]

[0708] or a pharmaceutically acceptable salt thereof.

[0709] In a further embodiment, the compound of Formula (I), (!- b), (l-h), or (ll-a), or a pharmaceutically acceptable salt thereof is Compound No. 86,

[0710]

[0711] or a pharmaceutically acceptable salt thereof.

[0712] In a further embodiment, the compound of formula (I), (l-b), (l-h), or (II-a) is Compound No. 86,

[0713]

[0714] In a further embodiment, the compound of Formula (I) or (l-b), or a pharmaceutically acceptable salt thereof, is Compound No. 86,

[0715]

[0716] or a pharmaceutically acceptable salt thereof.

[0717] Representative compounds of Formula (I) are presented in Table 1 below. 70504W001

[0718] Table 1.

[0719] Compound No.

[0720] / Example No. Chemical Name Structure

[0721] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 1 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- A ^ ^ pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0722] tetradecanoate

[0723] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 2 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0724] palmitate

[0725] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 3 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- Ox JL pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl r 1

[0726] stearate y y

[0727] F 0 J — / (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 4 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0728] nonadecanoate

[0729] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 5 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0730] icosanoate

[0731] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 6 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0732] henicosanoate

[0733] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 7 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0734] docosanoate

[0735] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- O^O 0 8 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- 1^ H H1L. H pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl 3- (2-(2-methoxyethoxy)ethoxy)propanoate

[0736] F 0 / oJ-7

[0737]

[0738] 70504W001

[0739] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 9 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0740] 2,5,8,ll,14-pentaoxaheptadecan-17-oate

[0741] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 10 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0742] 2,5,8,ll,14,17,20-heptaoxatricosan-23-oate

[0743] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 11 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0744] 2,5,8,11,14,17,20,23,26-nonaoxanonacosan- 29-oate

[0745] /

[0746] o

[0747] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 0^0 0 12 o

[0748] methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- H 1 L*H pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0749] isobutyrateFo

[0750] 0'oJ-7\ f O -n—

[0751] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- O ZI 13 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- p< °oc / pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0752] Ox°-o hexanoate Lz\ )o=

[0753] / z \ (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 14 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0754] heptanoate F 0 ) — '

[0755] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 15 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0756] octanoate

[0757] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 16 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0758] tricosanoate

[0759]

[0760] 70504W001

[0761] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 17 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0762] tetracosanoate

[0763] O

[0764] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 18 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-ylCIA^N^N.N>Htridecanoate ) — 1

[0765] 7°^ (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 19 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0766] undecanoate

[0767] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 20 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0768] nonanoate

[0769] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 21 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl ^ ^ decanoate n H Y TN> H

[0770] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 22 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl ^ ^ dodecanoate

[0771]

[0772] 70504W001

[0773] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 23 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0774] pivalate

[0775] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 24 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0776] pentadecanoate

[0777] isopropyl (((((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 25 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H- pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6- yl)oxy)methoxy)carbonyl)-L-methioninate

[0778] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 26 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0779] heptadecanoate

[0780] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 27 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- ^ pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0781] (ls,4S)-4-pentylcyclohexane-l-carboxylate

[0782] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 28 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0783] benzoate

[0784]

[0785] 70504W001

[0786] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 29 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0787] bicyclo[2.2.2]octane-l-carboxylate

[0788] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 30 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- ^ pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0789] spiro[3.3]heptane-2-carboxylate

[0790] lS,3aS)-8-((3-chloro-2- ^ fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 310JL methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl Q decanoyl-L-prolinate

[0791] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 32 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0792] spiro[4.5]decane-8-carboxylate Lz—L \z\

[0793] >

[0794] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 33 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- CT 'O pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0795] 4,4-difluorocyclohexane-l-carboxylate

[0796] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 34 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0797] (lr,4S)-4-(tert-butyl)cyclohexane-l-carboxylate

[0798] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 35 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0799] isopropyl carbonate

[0800]

[0801] 70504W001

[0802] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 36 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl / \ 1z\ \ H cyclopentyl carbonate \(O=

[0803] < )\ oV °

[0804] ) o oo=

[0805] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 37 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0806] nonyl carbonate o

[0807] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 38 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0808] decyl carbonate

[0809] o

[0810] (lS,3aS)-8-((3-chloro-2- o o fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 39 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl ZT

[0811] 2 o o o= octadecyl carbonate

[0812] o2 / ) y<xo o o o o o= °==— \ / / o

[0813] ( / z\—< \ ) < ) XoOz~ O= O- (lS,3aS)-8-((3-chloro-2- L (zLz1 \—\ fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-o / =40 \ methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0814] phenyl carbonate

[0815] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 41 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0816] (tetrahydro-2H-pyran-4-yl) carbonate

[0817] tert-butyl ((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 42 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl)

[0818] carbonate

[0819]

[0820] 70504W001

[0821] (lS,3aS)-8-((3-chloro-2- zY 1 - fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- O / = 43 7 z methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- 1 ZY- / o=\ )\ ° ° pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl(2- ) < o oo= (2-methoxyethoxy)ethyl)carbonate f )\ o- °

[0822] /

[0823] ) < o oo= / / ( oo-(lS,3aS)-8-((3-chloro-2- \ o fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 44 $ *

[0824] methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- I 4 o

[0825] o

[0826] pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yl(2,5,8,ll-tetraoxatridecan-13-yl)carbonate o

[0827] /

[0828] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 45 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0829] (2,5,8,ll,14,17-hexaoxanonadecan-19-yl)

[0830] carbonate / O o

[0831] (lS,3aS)-8-((3-chloro-2- o

[0832] fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 0^0 0

[0833] 46 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- ZI o H 1 L*H pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl ( o o o=

[0834] undecyl carbonate F 0 ) — '

[0835] > \ o

[0836] < / z—

[0837] \o / =

[0838] (lS,3aS)-8-((3-chloro-2- \ \ fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 47 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl Co° °=v / tetradecyl carbonate ° \ / O c / z— z 1 (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 48 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0839] icosyl carbonate

[0840] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 0^0 0 49 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0841] octyl carbonatef°

[0842] o

[0843] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 50 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- 0^0 0 pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl (1- decanoylpiperidin-4-yl) carbonate C 1n'Y ***''N'N

[0844]

[0845] 70504W001

[0846] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 51 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- 1 z¥- o / \ z=- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl 7 z methyl carbonate ( > o- ) o oo= / '(°~ iz (lS,3aS)-8-((3-chloro-2- k, fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 52 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl o

[0847] ethyl carbonate

[0848] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 53 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0849] isopentyl carbonate

[0850] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 54 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl ZI

[0851] hexadecyl carbonate ( o o o=

[0852] x° \ / / o (lS,3aS)-8-((3-chloro-2- \ \ fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 55 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0853] ((lR,2S,5R)-2-isopropyl-5-methylcyclohexyl)

[0854] carbonate

[0855] benzyl ((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 9 56 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl)

[0856] carbonate

[0857] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 57 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0858] dodecyl carbonate

[0859]

[0860] 70504W001

[0861] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 58 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl 7 z (((di-tert-butoxyphosphoryl)oxyjmethyl)

[0862] carbonate 7

[0863] ^

[0864] (lS,3aS)-8-((3-chloro-2- 0 fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 59 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- ylmorpholine-4-carboxylate

[0865] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 60 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0866] dodecylcarbamate

[0867] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 61 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0868] methylcarbamate

[0869] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 62 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl ((2S,3S)-l-(isopentylamino)-3- methyl-l-oxopentan-2-yl)carbamate

[0870] (lS,3aS)-8-((3-chloro-2- 3 fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 63 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0871] isopropylcarbamate

[0872] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- J

[0873] 64 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl °0A J / (tert-butoxycarbonylj(isopentyl)carbamate

[0874]

[0875] 70504W001

[0876] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 65 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H- 10\ 1zpyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0877] benzyl(tert-butoxycarbonyl)carbamate c iN N'NF\ / / 0A ° ° ° — —Qx°- ° (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-TAA, methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- Ip 4 A-66

[0878] pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl ((S)-l-(isopentylamino)-4- (methylthio)-l-oxobutan-2-yl)carbamate

[0879] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- 67

[0880] pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl 3- (2-acetoxy-4,6-dimethylphenyl)-3- QH°X^> H methylbutanoate

[0881] F° / 0^ (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- 68 pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl 3- (2,4-dimethyl-6-((4- (pivaloyloxy)benzyl)oxy)phenyl)-3- methylbutanoate

[0882] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 69 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl cyclohexylcarbamate

[0883] 2-(4-(((lS,3aS)-8-((3-Chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- 70

[0884] pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yl)oxy)-2-methyl-4-oxobutan-2-yl)-3,5- dimethylphenyl 1-naphthoate

[0885]

[0886] 70504W001

[0887] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- / A 71 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl 3- (2,4-dimethyl-6-(pivaloyloxy)phenyl)-3- Q methylbutanoate

[0888] 2-(4-(((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- 72 pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- OAD yl)oxy)-2-methyl-4-oxobutan-2-yl)-3,5- dimethylphenyl 2- ((pivaloyloxyjmethyljbenzoateF° ^J-7

[0889] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 73 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl 3- (2-((diethoxyphosphoryl)oxy)-4,6- dimethylphenyl)-3-methylbutanoate

[0890] (lS,3aS)-8-((3-chloro-2- O fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 74 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- A pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl 3- (2,4-dimethyl-6-(phosphonooxy)phenyl)-3- methylbutanoate

[0891] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 75 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl 2- A ((pivaloyloxyjmethyljbenzoate

[0892] J

[0893] 2-(4-(((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 76 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yl)oxy)-2-methyl-4-oxobutan-2-yl)-3,5- dimethylphenyl decanoate

[0894]

[0895] 70504W001

[0896] 2-(4-(((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 77 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- ^ \ 1zpyrido 2 l f o / = °= \ / z[, - ]pyrrolo[l,2-b] [l,2,4]triazin-6- yl)oxy)-2-methyl-4-oxobutan-2-yl)-3,5- / < dimethylphenyl benzoatec \ / \ i°q— — ' /

[0897] IZ ' \

[0898] (5-(tert-butyl)-2-oxo-l,3-dioxol-4-yl)methyl o % &

[0899] ((lS,3aS)-8-((3-chloro-2- o

[0900] 78 fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl)

[0901] carbonate

[0902] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 79 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0903] 3,3-dimethylbutanoate

[0904] o

[0905] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 80 ZT o methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- / oo= _ pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl 2- H H1L*H cyclopentylacetate

[0906] F 0

[0907] I

[0908] ^0 \ (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 81 0^0 0 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl 3-CI5 n^ HN^0YVN.Nj>r'Hmethoxypropanoate

[0909] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 82 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[0910] acetate

[0911] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- O^o o 83 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl A H YVN> Hbutyrate F O J — /

[0912]

[0913] (1S,3aS)-8-((3-chloro-2-

[0914] fluorobenzyl)carbamoyl)-1-(methoxymethyl)-4-

[0915] Z-Y z -Y 1 \

[0916] z -Y

[0917] methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-

[0918] = / / z' > o= / O=( °=Z z-Ao=( / z' >

[0919] pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6-

[0920] o— °\ °A / > °\

[0921] yl pentanoate

[0922] > — ' o oz / =o — / o o' )=o < k ol o b 4 b

[0923] O zi iz b r

[0924] ' IZ IZ ' IZ ' IZ O zi iz

[0925] 4% A

[0926] 4 A a. 4- A ° o

[0927] o Q O o b3

[0928] 4, rn 4, < N

[0929] 51>- 51>- rx •i =t, 5

[0930] * H 5 £ t 5 £ t

[0931]

[0932] 2 5 2 * H 5 £ 1 d

[0933] p -O -- E -g. -E - E -g. -E a, E >» r>4 E -§. -s 2 E -° -E CN 1 ■§- | S

[0934] X -E 5* -c ro ■£

[0935] o -= CD.s s- x S -= CD.2 S- x S -= CD.2 S- x.2 ■- V o s t ™ 2 8 g t E o gtE 9 x -t-j~ X 3-19 X 3-1m i— O -c J " CD

[0936] S £ OJ T S _C QJ -C 0) -0- * Q. 5 - 5 - 5 - 5 - 5 (J c J < N — c J < N — oo p < £ E r< E r£ C l\ *.■ CbO1c f\ _ r bo E A 3

[0937] T 'T' T LT? i — ■ T LT). —. _j £2- " V — i _j < Z> 1. LA I — 1 _|

[0938] *7* _Q *7* «sT _Q *7* «sT _Q 'V' ^T1'E' _Q CN ’T* -Q ri*

[0939] m 5. -9 4 1 ro CN 1 ro CN 1 S. CM 2 >- £ A § o "i ^r A' §" "3 § O " I H *> O " I rd O " I < H o ra <z m -— ■ n 2 E "1 o' 2 E "1 o' 2 E ". o S E "1 o' -2 Z E "1 o' -2 "1 ra <4 -2 o ra -5

[0940] A -2 6 2 3 ^ 6 ° ^ 6 2 X -2 6 2 3 z -2 6 2 S m s- 9 t

[0941] o CD § >. QJuro > S t 03 ¥ 3 S > o o g* X g d 2 □: s op -O pH; o 1 2 £2- - Z — £?? S -C ~r Er,< oj rb ' £ A >• c a; ob C A 23 op c 2;- A S

[0942] -A. QJ up rsi +-1-k a; op rxi ■£ a; op c §■ £ up CN £ A QJ fN 2 £ _g < £1 E cn -J- “ cn -A- “

[0943] CD o >“ O _£2 CD O •>' ° 9 cn o >“ o ■>; CD O ° V o ">■ o S: Q. " O >* O m s_ yu m s_ yu ■£ CM i- ■£ " O X E x o E ■£ x ™ E ■£

[0944] cn ~ a; o cn 2 cu h- cn § aj -c Tn § (D S n •— §aj>. ^

[0945] d- qi E Q. Q. d e E a: E qz E Q. q= E Q_ >• •Ti q= E a) q= E Q. >•

[0946] in ID 00 ai O

[0947] 00 co co 00 00 00 ai

[0948]

[0949] 70504W001

[0950] (((((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 91 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- \ 1zpyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yl)oxy)methoxy)carbonyl)-L-aspartic acid

[0951] A 4

[0952] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 92 3

[0953] methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- n WV yljoxyjmethyl

[0954] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 93 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl A YAF 0 / 0J^ (((lS,3aS)-8-((3-chloro-2- p ft ■ fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- O zz iz

[0955] / ^ o oo==

[0956] 94 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- < O yl)oxy)methyl((S)-l,4-bis(isopentylamino)-l,4- P L ) XOZ=- dioxobutan-2-yl)carbamate

[0957] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 95 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yl)oxy)methyl((S)-l,4-bis((2-ethylbutyl)amino)- A YA l,4-dioxobutan-2-yl)carbamate

[0958] bis(2-ethylbutyl) (((((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 96 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yl)oxy)methoxy)carbonyl)-L-glutamate

[0959]

[0960] 70504W001

[0961] diisopropyl (((((lS,3aS)-8-((3-chloro-2- \ 1zfluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- \ 1z97 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- f \ o \- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yl)oxy)methoxy)carbonyl)-L-aspartate

[0962] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 98 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl hexanoateF 0fj-1

[0963] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 99 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl undecanoate

[0964] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 100 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl tridecanoate

[0965] S

[0966] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- — \ 101 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl henicosanoate

[0967] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- o\ 102 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- n YA yljoxyjmethyl cyclohexanecarboxylateF 0pj-'

[0968] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 103 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-CIAA. N^N,NP yljoxyjmethyl pentanoate

[0969]

[0970] 70504W001

[0971] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 104 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl heptanoate

[0972] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 105 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- A yljoxyjmethyl nonanoate

[0973] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-o106 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- n H °YV^ yljoxyjmethyl benzoate

[0974] F 0

[0975] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 107 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- n HOYV^Hyljoxyjmethyl 4-methylpentanoate

[0976] F 0 /

[0977] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- GA 0 0 108 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- IOI HH°Y\1XNL". H yljoxyjmethyl bicyclo[2.2.2]octane-l- carboxylateCIAYNYN'NAf° / oA-7

[0978] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 109 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- r^i H H 1 I^H yl)oxy)methyl (1s,4S)-4-pentylcyclohexane-1- S carboxylate

[0979] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 110 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- W N" H1yl)oxy)methyl (1r,4S)-4-(tert-butyl)cyclohexane-1-carboxylate

[0980]

[0981] 70504W001

[0982] 0 (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- z¥ / - 111 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- X 0

[0983] 7 z pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- n ( }\ °— H °°YV^ yljoxyjmethyl 2,5,8,11,14-H) oo= pentaoxaheptadecan-17-oate / XIZF”0'

[0984] 0

[0985] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 112 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- <0 0 pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- n H°Y\VH yljoxyjmethyl 3-(2-(2- c iN N' N methoxyethoxyjethoxyjpropanoateF 0

[0986] (((lS,3aS)-8-((3-chloro-2- 0 fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 113 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- ^0 0 pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl 2,5,8,11,14,17,20- heptaoxatricosan-23-oateF 0

[0987] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 114 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl decanoyl-L-prolinate O zx z^

[0988] z j o o=

[0989] x°o \ /

[0990] < / z— l-(((lS,3aS)-8-((3-chloro-2- / 0^0 fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 115 ^^0 0 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- n. - YA'" yljoxyjethyl isobutyrate

[0991] F 0 / oX-7

[0992] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 116 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl decanoylglycinate

[0993] 0

[0994] (((lS,3aS)-8-((3-chloro-2- cP o fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 117 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- r

[0995] yljoxyjmethyl spiro[4.5]decane-8-carboxylateNH

[0996]

[0997] 70504W001

[0998] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 118 AZA \ methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- \ 1To / =zpyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- 7 z yljoxyjmethyl spiro[3.3]heptane-2-carboxylate

[0999] ) o / oo==

[1000] 0 (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- u

[1001] 119 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- o

[1002] pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl decanoateF 0fj-1

[1003] 0 (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 120 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl dodecanoate

[1004] F 0

[1005] 0(((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 121 0 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-C|A^N^N.N>Hyljoxyjmethyl 2-phenylacetate

[1006] F 0 / O--^ ' 0 (((lS,3aS)-8-((3-chloro-2- — ^0 fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- ^0 0 122 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl propionate

[1007] F 0^J-10 (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 123 A0methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl isobutyrate

[1008] F 0

[1009] 10(((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 124 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl 3-methylbutanoate

[1010] F 0

[1011]

[1012] 70504W001

[1013] 0 (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- ^0 0 125 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl 3-methylbutanoate JOLH

[1014] F 0 /

[1015] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 126 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl pivalate

[1016] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 127 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl acetate

[1017] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 128 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl nonadecanoate

[1018] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 129 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl 4,4-difluor°Cyclohexane-l- carboxylate

[1019] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 130 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl heptadecanoate

[1020] ^

[1021] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 131 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl methyl carbonate

[1022]

[1023] 70504W001

[1024] 0 (((lS,3aS)-8-((3-chloro-2- ^□A fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- o \ 132 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- 1 \ I z¥z- >( / pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-o■z=*

[1025] 77 z z(o=C 1N N' N( >\ o- ° >\ ° yljoxyjmethyl ethyl carbonate

[1026] \ \?? — —F 0 / OA-7A> o JO-<( / ) o oo o oo==== O IZ _ O IZ

[1027] 6

[1028] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- o o 133 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl isopropyl carbonate

[1029] 0 (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- ' ^0 0 134 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- jQ H °YV;ZHpyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl isobutyl carbonate

[1030] F 0

[1031] tert-butyl ((((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 135 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl) carbonate

[1032] F 0 / -A7

[1033] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 136 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl isopentyl carbonate

[1034] F 0

[1035] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 137 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl cyclohexyl carbonate

[1036] benzyl ((((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 138 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl) carbonate

[1037]

[1038] 70504W001

[1039] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- \ 139 \ 1z5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-, X O / = \ 1 methyl- o / Z="z / 7 z z pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- ( }( ) O O-- yljoxyjmethyl heptyl carbonate \ o

[1040] ( ) ( o o ) o o o—— —

[1041] O TZo—=

[1042] o iz

[1043] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 140 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl octyl carbonate

[1044] 0 (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- ^0 0 141 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl nonyl carbonate c iN N' NF 0'

[1045] (((lS,3aS)-8-((3-chloro-2- o fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 142 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl decyl carbonate C ZI>

[1046] ^ / o oo==

[1047] x° \ / o Lz\—(((lS,3aS)-8-((3-chloro-2- X °z-- / \ fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 143 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl undecyl carbonate

[1048] F° / 0 (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 144 ^0 0 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- n H °YV^Hyljoxyjmethyl dodecyl carbonate

[1049] F 0

[1050] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 145 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl tetradecyl carbonateF 0'

[1051]

[1052] 70504W001

[1053] o (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 146 ^o o methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-CI^ n^NY^N. >Hyljoxyjmethyl hexadecyl carbonate

[1054] F°

[1055] 0 (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 147 ^0 0 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- ciN N'N / yljoxyjmethyl octadecyl carbonateF 0

[1056] 0 (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 148 ^0 0 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl icosyl carbonate

[1057] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 149 ^0 0 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- r^ii H °Y^VJI"N^

[1058] C|A^ HN^N 1 L. H yljoxyjmethyl phenyl carbonate

[1059] F 0 J — ‘

[1060] (((lS,3aS)-8-((3-chloro-2-HN^o fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 0^0 150 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl (2-decanamidoethyl) carbonate

[1061] F 0

[1062] O'^ 0

[1063] (((lS,3aS)-8-((3-chloro-2- <? N^0A0fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 151 <0 0 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- A

[1064] yljoxyjmethyl (2-morpholinoethyl) carbonate

[1065] F 0yj-1

[1066] 0

[1067] l-(((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 152 ■^0 0 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- aN N'n) yljoxyjethyl ethyl carbonate

[1068] F 0 / 0-?-7

[1069]

[1070] 70504W001

[1071] 0 (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 1 <0 0 \ 53 ZY- methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- (o=pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- / z >\ oV ° >Hyljoxyjmethyl (2-methoxyethyl) carbonate

[1072] F 0\ Z —

[1073] ^ ) o oo== / oJ- O TZ7(((lS,3aS)-8-((3-chloro-2- ^ ^ o—==fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- o

[1074] 154 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- o

[1075] /

[1076] pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl (2-(2-methoxyethoxy)ethyl)

[1077] carbonate

[1078] o (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- X

[1079] 155 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-NA° pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl 6-azaspiro[2.5]octane-6- carboxylate

[1080] (((lS,3aS)-8-((3-chloro-2- O X fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- ^0^^^ 0 o

[1081] 156 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- o

[1082] pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl (2-(2-m~ / \ o methoxyethoxyjethyljcarbamateF

[1083] C0o zi iz / oJ- T^ Q°7o / O O= l-((((lS,3aS)-8-((3-chloro-2- Lzo—\ t / z—z y- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- / o / =

[1084] \ 157 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl) 2-decyl (S)-pyrrolidine-l,2- dicarboxylate

[1085] decyl (((((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 158 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H- pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6- yl)oxy)methoxy)carbonyl)-L-alaninate

[1086] 0 (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 159 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl decylcarbamate

[1087] F 0

[1088]

[1089] 70504W001

[1090] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 160 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- Q yljoxyjmethyl undecylcarbamateF 0^A-7

[1091] (((lS,3aS)-8-((3-chloro-2- V fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 161 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl tert-butylcarbamate

[1092] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 162 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- Q

[1093] yljoxyjmethyl isopentylcarbamate

[1094] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 163 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl ethylcarbamate

[1095] (((lS,3aS)-8-((3-chloro-2- A fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 164 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- Q

[1096] yljoxyjmethyl dimethylcarbamate

[1097] A

[1098] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- U

[1099] 165 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-CIA n^ ANYY^SN / ,NV>; yljoxyjmethyl benzylcarbamate

[1100] F° ^A-7(((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 166 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl octadecylcarbamate A

[1101]

[1102] 70504W001

[1103] 0 (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 167H ko methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl icosylcarbamate

[1104] (((lS,3aS)-8-((3-chloro-2- VN^NAO fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 168Hb methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl (2-morpholinoethyl)carbamateF° / 0J^ (((lS,3aS)-8-((3-chloro-2-HN^NAO fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 169 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl (2-decanamidoethyl)carbamate

[1105] (((lS,3aS)-8-((3-chloro-2- A fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 170 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- c iN N'N; yljoxyjmethyl methylcarbamate

[1106] Z

[1107] 0 L 'z\~ (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- > ^0 0 171 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl diethylcarbamate JOLH

[1108] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 172 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl 4-methylpiperazine-l- carboxylate

[1109] o (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 173 o0methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl piperidine-l-carboxylate c iN N'N /

[1110] F 0 / OJ~J

[1111]

[1112] 70504W001

[1113] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 174 A

[1114] methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl morpholine-4-carboxylateF° fj-1

[1115] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 175 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl tetradecylcarbamate

[1116] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 176 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-CI^^NY^ > -H yljoxyjmethyl dodecylcarbamate

[1117] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 177 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl heptylcarbamate P! - yO~ (((lS,3aS)-8-((3-chloro-2- Lz—\ fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- <° r 178 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- Lz~\ pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl octylcarbamate

[1118] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 179 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl cyclohexylcarbamate

[1119] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 180 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl nonylcarbamate

[1120]

[1121] 70504W001

[1122] o

[1123] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 181Ho methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- n H°YV;ZHyljoxyjmethyl hexylcarbamateF 0

[1124] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 182 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl isobutylcarbamate

[1125] 0 (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 183 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl hexadecylcarbamateF 0

[1126] / o 0

[1127] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- o o

[1128] 184H<0 0 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- JOzo oL

[1129] yljoxyjmethyl (2-methoxyethyl)carbamateFZI IZ

[1130] O / ^ -n—0

[1131] o oo—=

[1132] 1 0 < )o~ O ZI IZ (((lS,3aS)-8-((3-chloro-2- AA )^ \' o oo0z==”- z fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 185 " '■•0 0

[1133] methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- H°Y\AN-Qr \ o Lz\—pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- \ )oz=-- / yljoxyjmethyl isopropylcarbamat \

[1134] F°

[1135] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 186 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl (2,5,8,ll-tetraoxatridecan-13- yljcarbamate

[1136] 4-((((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 187 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- Cl.0 0 pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yl)oxy)methyl)phenyl pivalate

[1137] 0

[1138]

[1139] 70504W001

[1140] (lS,3aS)-N-(3-chloro-2-fluorobenzyl)-l- (methoxymethyl)-4-methyl-6-((5-methyl-2-oxo- 188 l,3-dioxol-4-yl)methoxy)-5,7-dioxo- 2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l- f]pyrrolo[l,2-b][l,2,4]triazine-8-carboxamideF° ° T o °s° 0

[1141] (lS,3aS)-8-((3-chloro-2- V? fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- c> o o 189 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- H °vS pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl H 1X^'N L / * H acetyl-L-prolinate

[1142] F O 3—7 o~z

[1143] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l- (methoxymethyl)- 190 4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[1144] isonicotinate o

[1145] 2-(benzyloxy)ethyl ((((lS,3aS)-8-((3-chloro-2- l L^ JllIo0 I fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- '^x' ZTo 0 0 0 191 ^ O O O= - - methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- \ ) ( f z —— pyrido[2,l-f]pyrrolo[l,2- b] [l,2,4]triazin-6- ) <x°-o yljoxyjmethyl) carbonateF 0Lz\° / = \ (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 0^0 0 192 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[1146] isopentylcarbamateF 0

[1147] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 193 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl ((S)-l-(isopentylamino)-l-oxo-3- phenylpropan-2-yl)carbamate

[1148] F°

[1149] isopropyl (((((lS,3aS)-8-((3-chloro-2- ^Y° o fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 194 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H- pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6- yl)oxy)methoxy)carbonyl)-L-valinate

[1150] F 0

[1151]

[1152] 70504W001

[1153] 2-ethylbutyl (((((lS,3aS)-8-((3- chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- A 195 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- \ 1

[1154] \ 1z zpyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yl)oxy)methoxy)carbonyl)-L-valinate

[1155] ( o 0=? \ \ / ° —~^ —

[1156] (((lS,3aS)-8-((3-chloro-2- C 488L < N °0fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- A 196 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl ((S)-l-((2-ethylbutyl)amino)-3- A

[1157] methyl-l-oxobutan-2-yl)carbamate

[1158] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- A

[1159] 197 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yl)oxy)methyl ((S)-1-(isopentylamino)-3- methyl-1-oxobutan-2-yl)carbamate >

[1160] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- AZ 198 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yl)oxy)methyl ((S)-1-((2-ethylbutyl)amino)-4- (methylthio)-1-oxobutan-2-yl)carbamate

[1161] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 199 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yl)oxy)methyl ((S)-1-((2-ethylbutyl)amino)-1- oxo-3-phenylpropan-2-yl)carbamate

[1162] isopropyl (((((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 200 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H- pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6- yl)oxy)methoxy)carbonyl)-L-leucinate

[1163]

[1164] 70504W001

[1165] 2-ethylbutyl (((((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 201 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- \ 1zpyrido[2,l-f]pyrrolo[l,2- b] [l,2,4]triazin-6- yl)oxy)methoxy)carbonyl)-L-leucinate \ ) —

[1166] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- Az 202 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- A pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yl)oxy)methyl ((S)-1-(isopentylamino)-4- methyl-1-oxopentan-2-yl)carbamate

[1167] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- V 203 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- X pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yl)oxy)methyl ((S)-1-((2-ethylbutyl)amino)-4- methyl-1-oxopentan-2-yl)carbamate

[1168] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 204 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yl)oxy)methyl ((S)-1-((2-ethylbutyl)amino)-4- methyl-1-oxopentan-2-yl)carbamateF 0pj-1

[1169] 2-ethylbutyl(((((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 205 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- / pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yl)oxy)methoxy)carbonyl)-L-isoleucinate Y ^N'N}

[1170] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- J Z 206 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2- b] [l,2,4]triazin-6- yl)oxy)methyl ((S)-1-((2-ethylbutyl)amino)-1- oxopropan-2-yl)carbamate

[1171] (((lS,3aS)-8-((3-chloro-2- 4 fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- ZIHNY°

[1172] FIJZNA

[1173] 207 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-0pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yl)oxy)methyl ((S)-3-(3,5-difluorophenyl)-1- (isopentylamino)-1-oxopropan-2-yl)carbamate

[1174]

[1175] 70504W001

[1176] isopropyl (((((lS,3aS)-8-((3-chloro-2- o fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 208 I methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- >H<0 0 pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yl)oxy)methoxy)carbonyl)-L-isoleucinate \? ° (— — ^ \( / o° °=F 0 / O^A ^4

[1177] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- vU 209 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- / pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yl)oxy)methyl ((2S,3S)-1-((2-ethylbutyl)amino)- 3-methyl-1-oxopentan-2-yl)carbamate

[1178] N'^i Il J (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)- 210 CT 'O 0 4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[1179] nicotinate

[1180] F 0

[1181] (((((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 211 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H- pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6- yl)oxy)methoxy)carbonyl)-L-phenylalaninate

[1182] F 0pj-j isopropyl (S)-2-((((((lS,3aS)-8-((3- chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 212 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yl)oxy)methoxy)carbonyl)amino)-3-(3,5- difluorophenyl)propanoate

[1183] 2-ethylbutyl (S)-2-((((((lS,3aS)-8-((3- chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 213 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yl)oxy)methoxy)carbonyl)amino)-3-(3,5- difluorophenyl)propanoate

[1184]

[1185] 70504W001

[1186] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- M 214 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6- yl)oxy)methyl ((S)-1-(isopentylamino)-1- oxopropan-2-yl)carbamate

[1187] l-((((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 215 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l- f]pyrrolo[l,2-b] [l,2,4]triazin-6- n W yl)oxy)methyl) 2-(2-ethylbutyl) (S)-pyrrolidine- 1,2-dicarboxylate

[1188] (((lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 216 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l- f]pyrrolo[l,2-b] [l,2,4]triazin-6- yl)oxy)methyl (S)-2- (isopentylcarbamoyl)pyrrolidine-1-carboxylate

[1189] 2-ethylbutyl (((((lS,3aS)-8-((3-chloro-2- C fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- A 217 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H- pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6- yl)oxy)methoxy)carbonyl)-L-methioninate

[1190] 2-ethylbutyl (((((lS,3aS)-8-((3-chloro-2- Cu fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 218 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H- pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6- yl)oxy)methoxy)carbonyl)-L-alaninate

[1191] isopropyl (((((lS,3aS)-8-((3-chloro-2- zx fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 219 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H- pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6- yl)oxy)methoxy)carbonyl)-L-alaninate

[1192] Z

[1193] 2-ethylbutyl (((((lS,3aS)-8-((3-chloro-2- V fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- UAz 220 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H- pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6- yl)oxy)methoxy)carbonyl)-L-phenylalaninate

[1194]

[1195] 70504W001

[1196] { H Q

[1197] (((lS,3aS)-8-((3-chloro-2- L. W 0 fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 221 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- 0 0 pyrido[2,l- f]pyrrolo[l,2-b] [l,2,4]triazin-6- yljoxyjmethyl (S)-2-((2- \ / )\o—° ethylbutyl)carbamoyl)pyrrolidine-l-carboxylateF(o=

[1198] / °0 / oJ-7TZ '

[1199] (((lS,3aS)-8-((3-chloro-2- F

[1200] A js HN^O fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- r ii o

[1201] 222 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- UJ

[1202] pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-H0 yl)oxy)methyl ((S)-3-(3,5-difluorophenyl)-1-((2- ethylbutyl)amino)-1-oxopropan-2-yl)carbamate

[1203] F 0pj-l

[1204] 0

[1205] (S)-9-((2,4-difluorobenzyl)carbamoyl)-5-methyl- 0 223 6,8-dioxo-l,2,3,4,4a,5,6,8- octahydrodipyrido[l,2-b:2',l'- / ][l,2,4]triazin-7-FV^jl H

[1206] yl propionate

[1207] F 0

[1208] (S)-9-((2,4-difluorobenzyl)carbamoyl)-5-methyl- 224 6,8-dioxo-l,2,3,4,4a,5,6,8- octahydrodipyrido[1,2-b:2',1'-f][1,2,4]triazin-7- yl octanoate

[1209] 0 (S)-9-((2,4-difluorobenzyl)carbamoyl)-5-methyl- 225 6,8-dioxo-l,2,3,4,4a,5,6,8- F\ CK / L A s octahydrodipyrido[1,2-b:2',1'-f][1,2,4]triazin-7- yl stearate

[1210] F 0

[1211] (lS,3aS)-8-((2,4-difluorobenzyl)carbamoyl)-l- 226 (methoxymethyl)-4-methyl-5,7-dioxo- 2,3,3a,4,5,7-hexahydro-1H-pyrido[2,1- f]pyrrolo[1,2-b][1,2,4]triazin-6-yl propionate

[1212] 0

[1213] (lS,3aS)-8-((2,4-difluorobenzyl)carbamoyl)-l- 227 (methoxymethyl)-4-methyl-5,7-dioxo- 2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-F~rnLh

[1214] fl pyrrolo[l,2-b] [l,2,4]triazin-6-yl octanoate

[1215] F 0 / o^~ /

[1216] o (lS,3aS)-8-((2,4-difluorobenzyl)carbamoyl)-l- - - Q 228 (methoxymethyl)-4-methyl-5,7-dioxo- 2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l- W r fl pyrrolo[l,2-b] [l,2,4]triazin-6-yl stearate

[1217] F 0

[1218]

[1219] 70504W001

[1220] (lS,3aS)-8-((3-chloro-2- \ 1 \ 1z zfluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 0 <o=229 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- O^O do 0 pyrido[2,l- / ]pyrrolo[l,2-b] [l,2,4]triazin-6-yl 4- vJ ° (tert-butyl)benzoate H 1 / \ 2 ) o oo° oo / == ~Xz>. H IZH

[1221] \ / TZ

[1222] F 0'

[1223] (lS,3aS)-8-((3-chloro-2- o o fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 230 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H- pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6-yl 3- cyclopentylpropanoate

[1224] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- o

[1225] o

[1226] 231 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- 0^0 0 pyrido[2,l- / ]pyrrolo[l,2-b] [l,2,4]triazin-6-yl H H °V'S1XNL. H 3,5-dimethylbenzoate /

[1227] JFZI Z^i

[1228] ^ J <0

[1229] (X O p O= / - / oJ-7o° °= / \ / CX0-o#- (lS,3aS)-8-((3-chloro-2- °= / o / fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-=232 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- \ pyrido[2,l- / ]pyrrolo[l,2-b] [l,2,4]triazin-6-yl

[1230] 2,2,3,3-tetramethylcyclopropane-l-carboxylate

[1231] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 233 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H- pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6-yl 3- cyclopropyl-3-methylbutanoate

[1232] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 234 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H- pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6-yl 2- cycloheptylacetate

[1233]

[1234] 70504W001

[1235] (lS,3aS)-8-((3-chloro-2- z¥ J - \ fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- O / = 235 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H- pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6-yl 2- cyclobutylacetate

[1236] J2Z / °q°x /

[1237] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- 6

[1238] 236 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H- pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6-yl 2- cyclopropylacetate

[1239] (lS,3aS)-8-((3-chloro-2- fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4- o

[1240] 237 methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H- pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6-yl 2- ((3S,5S,7S)-adamantan-1-yl)acetate n o

[1241] F- YA".

[1242] ° °° ° / \ / \ <3^

[1243]

[1244] °= / CRYSTALLINE FORMS \ In an embodiment, certain compounds of the present invention are provided in crystalline form. In an alternative embodiment, certain compounds of the present invention are provided in amorphous form. In an embodiment, the compound is selected from the group consisting of compound nos. 5, 7, 14, 35, 80, 86, 230, 231, 232, 233, 234, 235, 236, and 237: 70504W001

[1245]

[1246] 70504W001

[1247]

[1248] a crystalline form.

[1249] In a further embodiment, the compound is selected from the group consisting of compound nos. 5, 7, 14, 35, 80, and 86:

[1250]

[1251] 70504W001

[1252]

[1253] wherein the compound is in a crystalline form.

[1254] An X-ray powder diffraction (XRPD) pattern will be understood to comprise a diffraction angle (expressed in degrees 20) of "about" a value specified herein when the XRPD pattern comprises a diffraction angle within ± 0.2 degrees 20 of the specified value. Further, it is well known and understood to those skilled in the art that the apparatus employed, humidity, temperature, orientation of the powder crystals, and other parameters involved in obtaining an XRPD pattern may cause some variability in the appearance, intensities, and positions of the lines in the diffraction pattern. An XRPD pattern that is "substantially in accordance" with that of a Figure provided herein is an XRPD pattern that would be considered by one skilled in the art to represent a compound possessing the same crystal form as the compound that provided the XRPD pattern of the Figure. That is, the XRPD pattern may be identical to that of the Figure or more likely it may be somewhat different. Such an XRPD pattern may not necessarily show each of the lines of the diffraction pattern presented herein, and / or may show a slight change in appearance, intensity, or a shift in position of said lines resulting from differences in the conditions involved in obtaining the data. A person skilled in the art is capable of determining if a sample of a crystalline compound has the same form as, or a different form from, the form disclosed herein by comparison of their XRPD patterns. For example, one skilled in the art can overlay an XRPD pattern of a sample of a different form of the specific compound, with the figure and, using expertise and knowledge in the art, readily determine whether the XRPD pattern of the sample is substantially in accordance with the XRPD pattern. If the XRPD pattern is substantially in accordance with the figure, the sample form can be readily and accurately identified as being the same form of the specific compound.

[1255] XRPD Measurements 70504W001

[1256] X-ray powder diffractions (XRPDs) were performed on a Rigaku MiniFlex 600 XRPD: Tube anode=Cu (40 kV / 15 mA); Detector=D / teXUItra2. The XRPD plots were obtained by the following method: 9 / 29, ° = 3.0-40.0, with a step of 0.01° at a speed of 10.0° / min. The detector was filtered with a 8 SS opening and Cu K-beta (K ) filter.

[1257] Crystalline form of Compound 5

[1258] In an embodiment, the compound is (15,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl icosanoate, wherein the compound is in a crystalline form. In a further embodiment, the crystalline form of (15,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl icosanoate is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at angles of about 3.7, 4.0, 5.4, 6.0, 8.0, 10.0, 19.7, 20.3, 22.3, and 23.3 degrees 28. In a further embodiment, the crystalline form of (15,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl icosanoate is characterized by an X-ray powder diffraction (XRPD) pattern having peaks at angles of about 4.0, 6.0, 10.0, and 19.7 degrees 29. In a further embodiment, the crystalline form of (15,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl icosanoate is characterized by an XRPD pattern having peaks at angles of 4.0, 6.0, 10.0, and 19.7 degrees 28, In a further embodiment, the crystalline form of (15,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl icosanoate is characterized by an XRPD pattern substantially in accordance with FIG. 1.

[1259] The corresponding reflections and heights of the XRPD pattern of the crystalline form of Compound 5 are provided in Table 2 below.

[1260] Table 2.

[1261] Peak Relative 7.95 0.32 13.14 0.14 (6 / 29, ’) Intensity, 8,99 0.24 13.95 0.09

[1262] cps 9.95 0.93 14.47 0.09 3.66 0.42 10.37 0.25 15.35 0.09 3.99 0.88 10.81 0.14 15.95 0.12 5.39 0.32 11.58 0.16 16.76 0.15 5.96 1.00 11.95 0.21 17.34 0.15

[1263]

[1264] 7.19 0.13

[1265]

[1266] 12.66 0.18

[1267]

[1268] 17.81 0.24 70504W001

[1269] 18.40 0.15 25.39 0.13 31.81 0.10 19.74 0.89 25.86 0.16 32.96 0.11 20.31 0,35 26.48 0.15 33.48 0.09 20.58 0.23 26.83 0.12 34.28 0.10 21.34 0.19 27.42 0.11 35.53 0.10 22.25 0.30 28.09 0.16 38.49 0.08 23.29 0.43 28.79 0.12 39.02 0.09 24.12 0.25 29.64 0.09

[1270]

[1271] 39.56 0.11

[1272]

[1273] 24.55 0,22

[1274]

[1275] 30.61 0.12

[1276] Crystalline form of Compound 14

[1277] In an embodiment, the compound is (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl heptanoate, wherein the compound is in a crystalline form. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl heptanoate is characterized by an XRPD pattern having peaks at angles of about 6.4, 7.1, 11.0, 14.4, 14.8, 17.0, 18.0, 18.9, 20.0, and 20.6 degrees 28. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl heptanoate is characterized by an XRPD pattern having peaks at angles of about 7.1, 14.4, and 18.9 degrees 20. In a further embodiment, die crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl heptanoate is characterized by an XRPD pattern having peaks at angles of 7.1, 14.4, and 18.9 degrees 28. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl heptanoate is characterized by an XRPD pattern substantially in accordance with FIG. 2.

[1278] The corresponding reflections and heights of the XRPD pattern of the crystalline form of Compound 14 are provided in Table 3 below.

[1279] Table 3.

[1280] Peak Relative 9.88 0.09 14.40 0.56 (8 / 29, Intensity, 10.65 0.17 14.81 0.28

[1281] CpS 10.95 0.24 15.33 0.07 6.39 0.28 11.46 0.12 16.18 0.09 7.08 1.00 11.73 0.10 17.00 0.23 8.65 0.06 12.99 0.15 17.99 0.25

[1282]

[1283] 9.62 0.13

[1284]

[1285] 13.35 0.10

[1286]

[1287] 18.86 0.47 70504W001

[1288] 19.37 0.12 26.34 0.17 33.25 0.07 20.03 0.23 27.55 0.11 33.61 0.06 20.63 0.46 27.84 0.10 33.88 0.06 21.05 0.12 28.23 0.23 34.53 0.07 21.44 0.14 28.58 0.13 35.44 0.07 21.75 0.20 28.99 0.08 35.78 0.07 21.99 0.12 29.20 0.09 36.57 0.06 22.88 0.21 29.53 0.08 36.80 0.06 23.40 0.28 29.89 0.06 37.29 0.06 23.68 0.12 30.50 0.07 37.51 0.06 24.38 0.15 31.25 0.07 38.01 0.06 24.89 0.21 31.84 0.08 38.43 0.08 25.44 0.11 32.47 0.06

[1289]

[1290] 39.21 0.08

[1291]

[1292] 25.94 0.12

[1293]

[1294] 32.81 0.11

[1295] Crystalline form of Compound 35

[1296] In an embodiment,, the compound is (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl isopropyl carbonate, wherein the compound is in a crystalline form. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl isopropyl carbonate is characterized by an XRPD patern having peaks at angles of about 8.0, 14.2, 16.0, 17.3, 18.4, 18.7, 20.0, 21.4, 23.4, and 26.5 degrees 26. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl isopropyl carbonate is characterized by an XRPD pattern having peaks at angles of about 8.0, 14.2, 16.0, and 18.7 degrees 29. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl isopropyl carbonate is characterized by an XRPD pattern having peaks at angles of 8.0, 14.2, 16.0, and 18.7 degrees 20. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl isopropyl carbonate is characterized by an XRPD pattern substantially in accordance with FIG. 3,

[1297] The corresponding reflections and heights of the XRPD pattern of the crystalline form of Compound 35 are provided in Table 4 below.

[1298] Table 4. 70504W001

[1299] Peak Relative 20.74 0.09 30.73 0.06 (6 / 28, •) Intensity, 21.35 0.17 31.78 0.05

[1300] cps 21.76 0.12 32.03 0.06 7.98 1.00 22.38 0.09 32.43 0.05 10.59 0.04 22.53 0.08 32.76 0.04 12.36 0.09 22.96 0.06 33.19 0.05 13.85 0.12 23.37 0.27 33.68 0.06 14.21 0.27 24.31 0.13 34.17 0.04 14.43 0.12 24.58 0.06 34.74 0.05 15.32 0.05 24.97 0.08 35.03 0.05 16.04 0.40 25.26 0.12 35.29 0.04 16.84 0.04 26.02 0.07 35.58 0.06 17.26 0.24 26.48 0.19 35.98 0.04 17.54 0.10 27.04 0.13 36.73 0.04 18.40 0.23 27.90 0.07 37.30 0.05 18.65 0.27 28.22 0.06 37.64 0.03 18.91 0.05 28.66 0.09 37.84 0.03 19.98 0.22 29.12 0.06 38.63 0.06

[1301]

[1302] 20.60 0.07

[1303]

[1304] 29.69 0.13

[1305]

[1306] 38.91 0.04

[1307] Crystalline form of Compound 80

[1308] In an embodiment, the compound is (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 2-cyclopentylacetate, wherein the compound is in a crystalline form. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 2-cyclopentylacetate is characterized by an XRPD pattern having peaks at angles of about 7.9, 13.5, 13.9, 14.1, 15.7, 16.8, 18.2, 19.7, 21.1, and 23.1 degrees 28. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 2-cyclopentylacetate is characterized by an XRPD pattern having peaks at angles of about 7.9, 13.5, 13.9, and 18.2 degrees 2S. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 2-cyclopentylacetate is characterized by an XRPD pattern having peaks at angles of 7.9, 13.5, 13.9, and 18.2 degrees 28. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 2-cyclopentylacetate is characterized by an XRPD pattern substantially in accordance with FIG. 4. 70504W001

[1309] The corresponding reflections and heights of the XRPD pattern of the crystalline form of Compound 80 are provided in Table 5 below.

[1310] Table 5.

[1311] Peak Relative 18.19 0.61 29.89 0.10 (8 / 29, Intensity, 19.06 0.12 30.17 0.12

[1312] cps 19.66 0.37 30.49 0.10 7.11 0.26 20.30 0.17 31.30 0.07 7.86 1.00 20.77 0.17 31.75 0.11 8.11 0.09 21.13 0.40 32.77 0.11 9.45 0.07 21.92 0.26 33.15 0.11 10.27 0.08 22.47 0.13 34.07 0.13 10.48 0.13 23.05 0.41 34.37 0.12 10.87 0.07 23.73 0.23 34.82 0.08 11.21 0.08 24.14 0.15 35.16 0.09 11.38 0.08 24.39 0.17 35.54 0.11 12.10 0.17 25.07 0.15 35.93 0.07 12.55 0.16 25.38 0.16 36.31 0.07 13.54 0.55 25.98 0.21 36.61 0.08 13.91 0.51 26.71 0.16 36.94 0.11 14.14 0.30 27.25 0.14 37.64 0.08 15.10 0.19 27.61 0.16 37.94 0.08 15.72 0.37 27.87 0.17 38.29 0.07 16.46 0.21 28.03 0.16 39.04 0.11 16.83 0.30 28.73 0.13

[1313]

[1314] 39.97 0.14 17.39 0.13 29.18 0.16

[1315]

[1316] 17.74 0.13

[1317]

[1318] 29.62 0.10

[1319] Crystalline form of Compound 86

[1320] In an embodiment, the compound is (15,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 3-methylbutanoate, wherein the compound Is in a crystalline form. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 3-methylbutanoate is characterized by an XRPD pattern having peaks at angles of about 7.3, 8.1, 14.1, 14.7, 16.3, 18.6, 19.8, 21.3, 23.3, and 26.7 degrees 20. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 3-methylbutanoate is characterized by an XRPD pattern having peaks at angles of about 8.1, 14.1, and 16.3 degrees 2θ. In a further embodiment, the crystalline form of (1S,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-1-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6-yl 3-methylbutanoate is characterized by an XRPD 70504W001

[1321] pattern having peaks at angles of 8.1, 14.1, and 16.3 degrees 2θ. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 3-methylbutanoate is characterized by an XRPD patern substantially in accordance with FIG. 5.

[1322] The corresponding reflections and heights of the XRPD pattern of the crystalline form of Compound 86 are provided in Fable 6 below.

[1323] Table 6.

[1324] Peak Relative 18.62 0.37 30.24 0.09 (0 / 29, “) Intensity, 19.23 0.08 30.62 0.05

[1325] CpS 19.83 0.29 30.87 0.05 7.33 0.23 20.11 0.08 31.09 0.05 8.10 1.00 20.74 0.12 32.78 0.05 8.43 0.05 21.02 0.09 33.13 0.06 10.45 0.04 21.31 0.28 33.72 0.06 10.66 0.05 22.06 0.16 34.52 0.08 11.06 0.05 22.71 0.08 35.09 0.06 11.58 0.06 23.27 0.25 35.51 0.08 12.25 0.11 23.61 0.06 35.99 0.04 12.71 0.11 24.13 0.12 36.32 0.04 13.23 0.06 24.53 0.20 36.94 0.06 14.08 0.42 25.19 0.09 37.28 0.04 14.65 0.21 25.53 0.08 37.47 0.04 15.12 0.09 26.21 0.05 37.88 0.05 15.62 0.07 26.74 0.26 38.88 0.05 16.25 0.38 27.33 0.07 39.07 0.05 16.78 0.11 28.41 0.14 39.40 0.04 17.32 0.19 28.93 0.05

[1326]

[1327] 39.91 0.07 17.51 0.10 29.62 0.12

[1328]

[1329] 17.88 0.08

[1330]

[1331] 29.85 0.06

[1332] Crystalline form of Compound 230

[1333] In an embodiment, the compound is (lS,3aS)-8-((3-chioro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyi)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b] [1,2,4] triazin-6-yl 3-cyclopentylpropanoate, wherein the compound is in a crystalline form. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dloxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrofo[l,2-b] [l,2,4]triazin-6-yl 3-cyclopentylpropanoate is characterized by an XRPD pattern having peaks at angles of about 6.9, 9.6, 10.8, 14.4, 16.8, 18.3, 20.2, 22.1, 22.6, and 25.5 degrees 2θ. in a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)"l- (methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2- 70504W001

[1334] b] [l,2,43triazin-6-yl 3-cyclopentylpropanoate is characterized by an XRPD pattern having peaks at angles of about 6.9, 14.4, and 18.3 degrees 20. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-ffoorobenzyl)carbamoyi)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7- hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-bj[l,2,4]triazin-6-yl 3-cydopentylpropanoate is characterized by an XRPD pattern having peaks at angles of 6.9, 14.4, and 18.3 degrees 28. In a further embodiment, the crystalline form of (lS,3aS)-8-( 3-chloro-2-fluorobenzyi)carbamoyi)-.l- (methoxymethyi)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4jtriazin-6-yi 3-cyciopentyipropanoate is characterized by an XRPD pattern substantially in accordance with FIG. 6.

[1335] The corresponding reflections and heights of the XRPD pattern of the crystalline form of Compound 230 are provided in Table 7 below.

[1336] Table 7.

[1337] Peak Relative 20.67 0.04 30.53 0.04 (0 / 20, °) Intensity, 21.90 0.13 31.20 0.06

[1338] cps 22.10 0.38 31.42 0.07 6.86 1.00 22.64 0.26 32.03 0.11 9.57 0.18 22.95 0.06 32.42 0.05 9.87 0.07 23.80 0.08 32.97 0.08 10.76 0.35 24.24 0.15 33.28 0.06 11.72 0.06 24.74 0.11 34.04 0.05 13.78 0.17 25.46 0.19 35.00 0.04 14.41 0.52 26.19 0.14 35.13 0.04 15.63 0.04 26.59 0.07 35.66 0.08 16.79 0.29 26.79 0.13 35.97 0.04 17.55 0.12 27.24 0.11 36.69 0.05 18.02 0.17 27.79 0.14 37.29 0.06 18.33 0.51 28.48 0.07 38.39 0.05 19.70 0.06 29.21 0.05 38.89 0.06 19.91 0.10 29.67 0.06 39.52 0.05

[1339]

[1340] 20.22 0.35

[1341]

[1342] 30.17 0.05

[1343]

[1344] 39.81 0.05

[1345] Crystalline form of Compound 231

[1346] In an embodiment, the compound is (1S,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-1-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6-yl 3,5-dimethylbenzoate, wherein the compound is in a crystalline form. In a further embodiment, the crystalline form of (1S,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-1-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6-yl 3,5-dimethylbenzoate is characterized by an XRPD pattern having peaks at angles 70504W001

[1347] of about 7.9, 13.6, 18.1, 18.9, 19.3, 20.5, 22.7, 23.7, 24.6, and 27.5 degrees 2θ. In a further embodiment, the crystalline form of (1S,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-1-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6-yl 3,5-dimethylbenzoate is characterized by an XRPD pattern having peaks at angles of about 7.9, 18.1, and 19.3 degrees 26. In a further embodiment, the crystalline form of (1S,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-1-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6-yl 3,5-dimethylbenzoate is characterized by an XRPD pattern having peaks at angles of 7.9, 18.1, and 19.3 degrees 28. In a further embodiment, the crystalline form of (1S,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-1-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6-yl 3,5-dimethylbenzoate is characterized by an XRPD pattern substantially in accordance with FIG. 7.

[1348] The corresponding reflections and heights of the XRPD pattern of the crystalline form of Compound 231 are provided in Table 8 below.

[1349] Table 8.

[1350] Peak Relative 18.92 0.40 29.96 0.17 (6 / 26, °) Intensity, 19.30 0.61 30.38 0.11

[1351] cps 20.10 0.21 31.04 0.11 7.85 0.92 20.50 0.25 31.67 0.07 10.36 0.15 20.79 0.23 32.31 0.14 11.15 0.06 22.73 0.54 32.87 0.13 11.78 0.14 23.74 0.26 33.30 0.13 13.60 0.46 24.63 0.38 34.14 0.21 14.22 0.20 25.58 0.07 34.72 0.11 14.66 0.23 26.07 0.16 35.93 0.13 15.75 0.21 26.51 0.08 36.37 0.08 16.21 0.10 27.51 0.37 36.69 0.08 16.74 0.22 27.79 0.18 38.54 0.11 17.08 0.16 28.75 0.18 38.91 0.09

[1352]

[1353] 18.07 1.00

[1354]

[1355] 29.29 0.07

[1356]

[1357] 39.19 0.12

[1358]

[1359] Crystalline form of Compound 232

[1360] In an embodiment, the compound is (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 2,2,3,3-tetramethylcyclopropane-l-carboxylate, wherein the compound is in a crystalline form, in a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 2,2,3,3-tetramethylcyclopropane-l-carboxylate is 70504W001

[1361] characterized by an XRPD pattern having peaks at angles of about 8.2, 11.2, 13.3, 14.7, 16.6, 17.3, 18.2, 18.7, 19.9, and 21.0 degrees 2θ. in a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexa hydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 2,2,3,3-tetramethylcyclopropane-l-carboxylate is characterized by an XRPD pattern having peaks at angles of about 8.2, 13.3, 16.6, and 18.2 degrees 2θ. in a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 2,2,3,3-tetramethylcyclopropane-l-carboxylate is characterized by an XRPD pattern having peaks at angles of 8.2, 13.3, 16.6, and 18.2 degrees 2θ. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 2,2,3,3-tetramethylcyclopropane-l-carboxylate is characterized by an XRPD pattern substantially in accordance with FIG, 8.

[1362] The corresponding reflections and heights of the XRPD pattern of the crystalline form of Compound 232 are provided in Table 9 below.

[1363] Table 9.

[1364] Peak Relative 20.52 0.12 29.90 0.17 (0 / 20, °) Intensity, 20.77 0.12 30.35 0.14

[1365] cps 21.02 0.34 30.86 0.09 8.21 0.84 21.22 0.24 31.34 0.13 8.59 0.06 22.40 0.13 31.73 0.11 10.30 0.08 23.08 0.17 32.00 0.08 11.15 0.27 23.44 0.22 32.15 0.09 13.34 0.55 23.62 0.14 32.63 0.09 14.19 0.05 24.42 0.16 33.78 0.08 14.51 0.18 24.93 0.09 34.12 0.19 14.74 0.45 25.59 0.13 34.46 0.11 15.07 0.17 26.18 0.07 35.08 0.11 15.64 0.05 26.55 0.22 35.95 0.08 16.61 1.00 26.98 0.20 37.06 0.07 17.30 0.28 27.26 0.17 37.55 0.05 18.17 0.51 27.62 0.09 37.95 0.06 18.38 0.17 28.32 0.08 38.27 0.08 18.72 0.31 28.60 0.08 38.60 0.05 19.05 0.05 29.33 0.10 39.21 0.06

[1366]

[1367] 19.88 0.40

[1368]

[1369] 29.66 0.09

[1370]

[1371] 39.47 0.07 70504W001

[1372] Crystalline form of Compound 233

[1373] In an embodiment, the compound is (1S,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-1-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H-pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6-yl 3-cyclopropyl-3-methylbutanoate, wherein the compound is in a crystalline form. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 3-cyclopropyl-3-methylbutanoate is characterized by an XRPD pattern having peaks at angles of about 8.2, 11.3, 13.5, 14.6, 15.0, 16.6, 18.1, 19.2, 20.0, and 21.4 degrees 2θ. in a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 3-cyclopropyl-3-methylbutanoate is characterized by an XRPD pattern having peaks at angles of about 8.2, 16.6, and 18.1 degrees 2θ. in a further embodiment, the crystaiiine form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 3-cyclopropyl-3-methylbutanoate is characterized by an XRPD pattern having peaks at angles of 8.2, 16.6, and 18.1 degrees 2θ. in a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 3-cyclopropyl-3-methylbutanoate is characterized by an XRPD pattern substantially In accordance with FIG. 9.

[1374] The corresponding reflections and heights of the XRPD pattern of the crystalline form of Compound 233 are provided in Table 10 below.

[1375] Table 10.

[1376] Peak Relative 18.11 0.64 27.13 0.17 (0 / 20, °) Intensity, 18.42 0.12 27.82 0.18

[1377] cps 19.17 0.28 28.84 0.08 8.17 1.00 20.01 0.38 29.19 0.10 8.89 0.07 20.45 0.07 30.07 0.10 10.49 0.05 21.02 0.08 30.35 0.17 11.03 0.10 21.44 0.22 31.04 0.12 11.31 0.21 22.41 0.14 31.97 0.09 11.62 0.04 22.72 0.16 32.56 0.08 13.50 0.41 23.41 0.21 32.87 0.09 13.73 0.06 23.80 0.13 34.19 0.11 14.55 0.22 24.60 0.17 34.93 0.11 14.98 0.28 25.59 0.11 35.46 0.06 15.69 0.07 26.16 0.07 36.23 0.06 16.56 0.65

[1378]

[1379] 26.60 0.18

[1380]

[1381] 36.99 0.07

[1382]

[1383] 17.79 0.17 70504W001

[1384] | 38.02 | 0.06 | | 38.59 | 0.06

[1385]

[1386] 39.10

[1387]

[1388] 0.08

[1389]

[1390] Crystalline form of Compound 234

[1391] In an embodiment, the compound is (15,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl 2-cycloheptylacetate, wherein the compound is in a crystalline form. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 2-cycloheptylacetate Is characterized by an XRPD pattern having peaks at angles of about 6.8, 10.8, 13.7, 14.1, 14.5, 17.6, 18.3, 19.6, 20.2, and 22.0 degrees 26. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 2-cycloheptylacetate is characterized by an XRPD pattern having peaks at angles of about 6.8, 14.5, and 17.6 degrees 28, In a further embodiment, the crystalline form of (15,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexa hydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 2-cycloheptylacetate is characterized by an XRPD pattern having peaks at angles of 6.8, 14.5, and 17.6 degrees 28. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 2-cycloheptylacetate is characterized by an XRPD pattern substantially in accordance with FIG. 10.

[1392] The corresponding reflections and heights of the XRPD pattern of the crystalline form of Compound 234 are provided in Table 11 below.

[1393] Table 11.

[1394] Peak Relative 15.40 0.04 21.98 0.25 (0 / 20, °) Intensity, 16.33 0.17 22.56 0.15

[1395] cps 16.87 0.20 23.12 0.08 4.74 0.09 17.58 0.39 24.11 0.11 6.80 1.00 17.91 0.08 24.33 0.11 9.70 0.14 18.31 0.23 24.87 0.14 10.43 0.12 19.00 0.06 25.15 0.11 10.83 0.23 19.24 0.11 25.72 0.07 11.30 0.06 19.58 0.26 26.30 0.13 13.01 0.05 20.18 0.25 26.86 0.09 13.72 0.27 20.57 0.06 27.07 0.09 13.95 0.23 21.16 0.19 27.53 0.12 14.12 0.25 21.44 0.10 27.78 0.14

[1396]

[1397] 14.46 0.30

[1398]

[1399] 21.74 0.20

[1400]

[1401] 28.44 0.07 70504W001

[1402] 28.68 0.08 32.58 0.06 36.43 0.06 30.53 0.07 32.87 0.06 37.29 0.05 30.85 0.08 33.21 0.08 37.49 0.05 31.12 0.06 34.02 0.08 38.33 0.05 31.60 0.09 34.86 0.07 38.94 0.05

[1403]

[1404] 32.04 0.07

[1405]

[1406] 35.66 0.07

[1407]

[1408] 39.84 0.07

[1409] Crystalline form of Compound 235

[1410] In an embodiment, the compound is (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 2-cyclobutylacetate, wherein the compound is in a crystalline form. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 2-cyclobutylacetate is characterized by an XRPD pattern having peaks at angles of about 7.9, 13.5, 14.1, 15.8, 16.8, 18.3, 20.0, 21.3, 23.2, and 23.6 degrees 2θ. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 2-cyclobutylacetate is characterized by an XRPD pattern having peaks at angles of about 7.9, 14.1, and 18.3 degrees 28, In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexa hydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 2-cyclobutylacetate is characterized by an XRPD pattern having peaks at angles of 7.9, 14.1, and 18.3 degrees 28. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 2-cyclobutylacetate is characterized by an XRPD pattern substantially in accordance with FIG. 11.

[1411] The corresponding reflections and heights of the XRPD pattern of the crystalline form of Compound 235 are provided in Table 12 below.

[1412] Table 12.

[1413] Peak Relative 15.37 0.13 21.33 0.35 (0 / 20, °) Intensity, 15.77 0.33 21.65 0.20

[1414] cps 16.82 0.31 22.25 0.22 7.91 1.00 17.75 0.10 23.21 0.24 10.61 0.09 18.27 0.59 23.59 0.31 11.40 0.08 18.82 0.13 24.72 0.20 12.12 0.12 19.71 0.11 25.60 0.17 13.47 0.30 20.02 0.38 26.14 0.22

[1415]

[1416] 14.06 0.58

[1417]

[1418] 20.47 0.15

[1419]

[1420] 27.27 0.21 70504W001

[1421] 27.80 0.20 31.13 0.10 35.48 0.10 28.37 0.14 31.86 0.09 37.11 0.10 28.95 0.15 33.45 0.15 37.55 0.09 29.79 0.17 34.28 0.11 38.20 0.09

[1422]

[1423] 30.41 0.09

[1424]

[1425] 34.91 0.13

[1426]

[1427] 39.16 0.12

[1428] Crystalline form of Compound 236

[1429] In an embodiment, the compound is (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-fjpyrrolc>[l,2- b][l,2,4]triazin-6-yi 2-cyclopropylacetate, wherein the compound is in a crystalline form. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyi)carbamoyl)-l- (methoxymethyi)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo l,2-b] l,2,4]triazin-6-yl 2-cyclopropylacetate is characterized by an XRPD pattern having peaks at angles of about 8.0, 14.2, 16.1, 17.2, 18.6, 20.0, 21.6, 22.4, 23.5, and 26.6 degrees 20. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyf)carbamoyl)-l-(methoxymethyi)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-fjpyrroio[l,2- b][l,2,4]triazin -6-yl 2-cyclopropylacetate is characterized by an XRPD pattern having peaks at angles of about 8.0, 14.2, and 18.6 degrees 28. In a further embodiment, the crystalline form of (lS,3aS)-8- ((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyi)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexa hydro- lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yf 2-cyclopropylacetate is characterized by an XRPD pattern having peaks at angles of 8,0,.14.2, and 18.6 degrees 20. In a further embodiment, the crystalline form of (lS,3aS)-8-({3-chloro-2-f1uorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxO"2,3,3a,4,5,7-hexahydro-lH"pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6“yl 2-cyclopropylacetate is characterized by an XRPD pattern substantially in accordance with FIG. 12.

[1430] The corresponding reflections and heights of the XRPD pattern of the crystalline form of Compound 235 are provided in Table 13 below.

[1431] Table 13.

[1432] Peak Relative 15.33 0.11 21.55 0.47 (0 / 20, °) Intensity, 16.09 0.39 22.38 0.28

[1433] cps 16.86 0.08 22.91 0.07 8.03 1.00 17.23 0.25 23.45 0.45 10.64 0.05 17.67 0.10 24.37 0.16 11.61 0.10 18.61 0.41 24.82 0.17 12.29 0.15 19.11 0.05 25.45 0.11 13.92 0.19 20.01 0.38 25.85 0.08 14.16 0.54 20.37 0.14 26.57 0.25

[1434]

[1435] 14.45 0.20

[1436]

[1437] 20.75 0.17

[1438]

[1439] 27.18 0.23 70504W001

[1440] 27.79 0.10 31.93 0.06 36.43 0.06 28.29 0.12 32.62 0.08 37.31 0.08 28.56 0.18 33.38 0.08 37.78 0.09 29.38 0.11 33.84 0.09 38.68 0.06 29.81 0.19 34.13 0.08 39.05 0.06 30.23 0.09 35.03 0.14 39.58 0.06 30.99 0.11 35.74 0.11

[1441]

[1442] 39.86 0.09

[1443]

[1444] 31.65 0.06

[1445]

[1446] 36.18 0.06

[1447] Crystalline form of Compound 237

[1448] In an embodiment,, the compound is (lS,3aS)-8-((3-chloro-2.-fluorobenzy!)carbamoyl)-l- (methoxymethyl)"4-methyl-5,7"dioxo-2,3,3a,4,5,7-hexahydro-lH"pyrido[2,l-f]pyrroio(l,2- b][l,2,4]triazin-6-yi 2-((3S, SS,7SJ-adamantan-l-yl)acetate, wherein the compound is in a crystalline form. In a further embodiment, the crystalline form of (! S,3aS)-8-((3-chloro-2- f!uorobenzyi)carbamoyi;-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b][.l,2,4]triazin-6-y! 2-((3S,5S,7S)-adamantan-l-yi)acetate is characterized by an XRPD pattern having peaks at angles of about 7.6, 10.7, 13.3, 4.5, 15.2, 15.5, 17.2, 18.9, 20.1, and 30.3 degrees 26. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2- fluorcbenzyQcarba cyl)-l- methoxy ethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]trlazin-6-yf 2- (3S.,5S,7S)-adamantan-l-yl)acetate is characterized by an XRPD pattern having peaks at angles of about 15,2,.15.5, and 17.2 degrees 20. In a further embodiment, the crystalline form of (lS,3aS)-8-((3-chloro-2-fluorobenzyi)carbamoyl)-l-(methoxymethyi)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydrcs-lH-pyrido 2,l-f]pyrralo[l,2- b][l,2,4jtriazin-6-yl 2-|(3S,5S,7S)-adamantan-l-yl!acetate is characterized by an XRPD pattern having peaks at angles of 15.2, 15.5, and 17.2 degrees 26. In a further embodiment, the crystalline form of (15,3a5)-8 (3mh ro<t-ffoorobenzyljcarbamoylj-l-(metlmxymethyl)-4H'nethyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrroio[l,2-b][l,2,4]triazin-6-yl 2-((3S,5S,7S)-adamantan-.l-yl)acetate is characterized by an XRPD pattern substantially in accordance with FIG. 13.

[1449] The corresponding reflections and heights of the XRPD pattern of the crystalline form of Compound 237 are provided in Table 14 beiow.

[1450] Table 14.

[1451] Peak Relative 10.70 0.16 16.11 0.09 (θ / 2θ, °) Intensity, 12.59 0.09 16.44 0.12

[1452] cps 13.26 0.32 17.22 1.00 7.62 0.38 14.50 0.13 17.81 0.10 8.64 0.11 15.18 0.52 18.20 0.10

[1453]

[1454] 9.98 0.06

[1455]

[1456] 15.45 0.59

[1457]

[1458] 18.92 0.42 70504W001

[1459] 19.83 0.10 26.22 0.10 33.22 0.07 20.13 0.36 26.73 0.18 34.36 0.10 20.53 0.11 27.10 0.13 34.86 0.08 21.02 0.11 27.67 0.14 35.25 0.07 21.32 0.08 28.12 0.10 36.04 0.07 21.91 0.18 28.74 0.09 36.43 0.05 22.36 0.07 29.16 0.06 36.94 0.07 23.01 0.21 29.90 0.09 37.44 0.09 24.05 0.13 30.34 0.21 37.82 0.05 24.35 0.05 30.72 0.06 38.51 0.04 25.06 0.06 31.42 0.06

[1460]

[1461] 39.19 0.07 25.41 0.07 32.13 0.08

[1462]

[1463] 25.85 0.15

[1464]

[1465] 32.80 0.09

[1466] In a third aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, In an embodiment, a compound of the invention is present in the pharmaceutical composition in amorphous form. In a further embodiment, the compound of the invention is present in the pharmaceutical composition in crystalline form. In a further embodiment, the pharmaceutical composition is in a tablet form. In a further embodiment, the pharmaceutical composition is in parenteral (e.g., injectable) form. In a further embodiment, the pharmaceutical composition is present as a spray-dried dispersion.

[1467] Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of a chemical entity described herein. Such excipients may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.

[1468] in an embodiment, solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semi-solid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Liquid carriers, for injectable solutions, include water, saline, aqueous dextrose, and glycols. Compressed gases may be used to disperse a chemical entity described herein in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18thed., 1990), the disclosure of which is incorporated by reference with respect to pharmaceutical excipients. 70504W001

[1469] In a fourth aspect, the present invention provides a method of treating an HIV infection in a subject in need thereof, comprising administer ing to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof. In an embodiment, the present invention provides a method of treating an HIV infection in a subject in need thereof, comprising administering a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[1470] In another embodiment, the present invention provides a method of treating an HIV infection in a subject in need thereof, comprising administering to the subject (a) a therapeutically effective amount of a compound of the invention or pharmaceutically acceptable salt thereof and (b) an antiHIV agent. (An anti-HIV agent is a compound which inhibits HIV.) Examples of anti-HIV agents that may be used in combination with a compound of the instant invention or pharmaceutically acceptable salt thereof include, without limitation:

[1471] (I) Nucleoside-analog reverse transcriptase inhibitors (NRTIs)

[1472] NRTIs refer to nucleosides and nucleotides and analogues thereof that inhibit the activity of reverse transcriptase, particular HIV-1 reverse transcriptase. NRTIs comprise a sugar and a base. Examples of nucleoside-analog reverse transcriptase inhibitors include, without limitation, adefovir dipivoxil, adefovir, lamivudine (e.g., the prodrug described in PCT / US2015 / 54826, WO 2016 / 057866), telbivudine, entecavir, tenofovlr, stavudine, abacavir (e.g., the prodrug described in PCT / US2015 / 54826, WO 2016 / 057866), didanosine, emtricitabine, zalcitabine, and zidovudine.

[1473] (II) Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

[1474] NNRTIs are allosteric inhibitors which bind reversibly at a nonsubstrate-binding site on reverse transcriptase, particularly the HIV reverse transcriptase, thereby altering the shape of the active site or blocking polymerase activity. Examples of NNRTIs include, without limitation, delavirdine (BHAP, U-90152; RESCRIPTOR®), efavirenz (DM P-266, SUSTIVA®), nevirapine (VIRAMUNE®), PNU-142721, capravirine (S-1153, AG-1549), emivirine (+)-calanolide A (NSC-675451) and B, etravirine (TMC-125), rilpivirine (TMC278, Edurant™), DAPY (TMC120), BILR-355 85, PHI-236, and PHI-443 (TMC-278).

[1475] (III) Protease inhibitors (Pls)

[1476] Protease inhibitors are inhibitors of a viral protease, particularly the HIV-1 protease. Examples of protease inhibitors include, without limitation, darunavir, amprenavir (141WS4, AGENERASE®), tipranavir (PNU-140690, APTIVUS®), indinavir (MK-639; CRIXIVAN®), saquinavir (INVIRASE®, FORTOVASE®), fosamprenavir (LEXIVA®), lopinavlr (ABT-378), ritonavir (ABT-538, NORVIR®), 70504W001

[1477] atazanavir (REYATAZ®), nelfinavir (AG-1343, VIRACEPT®), lasinavir (BMS-234475 / CGP-61755), BMS-2322623, GW-640385X (VX-385), AG-001859, and SM-309515.

[1478] (IV) Fusion or entry inhibitors

[1479] Fusion or entry inhibitors are compounds, such as peptides, which block HIV entry into a cell (e.g., by binding to HIV envelope protein and blocking the structural changes necessary for the virus to fuse with the host cell). Examples of fusion inhibitors include, without limitation, CCR5 receptor antagonists (e.g., maraviroc (SELZENTRY®, Ceisentri)), enfuvirtide (INN, FUZEON®), T-20 (DP-178, FUZEON®), and T-1249.

[1480] (V) Integrase strand transfer inhibitors (I NSTIs)

[1481] INSTIs are a class of antiretroviral drug designed to block the action of integrase (e.g., HIV integrase), a viral enzyme that inserts the viral genome into the DNA of the host cell. Examples of INSTIs include, without limitation, raltegravir, elvitegravir, and MK-2048.

[1482] Anti-HIV agents also include maturation inhibitors [e.g., bevirimat) and capsid inhibitors [e.g., lenacapavir). Maturation inhibitors are typically compounds which bind HIV gag and disrupt its processing during the maturation of the virus. Capsid inhibitors are typically compounds that target the capsid shell of the virus, inhibiting the functional disassembly of the capsid in infected cells, Anti- HIV agents also include HIV vaccines such as, without limitation, ALVAC® HIV (vCP1521), AIDSVAX® B / E (gp12), and combinations thereof. Anti-HIV agents also include HIV antibodies (e.g., antibodies against gp120 or gp41), particularly broadly neutralizing antibodies.

[1483] More than one anti-HIV agent mas / be used, particularly where the agents have different mechanisms of action. The other anti-HIV agents may be administered concurrently and / or separately with a compound of the instant invention or pharmaceutically acceptable salt thereof. The other anti-HIV agents may be formulated with a compound of the instant invention or pharmaceutically acceptable salt thereof. The other anti-HIV agents may be contained within a pharmaceutical composition with a compound of the present invention or pharmaceutically acceptable salt thereof. The other anti- HIV agents may be administered separately from a compound of the present invention or pharmaceutically acceptable salt thereof. Administration of the other anti-HIV agent or agents and a compound of the instant invention or pharmaceutically acceptable salt thereof may be at the same time or at different times (e.g., sequentially).

[1484] In a fifth aspect, the present invention provides a method of preventing an HIV infection in a subject at risk for developing an HIV Infection, comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof. Pre- 70504W001

[1485] exposure prophylaxis (or PrEP) is when individuals at risk for HIV infection take or are administered medicine (e.g., daily, weekly, monthly, every 2, 3, 4, 5, or 6 months, etc.) to iower their chances of being infected with HIV.

[1486] In a sixth aspect, there is provided a compound of the invention or a pharmaceutically acceptable salt thereof for use in therapy.

[1487] In a seventh aspect, there is provided a compound of the invention or a pharmaceutically acceptable salt thereof for use in treating an HIV infection, in one embodiment, the compound of the invention or pharmaceutically acceptable salt thereof is suitable for use as a tablet, in another embodiment, the compound of the invention or pharmaceutically acceptable salt thereof is suitable for use in an injection, in a further embodiment, the use comprises administering the compound of the invention or pharmaceutically acceptable salt thereof intramuscularly, in another further embodiment, the use comprises administering the compound of the invention or pharmaceutically acceptable salt thereof subcutaneously.

[1488] In an eighth aspect, there is provided a compound of the invention or a pharmaceutically acceptable salt thereof for use in preventing an HIV infection. In one embodiment, the compound of the invention or pharmaceutically acceptable salt thereof is suitable for use as a tablet. In another embodiment, the compound of the invention or pharmaceutically acceptable salt thereof is suitable for use in an injection. In a further embodiment, the use comprises administering the compound of the invention or pharmaceutically acceptable salt thereof intramuscularly, in another further embodiment, the use comprises administering the compound of the invention or pharmaceutically acceptable salt thereof subcutaneously.

[1489] In a ninth aspect, there is provided the use of a compound of the invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating an HIV infection.

[1490] In a tenth aspect, there is provided the use of a compound of the invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing an HIV infection.

[1491] The compound of the present invention is provided in both its free base or free acid or a pharmaceutically acceptable salt thereof. In an embodiment, the compound is provided as a free base or free acid. In an embodiment, the compound Is provided as a pharmaceutically acceptable salt thereof.

[1492] Where the compound functionality allows, suitable pharmaceutically acceptable salts of the compound of the present invention can be formed, which include acid or base addition salts. Acid addition salts may be formed by reaction with the appropriate acid, optionally in a suitable solvent 70504W001

[1493] such as an organic solvent, to give the salt which can be isolated by crystallisation and filtration. Base addition salts may be formed by reaction with the appropriate base, optionally in a suitable solvent such as an organic solvent, to give the salt which can be isolated by crystallisation and filtration.

[1494] These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.

[1495] Illustrative pharmaceutically acceptable acid salts of the compounds of the present invention can be prepared from the following acids, including, without limitation: formic, acetic, propionic, benzoic, succinic, glycolic, gluconic, lactic, maleic, malic, tartaric, citric, nitric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, hydrochloric, hydrobromic, hydroiodic, isocitric, trifluoroacetic, pamoic, propionic, anthranilic, mesylic, oxalacetic, oleic, stearic, salicylic, p- hydroxybenzoic, nicotinic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, phosphoric, phosphonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, sulfuric, salicylic, cyclohexylaminosulfonic, algenic, β-hydroxybutyric, galactaric and galacturonic acids. Preferred pharmaceutically acceptable salts include the salts of hydrochloric acid and trifluoroacetic acid.

[1496] Illustrative pharmaceutically acceptable inorganic base salts of the compounds of the present invention include metallic ions. More preferred metallic ions include, but are not limited to, appropriate alkali metal salts, alkaline earth metal salts and other physiological acceptable metal ions. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like and in their usual valences. Exemplary base salts include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, Other exemplary base salts include the ammonium, calcium, magnesium, potassium, and sodium salts. Still other exemplary base salts include, for example, hydroxides, carbonates, hydrides, and alkoxides including NaOH, KOH, Na2CO3, K2CO3, NaH, and potassium-t-butoxide.

[1497] Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, including in part, trimethyiamine, diethylamine, N, N’~ dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine; substituted amines including naturally occurring substituted amines; cyclic amines; quaternary ammonium cations; and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N, N-dibenzylethyienediamine, diethylamine, 2-diethylaminoethanol, 2- 70504W001

[1498] dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[1499] All of the above salts can be prepared by those skilled in the art by conventional means from the corresponding compound of the present invention. For example, the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the salt may vary from completely ionised to almost non-lonised. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, IS1" ed., 1990), the disclosure of which is hereby incorporated by reference with regards to the lists of suitable salts.

[1500] The compounds of Formula (I), (l-a), (i- b), (l-c), (l-d), (i-e), (l-f), (l-g), (i-h), (l-i), (l-j), (i- k), (H-a), (II- b), (ll-c), or (ll-d) of the invention mas / exist in both unsolvated and solvated forms. The compounds of Formula (I), (l-a), (l-b), (l-c), or (l-d) of the invention may exist in both unsolvated and solvated forms. The term ’solvate' comprises the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' Is employed when said solvent Is water, Pharmaceutically acceptable solvates include hydrates and other solvates wherein the solvent of crystallization may be isctopically substituted, e.g., D2O, d6-acetone, de-DMSO.

[1501] Compounds of Formula (I), (l-a), (l-b), (l-c), (l-d), (l-e), or (l-f), (l-g), (l-h), (l-i), (l-j), (l-k), (ll-a), (ll-b), (ll-c), or (ll-d) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of Formula (I), (l-a), (l-b), (l-c), (l-d), (l-e), or (l-f), (l-g), (l-h), (l-i), (l-j), (l-k), (ll-a), (ll-b), (ll-c), or (ll-d) contains an alkenyl or alkenylene group or a cycloalkyl group, geometric cis / trans (or Z / E) isomers are possible. Compounds of Formula (I), (i-a), (i-b), (l-c), or (i-d) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of Formula (I), (l-a), (l-b), (l-c), or (l-d) contains an alkenyl or alkenylene group or a cycloalkyl group, geometric cis / trans (or Z / E) isomers are possible. Where the compound contains, for example, a keto or oxime group or an "aromatic moiety, tautomeric isomerism ("tautomerism") can occur. It follows that a single compound may exhibit more than one type of isomerism. 70504W001

[1502] Included within the scope of the claimed compounds present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of Formula (!), (i--a)_. (l-b), (l-c), (l-d), (l-e), (l-f), ‘g), (l-h), (l-i), (l-j), (l-k), (I l-a), (ll-b), (li-c), or (I l-d), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof, included within the scope of the claimed compounds present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of Formula (1), (l-a), (l-b), (l-c), or (l-d), including compounds exhibiting more than one type of isomerism, a d mixtures of one or more thereof Also included are acid addition or base salts wherein the counterion is optically active, for example, D-iactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.

[1503] Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.

[1504] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

[1505] Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of Formula (I), (l-a), (l-b), (I-c), (l-d), (i-e), (l-f), (:-g), (i-h), (l-i), (l-j), (:-k), (i l-a), (il-b), (ll-c), or (: l-d) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of Formula (I), (l-a), (l-b), (l-c), or (l-d) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and / or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.

[1506] Chiral compounds of the Invention (and chiral precursors thereof) may be obtained In enaritiomerically-enriched form using chromatography, typically HPLC, on a resin with an asymmetric stationary phase and with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.

[1507] Mixtures of stereoisomers may be separated by conventional techniques known to those skilled in the art. [See, for example, " Stereochemistry of Organic Compounds" by E L Eiiei (Wiley, New York, 1994).) 70504W001

[1508] The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of Formula (I), (l-a), (I- b), (l-c), (!- d), (!-e), (l-f), (l-g), (l-h), (l-i), (l-j), (I- k) (II -a), (li-b), (ll-c), or (li-d), wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. The present invention includes ail pharmaceutically acceptable isotopica lly-labelled compounds of Formula (I), (l-a), (l-b), (l-c), or (l-d) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

[1509] Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as2H and3H, carbon, such as11C,13C and14C, chlorine, such as36Cl, fluorine, such as18F, iodine, such as123I and125I, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulphur, such as35S.

[1510] Certain isotopicaily-labelied compounds of Formula (I), (l-a), (l-b), (l-c), (l-d), (l-e), (l-f), (l-g), (l-h), (l-i), (l-j), (l-k), (l-m), (ll-a), (ll-b), (ll-c), or (ll-d), for example, those incorporating a radioactive isotope, are useful In drug and / or substrate tissue distribution studies. Certain isotopicaily-labelied compounds of Formula (I), (ha), (l-b), (l-c), or (l-d), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.,3H, and carbon-14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[1511] Substitution with heavier isotopes such as deuterium, i.e.,2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

[1512] Isotopicaily-labelied compounds of Formula (I), (l-a), (l-b), (l-c), (l-d), (l-e), (l-f), (l-g), (l-h), (l-i), (l-j), (l-k), (ll-a), (ll-b), (ll-c), or (ll-d) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopicaily-labelied reagents in place of the non-labelled reagent previously employed. Isotopicaily-labelied compounds of Formula (I), (l-a), (l-b), (l-c), or (l-d) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopicaily-labelied reagents in place of the non-labelled reagent previously employed.

[1513] Furthermore, the compounds of the invention can exist in particular geometric or stereoisomeric forms. The invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)- 70504W001

[1514] enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, as falling within the scope of the invention. Additional asymmetric carbon atoms can be present in a substituent such as an alkyl group. Ail such isomers, as well as mixtures thereof) are intended to be included in this invention.

[1515] Optically active (R)- and (S)-isomers and (D)- and (L)-isomers can be prepared using chiral synthcns or chiral reagents,, or resolved using conventional techniques, if, for instance, a particular enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers. In addition, separation of enantiomers and diastereomers is frequently accomplished using chromatography employing chiral, stationary phases, optionally in combination with chemical derivatization (e.g., formation of carbamates from amines).

[1516] The compounds of the present invention and their salts, solvates, or other pharmaceutically acceptable derivatives thereof) may be employed alone or in combination with other therapeutic agents. Therefore, in other embodiments, the methods of treating and / or preventing an HIV Infection in a subject may in addition to administration of a compound of the invention further comprise administration of one or more additional pharmaceutical agents active against HIV.

[1517] Certain compounds of the present invention are prodrugs of the parent compound, Compound A,

[1518]

[1519] (Compound A).

[1520] Parent Compound A is also known as (15,3aS)-N-(3-chloro-2-fluorobenzyl)-6-hydroxy-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazine-8-carboxamide. Compound A may be synthesized according to the international patent application published as WO2019230858A1, wherein Compound A is disclosed as example II-031. WO2019230858A1 provides integrase inhibitors for use in treating or preventing HIV. Integrase inhibitors (integrase strand transfer inhibitors (INSTIs)) are a class of antiretroviral drug designed to 70504W001

[1521] block the action of integrase (e.g., HIV integrase), a viral enzyme that inserts the viral genome into the DNA of the host cell.

[1522] Certain compounds of the present invention advantageously extend the half-life of parent Compound A, which in the field of HIV will benefit people who have to receive daily high doses or even several doses a day.

[1523] In the field of long-acting injectables, it is advantageous for the administered compound to be less soluble than the parent compound (Compound A). For parenteral administration, it is believed to be advantageous to have drug substances with high lipophilicity or crystallinity in order to reduce solubility and limit the release rate within interstitial fluid. Prodrugs offer the ability to form unique crystalline formations that enhance insolubility profiles to allow for therapeutic drug release rates that are amenable to injectable dosing intervals every 1, 2, 3, 4, 5, 6, or 12 months.

[1524] COMPOUND PREPARATION

[1525] The names of the compounds and intermediates as disclosed herein have been obtained using the compound naming program within " ChemDraw". A person of ordinary skill in the art will recognize that the compound of the present invention may have alternative names when different naming software is used.

[1526] Abbreviations

[1527] ACN (or MeCN) acetonitrile

[1528] aq. aqueous

[1529] Boc2O di-tert-butyl dicarbonate

[1530] CPME cyclopentyl methyl ether

[1531] DCM or CH2CI2dichloromethane

[1532] DIEAor DIPEA diisopropylethylamine

[1533] DMAP dimethylaminopyridine

[1534] DMF N, / V-dimethylformamide

[1535] DMSO dimethylsulfoxide

[1536] DPPA diphenylphosphoryl azide

[1537] EA or EtOAc ethyl acetate

[1538] EDC or EDCI l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[1539] EDTA ethylenediaminetetraacetic acid

[1540] Equiv equivalents

[1541] g gram(s) 70504W001

[1542] h hour(s)

[1543] LCMS liquid chromatography-mass spectrometry

[1544] M molar

[1545] MeCN (or ACN) acetonitrile

[1546] min minute(s)

[1547] mL milliliter(s)

[1548] mmol millimole(s)

[1549] mol mole(s)

[1550] PCC pyridinium chlorochromate

[1551] Pd / C palladium on carbon

[1552] PE petroleum ether

[1553] PMA phosphomolybdic acid

[1554] RT (or rt) room temperature

[1555] TBAHS tetrabutylammonium hydrogen sulfate

[1556] TEA triethylamine

[1557] TFA trifluoroacetic acid

[1558] THF tetra hydrofuran

[1559] TLC thin layer chromatography

[1560] TMSI trimethylsilyl iodide

[1561] EXAMPLES LCMS Method A:

[1562] Column: XBridge C18 (4.6 x 50 mm, 3.5 micron particles); Solvent A = water (10 mM NH4HCO3). Solvent B = MeCN. Flow Rate = 1.8 mL / min. Start % B = 10. Final % B = 95. Gradient Time = 1.5 min with a 1.5 min hold at 95% solvent B. Column oven temp = 50 °C. Wavelength = 214 nm and 254 nm.

[1563] LCMS Method B:

[1564] Column: Sunfire C18 (4.6 x 50 mm, 3.5 micron particles); Solvent A = water (0.01% TFA). Solvent B = MeCN (0.01% TFA). Flow Rate = 2.0 mL / min. Start % B = 5. Final % B = 95. Gradient Time = 1.3 min with 1.7 min hold at 95% solvent B. Column oven temp = 50 °C. Wavelength = 214 nm and 254 nm.

[1565] LCMS Method C:

[1566] Column: Acquity BEH C18 (1.7 uM 2.1x100mm); Solvent A = 95:5 Water: Acetonitrile with 0.1% Formic Acid; Solvent B = 5:95 Water: Acetonitrile with 0.1% Formic Acid. Flow Rate = 0.8 mL / min. Start % B = 70504W001

[1567] 0. Final % B = 100. Gradient Time = 3.5 min with a 1.0 min hold at 100% solvent B. Column oven temp = 40 °C. Wavelength = 220 nm and 254 nm.

[1568] HPLC Method A:

[1569] Column: XBridge C18 (4.6 x 150 mm, 3.5 micron particles); Solvent A = water (10 mM NH4HCO3). Solvent B = MeCN. Flow Rate = 1.2 mL / min. Start % B = 10. Final % B = 90. Gradient Time = 9.0 min then 6 min hold at 90% solvent B. Column oven temp = 50 °C. Wavelength = 214 nm and 254 nm.

[1570] HPLC Method B:

[1571] Column: XBridge C18 (4.6 x 150 mm, 3.5 micron particles); Solvent A = water (0.01% TFA). Solvent B = MeCN (0.01% TFA). Flow Rate = 1.0 mL / min. Start % B = 10. Final % B = 95. Gradient Time = 8.0 min then 7 min hold at 95% solvent B. Column oven temp = 40 °C. Wavelength = 214 nm and 254 nm.

[1572] HPLC Method C:

[1573] Column: Sunfire C18 (4.6 x 150 mm, 3.5 micron particles); Solvent A = water (0.05% TFA). Solvent B = MeCN (0.05% TFA). Flow Rate = 1.0 mL / min. Start % B = 5. Final % B = 95. Gradient Time = 10 min then 5 min hold at 95% solvent B. Column oven temp = 45 °C. Wavelength = 214 nm and 254 nm.

[1574] UHPLC Purity Method A:

[1575] Column: Acquity BEH C18 (1.7 uM 2.1x150mm); Solvent A = 95:5 Water: Acetonitrile with 0.1% Formic Acid; Solvent B = 5:95 Water: Acetonitrile with 0.1% Formic Acid. Flow Rate = 0.5 mL / min. Start % B = 0. Final % B = 100. Gradient Time = 15 min with a 5 min hold at 100% solvent B. Column oven temp = 40 °C. Wavelength = 220 nm and 254 nm.

[1576] Compound 1:

[1577] (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo- 2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl tetradecanoate

[1578]

[1579] Step 1 70504W001

[1580] To a solution of tetradecanoic acid (221 mg, 0.968 mmol) in DCM (30 mL) was added DMAP (79 mg, 0.645 mmol) and EDC (186 mg, 0.968 mmol) at 0 °C. The resulting reaction mixture was stirred at the same temperature for 0.5 h. Then, (lS,3aS)-N-(3-chloro-2-fluorobenzyl)-6-hydroxy-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazine-8-carboxamide (300 mg, 0.645 mmol) was added and the resulting reaction mixture was stirred at 25 °C for 16 h. LCMS showed the reaction was completed. The reaction mixture was concentrated in vacuum. The residue was dissolved in MeOH, loaded to reverse SepaFlash® C18 column (Boston, 40 g) and purified by flash (Biotage) chromatography (0-90% ACN in water (10 mM NH4HCO3); flow rate: 40 mL / min) to give (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl tetradecanoate (147 mg, 0.208 mmol, 32.2 % yield) as colorless oil. LCMS (M+H) = 675.3; Retention time (LCMS Method A) = 2.56 min; purity: 95.76 % (254 nm). HPLC Retention time (HPLC Method A) = 13.66 min; purity: 95.53 % (254 nm).

[1581]

[1582] NMR (400 MHz, CDCI3) 6 10.22 (t, J = 5.2 Hz, 1H), 8.62 (s, 1H), 7.31-7.24 (m, 2H), 7.02 (dt, J = 8.0, 0.8 Hz, 1H), 5.10 (d, J = 3.6 Hz, 1H), 4.68 (s, 2H), 3.54-3.44 (m, 3H), 3.34 (s, 3H), 3.03 (s, 3H), 2.70 (t, J = 7.6 Hz, 2H), 2.38-2.30 (m, 1H), 2.25-2.05 (m, 2H), 1.87 (s, 1H), 1.78 (quint, J = 7.6 Hz, 2H), 1.47-1.38 (m, 2H), 1.37-1.22 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H).

[1583] The compounds set forth in Table 15 were prepared analogously to Compound 1.

[1584] Table 15.

[1585] Compound LCMS m / z1H-NMR (400 MHz) HPLC No. [M+H]+

[1586] 2 703.0JH NMR (400 MHz, CDCl3) 610.22 (t, J = 5.2 Hz, 1H), 8.62 HPLC Method A, (s, 1H), 7.31-7.24 (m, 2H), 7.02 (dt, J = 8.0, 1.2 Hz, 1H), retention time = Retention 5.10 (d, J = 3.6 Hz, 1H), 4.68 (s, 2H), 3.54-3.44 (m, 3H), 12.43 min time (LCMS 3.34 (s, 3H), 3.03 (s, 3H), 2.70 (t, J = 7.6 Hz, 2H), 2.38- Method A) = 2.30 (m, 1H), 2.24-2.04 (m, 2H), 1.87 (s, 1H), 1.78 (quint,

[1587] 3.42 min J = 7.6 Hz, 2H), 1.47-1.38 (m, 2H), 1.34-1.22 (m, 22H),

[1588] 0.88 (t, J = 6.8 Hz, 3H)

[1589] 3 731.0JH NMR (400 MHz, CDCl3) 610.22 (t, J = 5.6 Hz, 1H), 8.62 HPLC Method A, (s, 1H), 7.31-7.24 (m, 2H), 7.02 (dt, J = 8.0, 0.8 Hz, 1H), retention time = Retention 5.09 (d, J = 3.2 Hz, 1H), 4.68 (s, 2H), 3.53-3.43 (m, 3H), 14.77 min time (LCMS 3.34 (s, 3H), 3.03 (s, 3H), 2.70 (t, J = 7.6 Hz, 2H), 2.38- Method A) = 2.30 (m, 1H), 2.24-2.06 (m, 2H), 1.87 (s, 1H), 1.78 (quint,

[1590] 2.61 min J = 7.6 Hz, 2H), 1.47-1.38 (m, 2H), 1.35-1.22 (m, 26H),

[1591] 0.88 (t, J = 7.2 Hz, 3H)

[1592] 4 745.3JH NMR (400 MHz, CDCl3) 510.23 (t, J = 5.6 Hz, 1H), 8.62 HPLC Method A, (s, 1H), 7.31-7.24 (m, 2H), 7.02 (dt, J = 8.0, 0.8 Hz, 1H), retention time = Retention 5.10 (d, J = 3.2 Hz, 1H), 4.68 (s, 2H), 3.51-3.42 (m, 3H), 14.77 min time (LCMS 3.34 (s, 3H), 3.03 (s, 3H), 2.70 (t, J = 7.6 Hz, 2H), 2.38- Method A) = 2.30 (m, 1H), 2.25-2.07 (m, 2H), 1.87 (s, 1H), 1.78 (quint,

[1593] 4.01 min J = 7.6 Hz, 2H), 1.46-1.38 (m, 2H), 1.35-1.22 (m, 28H),

[1594]

[1595] 0.88 (t, J = 6.8 Hz, 3H) 70504W001

[1596] 6 773.3JH NMR (400 MHz, CDCl3) 610.22 (t, J = 5.2 Hz, 1H), 8.62 HPLC Method A,

[1597] (s, 1H), 7.31-7.24 (m, 2H), 7.02 (dt, J = 8.0, 0.8 Hz, 1H), retention time = Retention 5.09 (d, J = 3.6 Hz, 1H), 4.68 (s, 2H), 3.53-3.44 (m, 3H), 17.75 min time (LCMS 3.34 (s, 3H), 3.03 (s, 3H), 2.70 (t, J = 7.6 Hz, 2H), 2.35- Method A) = 2.30 (m, 1H), 2.25-2.05 (m, 2H), 1.86 (s, 1H), 1.78 (quint,

[1598] 3.96 min J = 7.6 Hz, 2H), 1.46-1.39 (m, 2H), 1.35-1.22 (m, 32H),

[1599] 0.88 (t, J = 6.8 Hz, 3H)

[1600] 8 639.2JH NMR (400 MHz, CDCl3) 610.20 (t, J = 5.6 Hz, 1H), 8.62 HPLC Method A,

[1601] (s, 1H), 7.32-7.24 (m, 2H), 7.03 (dt, J = 8.0, 0.8 Hz, 1H), retention time = Retention 5.09 (d, J = 3.6 Hz, 1H), 4.68 (s, 2H), 3.91 (t, J = 7.2 Hz, 8.51 min time (LCMS 2H), 3.71-3.64 (m, 6H), 3.57-3.54 (m, 2H), 3.54-3.44

[1602] Method A) = (m, 3H), 3.38 (s, 3H), 3.34 (s, 3H), 3.06-3.00 (m, 5H),

[1603] 1.73 min 2.38-2.30 (m, 1H), 2.24-2.04 (m, 2H), 1.90-1.80 (m, 1H)

[1604] 9 726.7JH NMR (400 MHz, CDCl3) 510.20 (t, J = 5.6 Hz, 1H), 8.62 HPLC Method A,

[1605] (s, 1H), 7.32-7.24 (m, 2H), 7.02 (t, J = 8.0 Hz, 1H), 5.09 retention time = Retention (d, J = 3.6 Hz, 1H), 4.68 (s, 2H), 3.91 (t, J = 7.2 Hz, 2H), 8.40 min time (LCMS 3.68-3.64 (m, 14H), 3.57-3.53 (m, 2H), 3.52-3.44 (m,

[1606] Method A) = 3H), 3.38 (s, 3H), 3.34 (s, 3H), 3.05-3.00 (m, 5H), 2.38- 1.66 min 2.30 (m, 1H), 2.24-2.06 (m, 2H), 1.91-1.82 (m, 1H)

[1607] 10 815.2JH NMR (400 MHz, CDCl3) 510.20 (t, J = 5.6 Hz, 1H), 8.62 HPLC Method A,

[1608] (s, 1H), 7.32-7.24 (m, 2H), 7.02 (dt, J = 8.0, 1.2 Hz, 1H), retention time = Retention 5.09 (d, J = 3.6 Hz, 1H), 4.68 (s, 2H), 3.91 (t, J = 7.2 Hz, 8.52 min time (LCMS 2H), 3.67-3.64 (m, 22H), 3.57-3.53 (m, 2H), 3.52-3.45

[1609] Method A) = (m, 3H), 3.38 (s, 3H), 3.34 (s, 3H), 3.05-3.00 (m, 5H),

[1610] 1.69 min 2.38-2.30 (m, 1H), 2.22-2.07 (m, 2H), 1.91-1.82 (m, 1H)

[1611] 11 903.3JH NMR (400 MHz, CDCl3) 510.20 (t, J = 5.6 Hz, 1H), 8.62 HPLC Method A,

[1612] (s, 1H), 7.32-7.24 (m, 2H), 7.02 (dt, J = 8.0, 0.8 Hz, 1H), retention time = Retention 5.09 (d, J = 3.2 Hz, 1H), 4.68 (s, 2H), 3.91 (t, J = 7.2 Hz, 8.37 min time (LCMS 2H), 3.70-3.62 (m, 30H), 3.57-3.53 (m, 2H), 3.52-3.44

[1613] Method A) = (m, 3H), 3.38 (s, 3H), 3.34 (s, 3H), 3.05-3.00 (m, 5H),

[1614] 1.73 min 2.38-2.30 (m, 1H), 2.24-2.07 (m, 2H), 1.92-1.82 (m, 1H)

[1615] 16 801.2,JH NMR (400 MHz, CDCI3) 6 10.20 (s, 1H), 8.62 (s, 1H), HPLC Method A,

[1616] Retention 7.34 - 7.26 (m, 2H), 7.02 (td, J = 7.9, 1.0 Hz, 1H), 5.09 (s, retention time = time (LCMS 1H), 4.83 - 4.52 (m, 2H), 3.60 - 3.40 (m, 3H), 3.33 (s, 3H), 20.71 min Method A) = 3.02 (s, 3H), 2.70 (t, J = 12.2, 3.5 Hz, 2H), 2.41 - 2.30 (m,

[1617] 5.004 min 1H) 2.25 - 2.05 (m, 2H), 1.87 (s, 1H), 1.82 - 1.70 (m, 2H),

[1618] 1.43 (s, 2H), 1.28 (d, J = 19.8, 13.6, 6.3 Hz, 36H), 0.88 (t,

[1619] J = 7.0 Hz, 3H)

[1620] 17 815.4JH NMR (400 MHz, CDCI3) 6 10.20 (s, 1H), 8.62 (s, 1H), HPLC Method A,

[1621] 7.34 - 7.26 (m, 2H), 7.02 (td, J = 7.9, 1.0 Hz, 1H), 5.09 (s, retention time = Retention 1H), 4.83 - 4.52 (m, 2H), 3.60 - 3.40 (m, 3H), 3.33 (s, 3H), 23.21 min time (LCMS 3.02 (s, 3H), 2.70 (t, J = 12.2, 3.5 Hz, 2H), 2.41 - 2.30 (m,

[1622] Method A) = 1H) 2.25 - 2.05 (m, 2H), 1.87 (s, 1H), 1.82 - 1.70 (m, 2H),

[1623] 5.788 min 1.43 (s, 2H), 1.28 (d, J = 19.8, 13.6, 6.3 Hz, 38H), 0.88 (t,

[1624] J = 7.0 Hz, 3H)

[1625] 18 661.0JH NMR (400 MHz, CDCI3) 510.20 (s, 1H), 8.62 (s, 1H), HPLC Method C,

[1626] 7.34 - 7.26 (m, 2H), 7.02 (td, J = 7.9, 1.0 Hz, 1H), 5.09 retention time = Retention (s, 1H), 4.83 - 4.52 (m, 2H), 3.60 - 3.40 (m, 3H), 3.33 14.14 min time (LCMS (d, J = 8.2 Hz, 3H), 3.02 (s, 3H), 2.63 (t, J = 12.2, 3.5 Hz,

[1627] Method A) = 2H), 2.43 - 2.27 (m, 1H), 2.26 - 2.03 (m, 2H), 1.87 (s,

[1628] 2.766 min 1H), 1.78 (dt, J = 15.4, 7.7 Hz, 2H), 1.42 (m,2H), 1.26 (d,

[1629] J = 11.0 Hz, 16H), 0.88 (t, J = 7.0 Hz, 3H)

[1630] 27 645.2JH NMR (400 MHz, CDCI3) 5 10.20 (s, 1H), 8.62 (s, 1H), HPLC Method A,

[1631] 7.34-7.26 (m, 2H), 7.02 (td, J = 7.9, 1.0 Hz, 1H), 5.09 (s, retention time = Retention 1H), 4.83-4.52 (m, 2H), 3.60-3.40 (m, 3H), 3.33 (d, J = 10.582 min

[1632]

[1633] time (LCMS 8.2 Hz, 3H), 3.02 (d, J = 11.0 Hz, 3H), 2.63 (tt, J = 12.2, 70504W001

[1634] Method A) = 3.5 Hz, 1H), 2.41-1.96 (m, 5H), 1.86 (d, J = 13.0 Hz, 1H),

[1635] 2.592 min 1.63 (dd, J = 12.8, 9.7 Hz, 4H), 1.24 (tdd, J = 19.8, 13.6,

[1636] 6.3 Hz, 9H), 0.96 (ddd, J = 16.6, 9.7, 3.2 Hz, 2H), 0.88 (t,

[1637]

[1638] 1 = 7.0 Hz, 3H)

[1639] Compound 5:

[1640] (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo- 2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl icosanoate

[1641]

[1642] Step 1

[1643] To a solution of icosanoic acid (303 mg, 0.968 mmol) in DCM (30 mL) was added DMAP (79 mg, 0.645 mmol) and EDC (247 mg, 1.291 mmol) at 0 °C. The resulting reaction mixture was stirred at the same temperature for 0.5 h. Then, (lS,3aS)-N-(3-chloro-2-fluorobenzyl)-6-hydroxy-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazine-8-carboxamide (300 mg, 0.645 mmol) was added and the resulting reaction mixture was stirred at 25 °C for 6 h. LCMS showed the reaction was completed. The reaction mixture was concentrated in vacuum. The residue was dissolved in MeOH, loaded to reverse SepaFlash® C18 column (Boston, 40 g) and purified by flash (Biotage) chromatography (0-99% MeOH in water (10 mM NH4HCO3); flow rate: 40 mL / min) to give solid. The product was crystallized with ACN and solids collected by filtration to afford (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl icosanoate (128 mg, 0.169 mmol, 26.1 % yield) as a white solid. Melting Point: 78 - 80 °C. LCMS (M+H) = 759.0; Retention time (LCMS Method A) = 4.26 min; purity: 100 % (254 nm). HPLC Retention time (HPLC Method A) = 15.95 min; purity: 100 % (254 nm). NMR (400 MHz, CDCI3) 6 10.22 (t, J = 5.6 Hz, 1H), 8.62 (s, 1H), 7.31-7.24 (m, 2H), 7.02 (dt, J = 8.0, 0.8 Hz, 1H), 5.09 (d, J = 3.2 Hz, 1H), 4.68 (s, 2H), 3.54-3.44 (m, 3H), 3.34 (s, 3H), 3.03 (s, 3H), 2.70 (t, J = 7.6 Hz, 2H), 2.38-2.30 (m, 1H), 2.24-2.04 (m, 2H), 1.87 (s, 1H), 1.78 (quint, J = 7.6 Hz, 2H), 1.48-1.38 (m, 2H), 1.36-1.20 (m, 30H), 0.88 (t, J = 6.8 Hz, 3H).

[1644] Compound 7:

[1645] (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl docosanoate 70504W001

[1646]

[1647] Step 1

[1648] To a solution of docosanoic acid (330 mg, 0.968 mmol) in DCM (20 mL) was added DMAP (79 mg, 0.645 mmol) and EDC (247 mg, 1.291 mmol) at 0 °C. The resulting reaction mixture was stirred at the same temperature for 0.5 h. Then, (lS,3aS)-N-(3-chloro-2-fluorobenzyl)-6-hydroxy-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazine-8-carboxamide

[1649] (300 mg, 0.645 mmol) was added and the resulting reaction mixture was stirred at 25 °C for 16 h. LCMS showed the reaction was completed. The reaction mixture was concentrated in vacuum. The residue was dissolved in THF, loaded to reverse SepaFlash® C18 column (Boston, 40 g) and purified by flash (Biotage) chromatography (0-85% (MeOH / THF=l / l) in water (10 mM NH4HCO3); flow rate: 40 mL / min). The product was dissolved in DCM, loaded to silica gel column (SanTai, 40 g) and repurified by flash (Biotage) chromatography (0-2% MeOH in DCM; flow rate: 40 mL / min) to give solid. The product was crystallized with ACN and solids collected by filtration to afford (15,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl docosanoate (140 mg, 0.178 mmol, 27.5 % yield) as a white solid. Melting Point: 82.5 - 84.0 °C. LCMS (M+H) = 787.3; Retention time (LCMS Method A) = 4.40 min; purity: 100 % (254 nm). HPLC Retention time (HPLC Method A) = 19.32 min; purity: 100 % (254 nm). NMR (400 MHz, CDCI3) 6 10.22 (t, J = 5.6 Hz, 1H), 8.62 (s, 1H), 7.31-7.24 (m, 2H), 7.02 (dt, J = 8.0, 0.8 Hz, 1H), 5.09 (d, J = 2.8 Hz, 1H), 4.68 (s, 2H), 3.54-3.43 (m, 3H), 3.34 (s, 3H), 3.03 (s, 3H), 2.70

[1650] (t, J = 7.6 Hz, 2H), 2.38-2.30 (m, 1H), 2.24-2.03 (m, 2H), 1.86 (s, 1H), 1.78 (quint, J = 7.6 Hz, 2H), 1.47-1.38 (m, 2H), 1.36-1.22 (m, 34H), 0.88 (t, J = 6.8 Hz, 3H).

[1651] Compound 12:

[1652] (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo- 2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl isobutyrate 70504W001

[1653]

[1654] Step 1

[1655] To a stirred solution of (lS,3aS)-N-(3-chloro-2-fluorobenzyl)-6-hydroxy-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazine-8-carboxamide (300 mg, 0.645 mmol) in DCM (5 mL) was added DIPEA (0.225 mL, 1.291 mmol) and isobutyryl chloride (76 mg, 0.710 mmol) at 25 °C and stirred for 16 h. LCMS showed the reaction was completed. The reaction mixture was concentrated under vacuum to give crude product. The residue was dissolved in DCM, loaded to silica gel column (SanTai, 25 g) and purified by flash (Biotage) chromatography (0-2% MeOH / DCM; flow rate: 30 mL / min) to give product as a yellow oil. The compound was crystallized from 4:1 n-hexane / EtOAc to afford (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl isobutyrate (124 mg, 0.232 mmol, 35.9 % yield) as yellow solid. Melting Point: 181.6 - 183.9 °C. LCMS: (M+H) = 535.2, Retention time (LCMS Method A) = 1.818 min, purity: 100 % (254 nm). HPLC Retention time (HPLC Method C) = 9.95 min; purity: 100.00 % (254 nm).

[1656]

[1657] NMR (400 MHz, CDCl3) δ 10.21 (s, 1H), 8.63 (s, 1H), 7.28 (d, J = 6.1 Hz, 2H), 7.03 (t, J = 7.8 Hz, 1H), 5.10 (s, 1H), 4.70 (s, 2H), 3.49 (s, 3H), 3.35 (s, 3H), 3.04 (s, 3H), 2.45 - 2.29 (m, 1H), 2.28 - 2.00 (m, 2H), 1.65 (s, 2H), 1.49 - 1.32 (m, 6H).

[1658] Compound 13:

[1659] (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo- 2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl hexanoate

[1660]

[1661] Step 1

[1662] To a stirred solution of (lS,3aS)-N-(3-chloro-2-fluorobenzyl)-6-hydroxy-l-(methoxymethyl)-4-methyl- 5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazine-8-carboxamide (300 mg, 0.645 mmol) in DCM (5 mL) was added DIPEA (0.225 mL, 1.291 mmol) and hexanoyl chloride (96 70504W001

[1663] mg, 0.710 mmol) at 25 °C and stirred for 16 h. LCMS showed the reaction was completed. The reaction mixture was concentrated under vacuum to give crude product. The residue was dissolved in DCM, loaded to silica gel column (SanTai, 25 g) and purified by flash (Biotage) chromatography (0-2% MeOH / DCM; flow rate: 30 mL / min) to give product as a yellow oil. The compound was crystallized from 4:1 n-hexane / EtOAc to afford (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl hexanoate (151 mg, 0.268 mmol, 41.6 % yield) as a yellow solid. Melting Point: 135.0 - 143.7 °C. LCMS: (M+H) = 563.2, Retention time (LCMS Method A) = 1.939 min, purity: 100 % (254 nm). HPLC Retention time (HPLC Method C) = 10.85 min; purity: 100.00 % (254 nm).

[1664]

[1665] NMR (400 MHz, CDCl3) δ 10.23 (s, 1H), 8.63 (s, 1H), 7.32 - 7.27 (m, 2H), 7.09 - 6.97 (m, 1H), 5.10 (d, J = 3.4 Hz, 1H), 4.69 (s, 2H), 3.49 (dd, J = 13.7, 9.8 Hz, 3H), 3.34 (d, J = 7.6 Hz, 3H), 3.06 (d, J = 22.4 Hz, 3H), 2.78 -2.63 (m, 2H), 2.35 (dd, J = 13.8, 8.7 Hz, 1H), 2.28 - 2.02 (m, 2H), 1.94 - 1.75 (m, 3H), 1.50 - 1.30 (m, 4H), 0.92 (t, J = 7.1 Hz, 3H).

[1666] Compound 14:

[1667] (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl heptanoate

[1668]

[1669] Step 1

[1670] To a stirred solution of (lS,3aS)-N-(3-chloro-2-fluorobenzyl)-6-hydroxy-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazine-8-carboxamide (300 mg, 0.645 mmol) in DCM (5 mL) was added DIPEA (0.225 mL, 1.291 mmol) and heptanoyl chloride (106 mg, 0.710mmol) at 25 °C and stirred for 16 h. LCMS showed the reaction was completed. The reaction mixture was concentrated under vacuum to give crude product. The residue was dissolved in DCM, loaded to silica gel column (SanTai, 25 g) and purified by flash (Biotage) chromatography (0-2% MeOH / DCM; flow rate: 30 mL / min) to give product as a yellow oil. The compound was crystallized from 4:1 n-hexane / EtOAc to afford (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl heptanoate (137 mg, 0.237 mmol, 36.8 % yield) as yellow solid. Melting Point: 107.9-116.4 °C. LCMS: (M+H) = 577.3, Retention time (LCMS Method A) = 2.003 min, purity: 100 % 70504W001

[1671] (254 nm). HPLC Retention time (HPLC Method C) = 11.31 min; purity: 100.00 % (254 nm).

[1672]

[1673] NMR (400 MHz, CDCl3) δ 10.23 (s, 1H), 8.63 (s, 1H), 7.40 - 7.20 (m, 2H), 7.12 - 6.91 (m, 1H), 5.11 (d, J = 3.4 Hz, 1H), 4.69 (s, 2H), 3.49 (t, J = 11.7 Hz, 3H), 3.34 (d, J = 7.3 Hz, 3H), 3.04 (s, 3H), 2.79 - 2.65 (m, 2H), 2.35 (dd, J = 12.8, 8.1 Hz, 1H), 2.28 - 2.02 (m, 2H), 1.87 (s, 1H), 1.82 - 1.70 (m, 2H), 1.52 - 1.39 (m, 2H), 1.34 (dd, J = 9.1, 5.2 Hz, 4H), 0.90 (t, J = 7.0 Hz, 3H).

[1674] The compounds set forth in Table 16 were prepared analogously to Compound 14.

[1675] Table 16.

[1676] Compound LCMS m / z1H-NMR (400 MHz) HPLC No. [M+H]+

[1677] 15 592.11H NMR (400 MHz, CDCl3) 6 10.22 (s, 1H), 8.62 (s, 1H), HPLC Method A,

[1678] 7.34 - 7.26 (m, 2H), 7.08 - 6.94 (m, 1H), 5.10 (d, J = 3.4 retention time = Retention Hz, 1H), 4.68 (s, 2H), 3.55 - 3.43 (m, 3H), 3.33 (d, J = 7.3 10.88 min time (LCMS Hz, 3H), 3.06 (s, 3H), 2.76 - 2.62 (m, 2H), 2.43 - 2.27 (m,

[1679] Method A) = 1H), 2.26 - 2.03 (m, 2H), 1.87 (s, 1H), 1.78 (dt, J = 15.4,

[1680] 1.775 min 7.7 Hz, 2H), 1.42 (dd, J = 14.9, 7.1 Hz, 2H), 1.34 (dd, J =

[1681] 22.6, 10.9 Hz, 6H), 0.88 (t, J = 6.8 Hz, 3H)

[1682] 19 633.01H NMR (400 MHz, CDCl3) 6 10.20 (s, 1H), 8.62 (s, 1H), HPLC Method A,

[1683] 7.34 - 7.26 (m, 2H), 7.02 (td, J = 7.9, 1.0 Hz, 1H), 5.09 (s, retention time = Retention 1H), 4.83 - 4.52 (m, 2H), 3.60 - 3.40 (m, 3H), 3.33 (s, 3H), 12.36 min time (LCMS 3.02 (s, 3H), 2.70 (t, J = 12.2, 3.5 Hz, 2H), 2.41 - 2.30 (m,

[1684] Method A) = 1H) 2.25 - 2.05 (m, 2H), 1.87 (s, 1H), 1.825 - 1.700 (m,

[1685] 2.148 min 2H), 1.475 - 1.375 (m, 2H), 1.28 (d, J = 19.8, 13.6, 6.3 Hz,

[1686] 12H), 0.88 (t, J = 7.0 Hz, 3H)

[1687] 20 605.01H NMR(400 MHz, CDCl3) 5 10.22 (s, 1H), 8.62 (s, 1H), HPLC Method A,

[1688] 7.29 (d, J = 7.1 Hz, 1H), 7.26 - 7.23 (m, 1H), 7.02 (t, J = retention time = Retention 8.0 Hz, 1H), 5.09 (d, J = 3.2 Hz, 1H), 4.68 (s, 2H), 3.48 (t, 11.67 min time (LCMS J = 11.7 Hz, 3H), 3.34 (s, 3H), 3.06 (d, J = 24.4 Hz, 3H),

[1689] Method B) = 2.70 (t, J = 7.7 Hz, 2H), 2.41 - 2.03 (m, 3H), 1.94 - 1.73

[1690] 2.323 (m, 3H), 1.42 (d, J = 7.3 Hz, 2H), 1.33 - 1.23 (m, 8H), 0.88

[1691] (t, J = 6.7 Hz, 3H)

[1692] 21 619.21H NMR (400 MHz, CDCl3) 5 10.22 (s, 1H), 8.62 (s, 1H), HPLC Method A,

[1693] 7.29 (d, J = 7.0 Hz, 2H), 7.02 (t, J = 8.3 Hz, 1H), 5.09 (d, J retention time = Retention = 3.4 Hz, 1H), 4.68 (s, 2H), 3.48 (t, J = 11.7 Hz, 3H), 3.34 12.053 min time (LCMS (s, 3H), 3.03 (s, 3H), 2.70 (t, J = 7.7 Hz, 2H), 2.42 - 2.27

[1694] Method B) (m, 1H), 2.26 - 2.03 (m, 2H), 1.78 (dt, J = 15.5, 7.7 Hz,

[1695] =2.428 min 3H), 1.42 (d, J = 7.6 Hz, 2H), 1.28 (d, J = 12.5 Hz, 10H),

[1696] 0.88 (t, J = 6.8 Hz, 3H)

[1697] 22 647.11H NMR (400 MHz, CDCl3) 5 10.22 (s, 1H), 8.62 (s, 1H), HPLC Method A,

[1698] 7.29 (d, J = 7.2 Hz, 2H), 7.02 (t, J = 8.4 Hz, 1H), 5.09 (d, J retention time = Retention = 3.4 Hz, 1H), 4.68 (s, 2H), 3.48 (t, J = 11.7 Hz, 3H), 3.34 12.879 min time (LCMS (s, 3H), 3.03 (s, 3H), 2.77 - 2.62 (m, 2H), 2.32 (d, J = 7.7

[1699] Method B) Hz, 1H), 2.18 (dd, J = 18.6, 8.6 Hz, 2H), 1.77 (dd, J = 15.1,

[1700] =2.701 7.6 Hz, 3H), 1.42 (d, J = 7.8 Hz, 2H), 1.28 (d, J = 15.8 Hz,

[1701] 14H), 0.88 (t, J = 6.8 Hz, 3H)

[1702] 24 689.81H NMR (400 MHz, CDCl3) 5 10.45 - 9.92 (m, 1H), 8.62 HPLC Method A, (s, 1H), 7.28 (s, 1H), 7.27 - 7.23 (m, 1H), 7.02 (d, J = 1.0 retention time = Retention Hz, 1H), 5.16 - 5.02 (m, 1H), 4.81-4.59 (m, 2H), 3.47 (d, 12.088 min time (LCMS J = 4.0 Hz, 3H), 3.34 (s, 3H), 3.03 (s, 3H), 2.76 - 2.62 (m,

[1703] Method B) = 2H), 2.41 - 2.29 (m, 1H), 2.28-2.00 (m, 2H), 1.95 - 1.82

[1704] 2.546 min (m, 1H), 1.78 (s, 2H), 1.65 (s, 2H), 1.48 - 1.37 (m, 2H),

[1705]

[1706] 1.28 (d, J = 18.5 Hz, 18H), 0.88 (t, J = 6.8 Hz, 3H) 70504W001

[1707] 718.31H NMR (400 MHz, CDCl3) δ 10.45 - 9.92 (m, 1H), 8.62 HPLC Method A, (s, 1H), 7.28 (s, 1H), 7.27 - 7.23 (m, 1H), 7.02 (d, J = 1.0 retention time = Retention Hz, 1H), 5.16 - 5.02 (m, 1H), 4.81-4.59 (m, 2H), 3.47 (d, 12.988 min time (LCMS J = 4.0 Hz, 3H), 3.34 (s, 3H), 3.03 (s, 3H), 2.76 - 2.62 (m,

[1708] Method A) = 2H), 2.41 - 2.29 (m, 1H), 2.28-2.00 (m, 2H), 1.95 - 1.82

[1709] 4.403 min (m, 1H), 1.78 (s, 2H), 1.65 (s, 2H), 1.48 - 1.37 (m, 2H),

[1710]

[1711] 1.28 (d, J = 18.5 Hz, 22H), 0.88 (t, J = 6.8 Hz, 3H)

[1712] The compounds set forth in Table 17 were prepared analogously to Compound 14.

[1713] Table 17.

[1714] Compound LCMS m / z1H-NMR (400 MHz) UHPLC Purity No. [M+H]+

[1715] 229 625.21H NMR (500 MHz, chloroform-d) 6 ppm 1.33 - 1.35 (UHPLC Purity (m, 9 H) 1.82 - 1.94 (m, 1 H) 2.07 - 2.15 (m, 1 H) 2.16 Method A): 92.8% Retention - 2.25 (m, 1 H) 2.29 - 2.38 (m, 1 H) 3.00 (br d, J=16.69 (220 nm) time (LCMS Hz, 3 H) 3.36 (br d, J=19.67 Hz, 3 H) 3.46 - 3.59 (m,

[1716] Method C) 3 H) 4.59 - 4.76 (m, 2 H) 5.09 - 5.16 (m, 1 H) 7.00 (t,

[1717] = 3.884 min J=7.75 Hz, 1 H) 7.26 - 7.30 (m, 2 H) 7.47 - 7.53 (m, 2

[1718] H) 8.14 (br dd, J=15.35, 8.20 Hz, 2 H) 8.67 (s, 1 H)

[1719] 10.18 - 10.28 (m, 1 H)

[1720] 230 589.21H NMR (500 MHz, chloroform-d) 6 ppm 1.11 - 1.19 (UHPLC Purity (m, 2 H) 1.49 - 1.58 (m, 2 H) 1.58 - 1.64 (m, 2 H) 1.77 Method A): 100% Retention - 1.92 (m, 6 H) 2.04 - 2.14 (m, 1 H) 2.15 - 2.23 (m, 1 (220 nm) time (LCMS H) 2.30 - 2.38 (m, 1 H) 2.68 - 2.77 (m, 2 H) 3.03 (br

[1721] Method C) s, 3 H) 3.34 (br s, 3 H) 3.42 - 3.53 (m, 3 H) 4.60 - 4.77 Retention time = 3.810 min (m, 2 H) 5.05 - 5.14 (m, 1 H) 7.02 (td, J=7.82, 1.04 (UHPLC Purity Hz, 1 H) 7.25 - 7.32 (m, 2 H) 8.62 (s, 1 H) 10.18 - Method A) = 11.7 10.26 (m, 1 H) min

[1722] 231 597.21H NMR (500 MHz, chloroform-d) 6 ppm 1.80 - 1.95 (UHPLC Purity (m, 1 H) 2.04 - 2.15 (m, 1 H) 2.15 - 2.25 (m, 1 H) 2.36 Method A): 100% Retention (d, 7=2.98 Hz, 6 H) 3.01 (d, 7=14.60 Hz, 3 H) 3.29 - (220 nm) time (LCMS 3.41 (m, 3 H) 3.45 - 3.60 (m, 3 H) 4.58 - 4.76 (m, 2

[1723] Method C) H) 5.13 (br dd, 7=17.44, 3.73 Hz, 1 H) 7.01 (t, 7=7.90 Retention time = 3.71 min Hz, 1 H) 7.23 - 7.30 (m, 3 H) 7.84 (br d, 7=14.90 Hz, (UHPLC Purity 2 H) 8.67 (s, 1 H) 10.16 - 10.30 (m, 1 H) Method A) =

[1724] 11.284 min. 232 589.21H NMR (500 MHz, chloroform-d) 6 ppm 1.22 - 1.35 (UHPLC Purity (m, 12 H) 1.60 - 1.67 (m, 1 H) 1.82 - 1.90 (m, 1 H) Method A): 99.8% Retention 2.09 (dt, J=12.59, 9.50 Hz, 1 H) 2.13 - 2.21 (m, 1 H) (220 nm) time (LCMS 2.29 - 2.36 (m, 1 H) 3.02 (s, 3 H) 3.33 (s, 3 H) 3.41 - Method C) 3.53 (m, 3 H) 4.58 - 4.76 (m, 2 H) 5.09 (br d, J=3.28 Retention time = 3.72 min Hz, 1 H) 7.02 (td, J=7.82, 1.04 Hz, 1 H) 7.26 - 7.30 (UHPLC Purity (m, 2 H) 8.60 (s, 1 H) 10.24 - 10.33 (m, 1 H) Method A):

[1725] 11.175 min 233 589.11H NMR (500 MHz, chloroform-d) 6 ppm 0.27 - 0.32 (UHPLC Purity (m, 2 H) 0.32 - 0.37 (m, 2 H) 0.98 (ddd, J=14.16, Method A): 100% Retention 8.64, 5.81 Hz, 1 H) 1.04 (s, 6 H) 1.81 - 1.91 (m, 1 H) (220 nm) time (LCMS 2.03 - 2.13 (m, 1 H) 2.14 - 2.23 (m, 1 H) 2.29 - 2.37

[1726] Method C) (m, 1 H) 2.59 - 2.75 (m, 2 H) 3.03 (br s, 3 H) 3.33 (br Retention time

[1727]

[1728] = 3.29 min s, 3 H) 3.43 - 3.53 (m, 3 H) 4.59 - 4.77 (m, 2 H) 5.05 (UHPLC Purity 70504W001

[1729] - 5.13 (m, 1 H) 7.02 (td, J=7.90, 1.19 Hz, 1 H) 7.24 - Method A) = 7.31 (m, 2 H) 8.61 (s, 1 H) 10.19 - 10.27 (m, 1 H) 11.493 min 233

[1730] 234 603.21H NMR (500 MHz, chloroform-d) 6 ppm 1.30 - 1.40 (UHPLC Purity (m, 2 H) 1.46 - 1.56 (m, 4 H) 1.59 - 1.63 (m, 2 H) 1.64 Method A): 99.4% Retention - 1.72 (m, 2 H) 1.81 - 1.95 (m, 3 H) 2.04 - 2.12 (m, 1 (220 nm) time (LCMS H) 2.13 - 2.23 (m, 2 H) 2.29 - 2.37 (m, 1 H) 2.63 (br

[1731] Method C) d, 1=6.85 Hz, 2 H) 3.02 (br s, 3 H) 3.33 (br s, 3 H) 3.43 Retention time = 3.91 min - 3.53 (m, 3 H) 4.59 - 4.78 (m, 2 H) 5.06 - 5.13 (m, 1 (UHPLC Purity H) 7.02 (td, 1=7.82, 1.04 Hz, 1 H) 7.25 - 7.31 (m, 2 H) Method A) = 8.61 (s, 1 H) 10.18 - 10.26 (m, 1 H) 12.254 min 235 561.11H NMR (500 MHz, chloroform-d) 6 ppm 1.78 - 1.97 (UHPLC Purity (m, 5 H) 2.04 - 2.13 (m, 1 H) 2.14 - 2.27 (m, 3 H) 2.29 Method A): 98.5% Retention - 2.37 (m, 1 H) 2.79 - 2.91 (m, 3 H) 3.02 (br s, 3 H) (220 nm) time (LCMS 3.34 (s, 3 H) 3.43 - 3.54 (m, 3 H) 4.60 - 4.75 (m, 2 H)

[1732] Method C) 5.06 - 5.12 (m, 1 H) 7.02 (td, J=7.90, 1.19 Hz, 1 H) Retention time = 3.53 min 7.24 - 7.30 (m, 2 H) 8.61 (s, 1 H) 10.17 - 10.27 (m, 1 (UHPLC Purity H) Method A): 3.53 min

[1733] 236 547.11H NMR (500 MHz, chloroform-d) 6 ppm 0.24 - 0.34 (UHPLC Purity (m, 2 H) 0.57 - 0.67 (m, 2 H) 1.14 - 1.23 (m, 1 H) 1.81 Method A): 99.4% Retention - 1.93 (m, 1 H) 2.02 - 2.14 (m, 1 H) 2.15 - 2.28 (m, 1 (220 nm) time (LCMS H) 2.29 - 2.38 (m, 1 H) 2.63 (br d, 1=6.26 Hz, 2 H)

[1734] Method C) 3.03 (s, 3 H) 3.34 (s, 3 H) 3.43 - 3.55 (m, 3 H) 4.68 Retention time = 3.31 min (br d, 1=1.49 Hz, 2 H) 5.10 (br d, 1=3.87 Hz, 1 H) 7.02 (UHPLC Purity (td, 1=7.90, 1.19 Hz, 1 H) 7.25 - 7.32 (m, 2 H) 8.63 (s, Method A): 9.496 1 H) 10.16 - 10.27 (m, 1 H) min

[1735] 237 641.21H NMR (500 MHz, chloroform-d) 6 ppm 1.67 - 1.73 (UHPLC Purity (m, 6 H) 1.81 (br s, 6 H) 1.83 - 1.90 (m, 1 H) 2.01 (br Method A): 100% Retention s, 3 H) 2.05 - 2.13 (m, 1 H) 2.14 - 2.22 (m, 1 H) 2.29 (220 nm) time (LCMS - 2.37 (m, 1 H) 2.39 - 2.57 (m, 2 H) 3.03 (br s, 3 H)

[1736] Method C) 3.33 (br s, 3 H) 3.41 - 3.54 (m, 3 H) 4.56 - 4.79 (m, 2 (UHPLC Retention = 4.12 min H) 5.09 (br s, 1 H) 7.02 (td, 1=7.90, 1.19 Hz, 1 H) 7.26 time) = 13.143

[1737]

[1738] - 7.31 (m, 2 H) 8.61 (s, 1 H) 10.20 - 10.30 (m, 1 H) min Compound 23:

[1739] (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo- 2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl pivalate.

[1740]

[1741] Step 1 70504W001

[1742] To a mixture of (lS,3aS)-N-(3-chloro-2-fluorobenzyl)-6-hydroxy-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazine-8-carboxamide (500 mg, 1.076 mmol) and DIPEA (0.376 mL, 2.151 mmol) in DCM (10 mL) was added pivaloyl chloride (130 mg, 1.076 mmol) at 0 °C. It was stirred at 25 °C overnight. LCMS showed the reaction was completed. The reaction mixture concentrated in vacuum. The residue was dissolved in DCM (5 mL), loaded to silica column (SanTai, 40 g), purified by flash (Biotage) chromatography (0-2% MeOH / DCM, 50 mL / min) to give as colorless oil. The oil was triturated with 9% EtOAc in hexanes (10 mL) and solids collected by filtration to afford (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl pivalate (400 mg, 0.729 mmol, 67.7 % yield) as white solid. Melting Point: 156.8 - 158.3 °C. LCMS (M+H) = 549.0; Retention time (LCMS Method B) = 1.765 min; purity (254nm) = 100%. HPLC: Retention time (HPLC Method C) = 10.852, purity (254 nm) = 100%.

[1743]

[1744] NMR (400 MHz, CDCl3) δ 10.20 (s, 1H), 8.62 (s, 1H), 7.29 (d, J = 6.9 Hz, 1H), 7.25 (s, 1H), 7.02 (dt, J = 7.8, 3.9 Hz, 1H), 5.09 (s, 1H), 4.85 - 4.55 (m, 2H), 3.48 (dd, J = 14.5, 9.2 Hz, 3H), 3.33 (d, J = 14.3 Hz, 3H), 3.02 (d, J = 13.9 Hz, 3H), 2.44 - 2.25 (m, 1H), 2.24 - 2.00 (m, 2H), 1.96- 1.77 (m, 1H), 1.48 - 1.39 (m, 9H).

[1745] Compound 25:

[1746] isopropyl (((((lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H- pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6- yl)oxy)methoxy)carbonyl)-L-methioninate

[1747]

[1748] Step 1

[1749] To a solution of isopropyl L-methioninate (29.0 mg, 0.152 mmol) in Acetonitrile (2 mL) were added DMAP (37.0 mg, 0.303 mmol) and TEA (0.084 mL, 0.606 mmol) followed by (((lS,3aS)- 8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH- pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl)oxy)methyl (4-nitrophenyl) carbonate (100 mg, 0.152 mmol) at 0 °C. The resulting reaction mixture was stirred at 25 °C for 16h. The LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM, loaded to silica gel column (SanTai, 25 g) and purified by flash (Biotage) column chromatography (0-3% MeOH in DCM; flow rate: 30 mL / min). The product was recrystallized with 10% 70504W001

[1750] Ethyl acetate in hexanes and collected by filtration to afford the product isopropyl (((((lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-1H- pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazin-6- yl)oxy)methoxy)carbonyl)-L-methioninate (35 mg, 0.049 mmol, 32.4 % yield) as a white solid. LCMS (M+H)+= 712.3, Retention Time (LCMS Method A) = 1.674. NMR (400 MHz, CDCl3) δ 10.34 (s, 1H), 8.56 (s, 1H), 7.29 (d, J = 7.3 Hz, 2H), 7.04 (d, J = 8.3 Hz, 1H), 5.92 (d, J = 6.6 Hz, 1H), 5.82 (d, J = 6.6 Hz, 1H), 5.53 (d, J = 8.1 Hz, 1H), 5.04 (dd, J = 10.8, 4.7 Hz, 2H), 4.80-4.70 (m, 1H), 4.70-4.61 (m, 1H), 4.46-4.35 (m, 1H), 3.46 (d, J = 11.5 Hz, 3H), 3.35 (s, 3H), 3.03 (s, 3H), 2.56 (t, J = 7.6 Hz, 2H), 2.38 - 2.27 (m, 1H), 2.13 (s, 3H), 2.06 (s, 3H), 2.00 - 1.80 (m, 2H), 1.24 (dd, J = 6.2, 2.8 Hz, 6H).

[1751] The compounds set forth in Table 18 were prepared analogously to Compound 25.

[1752] Table 18.

[1753] Compound LCMS m / z1H-NMR (400 MHz) HPLC No. [M+H]+

[1754] 66 739.41H NMR (500 MHz, CDCl3) δ 10.28 (s, 1H), 8.58 (s, 1H), N / A

[1755] 7.33 - 7.27 (m, 2H), 7.04 (t, J = 7.9 Hz, 1H), 6.75 (s, 1H),

[1756] Retention 5.99 (d, J = 6.6 Hz, 1H), 5.71 (d, J = 6.6 Hz, 1H), 5.63 (d, J

[1757] Time (LCMS = 8.0 Hz, 1H), 5.06 (d, J = 3.5 Hz, 1H), 4.69 (dd, J = 14.6,

[1758] Method A) = 6.0 Hz, 2H), 4.32 (d, J = 5.3 Hz, 1H), 3.57 - 3.39 (m, 3H),

[1759] 1.639 3.35 (s, 3H), 3.24 (d, J = 5.9 Hz, 2H), 3.03 (s, 3H), 2.58 (t,

[1760] J = 7.0 Hz, 2H), 2.38 - 2.27 (m, 1H), 2.24 - 2.12 (m, 2H),

[1761] 2.10 (d, J = 14.3 Hz, 4H), 2.04 - 1.95 (m, 1H), 1.88 (d, J =

[1762] 13.1 Hz, 1H), 1.38 (dd, J = 14.5, 7.2 Hz, 3H), 0.88 (dd, J =

[1763] 6.5, 2.6 Hz, 6H)

[1764] 156 640.31H NMR (400 MHz, CDCl3) δ 10.38 (t, J = 6.4 Hz, 1H), 8.55 HPLC Method A, (s, 1H), 7.32-7.27 (m, 2H), 7.03 (t, J = 8.0 Hz, 1H), 5.84 retention time = Retention (d, J = 6.8 Hz, 1H), 5.79 (d, J = 6.4 Hz, 1H), 5.39 (t, J = 5.6 7.19 min time (LCMS Hz, 1H), 5.05 (d, J = 3.6 Hz, 1H), 4.75-4.63 (m, 2H), 3.61- Method A) = 3.56 (m, 2H), 3.55-3.43 (m, 7H), 3.37 (s, 3H), 3.35 (s,

[1765] 1.63 min 5H), 3.03 (s, 3H), 2.36-2.28 (m, 1H), 2.21-2.04 (m, 2H),

[1766] 1.92-1.83 (m, 1H)

[1767] 163 566.11H NMR (400 MHz, CDCl3) δ 10.38 (t, J = 5.6 Hz, 1H), 8.54 HPLC Method A, (s, 1H), 7.30-7.26 (m, 2H), 7.02 (t, J = 8 Hz, 1H), 5.79 (dd, retention time = Retention J = 6.4 Hz, 13.2 Hz, 2H), 5.05 (d, J = 3.6 Hz, 1H), 4.91 (t, J 7.776 min time (LCMS = 4.8 Hz, 1H), 4.69-4.67 (m, 2H), 3.50-3.43 (m, 3H), 3.34

[1768] Method A) = (s, 3H), 3.17-3.14 (m, 2H), 3.03 (s, 3H), 2.34-2.29 (m, 1H),

[1769] 1.802 min 2.18-2.06 (m, 2H), 1.90-1.87 (m, 1H), 1.09 (t, J = 7.6 Hz,

[1770] 3H)

[1771] 164 566.11H NMR (400 MHz, CDCl3) δ 10.40 (t, J = 5.6 Hz, 1H), 8.53 HPLC Method A, (s, 1H), 7.30-7.26 (m, 2H), 7.02 (t, J = 7.6 Hz, 1H), 5.81 retention time = Retention (dd, J = 6 Hz, 25.2 Hz, 2H), 5.05 (d, J = 3.6 Hz, 1H), 4.68 7.659 min time (LCMS (d, J = 6 Hz, 2H), 3.49-3.44 (m, 3H), 3.33 (s, 3H), 3.01 (s,

[1772] Method A) = 3H), 2.92 (s, 3H), 2.84 (s, 3H), 2.32-2.28 (m, 1H), 2.17- 1.779 min 2.08 (m, 2H), 1.87-1.85 (m, 1H)

[1773] 165 628.11H NMR (400 MHz, CDCl3) δ 10.37 (t, J = 6 Hz, 1H), 8.54 HPLC Method A, (s, 1H), 7.30-7.29 (d, J = 4.4 Hz, 5H), 7.25-7.23 (m, 2H), retention time = Retention 7.01 (t, J = 8 Hz, 1H), 5.85 (dd, J = 6.4, 17.6 Hz, 2H), 5.26 8.571 min time (LCMS (t, J = 6.4 Hz, 1H), 5.02 (d, J = 3.6 Hz, 1H), 4.69-4.65 (m,

[1774] Method A) = 2H), 4.34 (d, J = 6 Hz, 2H), 3.47-3.40 (m, 3H), 3.32 (s, 3H),

[1775]

[1776] 1.906 min 70504W001

[1777] 2.99 (s, 3H), 2.31-2.27 (m, 1H), 2.16-2.03 (m, 2H), 1.88- 1.81(m, 1H)

[1778] 166 790.71H NMR (400 MHz, CDCl3) δ 10.38 (t, J = 5.6 Hz, 1H), 8.54 HPLC Method A,

[1779] (s, 1H), 7.30-7.26 (m, 2H), 7.02 (t, J = 8 Hz, 1H), 5.79 (dd, retention time = Retention J = 6.4Hz, 19.2Hz, 2H), 5.05 (d, J = 3.6Hz, 1H), 4.93 (t, J = 8.319 min time (LCMS 5.6 Hz, 1H), 4.70-4.66 (m, 2H), 3.49-3.43 (m, 3H), 3.34

[1780] Method A) = (s, 3H), 3.09 (dd, J = 6.4Hz, 13.6Hz, 2H), 3.02 (s, 3H),

[1781] 4.145 min 2.32-2.29 (m, 1H), 2.18-2.07 (m, 2H), 1.88-1.86 (m, 1H),

[1782] 1.47-1.42 (m, 2H), 1.32-1.23 (m, 30H), 0.87 (t, J = 6.8 Hz,

[1783] 3H)

[1784] 167 818.71H NMR (400 MHz, CDCl3) δ 10.38 (t, J = 6 Hz, 1H), 8.54 HPLC Method A,

[1785] (s, 1H), 7.30-7.26 (m, 2H), 7.02 (t, J = 8 Hz, 1H), 5.80 (dd, retention time = Retention J = 6.8 Hz, 19.6 Hz, 2H), 5.05 (d, J = 3.2 Hz, 1H), 4.92 (t, J 10.914 min time (LCMS = 5.6 Hz, 1H), 4.70-4.67 (m, 2H), 3.49-3.43 (m, 3H), 3.34

[1786] Method A) = (s, 3H), 3.10 (dd, J = 6.8 Hz, 13.6 Hz, 2H), 3.02 (s, 3H),

[1787] 4.527 min 2.32-2.29 (m, 1H), 2.17-2.11 (m, 2H), 1.90-1.84 (m, 1H),

[1788] 1.47-1.42 (m, 2H), 1.33-1.24 (m, 34H), 0.87 (t, J = 6.8 Hz,

[1789] 3H)

[1790] 168 651.31H NMR (400 MHz, CDCl3) δ 10.36 (t, J = 6 Hz, 1H), 8.54 HPLC Method A,

[1791] (s, 1H), 7.31-7.26 (m, 2H), 7.02 (t, J = 8 Hz, 1H), 5.81 (dd, retention time = Retention J = 6.4, 23.6 Hz, 2H), 5.50 (s, 1H), 5.05 (d, J = 3.6 Hz, 1H), 7.327 min time (LCMS 4.74-4.62 (m, 2H), 3.70 (t, J = 4.4 Hz, 4H), 3.50-3.44 (m,

[1792] Method A) = 3H), 3.34 (s, 3H), 3.26 -3.25 (m, 2H), 3.02 (s, 3H), 2.47 (s,

[1793] 1.567 min 6H), 2.32-2.29 (m, 1H), 2.17-2.11 (m, 2H), 1.90- 1.84 (m,

[1794] 1H)

[1795] 170 552.31H NMR (400 MHz, CDCl3) δ 10.37 (t, J =5.2 Hz, 1H), 8.54 HPLC Method A,

[1796] (s, 1H), 7.30-7.26 (m, 2H), 7.02 (t, J = 8 Hz, 1H), 5.80 (dd, retention time = Retention J = 6.8, 24.4 Hz, 2H), 5.05 (d, J = 4 Hz, 1H), 4.90-4.89 (m, 7.509 min time (LCMS 1H), 4.69-4.67 (m, 2H), 3.50-3.44 (m, 3H), 3.34 (s, 3H),

[1797] Method A) = 3.02 (s, 3H), 2.75 (d, J = 4.8 Hz, 3H), 2.32-2.29 (m, 1H),

[1798] 1.588 min 2.18-2.08 (m, 2H), 1.88-1.86 (m, 1H)

[1799] 171 594.21H NMR (400 MHz, CDCl3) δ 10.41 (t, J = 5.6 Hz, 1H), 8.52 HPLC Method A,

[1800] (s, 1H), 7.30-7.26 (m, 2H), 7.02 (t, J = 8 Hz, 1H), 5.83 (dd, retention time = Retention J = 6.4, 12 Hz, 2H), 5.04 (d, J = 3.6 Hz, 1H), 4.67 (d, J = 6 8.594 min time (LCMS Hz, 2H), 3.49-3.43 (m, 3H), 3.33 (s, 3H), 3.29 (dd, J = 6.8,

[1801] Method A) = 14 Hz, 2H), 3.20 (dd, J= 6.8, 14 Hz, 2H), 3.01 (s, 3H), 2.31- 1.921 min 2.28 (m, 1H), 2.17-2.07 (m, 2H), 1.88-1.86 (m, 1H), 1.10

[1802] (t, J = 7.2 Hz, 3H), 1.03 (t, J = 7.2 Hz, 3H)

[1803] 172 621.11H NMR (400 MHz, CDCl3) δ 10.38 (t, J = 6 Hz, 1H), 8.54 HPLC Method A,

[1804] (s, 1H), 7.30-7.26 (m, 2H), 7.02 (t, J = 8 Hz, 1H), 5.84 (dd, retention time = Retention J = 6.4, 10.0 Hz, 2H), 5.06 (d, J = 3.6 Hz, 1H), 4.68- 4.66 7.387 min time (LCMS (m, 2H), 3.54 (s, 2H), 3.50-3.41 (m, 5H), 3.33 (s, 3H), 3.02

[1805] Method A) = (s, 3H), 2.38 (s, 4H), 2.32-2.28 (m, 1H), 2.27 (s, 3H), 2.16- 1.752 min 2.08 (m, 2H), 1.87-1.85 (m, 1H)

[1806] 186 728.21H NMR (400 MHz, CDCl3) δ 10.37 (t, J = 8.0 Hz, 1H), 8.54 HPLC Method A,

[1807] (s, 1H), 7.32-7.27 (m, 2H), 7.03 ( t, J = 8.0 Hz, 1H), 5.80 retention time = Retention (dd, J = 8.0 Hz, 28.0 Hz, 2H), 5.74-5.67 (m, 1H), 5.06 (d, 7.664 min time (LCMS J = 4.0 Hz, 1H), 4.73-4.63 (m, 2H), 3.66-3.57 (m, 11H),

[1808] Method A) = 3.56-3.42 (m, 8H), 3.36 (s, 3H), 3.34 (s, 3H), 3.02 (s, 3H),

[1809] 2.517min 2.35-2.27 (m, 1H), 2.21-2.05 (m, 2H), 1.91 - 1.80 (m,

[1810] 1H)

[1811] 193 755.31H NMR (400 MHz, CDCl3) δ 10.26 (t, J = 5.7 Hz, 1H), 8.57 HPLC Method A,

[1812] (s, 1H), 7.30 - 7.28 (m, 2H), 7.26 - 7.17 (m, 5H), 7.01 (t, J retention time = Retention = 7.8 Hz, 1H), 6.40 (s, 1H), 6.03 (d, J = 6.5 Hz, 1H), 5.62 9.534 min time (LCMS (d, J = 6.6 Hz, 1H), 5.26 (d, J = 7.9 Hz, 1H), 5.03 (d, J = 3.6

[1813]

[1814] Method A) = Hz, 1H), 4.66 (qd, J = 15.5, 6.0 Hz, 2H), 4.38 (dd, J = 13.8, 70504W001

[1815] 1.93 min 6.8 Hz, 1H), 3.53 - 3.41 (m, 3H), 3.35 (s, 3H), 3.29 (dd, J

[1816] = 13.6, 5.5 Hz, 1H), 3.20-3.11 (m, 2H), 3.02 (dd, J = 13.6,

[1817] 6.8 Hz, 1H), 2.95 (s, 3H), 2.34 - 2.27 (m, 1H), 2.20 - 2.04

[1818] (m, 2H), 1.88 (d, J = 13.5 Hz, 1H), 1.45-1.40 (m, 1H), 1.27- 1.21 (m, 2H), 0.83 (dd, J = 6.6, 1.1 Hz, 6H)

[1819] 194 680.31H NMR (400 MHz, DMSO) 5 10.30 (t, J = 5.9 Hz, 1H), HPLC Method A,

[1820] 8.36 (s, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.51 (t, J = 7.5 Hz, retention time = Retention 1H), 7.32 (t, J = 6.9 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 5.71 9.385 min time (LCMS (d, J = 6.4 Hz, 1H), 5.60 (d, J = 6.4 Hz, 1H), 5.17 (d, J = 2.7

[1821] Method A) = Hz, 1H), 4.98-4.71 (m, 1H), 4.60 (d, J = 5.9 Hz, 2H), 3.86

[1822] 1.984 min - 3.71 (m, 1H), 3.57 - 3.37 (m, 3H), 3.19 (s, 3H), 2.92 (s,

[1823] 3H), 2.32 (d, J = 4.8 Hz, 1H), 2.11 - 1.91 (m, 3H), 1.65 (s,

[1824] 1H), 1.25 - 1.05 (m, 6H), 0.82 (d, J = 6.8 Hz, 6H)

[1825] 195 722.31H NMR (400 MHz, DMSO) 5 10.31 (t, J = 5.9 Hz, 1H), HPLC Method A,

[1826] 8.36 (s, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.51 (t, J = 7.5 Hz, retention time = Retention 1H), 7.32 (t, J = 6.9 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 5.73 10.699 min time (LCMS (d, J = 6.4 Hz, 1H), 5.59 (d, J = 6.4 Hz, 1H), 5.17 (d, J = 2.5

[1827] Method A) = Hz, 1H), 4.60 (d, J = 5.8 Hz, 2H), 4.08 - 3.73 (m, 3H), 3.61

[1828] 2.149 min - 3.37 (m, 3H), 3.19 (s, 3H), 2.93 (d, J = 6.5 Hz, 3H), 2.33

[1829] (d, J = 4.6 Hz, 1H), 1.99 (dd, J = 13.4, 6.8 Hz, 3H), 1.66 (s,

[1830] 1H), 1.55 - 1.34 (m, 1H), 1.36- 1.18 (m, 4H), 0.94-0.64

[1831] (m, 12H)

[1832] 196 721.31H NMR (400 MHz, DMSO) 5 10.28 (t, J = 6.0 Hz, 1H), HPLC Method A,

[1833] 8.36 (s, 1H), 7.77 (s, 1H), 7.50 (dd, J = 10.8, 4.4 Hz, 1H), retention time = Retention 7.32 (d, J = 6.6 Hz, 1H), 7.21 (t, J = 8.2 Hz, 2H), 5.65 (dd, 9.494 min time (LCMS J = 13.4, 6.5 Hz, 2H), 5.17 (d, J = 2.7 Hz, 1H), 4.60 (d, J =

[1834] Method A) = 5.8 Hz, 2H), 3.75 (dd, J = 8.5, 6.8 Hz, 1H), 3.58 - 3.37 (m,

[1835] 1.99 min 3H), 3.19 (s, 3H), 3.04 (d, J = 6.4 Hz, 1H), 2.90 (d, J = 17.1

[1836] Hz, 4H), 2.33 (d, J = 4.0 Hz, 1H), 2.09 - 1.85 (m, 3H), 1.65

[1837] (s, 1H), 1.24 (ddd, J = 21.2, 12.7, 6.1 Hz, 6H), 0.79 (dd, J

[1838] = 9.0, 7.7 Hz, 12H)

[1839] 197 707.31H NMR (400 MHz, DMSO) 5 10.27 (t, J = 6.0 Hz, 1H), HPLC Method A,

[1840] 8.36 (d, J = 4.9 Hz, 1H), 7.83 (d, J = 5.8 Hz, 1H), 7.51 (t, J retention time = Retention = 7.6 Hz, 1H), 7.26 (ddd, J = 19.5, 14.6, 7.2 Hz, 3H), 5.78 9.045 min time (LCMS - 5.51 (m, 2H), 5.18 (dd, J = 6.6, 3.1 Hz, 1H), 4.60 (d, J =

[1841] Method B) = 5.8 Hz, 2H), 3.87-3.61 (m, 1H), 3.57-3.37 (m, 3H), 3.19

[1842] 1.940 min (s, 3H), 3.13 - 3.04 (m, 1H), 3.03 - 2.95 (m, 1H), 2.92 (d,

[1843] J = 3.2 Hz, 3H), 2.33 (d, J = 5.3 Hz, 1H), 2.10 - 1.81 (m,

[1844] 3H), 1.56 (dd, J = 31.9, 25.2 Hz, 2H), 1.25 (dd, J = 12.3,

[1845] 5.2 Hz, 3H), 0.80 (ddd, J = 9.8, 9.3, 4.4 Hz, 12H)

[1846] 198 753.31H NMR (400 MHz, CDCl3) δ 10.30 (t, J = 5.8 Hz, 1H), 8.58 HPLC Method A,

[1847] (s, 1H), 7.32 - 7.27 (m, 2H), 7.03 (t, J = 7.9 Hz, 1H), 6.64 retention time = Retention (s, 1H), 5.96 (d, J = 6.6 Hz, 1H), 5.74 (d, J = 6.6 Hz, 1H), 9.409 min time (LCMS 5.67 (d, J = 7.9 Hz, 1H), 5.06 (d, J = 3.2 Hz, 1H), 4.77 - Method A) = 4.62 (m, 2H), 4.33 (d, J = 6.0 Hz, 1H), 3.48 (m, 3H), 3.35

[1848] 1.93 min (s, 3H), 3.23 - 3.18 (m, 1H), 3.14 - 3.08 (m, 1H), 3.03 (s,

[1849] 3H), 2.58 (t, J = 6.2 Hz, 2H), 2.37 - 2.30 (m, 1H), 2.24 - 2.10 (m, 3H), 2.09 (s, 3H), 2.04 - 1.99 (m, 1H), 1.89 - 1.86 (m, 1H), 1.42 - 1.36 (m, 1H), 1.31 - 1.26 (m, 4H),

[1850] 0.85 (td, J = 7.4, 2.8 Hz, 6H)

[1851] 199 769.31H NMR (400 MHz, CDCl3) δ 10.27 (t, J = 5.8 Hz, 1H), 8.57 HPLC Method A,

[1852] (s, 1H), 7.30 - 7.28 (m, 2H), 7.24 - 7.19 (m, 5H), 7.01 (t, retention time = Retention J = 7.9 Hz, 1H), 6.22 (t, J = 5.2 Hz, 1H), 6.00 (d, J = 6.5 Hz, 9.893 min time (LCMS 1H), 5.66 (d, J = 6.5 Hz, 1H), 5.34 (d, J = 8.1 Hz, 1H), 5.03

[1853] Method A) = (d, J = 3.6 Hz, 1H), 4.67 (tt, J = 15.4, 7.8 Hz, 2H), 4.39 (dd,

[1854]

[1855] 1.99 min J = 13.3, 7.4 Hz, 1H), 3.50 - 3.41 (m, 3H), 3.34 (s, 3H), 70504W001

[1856] 3.29 (dd, J = 12.8, 6.0 Hz, 1H), 3.07 - 2.99 (m, 3H), 2.95

[1857] (s, 3H), 2.33-2.28 (m, 1H), 2.18 - 2.04 (m, 2H), 1.89 - 1.85 (m, 1H), 1.28- 1.25 (m, 1H), 1.15-1.08 (m, 4H), 0.78

[1858] (dt, J = 7.4, 3.7 Hz, 6H)

[1859] 200 694.31H NMR (400 MHz, CDCl3) δ 10.37 (t, J = 6.0 Hz, 1H), 8.55 HPLC Method A,

[1860] (s, 1H), 7.30-7.26 (m, 2H), 7.02 (t, J = 7.6 Hz, 1H), 5.86 retention time = Retention (dd, J = 6.4, 16.8 Hz, 2H), 5.29 (d, J = 8.4 Hz, 1H), 5.04 (d, 9.818 min time (LCMS J = 3.6 Hz, 1H), 4.99-4.94 (m, 1H), 4.79-4.73 (m, 1H),

[1861] Method B) = 4.64-4.59 (m, 1H), 4.30-4.24 (m, 1H), 3.50-3.44 (m, 3H),

[1862] 2.347 min 3.34 (s, 3H). 3.01 (s, 3H), 2.35-2.29 (m, 1H), 2.18-2.06

[1863] (m, 2H), 1.88-1.84 (m, 1H), 1.77-1.68 (m, 1H), 1.56-1.47

[1864] (m, 2H), 1.21 (d, J = 6.0 Hz, 6H), 0.91 (dd, J = 4.0, 6.4 Hz,

[1865] 6H)

[1866] 201 736.31H NMR (400 MHz, CDCl3) δ 10.36 (t, J = 6.0 Hz, 1H), 8.55 HPLC Method A,

[1867] (s, 1H), 7.30-7.26 (m, 2H), 7.02 (t, J = 7.6 Hz, 1H), 5.85 retention time = Retention (dd, J = 6.0, 21.2 Hz, 2H), 5.30 (d, J = 8.8 Hz, 1H), 5.04 (d, 11.016 min time (LCMS J = 3.2 Hz, 1H), 4.78-4.73 (m, 1H), 4.64-4.59 (m, 1H),

[1868] Method B) = 4.35-4.30 (m, 1H), 4.03-3.95 (m, 2H), 3.49-3.43 (m, 3H),

[1869] 2.658 min 3.34 (s, 3H). 3.01 (s, 3H), 2.32-2.29 (m, 1H), 2.17-2.09

[1870] (m, 2H), 1.88-1.86 (m, 1H), 1.75-1.71 (m, 1H), 1.59-1.46

[1871] (m, 3H), 1.36-1.28 (m, 4H), 0.90 (q, J = 3.2 Hz, 6H), 0.86

[1872] (t, J = 7.6 Hz, 6H)

[1873] 202 721.31H NMR (400 MHz, CDCl3) δ 10.28 (t, J = 6.0 Hz, 1H), 8.58 HPLC Method A,

[1874] (s, 1H), 7.31-7.27 (m, 2H), 7.03 (t, J = 8.0 Hz, 1H), 6.75 (s, retention time = Retention 1H), 6.04 (d, J = 6.4 Hz, 1H), 5.64 (d, J = 6.4 Hz, 1H), 5.12 9.419 min time (LCMS (d, J = 8.4 Hz, 1H), 5.05 (d, J = 3.6 Hz, 1H), 4.74-4.63 (m,

[1875] Method B) = 2H), 4.15-4.12 (m, 1H), 3.51-3.43 (m, 3H), 3.34 (s, 3H),

[1876] 2.211 min 3.21 (dd, J = 6.0, 14.4 Hz, 2H), 3.02 (s, 3H), 2.33-2.30 (m,

[1877] 1H), 2.18-2.07 (m, 2H), 1.89-1.75 (m, 2H), 1.57-1.45 (m,

[1878] 3H), 1.36 (dd, J = 7.2, 15.2 Hz, 2H), 0.91 (q, J = 3.6 Hz,

[1879] 6H), 0.86 (dd, J = 2.8, 6.4 Hz, 6H)

[1880] 203 735.31H NMR (400 MHz, CDCl3) δ 10.29 (t, J = 6.0 Hz, 1H), 8.58 HPLC Method A,

[1881] (s, 1H), 7.31-7.27 (m, 2H), 7.03 (t, J = 8.0 Hz, 1H), 6.63 (s, retention time = Retention 1H), 6.01 (d, J = 6.4 Hz, 1H), 5.67 (d, J = 6.8 Hz, 1H), 5.16 9.773 min time (LCMS (d, J = 8.0 Hz, 1H), 5.05 (d, J = 3.6 Hz, 1H), 4.71-4.65 (m,

[1882] Method B) = 2H), 4.15-4.11 (m, 1H), 3.51-3.43 (m, 3H), 3.34 (s, 3H),

[1883] 2.332 min 3.19-3.05 (m, 2H), 3.02 (s, 3H), 2.33-2.30 (m, 1H), 2.19- 2.05 (m, 2H), 1.89-1.85 (m, 1H), 1.76-1.65 (m, 2H), 1.51- 1.48 (m, 1H), 1.40-1.37 (m, 1H), 1.29-1.23 (m, 4H), 0.91

[1884] (dd, J = 2.4, 6.4 Hz, 6H), 0.83 (dt, J = 3.2, 6.8 Hz, 6H)

[1885] 204 678.31H NMR (400 MHz, CDCl3) δ 10.37 (t, J = 6.0 Hz, 1H), 8.51 HPLC Method A,

[1886] (d, J = 5.7 Hz, 1H), 7.27 (d, J = 7.3 Hz, 2H), 7.01 (t, J = 7.7 retention time = Retention Hz, 1H), 5.81 (ddd, J = 111.7, 79.2, 6.4 Hz, 2H), 5.05 (d, J 9.04 min time (LCMS = 15.5Hz, 1H), 4.98-4.86 (m, 1H), 4.66 (d, J = 4.9 Hz, 2H),

[1887] Method B)= 4.37-4.13 (m, 1H), 3.55 (s, 1H), 3.44 (d, J = 5.3 Hz, 4H),

[1888] 1.86 min 3.33 (d, J = 4.8 Hz, 3H), 3.00 (d, J = 9.3 Hz, 3H), 2.30 (s,

[1889] 1H), 2.12 (d, J =8.3 Hz, 3H), 1.97-1.76 (m, 4H), 1.20-1.11

[1890] (m, 6H)

[1891] 208 694.31H NMR (400 MHz, CDCl3) δ 10.37 (s, 1H), 8.55 (s, 1H), HPLC Method A,

[1892] 7.29 (d, J = 7.4 Hz, 2H), 7.02 (t, J = 8.3 Hz, 1H), 5.85 (dd, retention time = Retention J = 33.5, 6.5 Hz, 2H), 5.44 (d, J = 8.8 Hz, 1H), 5.07 - 4.95 9.87 min time (LCMS (m, 2H), 4.78 - 4.60 (m, 2H), 4.22 (dd, J = 8.9, 4.5 Hz,

[1893] Method B) = 1H), 3.47 (t, J = 11.6 Hz, 3H), 3.35 (s, 3H), 3.01 (s, 3H),

[1894] 1.97 min 2.30 (d, J = 7.4 Hz, 1H), 2.11 (s, 2H), 1.87 (s, 2H), 1.41 (s,

[1895] 1H), 1.22 (dd, J = 6.2, 3.6 Hz, 6H), 1.16 (s, 1H), 0.88 (t, J

[1896]

[1897] = 7.4 Hz, 6H) 70504W001

[1898] 211 728.21H1H NMR (400 MHz, CDCI3) δ 10.35 (t, J = 6.0 Hz, 1H), HPLC Method A,

[1899] 8.56 (s, 1H), 7.25-7.16 (m, 7H), 6.98 (t, J = 7.6 Hz, 1H), retention time = Retention 5.89 (d, J = 6.4 Hz, 1H), 5.84 (d, J = 6.4 Hz, 1H), 5.46 (d, 9.77 min time (LCMS J = 7.6 Hz, 1H), 5.04 (d, J = 3.6 Hz, 1H), 4.90 (quint, J =

[1900] Method A) = 6.0 Hz, 1H), 4.68 (dd, J = 15.2, 6.0 Hz, 1H), 4.61-4.51

[1901] 2.08 min (m, 2H), 3.52-3.44 (m, 3H), 3.36 (s, 3H), 3.12-3.06 (m,

[1902] 2H), 2.99 (s, 3H), 2.35-2.26 (m, 1H), 2.20-2.05 (m, 2H),

[1903] 1.92-1.82 (m, 1H), 1.14 (t, J = 6.0 Hz, 6H)

[1904] 212 764.31H NMR (400 MHz, CDCI3) 610.33 (t, J = 5.7 Hz, 1H), 8.57 HPLC Method A,

[1905] (d, J = 8.4 Hz, 1H), 7.29-7.25 (m, 2H), 7.00 (t, J = 7.7 Hz, retention time = Retention 1H), 6.79 (dd, J = 22.8, 6.2 Hz, 2H), 6.70 - 6.61 (m, 1H), 9.972 min time (LCMS 5.99 (dd, J = 24.9, 6.6 Hz, 1H), 5.79 (dd, J = 19.8, 6.6 Hz,

[1906] Method B) = 1H), 5.53 (t, J = 8.0 Hz, 1H), 5.06 (t, J = 4.5 Hz, 1H), 4.95

[1907] 2.326 min (dt, J = 12.5, 6.2 Hz, 1H), 4.76 - 4.55 (m, 3H), 3.55-3.40

[1908] (m, 3H), 3.35 (d, J = 9.1 Hz, 3H), 3.23 - 3.03 (m, 2H), 3.00

[1909] (s, 3H), 2.37 - 2.27 (m, 1H), 2.22 - 2.01 (m, 2H), 1.90- 1.80 (m, 1H), 1.19 (dd, J = 14.1, 6.4 Hz, 6H)

[1910] 213 806.31H NMR (400 MHz, CDCI3) 610.33 (t, J = 5.9 Hz, 1H), 8.58 HPLC Method A,

[1911] (s, 1H), 7.29-7.26 (m, 2H), 7.00 (t, J = 7.9 Hz, 1H), 6.79 retention time = Retention (d, J = 6.2 Hz, 2H), 6.66 (dd, J = 10.1, 7.9 Hz, 1H), 6.02 (d, 11.047 min time (LCMS J = 6.7 Hz, 1H), 5.81 (d, J = 6.7 Hz, 1H), 5.50 (d, J = 7.6 Hz,

[1912] Method B) = 1H), 5.05 (d, J = 3.3 Hz, 1H), 4.75 - 4.66 (m, 2H), 4.60

[1913] 2.579 min (dd, J = 15.4, 5.4 Hz, 1H), 4.03 (dd, J = 10.9, 5.8 Hz, 1H),

[1914] 3.91 (dd, J = 10.9, 5.7 Hz, 1H), 3.56 - 3.45 (m, 3H), 3.35

[1915] (d, J = 8.8 Hz, 3H), 3.20 (dd, J = 13.8, 5.5 Hz, 1H), 3.11

[1916] (dd, J = 13.7, 4.6 Hz, 1H), 3.00 (s, 3H), 2.38 - 2.26 (m,

[1917] 1H), 2.20-2.10 (m, 2H), 1.87 (s, 1H), 1.45 (dd, J = 12.4,

[1918] 6.2 Hz, 1H), 1.34-1.25 (m, 4H), 0.86 (td, J = 7.4, 2.9 Hz,

[1919] 6H)

[1920] 214 679.31H NMR (400 MHz, CDCI3) 6 10.30 (t, J = 5.9 Hz, 1H), HPLC Method A,

[1921] 8.58 (s, 1H), 7.33 - 7.27 (m, 2H), 7.03 (t, J = 7.9 Hz, 1H), retention time = Retention 6.65 (s, 1H), 6.00 (d, J = 6.6 Hz, 1H), 5.66 (d, J = 6.5 Hz, 8.436 min time (LCMS 1H), 5.23 (d, J = 6.7 Hz, 1H), 5.06 (d, J = 3.4 Hz, 1H),

[1922] Method B) = 4.68 (d, J = 5.7 Hz, 2H), 4.24 - 4.13 (m, 1H), 3.55 - 3.42

[1923] 2.078 min (m, 3H), 3.35 (s, 3H), 3.27 - 3.18 (m, 2H), 3.03 (s, 3H),

[1924] 2.39 - 2.28 (m, 1H), 2.25 - 2.03 (m, 2H), 1.92-1.84 (m,

[1925] 1H), 1.56-1.52 (m, 1H), 1.42-1.34 (m, 5H), 0.87 (dd, J =

[1926] 4.0 Hz, 8.0 Hz, 6H)

[1927] 215 720.01H NMR (400 MHz, CDCI3) 6 10.43-10.34 (m, 1H), 8.53 HPLC Method A,

[1928] (d, J = 4.9 Hz, 1H), 7.34-7.27 (m, 2H), 7.03 (t, J = 7.8 Hz, retention time = Retention 1H), 6.00 (dd, J = 51.5, 6.4 Hz, 1H), 5.63 (dd, J = 109.2, 10.32 min time (LCMS 6.4 Hz, 1H), 5.07 (dd, J = 18.6, 3.4 Hz, 1H), 4.72-4.63 (m,

[1929] Method A) = 2H), 4.34 (ddd, J = 73.0, 8.7, 3.7 Hz, 1H), 4.07-3.91 (m,

[1930] 1.80 min 2H), 3.63-3.53 (m, 1H), 3.52-3.41 (m, 4H), 3.35 (d, J = 5.8

[1931] Hz, 3H), 3.02 (d, J = 9.8 Hz, 3H), 2.37-2.25 (m, 1H), 2.22- 2.04 (m, 3H), 2.02-1.82 (m, 4H), 1.50-1.44 (m, 1H), 1.34- 1.27 (m, 4H), 0.88-0.82 (m, 6H)

[1932] 216 705.41H NMR (400 MHz, CDCI3) 6 10.36 - 10.24 (m, 1H), 8.58 HPLC Method A,

[1933] (d, J = 14.5 Hz, 1H), 7.36 -7.27 (m, 2H), 7.03 (t, J = 7.9 Hz, retention time = Retention 1H), 5.94 (dd, J = 145.1, 6.4 Hz, 1H), 5.62 (dd, J = 32.1, 8.80 min time (LCMS 6.5 Hz, 1H), 5.12-5.04 (m, 1H), 4.78-4.57 (m, 2H), 4.36

[1934] Method A) = (d, J = 8.5 Hz, 1H), 3.47 (s, 3H), 3.41-3.13 (m, 8H), 3.02

[1935] 1.63 min (s, 3H), 2.38-2.26 (m, 2H), 2.23-2.01 (m, 3H), 1.95-1.75

[1936] (m, 3H), 1.42-1.34 (m, 2H), 0.85 (d, J = 6.5 Hz, 6H)

[1937] 217 754.31H NMR (400 MHz, CDCI3) 6 10.35 (t, J = 5.9 Hz, 1H), HPLC Method A,

[1938]

[1939] 8.57 (s, 1H), 7.31-7.27 (m,2H), 7.03 (t, J = 7.5 Hz, 1H), retention time = 70504W001

[1940] Retention 5.92 (d, J = 6.6 Hz, 1H), 5.81 (d, J = 6.6 Hz, 1H), 5.55 (d, 10.519 min time (LCMS J = 8.0 Hz, 1H), 5.06 (d, J = 3.4 Hz, 1H), 4.76 (dd, J =

[1941] Method B) = 15.5, 6.2 Hz, 1H), 4.65 (dd, J = 15.6, 5.4 Hz, 1H), 4.47

[1942] 2.021 min (dd, J = 12.6, 7.7 Hz, 1H), 4.08 - 3.99 (m, 2H), 3.48 (dd,

[1943] J = 13.6, 9.4 Hz, 3H), 3.35 (s, 3H), 3.03 (s, 3H), 2.57 (t, J

[1944] = 7.6 Hz, 2H) 2.33 (dd, J = 13.7, 8.4 Hz, 1H), 2.22 - 2.09

[1945] (m, 3H), 2.06 (s, 3H), 2.00-1.85 (m, 2H), 1.56-1.48 (m,

[1946] 1H), 1.38 - 1.30 (m, 4H), 0.88 (t, J = 7.5 Hz, 6H)

[1947] 218 694.4JH NMR (400 MHz, CDCI3) 610.36 (t, J = 5.8 Hz, 1H), HPLC Method A,

[1948] 8.55 (s, 1H), 7.30 - 7.28 (m, 2H), 7.03 (t, J = 7.9 Hz, 1H), retention time = Retention 5.84 (dd, J = 20.3, 6.5 Hz, 2H), 5.51 (d, J = 7.6 Hz, 1H), 10.015 min time (LCMS 5.05 (d, J = 3.4 Hz, 1H), 4.69 (t, J = 4.9 Hz, 2H), 4.36 - Method A) 4.27 (m, 1H), 4.03 (ddd, J = 31.1, 10.9, 5.8 Hz, 2H), 3.51

[1949] =1.77 min - 3.44 (m, 3H), 3.35 (s, 3H), 3.02 (s, 3H), 2.35 - 2.29 (m,

[1950] 1H), 2.18 - 2.06 (m, 2H), 1.89 - 1.87 (m, 1H), 1.51 (dd, J

[1951] = 12.5, 6.2 Hz, 1H), 1.39 (d, J = 7.2 Hz, 3H), 1.36 - 1.30

[1952] (m, 4H), 0.88 (t, J = 7.5 Hz, 6H)

[1953] 219 652.0JH NMR (400 MHz, CDCI3) 610.36 (t, J = 5.6 Hz, 1H), HPLC Method A,

[1954] 8.55 (s, 1H), 7.30-7.28 (m, 2H), 7.02 (t, J = 8.0 Hz, 1H), retention time = Retention 5.83(dd, J = 17.2, 6.4 Hz, 2H), 5.25 (d, J = 7.6 Hz, 1H), 8.675 min time (LCMS 5.05-4.97 (m, 2H), 4.69-4.67 (m, 2H), 4.25(t, J =7.2, 1

[1955] Method A) = H), 3.50-3.44 (m, 3H), 3.34 (s, 3H), 3.01 (s, 3H), 2.35- 1.93 min 2.29 (m, 1H), 2.18-2.07 (m, 2H), 1.89-1.84 (m, 1H), 1.36

[1956] (d, J = 7.2 Hz, 3H), 1.23 (d, J = 6.4 Hz, 6H)

[1957] 220 770.2JH NMR (400 MHz, CDCI3) 610.35 (t, J = 5.6 Hz, 1H), HPLC Method A,

[1958] 8.56 (s, 1H), 7.25 - 7.20 (m, 5H), 7.17 (d, J = 6.6 Hz, retention time = Retention 2H), 6.98 (t, J = 7.6 Hz, 1H), 5.86 (dd, J = 25.7, 6.5 Hz, 10.961 min time (LCMS 2H), 5.44 (d, J = 8.2 Hz, 1H), 5.04 (d, J = 3.2 Hz, 1H),

[1959] Method A) = 4.72 - 4.60 (m, 2H), 4.56 (dd, J = 15.8, 5.6 Hz, 1H), 3.93

[1960] 2.18 min (ddd, J = 31.7, 10.8, 5.8 Hz, 2H), 3.53 - 3.44 (m, 3H),

[1961] 3.35 (s, 3H), 3.16 - 3.04 (m, 2H), 2.99 (s, 3H), 2.37 - 2.25 (m, 1H), 2.13 (dd, J = 18.6, 9.1 Hz, 2H), 1.89 - 1.84

[1962] (m, 1H), 1.43 - 1.38 (m, 1H), 1.25 (dq, J = 13.9, 7.0 Hz,

[1963] 4H), 0.83 (t, J = 7.4 Hz, 6H)

[1964] 221 719.4JH NMR (400 MHz, CDCI3) 610.36-10.21 (m, 1H), 8.56 HPLC Method A,

[1965] (d, J = 12.8 Hz, 1H), 7.78 (t, J = 5.6 Hz, 1H), 7.29 (dd, J = retention time = Retention 13.7, 6.0 Hz, 2H), 7.02 (t, J = 7.8 Hz, 1H), 6.10-5.58 (m, 9.131 min time (LCMS 2H), 5.10-5.04 (m, 1H), 4.76-4.56 (m, 2H), 4.35 (d, J =

[1966] Method A) = 8.6 Hz, 1H), 3.52-3.42 (m, 3H), 3.40-3.17 (m, 6H), 3.11- 1.67 min 2.97 (m, 4H), 2.38-2.26 (m, 2H), 2.23-2.00 (m, 3H),

[1967] 1.86-1.73 (m, 4H), 1.34-1.22 (m, 4H), 0.81 (td, J = 7.4,

[1968]

[1969] 4.9 Hz, 6H)

[1970] Compound 28:

[1971] (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo- 2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl benzoate 70504W001

[1972]

[1973] Step 1

[1974] To a stirred solution of (lS,3aS)-N-(3-chloro-2-fluorobenzyl)-6-hydroxy-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazine-8-carboxamide (300 mg, 0.645 mmol) in DCM (5 mL) was added DIPEA (0.225 mL, 1.291 mmol) and benzoyl chloride (100 mg, 0.710 mmol) at 0 °C. The resulting reaction mixture was stirred at 25 °C for 16 h. LCMS showed the reaction was completed. The reaction mixture was concentrated under vacuum to give crude product as an oil. The oil was dissolved in DMF and purified by reverse flash (Biotage, gradient: 0 % to 60 % ACN in water (10 mM NH4HCO3), flow rate: 30 mL / min, column: Boston C18, 40 g) to give pure product as a white solid. The compound was crystallized from pet. ether / EtOAc (3:1) at rt for a week and solids are collected by filtration under reduced pressure to afford (15,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl benzoate (197 mg, 0.346 mmol, 53.7 % yield) as a white solid. Melting point: 241.8-244.0 °C. LCMS (M+H) = 568.9, Retention time (LCMS Method A) = 1.677 min, purity: 100 % (254 nm). HPLC: Retention time (HPLC Method A) = 9.269 min, purity: 100 % (254 nm). NMR (400 MHz, CDCI3) 6 10.23 (t, J = 5.8 Hz, 1H), 8.68 (s, 1H), 8.31-8.16 (m, 2H), 7.67-7.56 (m, 1H), 7.55-7.40 (m, 2H), 7.33-7.25 (m, 2H), 7.01 (t, J = 7.9 Hz, 1H), 5.14 (s, 1H), 4.67 (q, J = 15.2 Hz, 2H), 3.65-3.44 (m, 3H), 3.36 (d, J = 16.3 Hz, 3H), 3.00 (d, J = 10.9 Hz, 3H), 2.34 (dd, J = 13.9, 8.7 Hz, 1H), 2.28-2.01 (m, 2H), 1.88 (d, J = 6.7 Hz, 1H).

[1975] Compound 29:

[1976] (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo- 2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl bicyclo[2.2.2]octane-l-carboxylate

[1977] DMAP / EDC / DCM

[1978]

[1979] 70504W001

[1980] Step 1

[1981] To a stirred solution of (lS,3aS)-N-(3-chloro-2-fluorobenzyl)-6-hydroxy-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazine-8-carboxamide (200 mg, 0.430 mmol) in DCM (5 mL) was added DMAP (52.6 mg, 0.430 mmol), EDC (165 mg, 0.860 mmol) and bicyclo[2.2.2]octane-l-carboxylic acid (100 mg, 0.645 mmol) at 0 °C. The resulting reaction mixture was stirred at 25 °C for 16 h. LCMS showed the reaction was completed. The reaction mixture was concentrated under vacuum to give crude product. The residue was dissolved in DCM, loaded to a silica gel column (SanTai, 25 g) and purified by flash (Biotage) column chromatography (0 % to 2 % MeOH in DCM, flow rate: 30 mL / min) to give desired product as a colorless oil. The compound was crystallized from pet. ether / EtOAc (3:1) at rt for a week and solids were collected by filtration under reduced pressure to afford (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl bicyclo[2.2.2]octane-l-carboxylate (189 mg, 0.314 mmol, 73.1 % yield) as a white solid. Melting point: 230.5-234.8 °C. LCMS (M+H) = 600.8, Retention time (LCMS Method A) = 1.815 min, purity: 100 % (254 nm). HPLC: Retention time (HPLC Method A) = 10.637 min, purity: 100 % (254 nm).1H NMR (400 MHz, CDCI3) 6 10.23 (t, J = 5.8 Hz, 1H), 8.60 (s, 1H), 7.33-7.26 (m, 2H), 7.02 (td, J = 7.9, 0.9 Hz, 1H), 5.08 (dd, J = 6.9, 3.8 Hz, 1H), 4.77-4.57 (m, 2H), 3.47 (dd, J = 12.2, 7.7 Hz, 3H), 3.32 (d, J = 11.8 Hz, 3H), 3.01 (d, J = 15.6 Hz, 3H), 2.38-2.27 (m, 1H), 2.23-2.12 (m, 2H), 2.06-1.96 (m, 6H), 1.81 (ddd, J = 15.5, 14.8, 8.8 Hz, 2H), 1.70-1.63 (m, 6H).

[1982] The compound set forth in Table 19 was prepared analogously to Compound 29.

[1983] Table 19.

[1984] Compound LCMS m / z1H-NMR (400 MHz) HPLC No. [M+H]+

[1985] 30 586.91H NMR (400 MHz, CDCl3) δ 10.21 (s, 1H), 8.61 (s, HPLC Method A,

[1986] 1H), 7.32-7.26 (m, 2H), 7.02 (t, J = 7.9 Hz, 1H), retention time = Retention 5.08 (s, 1H), 4.67 (s, 2H), 3.47 (dd, J = 13.8, 9.6 Hz, 10.240 min time (LCMS 3H), 3.34 (d, J = 5.6 Hz, 3H), 3.02 (s, 3H), 2.53 (dd,

[1987] Method A) J = 12.4, 8.4 Hz, 2H), 2.42-2.29 (m, 3H), 2.24-2.10

[1988] = 1.786 min (m, 2H), 2.06 (t, J = 7.4 Hz, 3H), 1.98 (t, J = 7.3 Hz,

[1989]

[1990] 2H), 1.85 (s, 1H), 1.85-1.78 (m, 2H)

[1991] Compound 31:

[1992] lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo- 2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl decanoyl-L-prolinate 70504W001

[1993]

[1994] Step 1

[1995] To a stirred solution of L-proline (4 g, 34.7 mmol) in water (5 mL) was added decanoyl chloride (6.63 g, 34.7 mmol) and NaOH (5.56 g, 34.7 mmol) at 0 °C. The resulting reaction mixture was stirred at 25 °C for 3 h. LCMS showed the reaction was completed. The mixture was neutralized with 75% sulfuric acid, water and ethyl acetate were added, and the aqueous layer was removed. The organic layer was evaporated under reduced pressure to give decanoyl-L-proline (5.7 g, 21.16 mmol, 60.9 % yield) as a colorless oil which was used in the next step without purification. LCMS (M+H) = 270.4, Retention time (LCMS Method A) = 1.642 min, purity: 100 % (254 nm).

[1996]

[1997] NMR (400 MHz, CDCI3) 64.64-4.55 (m, 1H), 4.12 (q, J = 7.1 Hz, 1H), 3.65-3.41 (m, 2H), 2.39-2.31 (m, 2H), 2.11-1.95 (m, 4H), 1.66 (dd, J = 14.4, 7.2 Hz, 2H), 1.38-1.22 (m, 12H), 0.88 (t, J = 6.6 Hz, 3H).

[1998] Step 2

[1999] To a stirred solution of decanoyl-L-proline (1 g, 3.71 mmol) in DCM (10 mL) was added oxalyl chloride (0.650 mL, 7.42 mmol) at 0 °C and the mixture was stirred for 1 h. LCMS showed the reaction was completed. The reaction mixture was concentrated in vacuum to give decanoyl-L-prolinoyl chloride (1.3 g, 0.549 mmol, 14.78 % yield) which was used in the next step without purification. LCMS (M+H)+= 284.4, Retention time (LCMS Method A) = 1.951 min, purity: 12.25 % (254 nm).

[2000] Step 3

[2001] To a stirred solution of (lS,3aS)-N-(3-chloro-2-fluorobenzyl)-6-hydroxy-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazine-8-carboxamide (150 mg, 0.323 mmol) in DCM (5 mL) was added DIPEA (0.225 mL, 1.291 mmol) and decanoyl-L-prolinoyl chloride (93 mg, 0.323 mmol) at 25 °C. The resulting reaction mixture was stirred for 16 h. LCMS showed the reaction was successful. The reaction mixture was concentrated under vacuum to give crude product. The crude product was dissolved in DMF and purified by reverse flash (Biotage, gradient: 0-80 % ACN in water (10 mM NH4HCO3); flow rate: 30 mL / min; column: Boston C18, 40 g) to give (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl decanoyl-L-prolinate (100 mg, 0.140 mmol, 43.3 % yield) as a brown oil.. LCMS (M+H) = 716.2, Retention time (LCMS Method A) = 2.277 min, purity: 19.80 % (254 nm). 70504W001

[2002] Compound 32:

[2003] (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo- 2, 3, 3a, 4, 5, 7-hexahydro-l H-pyrido[2,l -f]pyrrolo[ 1,2-b ][ 1,2,4 ]triazin-6-yl spiro [4.5 ]decane-8-carboxylate

[2004]

[2005] Step 1

[2006] To a solution of 2,2'-(cyclopentane-l,l-diyl)diacetic acid (2.50 g, 13.43 mmol) inTHF (20 mL) was added BH3*THF (4.62 g, 53.7 mmol) at 0 °C under N2atmosphere. After 15 min, the cold bath was removed and stirred at 25°C for 4 h. TLC showed the reaction was completed. The reaction mixture was concentrated under reduced pressure, added sat. NaHCO3(40 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated. The crude product was dissolved in DCM (4 mL), loaded to a silica column (SanTai, 80 g), purified by flash (Biotage, 40 g) using EtOAc / pet. ether (0% to 20%, 50 mL / min) to give 2,2'-(cyclopentane-l,l-diyl)bis(ethan-l-ol) (2.0 g, 12.64 mmol, 94 % yield) as a colorless oil.1H NMR (400 MHz, DMSO) 64.27 (t, J = 5.1 Hz, 2H), 3.47-3.39 (m, 4H), 1.57-1.50 (m, 4H), 1.47-1.39 (m, 4H), 1.35 (dd, J = 9.1, 4.7 Hz, 4H).

[2007] Step 2

[2008] To a solution of 2,2'-(cyclopentane-l,l-diyl)bis(ethan-l-ol) (2.0 g, 12.64 mmol) in DCM (20 mL) was added TEA (3.52 mL, 25.3 mmol) and 4-methylbenzenesulfonyl chloride (2.89 g, 15.17 mmol) at 0 °C. The resulting mixture was stirred at 25 °C 4 h. LCMS showed the reaction was completed. The reaction was concentrated in vacuum. The crude product was dissolved in DCM (5 mL), loaded to a silica gel column (SanTai, 80 g), purified by flash (Biotage) using EtOAc / pet. ether (0% to 20 %, 100 mL / min) to give cyclopentane- l,l-diylbis(ethane-2, 1-diyl) bis(4-methylbenzenesulfonate) (3.0 g, 6.43 mmol, 50.9 % yield) as an oil. LCMS: (M+H) = 465.1, 466.0 and 468.0; Retention time = 1.736, purity (254nm) =1 00%. 70504W001

[2009] Step 3

[2010] To a solution of cyclopentane-1,1-diylbis(ethane-2,1-diyl) bis(4-methylbenzenesulfonate) (lg, 2.143 mmol) in ethylene glycol (15 mL) was added sodium bromide (0.551 g, 5.36 mmol). The resulting reaction mixture was stirred at 170 °C for 16 h. TLC showed the reaction was completed. The reaction mixture was cooled to room temperature. Then the mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with NaCI (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was loaded to a silica gel column (SanTai, 25 g), purified by flash (Biotage) with 100 % pet. ether (30 mL / min) to give l,l-bis(2-bromoethyl)cyclopentane (500 mg, 1.760 mmol, 82 % yield) as an oil.1H NMR (400 MHz, CDCI3) 63.65 (t, J = 4.2 Hz, 4H), 1.64-1.59 (m, 4H), 1.49-1.44 (m, 8H).

[2011] Step 4

[2012] To a stirred solution of sodium hydride (0.141 g, 3.52 mmol) in DMF (20 mL) was added diethyl malonate (0.589 g, 3.68 mmol). The mixture was heated to 60 °C and l,l-bis(2-bromoethyl)cyclopentane (0.5 g, 1.760 mmol) was added dropwise. Then, the reaction mixture was slowly heated to 120 °C and stirred at this temperature for 12 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with NaCI (3 x 50 mL), dried over Na2SO4, filtered and evaporated at reduced pressure. The crude product was loaded to a silica gel column (SanTai, 25 g), purified by flash (Biotage) with EtOAc / pet. ether (0% to 10 %, 30 mL / min) to give diethyl spiro[4.5]decane-8,8-dicarboxylate (200 mg, 0.637 mmol, 36.2 % yield) as an oil. LCMS (M+H) = 283, Retention time (LCMS Method A) = 2.41 min.1H NMR (400 MHz, CDCI3) 64.18 (q, J = 7.2 Hz, 4H), 2.00 (t, J = 6.0 Hz, 4H), 1.61-1.50 (m, 4H), 1.45-1.32 (m, 8H), 1.24 (t, J = 7.2 Hz, 6H).

[2013] Step 5

[2014] To a stirred solution of diethyl spiro[4.5]decane-8,8-dicarboxylate (200 mg, 0.708 mmol) in DMSO (12 mL) was added lithium chloride (60.0 mg, 1.417 mmol) and H2O (0.038 mL, 2.125 mmol). The reaction was stirred at 200 °C for 16 h. LCMS showed the reaction was completed. After cooling, water (20 ml) and EtOAc (20 ml) added with stirring. The organic phase was separated and the aqueous layer was extracted with EtOAc (20 ml x 2). The organic phases were combined, washed with water (50 ml x3), dried over Na2SO4and concentrated. The crude product was dissolved in DMF, loaded to a C18 column (SanTai, 25 g), purified by flash (Biotage) with CH3CN / H2O (0% to 100 %, 30 mL / min) to give 70504W001

[2015] spiro[4.5]decane-8-carboxylic acid (121 mg, 0.597 mmol, 84 % yield) as a white solid. LCMS (M+H) = 183, Retention time (LCMS Method A) = 2.01 min.

[2016] Step 6

[2017] To a solution of spiro[4.5]decane-8-carboxylic acid (51.0 mg, 0.280 mmol) in DCM (5 mL) was added DMAP (39.4 mg, 0.323 mmol) and EDCI (82 mg, 0.430 mmol) at 0 °C and stirred for 0.5 h. Then, (lS,3aS)-N-(3-chloro-2-fluorobenzyl)-6-hydroxy-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazine-8-carboxamide (100 mg, 0.215 mmol) was added and the resulting reaction mixture was stirred at 25 °C for 16 h. LCMS showed the reaction was completed. The reaction mixture was concentrated in vacuum. The residue was dissolved in MeOH, loaded to reverse SepaFlash® C18 column chromatography (Boston, 25 g) and purified by flash (Biotage) column chromatography (0 % to 65 % ACN in water (10 mM NH4HCO3); flow rate: 30 mL / min) to give the desired product. The product was crystallized with 10 % cyclopentyl methyl ether (CPME) in hexane and solids collected by filtration to give (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl spiro[4.5]decane-8-carboxylate (30 mg, 0.048 mmol, 22.17 % yield) as a white solid. Melting point: 64.1-69.3 °C. LCMS (M+H) = 629.4, Retention time (LCMS Method A) = 2.18 min. HPLC: Retention time (HPLC Method A) = 11.60 min, purity: 100 %.

[2018]

[2019] NMR (400 MHz, CDCI3) 6 10.20 (s, 1H), 8.62 (s, 1H), 7.32-7.27 (m, 2H), 7.02 (dt, J = 7.6, 1.2 Hz, 1H), 5.09 (s, 1H), 4.76-4.60 (m, 2H), 3.53-3.43 (m, 3H), 3.37-3.30 (m, 3H), 3.07-2.99 (m, 3H), 2.66 (tt, J = 11.6, 4.0 Hz, 1H), 2.37-2.30 (m, 1H), 2.24-2.16 (m, 1H), 2.14-2.04 (m, 3H), 1.86 (s, 1H), 1.76 (dq, J = 25.2, 3.2 Hz, 2H), 1.64-1.58 (m, 6H), 1.46 (t, J = 6.8 Hz, 2H), 1.39-1.32 (m, 4H).

[2020] Compound 33:

[2021] (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo- 2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 4,4-difluorocyclohexane-l-carboxylate

[2022]

[2023] Step 1 70504W001

[2024] To a mixture of (15,3aS)-N-(3-chloro-2-fluorobenzyl)-6-hydroxy-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazine-8-carboxamide (200 mg, 0.430 mmol), DMAP (52.6 mg, 0.430 mmol) and EDC (247 mg, 1.291 mmol) in DCM (10 mL) was added 4,4-difluorocyclohexane-l-carboxylic acid (85 mg, 0.516 mmol) at 0 °C. The reaction mixture was stirred at 25 °C overnight. TLC showed the reaction was completed. The reaction mixture was concentrated under vacuum. The crude product was dissolved in DCM (5 mL), loaded to a silica column (SanTai, 40 g), purified by flash (Biotage) with MeOH / DCM (0 % to 2 %, 50 mL / min) to give product as a solid. The white solid was triturated with 9 % EtOAc in hexane (40 mL) and solids collected by filtration to give (15,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl 4,4-difluorocyclohexane-l-carboxylate (150 mg, 0.240 mmol, 55.7 % yield) as a white solid. Melting point: 165.6-168.2 °C. LCMS (M+H) = 611.1, Retention time (LCMS Method A) = 1.97, purity (254 nm) = 97.64 %. HPLC: Retention time (HPLC Method C) = 10.756 min, purity (254 nm) = 100.0 %.

[2025]

[2026] NMR (400 MHz, CDCI3) 6 10.15 (s, 1H), 8.63 (s, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.25 (s, 1H), 7.02 (t, J = 7.9 Hz, 1H), 5.10 (s, 1H), 4.68 (d, J = 18.6 Hz, 2H), 3.48 (t, J = 11.5 Hz, 3H), 3.33 (d, J = 8.0 Hz, 3H), 3.03 (s, 3H), 2.85 (s, 1H), 2.41-2.30 (m, 1H), 2.29-2.03 (m, 8H), 2.00-1.78 (m, 3H).

[2027] The compounds set forth in Table 20 were prepared analogously to Compound 33.

[2028] Table 20.

[2029] Compound LCMS m / z1H-NMR (400 MHz) HPLC No. [M+H]+

[2030] 34 631.41H NMR (400 MHz, CDCI3) 6 10.20 (s, 1H), 8.62 (s, 1H), HPLC Method C,

[2031] 7.29 (d, J = 6.9 Hz, 1H), 7.25 (s, 1H), 7.02 (t, J = 7.9 Hz, retention time = Retention 1H), 5.09 (s, 1H), 4.67 (d, J = 16.1 Hz, 2H), 3.48 (t, J = 11.9 13.410 min time (LCMS Hz, 3H), 3.34 (s, 3H), 3.03 (s, 3H), 2.67-2.53 (m, 1H), 2.32

[2032] Method A) = (d, J = 8.0 Hz, 3H), 2.25-2.00 (m, 2H), 1.97-1.78 (m, 3H),

[2033] 2.15 min 1.62-1.56 (m, 2H), 1.08 (d, J = 8.8 Hz, 3H), 0.86 (s, 9H)

[2034] 79 563.01H NMR (400 MHz, CDCl3) 610.25 (t, J = 5.6 Hz, 1H), 8.62 HPLC Method A, (s, 1H), 7.30-7.28 (m, 2H), 7.04-7.00 (m, 1H), 5.09 (s, 1H), retention time = Retention 4.68 (s, 2H), 3.50-3.44 (m, 3H), 3.33 (s, 3H), 3.02 (s, 3H), 10.121 min time (LCMS 2.60 (d, J =7.2 Hz, 2H), 2.34-2.30 (m, 1H), 2.20-2.01 (m,

[2035] Method B) = 3H), 1.17 (s, 9H)

[2036] 2.06 min

[2037] 83 535.01H NMR (400 MHz, CDCl3) 610.21 (t, J = 6.4 Hz, 1H), 8.62 HPLC Method A, (s, 1H), 7.27 (dd, J = 13.2, 7.2 Hz, 2H), 7.01 (t, J = 8.0 Hz, retention time = Retention 1H), 5.09 (d, J = 6.8 Hz, 1H), 4.67 (s, 2H), 3.46-3.45 (m, 9.132 min time (LCMS 3H), 3.33 (s, 3H), 3.02 (s, 3H), 2.68 (t, J = 7.2 Hz, 2H),

[2038] Method A) = 2.35-2.30 (m, 1H), 2.20-2.06 (m, 2H), 1.86-1.76 (m, 3H),

[2039] 1.97 min 1.05 (t, J = 7.2 Hz, 3H)

[2040] 84 549.21H NMR (400 MHz, CDCl3) δ10.21 (t, J = 4.8 Hz, 1H), 8.61 HPLC Method A, (s, 1H), 7.27 (dd, J = 12.0, 6.8 Hz, 2H), 7.01 (t, J = 8.0 Hz, retention time = Retention 1H), 5.09 (d, J = 3.6 Hz, 1H), 4.67 (s, 2H), 3.50-3.44 (m, 8.625 min time (LCMS 3H), 3.33 (s, 3H), 3.01 (s, 3H), 2.70 (t, J = 8.0 Hz, 2H),

[2041] Method A) = 2.33-2.30 (m, 1H), 2.20-2.08 (m, 2H), 1.88-1.85 (m, 1H),

[2042] 2.04 min 1.80-1.73 (m, 2H), 1.50-1.41 (m, 2H), 0.95 (t, J = 7.6 Hz,

[2043]

[2044] 3H) 70504W001

[2045] Compound 35:

[2046] (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo- 2, 3, 3a, 4, 5, 7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l, 2, 4]triazin-6-yl isopropyl carbonate

[2047] DIPEA / DCM

[2048]

[2049] Step 1

[2050] To a stirred solution of (lS,3aS)-N-(3-chloro-2-fluorobenzyl)-6-hydroxy-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazine-8-carboxamide (150 mg, 0.323 mmol) in DCM (5 mL) was added DIPEA (0.113 mL, 0.645 mmol) and isopropyl carbonochloridate (43.5 mg, 0.355 mmol) at 0 °C. The resulting reaction mixture was stirred at 25 °C for 16 h. LCMS showed the reaction was completed. The reaction mixture was concentrated under vacuum. The residue was dissolved in DCM, loaded to a silica gel column (SanTai, 25 g) and purified by flash (Biotage) column chromatography (0-2 % MeOH in DCM, flow rate: 30 mL / min) to give product as a colorless oil. The compound was crystallized from pet. ether / cyclopentyl methyl ether (3:1) at rt for a week and solids collected by filtration under reduced pressure to give (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl isopropyl carbonate (100 mg, 0.181 mmol, 56.2 % yield) as a white solid. Melting point: 238.4-240.8 °C. LCMS (M+H) = 551.2, Retention time (LCMS Method A) = 1.808 min, purity: 100 % (254 nm). HPLC: Retention time (HPLC Method A) = 8.865 min, purity: 100 % (254 nm).

[2051]

[2052] NMR (400 MHz, CDCI3) 610.23 (t, J = 5.8 Hz, 1H), 8.63 (s, 1H), 7.32-7.26 (m, 2H), 7.02 (td, J = 7.9, 1.0 Hz, 1H), 5.10 (d, J = 3.7 Hz, 1H), 5.00 (dq, J = 12.5, 6.3 Hz, 1H), 4.78-4.59 (m, 2H), 3.48 (td, J = 11.5, 6.6 Hz, 3H), 3.34 (s, 3H), 3.04 (s, 3H), 2.42-2.28 (m, 1H), 2.25-2.02 (m, 2H), 1.86 (t, J = 10.7 Hz, 1H), 1.42 (dd, J = 9.1, 6.3 Hz, 6H).

[2053] Compound 36:

[2054] (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo- 2, 3, 3a, 4, 5, 7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l, 2, 4]triazin-6-yl cyclopentyl carbonate 70504W001

[2055]

[2056] Step 1

[2057] To a stirred solution of (lS,3aS)-N-(3-chloro-2-fluorobenzyl)-6-hydroxy-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazine-8-carboxamide (200 mg, 0.430 mmol) in DCM (5 mL) were added DIPEA (0.150 mL, 0.860 mmol) and cyclopentyl carbonochloridate (70.3 mg, 0.473 mmol) at 0 °C. The resulting reaction mixture was stirred at 25 °C overnight. LCMS showed the reaction was complete. The reaction mixture was concentrated under vacuum to give crude product. The residue was dissolved in DCM, loaded to a silica gel column (SanTai, 25 g) and purified by flash (Biotage) column chromatography (0-2 % MeOH in DCM, flow rate: 30 mL / min) to give product as a colorless oil. The compound was crystallized from pet. ether / cyclopentyl methyl ether (3:1) at rt for a week and solids collected by filtration under reduced pressure to give (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl cyclopentyl carbonate (135 mg, 0.234 mmol, 54.4 % yield) as a white solid. Melting point: 207.5-211.7 °C. LCMS (M+H) = 577.2, Retention time (LCMS Method A) = 1.878 min, purity: 100 % (254 nm). HPLC: Retention time (HPLC Method A) = 9.433 min, purity: 100 % (254 nm). NMR (400 MHz, CDCI3) 6 10.22 (t, J = 5.8 Hz, 1H), 8.62 (s, 1H), 7.33-7.26 (m, 2H), 7.02 (td, J = 7.9, 1.1 Hz, 1H), 5.27-5.18 (m, 1H), 5.10 (d, J = 3.7 Hz, 1H), 4.75-4.64 (m, 2H), 3.56-3.43 (m, 3H), 3.34 (s, 3H), 3.05 (s, 3H), 2.41-2.29 (m, 1H), 2.27-1.74 (m, 11H).

[2058] Compound 37: (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo- 2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl nonyl carbonate

[2059]

[2060] Step 1 70504W001

[2061] To a stirred solution of (lS,3aS)-N-(3-chloro-2-fluorobenzyl)-6-hydroxy-l-(methoxymethyl)-4-methyl-5, 7-dioxo-2, 3, 3a, 4, 5, 7-hexahydro-l H-pyrido[2, 1-f] pyrrolo[l, 2-b] [1,2, 4]triazine-8-carboxamide (200 mg, 0.430 mmol) in DCM (5 mL) were added DIPEA (0.150 mL, 0.860 mmol) and nonyl carbonochloridate (98 mg, 0.473 mmol) at 0 °C. The resulting reaction mixture was stirred at 25 °C for 16 h. LCMS showed the reaction was completed. The reaction mixture was concentrated under vacuum to give crude product. The residue was dissolved in DCM, loaded to a silica gel column (SanTai, 25 g) and purified by flash (Biotage) column chromatography (0-2 % MeOH in DCM, flow rate: 30 mL / min) to give product as a colorless oil. The compound was crystallized from pet. ether / cyclopentyl methyl ether (3:1) at rt for a week and solids collected by filtration under reduced pressure to give (15,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl nonyl carbonate (112 mg, 0.176 mmol, 41.0 % yield) as a white solid. Melting point: 104.7-107.8 °C. LCMS (M+H) = 634.9, Retention time (LCMS Method A) = 1.988 min, purity: 100 % (254 nm). HPLC: Retention time (HPLC Method A) = 11.561 min, purity: 100 % (254 nm).

[2062]

[2063] NMR (400 MHz, CDCl3) δ 10.21 (t, J = 5.9 Hz, 1H), 8.63 (s, 1H), 7.33-7.26 (m, 2H), 7.02 (td, J = 7.9, 1.1 Hz, 1H), 5.10 (d, J = 3.7 Hz, 1H), 4.69 (d, J = 4.2 Hz, 2H), 4.29 (t, J = 6.8 Hz, 2H), 3.49 (ddd, J = 12.5, 8.3, 4.2 Hz, 3H), 3.34 (s, 3H), 3.05 (s, 3H), 2.40-2.30 (m, 1H), 2.25-2.05 (m, 2H), 1.93-1.84 (m, 1H), 1.84-1.73 (m, 2H), 1.41 (dd, J = 15.0, 7.1 Hz, 2H), 1.37-1.19 (m, 10H), 0.88 (t, J = 6.9 Hz, 3H).

[2064] Compound 38:

[2065] (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo- 2, 3, 3a, 4, 5, 7-hexahydro-l H-pyrido[2,l-f]pyrrolo[ 1,2-b ] [1,2,4 ]triazin-6-yl decyl carbonate

[2066]

[2067] Step 1

[2068] To a stirred solution of (lS,3aS)-N-(3-chloro-2-fluorobenzyl)-6-hydroxy-l-(methoxymethyl)-4-methyl-5, 7-dioxo-2, 3, 3a, 4, 5, 7-hexahydro-l H-pyrido[2, 1-f] pyrrolo[l, 2-b] [1,2, 4]triazine-8-carboxamide (200 mg, 0.430 mmol) in DCM (5 mL) were added DIPEA (0.150 mL, 0.860 mmol) and decyl carbonochloridate (104 mg, 0.473 mmol) at 0 °C. The resulting reaction mixture was stirred at 25 °C for 16 h. LCMS showed the reaction was completed. The reaction mixture was concentrated under vacuum to give crude product. The residue was dissolved in DCM, loaded to a silica gel column (SanTai, 70504W001

[2069] 25 g) and purified by flash (Biotage) column chromatography (0-2 % MeOH in DCM, flow rate: 30 mL / min) to give product as a colorless oil. The compound was crystallized from n-Hexane / cyclopentyl methyl ether (3:1) at rt for a week and solids collected by filtration under reduced pressure to give (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl decyl carbonate (70.4 mg, 0.108 mmol, 25.2 % yield) as a yellow solid. Melting point: 93.5-99.8 °C. LCMS (M+H) = 649.2, Retention time (LCMS Method A) = 2.500 min, purity: 100 % (254 nm). HPLC: Retention time (HPLC Method A) = 11.970 min, purity: 100 % (254 nm).

[2070]

[2071] NMR (400 MHz, CDCl3) δ 10.21 (t, J = 5.8 Hz, 1H), 8.63 (s, 1H), 7.38-7.22 (m, 2H), 7.02 (td, J = 7.9, 1.1 Hz, 1H), 5.10 (d, J = 3.7 Hz, 1H), 4.83-4.52 (m, 2H), 4.29 (t, J = 6.8 Hz, 2H), 3.62-3.42 (m, 3H), 3.34 (s, 3H), 3.05 (s, 3H), 2.35 (dd, J = 14.0, 9.0 Hz, 1H), 2.27-2.04 (m, 2H), 1.93- 1.82 (m, 1H), 1.82-1.71 (m, 2H), 1.48-1.37 (m, 2H), 1.36-1.18 (m, 12H), 0.88 (t, J = 6.9 Hz, 3H). The compounds set forth in Table 21 were prepared analogously to Compound 38.

[2072] Table 21.

[2073] Compound LCMS m / z1H-NMR (400 MHz) HPLC No. [M+H]+

[2074] 39 761.3JH NMR (400 MHz, CDCl3) 610.21 (t, J = 5.7 Hz, 1H), 8.63 HPLC Method A, (s, 1H), 7.32-7.26 (m, 2H), 7.02 (t, J = 7.9 Hz, 1H), 5.10 retention time = Retention (d, J = 3.7 Hz, 1H), 4.72-4.63 (m, 2H), 4.29 (t, J = 6.8 Hz, 13.931 min time (LCMS 2H), 3.49 (dd, J = 15.8, 7.4 Hz, 3H), 3.34 (s, 3H), 3.05 (s,

[2075] Method A) = 3H), 2.35 (dd, J = 13.5, 8.1 Hz, 1H), 2.26-2.04 (m, 2H),

[2076] 3.946 min 1.87 (d, J = 8.9 Hz, 1H), 1.76 (dd, J = 14.8, 7.1 Hz, 2H),

[2077] 1.48-1.36 (m, 2H), 1.25 (s, 28H), 0.88 (t, J = 6.8 Hz, 3H)

[2078] 40 585.0JH NMR (400 MHz, CDCl3) 610.21 (t, J = 5.9 Hz, 1H), 8.66 HPLC Method A, (s, 1H), 7.44-7.34 (m, 4H), 7.33-7.26 (m, 3H), 7.03 (td, J retention time = Retention = 7.9, 1.1 Hz, 1H), 5.12 (d, J = 3.7 Hz, 1H), 4.75-4.65 (m, 9.305 min time (LCMS 2H), 3.55-3.43 (m, 3H), 3.34 (s, 3H), 3.08 (s, 3H), 2.42- Method A) = 2.30 (m, 1H), 2.27-2.05 (m, 2H), 1.86 (t, J = 11.2 Hz, 1H)

[2079] 1.698 min

[2080] 51 549.0JH NMR (400 MHz, CDCI3) 6 10.19 (s, 1H), 8.64 (s, 1H), HPLC Method C,

[2081] 7.33-7.29 (m, 1H), 7.26 (s, 1H), 7.07-6.98 (m, 1H), 5.12 retention time = Retention (d, J = 3.6 Hz, 1H), 4.68 (d, J = 5.8 Hz, 2H), 3.95 (s, 2H), 9.01 min time (LCMS 3.57 (s, 1H), 3.49 (t, J = 11.4 Hz, 3H), 3.34 (d, J = 5.2 Hz,

[2082] Method A) = 3H), 3.06 (d, J = 10.8 Hz, 3H), 2.32 (s, 1H), 2.20 (d, J = 9.9

[2083] 1.743 min Hz, 2H), 1.86 (s, 1H)

[2084] 54 733.3JH NMR (400 MHz, CDCI3) 6 10.21 (s, 1H), 8.63 (s, 1H), HPLC Method A,

[2085] 7.32-7.27 (m, 2H), 7.02 (td, J = 8.0, 1.0 Hz, 1H), 5.10 (d, retention time = Retention J = 3.7 Hz, 1H), 4.68 (s, 2H), 4.29 (t, J = 6.8 Hz, 2H), 3.62- 12.527 min time (LCMS 3.44 (m, 3H), 3.34 (s, 3H), 3.05 (s, 3H), 2.33 (d, J = 7.6 Hz,

[2086] Method A) = 1H), 2.19 (d, J = 9.9 Hz, 2H), 1.80 (dd, J = 25.8, 18.6 Hz,

[2087] 4.322 min 3H), 1.41 (d, J = 7.9 Hz, 2H), 1.29 (d, J = 24.9 Hz, 24H),

[2088] 0.88 (t, J = 6.8 Hz, 3H)

[2089] 55 647.1JH NMR (400 MHz, CDCI3) 6 10.25 (s, 1H), 8.62 (s, 1H), HPLC Method A,

[2090] 7.33-7.27 (m, 2H), 7.03 (dt, J = 8.9, 4.5 Hz, 1H), 5.10 (d, retention time = Retention J = 3.7 Hz, 1H), 4.76-4.55 (m, 3H), 3.55-3.39 (m, 3H), 9.751 min time (LCMS 3.34 (s, 3H), 3.04 (s, 3H), 2.39-2.00 (m, 5H), 1.93-1.78

[2091] Method A) = (m, 1H), 1.71 (d, J = 10.3 Hz, 2H), 1.51 (d, J = 11.0 Hz,

[2092] 2.335 min 2H), 1.33-1.17 (m, 2H), 1.09 (s, 1H), 0.93 (t, J = 6.3 Hz,

[2093]

[2094] 6H), 0.85 (d, J = 6.9 Hz, 3H) 70504W001

[2095] 56 599.0JH NMR (400 MHz, CDCl3) 610.20 (t, J = 5.7 Hz, 1H), 8.63 HPLC Method A, (s, 1H), 7.45 (d, J = 6.6 Hz, 2H), 7.41-7.27 (m, 5H), 7.06- retention time = Retention 6.99 (m, 1H), 5.33 (s, 2H), 5.10 (d, J = 3.6 Hz, 1H), 4.68 8.419 min time (LCMS (d, J = 5.8 Hz, 2H), 3.48 (dd, J = 14.3, 9.3 Hz, 3H), 3.33 (d,

[2096] Method A) = J = 7.4 Hz, 3H), 3.05 (d, J = 18.3 Hz, 3H), 2.33 (dd, J = 13.7,

[2097] 2.709 min 8.9 Hz, 1H), 2.21-2.06 (m, 2H), 1.95-1.79 (m, 1H)

[2098] 57 677.2JH NMR (400 MHz, CDCl3) δ 10.21 (s, 1H), 8.63 (s, 1H), HPLC Method A,

[2099] 7.30 (d, J = 7.0 Hz, 2H), 7.02 (dd, J = 8.4, 7.5 Hz, 1H), 5.10 retention time = Retention (d, J = 3.7 Hz, 1H), 4.68 (s, 2H), 4.29 (t, J = 6.8 Hz, 2H), 10.689 min time (LCMS 3.60-3.41 (m, 3H), 3.34 (s, 3H), 3.05 (s, 3H), 2.32 (s, 1H),

[2100] Method B) = 2.26-1.96 (m, 2H), 1.95-1.70 (m, 3H), 1.41 (d, J = 8.1 Hz,

[2101] 2.782 min 2H), 1.32-1.20 (m, 16H), 0.88 (t, J = 6.8 Hz, 3H)

[2102] 75 683.0JH NMR (400 MHz, CDCI3) 610.26-10.17 (m, 1H), 8.67 (s, HPLC Method A,

[2103] 1H), 8.34 (dd, J = 42.1, 7.9 Hz, 1H), 7.64-7.55 (m, 2H), retention time = Retention 7.46-7.39 (m, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.26-7.23 (m, 10.735 min time (LCMS 1H), 7.01 (t, J = 7.9 Hz, 1H), 5.60 (s, 1H), 5.56 (d, J = 5.1

[2104] Method A) = Hz, 1H), 5.17-5.10 (m, 1H), 4.74-4.62 (m, 2H), 3.58-3.47

[2105] 2.18 min (m, 3H), 3.36 (d, J = 15.8 Hz, 3H), 3.01 (d, J = 8.8 Hz, 3H),

[2106] 2.39-2.30 (m, 1H), 2.26-2.07 (m, 2H), 1.94-1.81 (m, 1H),

[2107] 1.25 (d, J = 5.5 Hz, 9H)

[2108] 82 507.1JH NMR (400 MHz, CDCI3) 610.21 (t, J = 5.6 Hz, 1H), 8.63 HPLC Method A, (s, 1H), 7.31-7.28 (m, 2H), 7.04-7.00 (m, 1H), 5.10 (d, J = retention time = Retention 4 Hz, 1H), 4.68 (s, 2H), 3.51-3.45 (m, 3H), 3.34 (s, 3H), 8.135 min time (LCMS 3.03 (s, 3H), 2.41 (s, 3H), 2.37-2.31 (m, 1H), 2.21-2.07

[2109] Method B) = (m, 2H), 1.87 (t, 1 =3.6 Hz, 1H)

[2110] 1.778 min

[2111] 87 563.2JH NMR (400 MHz, CDCI3) 610.28-10.15 (m, 1H), 8.61 (s, HPLC Method A,

[2112] 1H), 7.33-7.26 (m, 2H), 7.01 (t, J = 7.8 Hz, 1H), 5.09 (s, retention time = Retention 1H), 4.68 (d, J = 18.0 Hz, 2H), 3.55-3.41 (m, 3H), 3.33 (s, 10.231 min time (LCMS 3H), 3.02 (s, 3H), 2.63-2.54 (m, 1H), 2.37-2.28 (m, 1H),

[2113] Method A) = 2.22-2.05 (m, 2H), 1.96-1.82 (m, 3H), 1.72 (s, 2H), 1.08

[2114]

[2115] 2.14 min (t, J = 6.9 Hz, 6H)

[2116] Compound 41:

[2117] (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo- 2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl (tetrahydro-2H-pyran-4-yl) carbonate

[2118] OH O Cl Cl

[2119]

[2120] Step 1

[2121] To a stirred solution of tetrahydro-2H-pyran-4-ol (101 mg, 0.990 mmol) in toluene (5.00 mL) was added bis(trichloromethyl) carbonate (128 mg, 0.430 mmol) at 0 °C. The resulting reaction mixture was stirred for 16 h. The mixture was added water (10 ml) and the aqueous layer was extracted with EtOAc (10 70504W001

[2122] mL x 3). Then the combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the mixture tetrahydro-2H-pyran-4-yl carbonochloridate (121 mg, 0.735 mmol, 74.3 % yield) as a colorless oil.

[2123] To a stirred solution of (lS,3aS)-N-(3-chloro-2-fluorobenzyl)-6-hydroxy-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazine-8-carboxamide (200 mg, 0.430 mmol) in DCM (5 mL) was added DIPEA (0.225 mL, 1.291 mmol) and tetrahydro-2H-pyran-4-yl carbonochloridate (121 mg, 0.735 mmol) at 0 °C. Then, the reaction mixture was stirred at 25 °C for 3 h. LCMS showed the reaction was completed. The reaction mixture was concentrated under vacuum to give crude product. The residue was dissolved in DCM, loaded to a silica gel column (SanTai, 25 g) and purified by flash (Biotage) column chromatography (0-2 % MeOH in DCM, flow rate: 30 mL / min) to give product (15,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl (tetrahydro-2H-pyran-4-yl) carbonate (104 mg, 0.162 mmol, 37.7 % yield) as a brown liquid. LCMS (M+H) = 594.0, Retention time (LCMS Method A) = 1.606 min, purity: 99.34 % (254 nm). HPLC: Retention time (HPLC Method A) = 8.585 min, purity: 93.20 % (254 nm). NMR (400 MHz, CDCI3) 6 10.20 (t, J = 8.0 Hz, 1H), 8.64 (s, 1H), 7.32-7.27 (m, 2H), 7.02 (dd, J = 8.3, 7.4 Hz, 1H), 5.10 (d, J = 3.6 Hz, 1H), 5.00-4.91 (m, 1H), 4.68 (t, J = 6.2 Hz, 2H), 4.04-3.93 (m, 2H), 3.64-3.53 (m, 2H), 3.54-3.43 (m, 3H), 3.34 (s, 3H), 3.05 (s, 3H), 2.35 (dd, J = 13.0, 8.0 Hz, 1H), 2.18-2.05 (m, 3H), 1.98-1.81 (m, 4H).

[2124] Compound 42: tert-butyl ((lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo- 2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl) carbonate

[2125]

[2126] Step 1

[2127] To a solution of (lS,3aS)-N-(3-chloro-2-fluorobenzyl)-6-hydroxy-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazine-8-carboxamide (70 mg, 0.151 mmol) in dichloromethane (DCM) (4 mL) were added triethylamine (45.7 mg, 0.452 mmol) and DMAP (18.40 mg, 0.151 mmol) followed by (Boc)2O (0.038 mL, 0.166 mmol) at 0 °C. The resulting reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM, loaded to a silica gel column (SanTai, 25 g) and purified 70504W001

[2128] by flash (Biotage) column chromatography (0 % to 3 % MeOH in DCM; flow rate: 30 mL / min). The product was crystallized with 50 % EtOAc in hexane and solids collected by filtration to give tert-butyl ((lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo- 2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl) carbonate (60 mg, 0.103 mmol, 68.5 % yield) as a white solid. Melting point: 181.3-183.6 °C. LCMS (M+H) = 565.2, Retention time (LCMS Method B) = 2.16 min. HPLC: Retention time (HPLC Method A) = 9.29 min, purity: 97.19 %. NMR (400 MHz, CDCI3) 6 10.28 (t, J = 6.0 Hz, 1H), 8.64 (s, 1H), 7.32-7.27 (m, 2H), 7.04 (t, J = 8.0 Hz, 1H), 5.11 (d, J = 3.6 Hz, 1H), 4.56-4.52 (m, 2H), 3.55-3.46 (m, 3H), 3.36 (s, 3H), 3.07 (s, 3H), 2.40-2.33 (m, 1H), 2.26-2.03 (m, 2H), 1.92-1.84 (m, 1H), 1.60 (s, 9H).

[2129] Compound 43:

[2130] (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo- 2, 3, 3a, 4, 5, 7-hexahydro-l H-pyrido[2,l -f]pyrrolo[ 1,2-b ] [1,2,4 ]triazin-6-yl(2-(2-methoxyethoxy)ethyl)carbonate

[2131] Toluene TEA / DCM 0 °C-RT 0 °C-RT

[2132]

[2133] Step 1

[2134] To a solution of 2-(2-methoxyethoxy)ethan-l-ol (2.5 g, 20.81 mmol) in anhydrous toluene (25 mL) was added bis(trichloromethyl) carbonate (2.78 g, 9.36 mmol) under N2atmosphere at 0 °C. The mixture was stirred at rt for 16 h. TLC showed the reaction was completed (DCM: MeOH = 10: 1). The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated to give 2-(2-methoxyethoxy)ethyl carbonochloridate (3.2 g, 12.27 mmol, 59.0 % yield) as a light yellow oil.1H NMR (400 MHz, CDCI3) 64.43-4.38 (m, 2H), 3.74-3.71 (m, 2H), 3.63-3.60 (m, 2H), 3.52-3.50 (m, 2H), 3.34 (s, 3H).

[2135] Step 2

[2136] To a stirred solution of (lS,3aS)-N-(3-chloro-2-fluorobenzyl)-6-hydroxy-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazine-8-carboxamide (150 mg, 0.323 mmol) in DCM (3 mL) was added 2-(2-methoxyethoxy)ethyl carbonochloridate (58.9 mg, 0.323 mmol) and then added dropwise a solution of TEA (0.090 mL, 0.645 mmol) in DCM (3 mL)) at 0 70504W001

[2137] °C under nitrogen atmosphere. The mixture was stirred at RT for 6 h. LCMS showed the reaction was completed. The reaction mixture was concentrated under vacuum to give crude product. The residue was purified by prep-HPLC (gradient: 40 % - 65 % ACN in water (10 mM NH4HCO3) in 8 min, stop at 16 min; retention time: 8.5 min; flow rate: 30 mL / min; column: Xtimate Prep C18 10pm 21.2*250nm). Then, the residue adsorbed on to silica gel and loaded to a silica gel column (SanTai, 40 g) and purified by flash (Biotage) column chromatography (0-5 % MeOH in DCM; flow rate: 40 mL / min) to give (15,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl (2-(2-methoxyethoxy)ethyl) carbonate (29.8 mg, 0.047 mmol, 14.45 % yield)) as a colorless oil. LCMS (M+H) = 611.1; Retention time (LCMS Method A) = 1.855 min. HPLC: Retention time (HPLC Method A) = 8.169 min, purity: 96.24 %.1H NMR (400 MHz, CDCI3) 6 10.19 (t, J = 5.6 Hz, 1H), 8.62 (s, 1H), 7.30-7.24 (m, 2H), 7.02 (t, J = 7.6 Hz, 1H), 5.11 (d, J = 3.2 Hz, 1H), 4.87 (d, J = 5.2 Hz, 2H), 4.45 (t, J = 4.4 Hz, 2H), 3.82 (t, J = 4.4 Hz, 2H), 3.70 (t, J = 4.0 Hz, 2H), 3.57-3.55 (m, 2H), 3.50-3.45 (m, 3H), 3.38 (s, 3H), 3.33 (s, 3H), 3.04 (s, 3H), 2.35-2.32 (m, 1H), 2.21-2.10 (m, 2H), 1.88-1.85 (m, 1H).

[2138] The compounds set forth in Table 22 were prepared analogously to Compound 43.

[2139] Table 22.

[2140] Compound LCMS m / z1H-NMR (400 MHz) HPLC No. [M+H]+

[2141] 44 699.1JH NMR (400 MHz, CDCl3) 610.19 (t, J = 5.6 Hz, 1H), 8.63 HPLC Method A, (s, 1H), 7.30-7.26 (m, 2H), 7.02 (t, J = 8.0 Hz, 1H), 5.10 retention time = Retention (d, J = 3.6 Hz, 1H), 4.68 (d, J = 6.0 Hz, 2H), 4.44 (t, J = 4.8 8.116 min time (LCMS Hz, 2H), 3.81 (t, J = 5.2 Hz, 2H), 3.72-3.70 (m, 2H), 3.68- Method A) = 3.63 (m, 8H), 3.56-3.53 (m, 2H), 3.50-3.45 (m, 3H), 3.37

[2142] 1.850 min (s, 3H), 3.34 (s, 3H), 3.04 (s, 3H), 2.35-2.31 (m, 1H), 2.21- 2.09 (m, 2H), 1.85 (m, 1H)

[2143] 45 804.0JH NMR (400 MHz, CDCl3) 610.20 (t, J = 6.0 Hz, 1H), 8.64 HPLC Method A, (s, 1H), 7.31-7.26 (m, 2H), 7.03 (t, J = 7.6 Hz, 1H), 5.10 retention time = Retention (d, J = 3.2 Hz, 1H), 4.68 (d, J = 5.6 Hz, 2H), 4.44 (t, J = 4.8 8.017 min time (LCMS Hz, 2H), 3.82 (t, J = 5.2 Hz, 2H), 3.71-3.70 (m, 2H), 3.66- Method A) = 3.65 (m, 16H), 3.56-3.54 (m, 2H), 3.49-3.46 (m, 3H), 3.78

[2144] 1.864 min (s, 3H), 3.34 (s, 3H), 3.05 (s, 3H), 2.35-2.32 (m, 1H), 2.22- 2.10 (m, 2H), 1.89-1.86 (m, 1H)

[2145] 46 663.2JH NMR (400 MHz, CDCl3) 510.21 (t, J = 6.0 Hz, 1H), 8.63 HPLC Method A, (s, 1H), 7.30-7.25 (m, 2H), 7.02 (t, J = 8.0 Hz, 1H), 5.10 retention time = Retention (d, J = 3.6 Hz, 1H), 4.69-4.67 (t, J = 4.0 Hz, 2H), 4.28 (t, J 12.34 min time (LCMS = 6.8 Hz, 2H), 3.51-3.45 (m, 3H), 3.34 (s, 3H), 3.04 (s, 3H),

[2146] Method A) = 2.35-2.32 (m, 1H), 2.21-2.09 (m, 2H), 1.86-1.73 (m, 3H),

[2147] 2.634 min 1.43-1.38 (m, 2H), 1.31-1.25 (m, 14H), 0.87 (t, J = 6.8 Hz,

[2148] 3H)

[2149] 47 705.7JH NMR (400 MHz, CDCl3) 510.21 (t, J = 5.2 Hz, 1H), 8.63 HPLC Method A, (s, 1H), 7.31-7.25 (m, 2H), 7.02 (t, J = 8.0 Hz, 1H), 5.09 retention time = Retention (d, J = 3.6 Hz, 1H), 4.67 (t, J = 4.8 Hz, 2H), 4.28 (t, J = 6.8 13.90 min time (LCMS Hz, 2H), 3.49-3.47 (m, 3H), 3.34 (s, 3H), 3.04 (s, 3H),

[2150] Method A) = 2.34-2.31 (m, 1H), 2.21-2.04 (m, 2H), 1.85-1.73 (m, 3H),

[2151]

[2152] 3.937 min 70504W001

[2153] 1.43-1.38 (m, 2H), 1.31-1.25 (m, 20H), 0.87 (t, J = 6.8 Hz,

[2154]

[2155] 3H)

[2156] Compound 48:

[2157] (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo- 2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl icosyl carbonate

[2158]

[2159] Step 1

[2160] To a solution of icosan-l-ol (2.5 g, 8.37 mmol) in anhydrous toluene (25 mL) was added bis(trichloromethyl) carbonate (1.118 g, 3.77 mmol) under N2atmosphere at 0 °C. The mixture was stirred at rt for 16 h. TLC showed the reaction was completed (DCM: MeOH = 10: 1). The mixture was cooled to room temperature and added water (30 mL). The aqueous layer was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated to give icosyl carbonochloridate (2.8 g, 5.43 mmol, 64.8 % yield) as a light yellow oil.

[2161]

[2162] NMR (400 MHz, CDCI3) 64.30 (dd, J = 6.8 Hz, 13.2 Hz, 2H), 1.74-1.70 (m, 2H), 1.25 (s, 34H), 0.88 (t, 7 = 6.8 Hz, 3H).

[2163] Step 2

[2164] To a stirred solution of (lS,3aS)-N-(3-chloro-2-fluorobenzyl)-6-hydroxy-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazine-8-carboxamide (150 mg, 0.323 mmol) in DCM (3 mL) was added icosyl carbonochloridate (128 mg, 0.355 mmol) and then added dropwise a solution of triethylamine (0.090 mL, 0.645 mmol) with DCM (3 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at RT for 16 h. LCMS showed the reaction was completed. The mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (15 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated to give the residue. The residue was dissolved in DCM, loaded to a silica gel column (SanTai, 25 g) and purified by flash (Biotage) column chromatography (0-5 % MeOH in DCM; flow rate: 30 mL / min). The product was crystallized with 10 % methyl ether in hexane cyclopentyl and solids collected by filtration to give (15,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl icosyl carbonate (82 mg, 0.099 mmol, 30.7 % yield) as a white solid. Melting point: 68.8-75.3 °C. LCMS (M+H) 70504W001

[2165] = 789.3, Retention time (LCMS Method A) = 4.569 min, purity: 95.50 %.JH NMR (400 MHz, CDCl3) δ 10.21 (t, 1 = 5.6 Hz, 1H), 8.63 (s, 1H), 7.30-7.25 (m, 2H), 7.03 (t, 1 = 7.6 Hz, 1H), 5.10 (d, 1 = 3.6 Hz, 1H), 4.68 (t, 1 = 4.0 Hz, 2H), 4.28 (t, 1 = 6.4 Hz, 2H), 3.50-3.48 (m, 3H), 3.34 (s, 3H), 3.04 (s, 3H), 2.33-2.31 (m, 1H), 2.20-2.17 (m, 2H), 1.86-1.75 (m, 3H), 1.43-1.38 (m, 2H), 1.32-1.25 (m, 32H), 0.87 (t, 1 = 6.4Hz, 3H).

[2166] Compound 49:

[2167] (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo- 2, 3, 3a, 4, 5, 7- hexa hydro-1 H-pyrido[2,l-f]pyrrolo[ 1,2-b ] [1,2,4 ]triazin-6-yl octyl carbonate

[2168]

[2169] Step 1

[2170] To a solution of octan-l-ol (1.5 g, 11.52 mmol) in anhydrous toluene (25 mL) was added bis(trichloromethyl) carbonate (1.538 g, 5.18 mmol) under N2atmosphere at 0 °C. The mixture was stirred at rt for 16 h. TLC showed the reaction was completed (DCM: MeOH = 10: 1). The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated to give octyl carbonochloridate (1.9 g, 6.90 mmol, 59.9 % yield) as a light yellow oil which was used in the next step without purification.

[2171]

[2172] NMR (400 MHz, CDCI3) 64.30 (dd, J = 6.8 Hz, 14.4 Hz, 2H), 1.75-1.68 (m, 2H), 1.38-1.27 (m, 10H), 0.87 (t, J = 7.2 Hz, 3H).

[2173] Step 2

[2174] To a stirred solution of (lS,3aS)-N-(3-chloro-2-fluorobenzyl)-6-hydroxy-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazine-8-carboxamide (150 mg, 0.323 mmol) in DCM (3 mL) was added octyl carbonochloridate (68.4 mg, 0.355 mmol) and then added dropwise a solution of triethylamine (0.090 mL, 0.645 mmol) with DCM (3 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at rtfor 16 h. LCMS showed the reaction was completed. The mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (15 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated to give the residue. The residue was dissolved in DCM, loaded to a silica gel column (SanTai, 25 g) and purified by flash (Biotage) column chromatography (0-5% MeOH in DCM; flow rate: 30 mL / min) to give the produc which was crystallized with 10 % cyclopentyl methyl ether in hexane and solids collected by filtration to give (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l- 70504W001

[2175] (methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b] [l,2,4]triazin-6-yl octyl carbonate (56 mg, 0.090 mmol, 27.9 % yield) as a white solid. Melting point: 119.8-127.2 °C. LCMS (M+H) = 621.2, Retention time (LCMS Method A) = 2.233 min, HPLC: Retention time (HPLC Method A) = 12.00 min, purity: 100 %.JH NMR (400 MHz, CDCl3) δ 10.21 (t, J = 6.0 Hz, 1H), 8.63 (s, 1H), 7.31-7.25 (m, 2H), 7.02 (t, J = 8.0 Hz, 1H), 5.10 (d, J = 3.6 Hz, 1H), 4.68 (m, 2H), 4.28 (t, J = 6.8 Hz, 2H), 3.51-3.45 (m, 3H), 3.34 (s, 3H), 3.05 (s, 3H), 2.35-2.31 (m, 1H), 2.21-2.04 (m, 2H). 1.88-1.86 (m, 1H), 1.79-1.73 (m, 2H), 1.42-1.40 (m, 2H), 1.31-1.26 (m, 8H), 0.87 (t, J = 6.4 Hz, 3H).

[2176] Compound 50:

[2177] (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo- 2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl (l-decanoylpiperidin-4-yl) carbonate

[2178]

[2179] Step 1

[2180] To a solution of decanoyl chloride (1 g, 5.24 mmol) in DCM (10 mL) was added piperidin-4-ol (0.583 g, 5.77 mmol) and triethylamine (1.458 mL, 10.49 mmol) at 0-5 °C over under N2atmosphere, The mixture was stirred at 0 °C for 16 h. TLC showed the reaction was completed (DCM: MeOH = 10: 1). The solvent was removed under reduced pressure. The residue was dissolved in DCM, loaded to a silica gel column (SanTai, 25 g) and purified by flash (Biotage) column chromatography (0-5 % MeOH in DCM; flow rate: 30 mL / min) to give l-(4-hydroxypiperidin-l-yl) decan-l-one (800 mg, 2.193 mmol, 41.8 % yield) as a colorless oil.

[2181]

[2182] NMR (400 MHz, CDCI3) 64.76 (s, 1H), 4.11-4.08 (m, 1H), 3.95-3.89 (m, 1H), 3.75-3.71 (m, 1H), 3.22-3.13 (m, 2H), 2.32 (t, J = 8.0 Hz, 2H), 1.88 (s, 2H), 1.64-1.57 (m, 2H), 1.51-1.46 (m, 2H), 1.29-1.25 (m, 12H), 0.87 (t, J = 6.4 Hz, 3H).

[2183] Step 2

[2184] To a solution of l-(4-hydroxypiperidin-l-yl)decan-l-one (287 mg, 1.123 mmol) in anhydrous toluene (25 mL) was added bis(trichloromethyl) carbonate (150 mg, 0.506 mmol) under N2atmosphere at 0 70504W001

[2185] °C. The mixture was stirred at rt for 16 h. TLC showed the reaction was completed (DCM: MeOH = 10: 1). The mixture diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated to give l-decanoylpiperidin-4-yl carbonochloridate (168 mg, 0.370 mmol, 32.9 % yield) as a light yellow oil.1H NMR (400 MHz, CDCI3) 6 4.77 (s, 1H), 4.12-4.09 (m, 1H), 3.94-3.90 (m, 1H), 3.75-3.71 (m, 1H), 3.23-3.17 (m, 2H), 2.32 (t, J = 7.6 Hz, 2H), 1.88 (s, 2H), 1.64-1.57 (m, 2H), 1.52-1.46 (m, 2H), 1.30-1.26 (m, 12H), 0.87 (t, 7 = 6.4 Hz, 3H).

[2186] Step 3

[2187] To a stirred solution of l-decanoylpiperidin-4-yl carbonochloridate (82 mg, 0.258 mmol) in DCM (2 mL) was added (lS,3aS)-N-(3-chloro-2-fluorobenzyl)-6-hydroxy-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazine-8-carboxamide (120 mg, 0.258 mmol) and then dropwise a solution of triethylamine (52.2 mg, 0.516 mmol) in DCM (2 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at RT for 16 h. LCMS showed the reaction was completed. The mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (15 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated to give the residue. The residue was dissolved in DCM, loaded to a silica gel column (SanTai, 25 g) and purified by flash (Biotage) column chromatography (0-5 % MeOH in DCM; flow rate: 30 mL / min). The product was crystallized with 10 % cyclopentyl methyl ether in hexane and solids collected by filtration to give (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazin-6-yl (1-decanoylpiperidin-4-yl) carbonate (120 mg, 0.161 mmol, 62.3 % yield) as a white solid. Melting point: 53.4-57.3 °C. LCMS (M+H) = 746.2, Retention time (LCMS Method A) = 2.271 min; HPLC: Retention time (HPLC Method A) = 11.28 min, purity: 100 %.JH NMR (400 MHz, CDCI3) 6 10.18 (t, J = 5.6 Hz, 1H), 8.64 (s, 1H), 7.31-7.26 (m, 2H), 7.02 (t, J = 7.6 Hz, 1H), 5.10 (s, 1H), 4.99 (s, 1H), 4.68 (t, J = 6.0 Hz, 2H), 3.81-3.78 (m, 1H), 3.73-3.68 (m, 2H), 3.52-3.41 (m, 4H), 3.34 (s, 3H), 3.04 (s, 3H), 2.33 (t, J = 8.0 Hz, 3H), 2.22-2.10 (m, 2H), 1.95-1.85 (m, 5H), 1.33-1.26 (m, 14H), 0.87 (t, J = 6.4 Hz, 3H).

[2188] Compound 52:

[2189] (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l-(methoxymethyl)-4-methyl-5,7-dioxo- 2, 3, 3a, 4, 5, 7- hexa hydro-1 H-pyrido[2,l-f]pyrrolo[ 1,2-b ] [1,2,4 ]triazin-6-yl ethyl carbonate. 70504W001

[2190]

[2191] Step 1

[2192] To a mixture of (lS,3aS)-N-(3-chloro-2-fluorobenzyl)-6-hydroxy-l-(methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2-b][l,2,4]triazine-8-carboxamide (150 mg, 0.323 mmol) and DIPEA (0.169 mL, 0.968 mmol) in DCM (10 mL) was added ethyl carbonochloridate (52.5 mg, 0.484 m mol) at 0 °C. The reaction mixture was stirred at 25 °C overnight. TLC showed the reaction was completed. The reaction mixture was concentrated in vacuum. The residue was dissolved in DCM (5 mL), loaded to a silica column (SanTai, 40 g), purified by flash (Biotage) with MeOH / DCM (0 % to 2 %, 50 mL / min) to give product as a colorless oil. The oil was triturated with 9 % EtOAc in hexane (4 mL) and solids collected by filtration to give (lS,3aS)-8-((3-chloro-2-fluorobenzyl)carbamoyl)-l- (methoxymethyl)-4-methyl-5,7-dioxo-2,3,3a,4,5,7-hexahydro-lH-pyrido[2,l-f]pyrrolo[l,2- b] [l,2,4]triazin-6-yl ethyl carbonate (108 mg, 0.201 mmol, 62.3 % yield) as a white solid. Melting point: 229.7-234.2 °C. LCMS (M+H) = 537.0, Retention time (LCMS Method A) = 1.81 min, purity (254 nm) =100 %. HPLC: Retention time (HPLC Method C) = 9.414 min, purity (254 nm) = 100 %.

[2193]

[2194] NMR (400 MHz, CDCI3) 610.21 (t, J = 5.8 Hz, 1H), 8.63 (s, 1H), 7.33–7.28 (m, 1H), 7.26 (s, 1H), 7.02 (td, J = 7.9, 1.0 Hz, 1H), 5.11 (d, J = 3.7 Hz, 1H), 4.68 (d, J = 4.8 Hz, 2H), 4.36 (q, J = 7.1 Hz, 2H), 3.49 (ddd, J = 12.4, 8.2, 4.1 Hz, 3H), 3.34 (s, 3H), 3.05 (s, 3H), 2.34 (dd, J = 9.5, 4.5 Hz, 1H), 2.17 (ddd, J = 23.5, 15.2, 3.9 Hz, 2H), 1.87 (d, J = 8.8 Hz, 1H), 1.41 (t, J = 7...

Claims

70504W001Claims:

1. A compound of Formula (I),or a pharmaceutically acceptable salt thereof,wherein:ring A is a substituted or unsubstituted 3- to 10-membered heterocycloalkyl;ring C is a benzene ring, a pyridine ring, or a 5-membered heteroaryl;L is a bond, -C(O)-, -C(O)R5-, -CH2-O-C(O)-, or -CH2-O-C(O)R5-;Y is selected from the group consisting of (Ci-24)alkyl, (C2.24)alkenyl, (Ci-io)alkoxy, 5- to 10- membered heteroaryl, (C1-8)alkylene-R8, (C2.s)alkenylene-R8, (C3-i4)cycloalkyl, bridged (C8- i4)tricycloalky I, (C6-i4)aryl, (C6-i4)bicycloalkyl, and 3- to 10-membered heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, wherein (C3-i4)cycloalkyl, bridged (Cs-i4)tricycloalkyl (C6-i4)aryl, (Cs-ujbicycloalkyl, or the 3- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -O-C(O)-(Ci. sjalkyl, (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -C(O)R7, oxo, and halogen;orY is (Y-2),zR11| - R1°R12(Y-2);or70504W001Y is (Y-3)> H2CH3C R13CH3 (Y-3);R1is independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, cyano, and haloalkoxy;R2aand R2bare each independently hydrogen, alkyl, or haloalkyl; orR2aand R2b, together with the carbon atom to which they are both adjacent, form a 3- to 8- membered cycloalkyl, a 6- to 10-membered bicycloalkyl, or a 3- to 10-membered heterocycloalkyl;R3is substituted or unsubstituted alkyl, substituted or unsubstituted 3- to 8-membered cycloalkyl, substituted or unsubstituted 6- to 10-membered bicycloalkyl, or substituted or unsubstituted heterocycloalkyl;R4is hydrogen, or substituted or unsubstituted alkyl; orR3and R4, or R3and a substituent on ring A may be taken together with the adjacent atoms to form a substituted or unsubstituted heterocycloalkyl;R5is -O- or -NR6-;R6is hydrogen or (Ci-6)alkyl;R7is (Ci-io)alkyl, (Ci-io)alkoxy, or -NH-(Ci-io)alkyl;R8is selected from the group consisting of (Ci-24)alkoxy, (C2-24)alkenyloxy, -NH-C(O)-(Ci-i4)alkyl, - C(O)-(C! -24)alkoxy, -O-(CH2CH2O)n-(Ci-i4)alkyl, (C3-i4)cycloalkyl, (C6-i4)bicycloalkyl, bridged (C8- i4)tricycloalky I, (C6-i4)aryl, 3- to 10-membered heterocycloalkyl, -O-(Ci-8)alkylene-(C6-i4)aryl, and -OP(O)(OR9)2, wherein (C3-i4)cycloalkyl, (C6-i4)bicycloalkyl, bridged (C8-i4)tricycloalkyl, (C6- i4)aryl, 3- to 10-membered heterocycloalkyl, or -O-(Ci-8)alkylene-(C6-i4)aryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -O-C(O)-(Ci-i0)alkyl, (Ci-6)alkylene-O-C(O)-(Ci-8)alkyl, -C(O)-(Ci-i0)alkoxy, -C(O)- NH-(Ci-io)alkyl, oxo, and halogen;R9is independently selected from hydrogen and (C1-8)alkyl;R10is -CH- or -N-;R11and R12are selected from the group consisting of (Ci-io)alkyl, -C(O)-O-(Ci-i0)alkyl, (Ci-6)alkylene- (C6-i4)aryl, -C(O)-NH-(Ci-i0)alkyl, (Ci-8)alkylene-S-(Ci-6)alkyl, -O-C(O)-(Ci-i0)alkoxy, -O-C(O)-(Ci-70504W001sjalkyl, (Ci-8)alkylene-C(0)-(Ci-io)alkoxy, (Ci-8)alkylene-C(0)-NH-(Ci-io)alkyl, -NH-(Ci-io)alkyl, (Ci-8)alkylene-C(0)0H, and -C(O)OH, wherein (Ci.6)alkylene-(C6-i4)aryl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of (Ci-e)alkyl and halogen;R13is (C6-i4)aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of:(Ci-io)alkyl,-0-C(0)-(Ci.io)alkyl,(Ci-6)alkylene-O-C(O)-(Ci-8)alkyl,-O-C(O)-(C6-i4)aryl optionally substituted by (Ci-6)alkylene-O-C(O)-(Ci-8)alkyl, -0-(Ci-6)alkylene-(C6-io)aryl optionally substituted by -0-C(0)-(Ci-io)alkyl, -O-C(O)-(C3-i4)cycloalkyl, and-OP(O)(OR9)2;m is an integer selected from 1-3; andn is an integer selected from 1-10.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (ll-a)Formula (li-b)(ll-bj,70504W001Formula (l:-c)or Formula {ll-d}or a pharmaceutically acceptable salt thereof,wherein:RA5a, RA5b, RA6a, RA6b, RA7aand RA7bare each independently hydrogen, alkyl, alkoxy, or alkoxyalkyl; RA5aand RA6a, or RA6aand RA7amay be taken together with the adjacent atoms to form a 6- to 14- membered aryl optionally substituted by halogen, a 3- to 8-membered cycloalkyl optionally substituted by halogen, a 6- to 10-membered bicycloalkyl optionally substituted by halogen, or a 4- to 6-membered heterocycloalkyl optionally substituted by halogen (provided that, when forming a 6- to 14-membered aryl, RA5band RA6b, or RA6band RA7bare taken together to form a bond);RA5band RA6bmay be taken together to form a bond;RA8a, RA8b, RA9a, RA9b, RA10a, RA10b, RA11aand RA11bare each independently hydrogen, alkyl, alkoxy, or alkoxyalkyl;RA8aand RA10amay be taken together to form a C1-C3 cross-link;RA10aand RA11amay be taken together with the adjacent atoms to form a 5-membered cycloalkyl;70504W001RA9aand RA9bmay be taken together with the adjacent atom to form a 4-membered cycloalkyl or a 5-membered heterocycloalkyl;RA8aand RA9amay be taken together to form a bond;R1is each independently halogen, alkyl, haloalkyl, alkoxy, cyano, or haloalkoxy;R4is hydrogen or alkyl;m is an integer of 1 to 3;L is a bond, -C(O)-, -C(O)R5-, -CH2-O-C(O)-, or -CH2-O-C(O)R5-;Y is selected from the group consisting of (C1-24)alkyl, (C2-24)alkenyl, (C1-10)alkoxy, 5- to 10-membered heteroaryl, (C1-8)alkylene-R8, (C2-8)alkenylene-R8, (C3-14)cycloalkyl, (C6-14)aryl, (C6-14)bicycloalkyl, bridged (C8-14)tricycloalkyl, and 3- to 10-membered heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, wherein (C3-i4)cycloalkyl, (C6-i4)aryl, (C6-i4)bicycloa Ikyl, bridged (C8-i4)tricycloalkyl, or the 3- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -O-C(O)-(Ci- s)alkyl, (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -C(O)R7, oxo, and halogen;orY is (Y-2),1 - ZR11R1°R12(Y-2);orY is (Y-3)SH2CH3^-C -|— R13CH3 (Y-3);R5is -O- or -NR6-;R6is hydrogen or (Ci-6)alkyl;R7is (Ci-io)alkyl, (Ci-io)alkoxy, or -NH-(Ci-io)alkyl;R8is selected from the group consisting of (Ci.24)alkoxy, (C2.24)alkenyloxy, -NH-C(O)-(Ci-i4)alkyl, - C(O)-(C1-24)alkoxy, -O-(CH2CH2O)n-(Ci-i4)alkyl, (C3-i4)cycloalkyl, (C6 i4)bicycloalkyl, bridged (Cs- i4)tricycloalky I, (C6-i4)aryl, 3- to 10-membered heterocycloalkyl, -O-(Ci-8)alkylene-(C6-i4)aryl, and -OP(O)(OR9)2, wherein (C3-i4)cycloalkyl, (C6-i4)bicycloa Ikyl, bridged (C8-i4)tricycloalkyl, (C6- i4)aryl, 3- to 10-membered heterocycloalkyl, or -O-(Ci-8)alkylene-(C6-i4)aryl is optionally70504W001substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -0-C(0)-(Ci-io)alkyl, (Ci-6)alkylene-O-C(O)-(Ci-8)alkyl, -C(0)-(Ci-io)alkoxy, -C(O)- NH-(Ci-io)alkyl, oxo, and halogen;R9is independently selected from hydrogen and (C1-8)alkyl;R10is -CH- or -N-;R11and R12are independently selected from the group consisting of (Ci-io)alkyl, -C(0)-0-(Ci-io)alkyl, (Ci.6)alkylene-(C6-i4)aryl, -C(0)-NH-(Ci-io)alkyl, (Ci-sJalkylene-S-fCi-eJalkyl, -O-C(O)-(Ci. io)alkoxy, -O-C(O)-(Ci-s)alkyl, (Ci-8)alkylene-C(0)-(Ci-io)alkoxy, (Ci-s)alkylene-C(O)-NH-(Ci- io)alkyl, -NH-(Ci-io)alkyl, (Ci-8)alkylene-C(O)OH, and -C(O)OH, wherein (Ci.6)alkylene-(C6-i4)aryl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of (Ci.6)alkyl and halogen;R13is (C6-i4)aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of:(Ci-io)alkyl,-0-C(0)-(Ci.io)alkyl,(Ci-6)alkylene-O-C(O)-(Ci-s)alkyl,-O-C(O)-(C6-i4)aryl optionally substituted by (Ci-6)alkylene-O-C(O)-(Ci-8)alkyl, -0-(Ci.6)alkylene-(C6-io)aryl optionally substituted by -0-C(0)-(Ci-io)alkyl, -O-C(O)-(C3-i4)cycloalkyl, and-OP(O)(OR9)2; andn is an integer selected from 1-10.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1 or claim 2, which is a compound of Formula (l-g),Y i(l-g).Formula (l-h),70504W001Formula (l-i),Formula (l-j),or Formula (l-k),or a pharmaceutically acceptable salt thereof,wherein:R1is each independently halogen, alkyl, haloaikyi, alkoxy, cyano, or haioalkoxy; m is art integer of.1 to 3;70504W001L is a bond, -C(O)-, -C(O)R5-, -CH2-O-C(O)-, or -CH2-O-C(O)R5-;Y is selected from the group consisting of (C1-24)alkyl, (C2-24)alkenyl, (C1-10)alkoxy, 5- to 10-membered heteroaryl, (C1-8)alkylene-R8, (C2-8)alkenylene-R8, (C3-14)cycloalkyl, (C6-14)aryl, (C6-14)bicycloalkyl, bridged (C8-14)tricycloalkyl, and 3- to 10-membered heterocycloalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S, wherein (C3-i4)cycloalkyl, (C6-i4)aryl, (Ce-ujbicycloalkyl, bridged (C8-14)tricycloalkyl, or the 3- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -O-C(O)-(Ci- sjalkyl, (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -C(O)R7, oxo, and halogen;orY is (Y-2),ZR11< -R\’ R12(Y-2);orY is (Y-3), H2CH3§-C R13CH3 (Y-3);R5is -O- or -NR6-;R6is hydrogen or (Ci-6)alkyl;R7is (Ci-io)alkyl, (Ci-io)alkoxy, or -NH-(Ci-io)alkyl;R8is selected from the group consisting of (Ci.24)alkoxy, (C2.24)alkenyloxy, -NH-C(O)-(Ci.i4)alkyl, - C(O)-(C!.24)alkoxy, -O-(CH2CH2O)n-(Ci-i4)alkyl, (C3-i4)cycloalkyl, (C6-i4)bicycloalkyl, bridged (C8- i4)tricycloalky I, (C6-i4)aryl, 3- to 10-membered heterocycloalkyl, -O-(Ci-8)alkylene-(C6-i4)aryl, and -OP(O)(OR9)2, wherein (C3-i4)cycloalkyl, (C6-i4)bicycloalkyl, bridged (Cs-ultricycloalkyl, (C6- i4)aryl, 3- to 10-membered heterocycloalkyl, or -O-(Ci-8)alkylene-(C6-i4)aryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (Ci-io)alkyl, -0-C(0)-(Ci-io)alkyl, (Ci.6)alkylene-O-C(O)-(Ci-8)alkyl, -C(0)-(Ci-io)alkoxy, -C(O)- NH-(Ci-io)alkyl, oxo, and halogen;R9is independently selected from hydrogen and (C1-8)alkyl;R10is -CH- or -N-;R11and R12are independently selected from the group consisting of (Ci-io)alkyl, -C(0)-0-(Ci-io)alkyl, (Ci-6)alkylene-(C6-i4)aryl, -C(0)-NH-(Ci-io)alkyl, (Ci-s)alkylene-S-(Ci-6)alkyl, -O-C(O)-(Ci- io)alkoxy, -O-C(O)-(Ci-8)alkyl, (Ci-8)alkylene-C(0)-(Ci-io)alkoxy, (Ci-8)alkylene-C(O)-NH-(Ci.70504W001io)alkyl, -NH-(Ci-io)alkyl, (Ci-8)alkylene-C(O)OH, and -C(O)OH, wherein (Ci.6)alkylene-(C6-i4)aryl is optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of (Ci-sjalkyl and halogen;R13is (C6-i4)aryl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of:(Ci-io)alkyl,-0-C(0)-(Ci.io)alkyl,(Ci-6)alkylene-O-C(O)-(Ci-8)alkyl,-O-C(O)-(C6-i4)aryl optionally substituted by (Ci-6)alkylene-O-C(O)-(Ci-8)alkyl, -0-(Ci.6)alkylene-(C6-io)aryl optionally substituted by -0-C(0)-(Ci-io)alkyl, -O-C(O)-(C3-i4)cycloalkyl, and-OP(O)(OR9)2; andn is an integer selected from 1-10.

4. The compound or pharmaceutically acceptable salt thereof according to claim 3, wherein R1is independently halogen;m is an integer of 1 to 3;L is -C(O)- or -C(O)R5-;Y is (C1-24)alkyl or (C1-8)alkylene-R8;R5is -O-;R8is (C3-14)cycloalkyl.

5. The compound of Formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of Formulae (l-a), (l-b), (l-c), (l-d), (l-e), and (l-f):70504W001or a pharmaceutically acceptable salt thereof.

6. The compound of Formula (l-b) according to claim 5,or a pharmaceutically acceptable salt thereof.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1- 6, wherein L is -C(O)- or -C(O)R5-.

8. The compound or pharmaceutically acceptable salt thereof according to claim any one of claims 1-7, wherein L is -C(O)R5-.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein L is -C(O)R5- and R5is -O-.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein L is -C(O)-.70504W00111. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1- 10, wherein Y is (C1-24)alkyl or (C1-8)alkylene-R8.

12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1- 11, wherein Y is (C1-24)alkyl.

13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1- 11, wherein Y is (C1-8)alkylene-R8.

14. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1- 11 and 13, wherein Y is (C1-8)alkylene-R8and R8is (C3-14)cycloalkyl.

15. A compound selected from the group consisting of:70504W001O OO^O O 0^""0 Oc|JpLN^i^H70504W00170504W001or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 15, which is selected from the group consisting of:70504W00117. The compound according to claim 15, wherein the compound isor a pharmaceutically acceptable salt thereof.

18. The compound according to claim 17, wherein the compound is19. The compound according to claim 15, wherein the compound is70504W001or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 19, wherein the compound is21. The compound according to claim 15, wherein the compound isor a pharmaceutically acceptable salt thereof.

22. The compound according to claim 21, wherein the compound is23. The compound according to claim 15, wherein the compound is70504W001or a pharmaceutically acceptable salt thereof.

24. The compound according to claim 23, wherein the compound is25. The compound according to claim 15, wherein the compound isor a pharmaceutically acceptable salt thereof.

26. The compound according to claim 25, wherein the compound is27. The compound according to claim 15, wherein the compound isor a pharmaceutically acceptable salt thereof.70504W00128. The compound according to claim 27, wherein the compound is29. The compound according to any one of claims 18, 20, 22, 24, 26, and 28, wherein the compound is crystalline.

30. A pharmaceutical composition comprising:a) a compound or pharmaceutically acceptable salt thereof according to any one of claims 1-29, andb) a pharmaceutically acceptable excipient.

31. A method of treating HIV infection in a human in need thereof comprising administering to said human a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1-29.

32. A method of preventing HIV infection in a human comprising administering to said human a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1-29.

33. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-29 or the pharmaceutical composition according to claim 30, for use in therapy.

34. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-29 or the pharmaceutical composition according to claim 30, for use in treating an HIV infection.

35. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-29 or the pharmaceutical composition according to claim 30, for use in preventing an HIV infection.

36. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1-29, in the manufacture of a medicament for use in the treatment of HIV infection.70504W00137. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1-29, in the manufacture of a medicament for use in the prevention of HIV infection.

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