TW201215604A - Compounds and methods for the treatment or prevention of flavivirus infections - Google Patents

Abstract

A compound is represented by Structural Formula (I): or a pharmaceutically acceptable salt thereof, wherein the variables of Structural Formula (I) are as described in the specification and the claims. A pharmaceutical composition comprises a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier of excipient. A method of treating a HCV infection in a subject comprises administering to the subject a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof. A method of inhibiting or reducing the activity of HCV polymerase in a subject or in a biological in vitro sample comprises administering to the subject or to the sample a therapeutically effective amount of a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof.

Description

201215604 VI. INSTRUCTIONS: RELATED APPLICATIONS This application claims the benefit of U.S.S.N. 61/359, 169, filed on Jun. 28, 2010, and the U.S.S.S.N. All teachings of these applications are hereby incorporated by reference. [Prior Art] Hepatitis C virus (HCV) is a positive-strand RNA virus belonging to the Flaviviridae family (F/aWWrWae), and includes hog cholera virus and bovine viral diarrhea. Virus; BVDV) has the closest relationship to the genus (pestiviruses). The HCV HCV is replicated by generating a complementary negative strand RNA template. Due to the efficient culture of the replication system lacking the virus, the HCV particle system was isolated from pooled human plasma and showed a diameter of about 50-60 nm by electron microscopy. The HCV genome is a 9,600 bp single-stranded sense RNA encoding a polymeric protein of 3009-3030 amino acids, which is cleaved into mature viral proteins (core protein, El, E2, p7, NS2) by co-translational and post-translational means. NS3, NS4A, NS4B, NS5A, NS5B). The serotonin glycoproteins E1 and E2 are embedded in the viral lipid envelope and form stable heterodimers. The core protein of the salty structure interacts with the viral RNA genome to form a nucleocapsid. Non-structural proteins termed NS2 to NS5 include proteins having enzyme functions involved in viral replication and protein processing, including polymerases, proteases, and helicases. The main source of pollution for HCV is blood. HCV Infection Regulations for Health Problems 157033.doc 201215604 The modelling is illustrated by the incidence of high-risk groups. For example, 60% to 90% of hemophiliacs and more than 80% of intravenous drug abusers in Western countries are chronically infected with HCV. The incidence of intravenous drug abusers is about 28% to 70°/depending on the study population. Not waiting. The proportion of new HCV infections associated with post-transfusion has recently decreased significantly due to the development of diagnostic tools for screening blood donors. The combination of pegylated interferon + ribavirin is the treatment of choice for chronic HCV infection. This therapy does not provide a sustained viral response (SVR) in most patients infected with the most prevalent genotype (la&lb). In addition, significant side effects impede compliance with current therapies and may require dose reduction or discontinuation in some patients. Therefore, it is highly desirable to develop an anti-viral agent for treating or preventing a flavivirus infection. SUMMARY OF THE INVENTION The large system of the present invention relates to compounds useful for the treatment or prevention of flavivirus infections such as HCv infection. ® In the examples - the present invention relates to a compound represented by the structural formula (1) or (11):

157033.doc 201215604 Ring A is further substituted with one or more substituents selected from the group consisting of _D(氘), halogen, -CN, C.6 alkyl and Cu haloalkyl, as appropriate. Y is a C3-8 carbocyclic ring, a 5-8 membered heterocyclic ring, a -(C2 aliphatic group)-Ri, a C6 i〇 aryl group or a 5-10 membered heteroaryl group, wherein the carbocyclic ring, heterocyclic ring, aryl group and hetero The aryl groups are each independently independently substituted by one or more groups selected from the group consisting of dentate, -CN, nitro, azide, Ra, _s〇2Ra, _〇Ra, -CORa, -NRRa, -C(0)〇Ra, _〇c(〇)Ra, _NRC(〇)Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0)〇Ra, -〇C 〇NRRa, -S02NRRa, -NRS02Ra, -NRS02NRRURC(=NR)NRRa, and wherein the c:2 aliphatic group is selected from one or more selected from the group consisting of halogen, _CN,

Substituents of the group consisting of a Cu-based group, a Cw-dentate group, a mesogenic group and a methoxy group are substituted. R is -H or Ci_6 leumino, 〇3-10 carbocyclyl, 4-1 fluorene heterocyclyl, c6 1 aryl or 5-10 membered heteroaryl, wherein the alkyl is optionally one or more Substituted by jlA, and wherein each of the carbocyclyl and heterocyclyl groups are, as the case may be, independently substituted with one or more J1B, and wherein the aryl and heteroaryl groups are each independently passed through one or more J 1 C replaced. 1^ is (^1-6 month steroid group, [3-1〇 carbocyclyl, 4-10 membered heterocyclic group, (^610 aryl or 5-10 membered heteroaryl), wherein the aliphatic group Where the case is substituted by one or more J2A, the ## carbocyclyl and heterocyclic groups are each independently substituted by one or more J, and the aryl and heteroaryl groups are independently independently treated as appropriate Substituting a plurality of j2e. R, R4, R5 and R6 are each independently _H, _D, or a Cw aliphatic group optionally substituted by one or more JDs. 157033.doc • 6 · 201215604 ^ and independently _Η^]·6 aliphatic group, C3.1Q carbocyclic group, 4. betheterocyclyl, '.aryl or 5-(tetra)heteroaryl, wherein the aliphatic group may be - or a plurality of j, as appropriate And wherein the carbocyclyl and heterocyclyl are each independently substituted with - or a plurality of P, and wherein the #aryl and heteroaryl are each independently substituted with one or more J7C; or And R8 together with the nitrogen atom to which it is attached form a 4_1()fluorene heterocycle (eg, monocyclic, bicyclic or tricyclic, fused, bridged or spiro), such as a 4-8 membered heterocyclic ring, optionally Or multiple JE substitutions.

When Y is -(C2 aliphatic)-Rl, R3&R7, together with the atom to which it is attached, optionally forms a 4-10 membered heterocyclic ring which is optionally substituted by one or more. R is .i)-H; iOC, ·6 aliphatic group' is replaced by one or more broad eight depending on the case; Carbocycles or 4.10 membered heterocycles, each optionally substituted by one or more J9B', or iv) C6•丨. The aryl or 5_1 member heteroaryl groups are each independently substituted with one or more J9Cs as appropriate. J1A, j2A, J7A and j9A are each independently a pendant oxy group, Q; or two J1A, two J2A, two J7A and two; respectively, forming 3.8 members independently from the atom to which they are connected - (4) The family ring, the (4) family is replaced by one or more jE. jlB, j2B, j7B and Cw aliphatic groups each independently substituted by a pendant oxy or heart or by one or more Q; or two jlB, two, two] 3^, two J7B And two independently forming a 3-8 member non-aromatic ring independently of the atoms to which they are attached. The non-aromatic ring is replaced by a plurality of JEs. 157033.doc 201215604 jic, J2C, J7C and J9C are each independently Q or a C!.6 aliphatic group substituted by one or more Qs; or two J1C:, two J2C:, two J7< And the two J9Cs, independently of the atoms to which they are attached, form a 3-8 member non-aromatic ring independently, which is optionally replaced by one or more JEs. Each Q is independently selected from the group consisting of dentate, cyano, nitro, -ORa, -SRa, -S(0)Ra, -S02Ra, -NRRa, -C(0)Ra, -C(0 ) ORa, -0C(0)Ra, -0C(0)0Ra, -NRC(0)Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0)0Ra, -NRC(=NR )NRRa, -OCONRRa, -C(0)NRC(0)0Ra, -C(=NR)Ra, -C(=NOR)Ra, -S02NRRa, -NRS02Ra, -NRS02NRRa, -0P(0)(0Ra) 0Ra, a C3-8 carbocyclic ring substituted by one or more JE, optionally a 4-8 membered heterocyclic ring substituted by one or more JE, optionally substituted by one or more C6_丨. An aryl group, and optionally a 5-10 membered heteroaryl group substituted by one or more. Alternatively, each Q is independently selected from the group consisting of halogen, cyano, nitro, -ORa, -SRa, -S(0)Ra, -S02Ra, -NRRa, -C(0)Ra, -C( 0) 0Ra, -OC(0)Ra, -NRC(0)Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0)0Ra, -NRC(=NR)NRRa, -OCONRRa, -C(0)NRC(0)0Ra, -C(=NR)Ra, -C(=NOR)Ra, -S02NRRa, -NRS02Ra, -NRS02NRRa, -OP(0)(ORa)ORa, as appropriate Or a C3.8 carbon ring substituted by a JE, optionally a 4-8 member heterocyclic ring substituted by one or more JE, optionally substituted by one or more C6.1Q aryl groups, and optionally A 5-10 membered heteroaryl group substituted by a plurality of JFs. Each 113 is independently: i)-H; ii) a CN6 aliphatic group, optionally substituted with one or more substituents independently selected from the group consisting of: a functional element, a pendant oxy group, -CN, -OR , -NRR·, -OCOR, -COR", -C02R, 157033.doc 201215604 -CONRR,, -NRC(0)R, as appropriate by one or more JEs (: 3.8 carbocyclic groups, as appropriate One or more JE substituted 4-8 membered heterocyclic groups, optionally substituted by one or more JF, C6.indenyl and optionally substituted by one or more JF; a C3_8 carbocyclic group or a 4-8 membered heterocyclic group, each of which is optionally substituted independently by one or more JE; or iv) a C61() aryl group or a 5-10 membered heteroaryl group, each independently of the case Substituting one or more JFs; or 1^ together with R and the nitrogen atom to which they are attached, form a 4-8 membered heterocyclic ring, which is optionally substituted with one or more JEs. Each R is independently -H or a C!_6 aliphatic group substituted with one or more JDs as appropriate. Each R' is independently -H or optionally substituted by one or more JD Cw aliphatic groups; or R, together with R and the nitrogen atom to which it is attached, form a 4-8 membered heterocyclic ring as appropriate. The situation is replaced by one or more jEs. Each R" is a Cl_6 aliphatic group substituted by one or more jDs as appropriate. Each is broadly and independently selected from the group consisting of: halogen, pendant oxy, _CN, -OH, -NH2, -NHCCVQ alkyl), -Ν((ν(:6 alkyl)2, -〇<:0 ((: 1-(:6 alkyl), -CC^CVCe alkyl), -C02H, -C02(CrC6 alkyl), alkyl), -〇(cvc6haloalkyl), (:3_7 cycloalkyl) , (: 3_7 ring (haloalkyl) and stupid. Each JE is independently selected from the group consisting of: halogen, pendant oxy, _CN, -oh, -NH2, -NI^CVCs alkyl), -NCCVC6 alkane Base 2, • 0C0 (C1_C6 alkyl), -CCKCVC6 alkyl), -co2h, -CCMCrC^alkyl), -OCCi-C^alkyl), -CKCVCeii alkyl) and optionally one or more jD substituted aliphatic group. 157033.doc -9- 201215604 Each JF is independently selected from the group consisting of halogen, -CN, -OH, -NH2, -NH (Ci-C6 alkyl), -Ν ((ϋι·〇6) 2, _〇CO (Ci-C6 alkyl), -CCKCrCe alkyl), -C02H, -C〇2 (C-C6 alkyl), -〇((:!-c6 alkyl), and optionally Ci-Ce aliphatic group substituted by one or more JDs. η is 0 or 1. Exemplary heterocycles formed by R3 and R7 together with the nitrogen atom to which they are attached include:

Is a hydrazine or a substituted Ci alkyl group. In other embodiments, R8 in ring di-D7 are each independently alkyl. In another embodiment, the present invention relates to a compound represented by the structural formula (ΠΙ) or (ly):

157033.doc (IV), 201215604 or its pharmaceutically acceptable compound 安^安的盐' wherein the meanings of the variables of structural formulae (III) and (IV) are independently as follows: - or more selected from - _D (occupation), dentate, -CN,

Substituents for the group of Cd groups and base groups are substituted. R is -H or CV6 alkyl, (: 31〇 carbocyclyl, 4_1〇 heterocyclyl, (7) aryl or 5 1 杂 heteroaryl] wherein the aliphatic group is subjected to one or more Substituting 'and wherein the carbocyclyl and heterocyclyl are each independently substituted with one or the next J, and wherein the aryl and heteroaryl are each independently substituted with one or more Jlc. R is a Cw aliphatic group, a C3 1〇 carbocyclic group, a 41 〇 member heterocyclic group, a Q aryl group or a 5-10 membered heteroaryl group, wherein the aliphatic group is optionally substituted by one or more j2A, Carbocyclyl and heterocyclic groups are each independently one or more depending on the situation

2 B is substituted, and the aryl and heteroaryl groups are each independently substituted with one or more j2C as appropriate. R3 'R4, R5 and R6 are each independently _H, _D(氘), or a CN6 aliphatic group substituted with one or more JDs as appropriate. R and R7, together with the atom to which they are attached, form a 4_1 member heterocyclic ring (e.g., a 4-8 member heterocyclic ring) as appropriate. The heterocyclic ring is optionally substituted with one or more jE. R7 and R8 are each independently _H or Ck aliphatic, c3.1() carbocyclyl, 4-1 fluorene heterocyclyl, (6. 1 () aryl or 5-10 membered heteroaryl) Wherein the aliphatic group is optionally substituted with one or more J7A, and wherein the carbocyclic and heterocyclic groups are each independently substituted with one or more J7B, and wherein the aryl and heteroaryl groups are substituted Each of them is independently substituted with one or more J7Cs as appropriate; or R7 and R8 together with the nitrogen atom to which they are attached form a 4-1 member heterocyclic ring I57033.doc n 201215604 (eg, monocyclic, bicyclic or tricyclic, A fused ring, a bridged ring or a spiro ring), such as a 4-8 membered heterocyclic ring, optionally substituted with one or more JEs. R9 is: i)-H; ii) C丨·6 aliphatic group, as appropriate - or more a broad eight substitution; iii) a C3_1() carbocyclic ring or a 4-10 membered heterocyclic ring 'each of which is optionally substituted by ~ or a plurality of J9Bs; or iv) a C6_1() aryl group or a 5-1 member heteroaryl Bases, each of which is independently replaced by one or more J9Cs as appropriate. ~2A, J7A and each independently form a side oxy group or ^ or two J1A, two J2A, two J7A and two J9A respectively, and the atoms connected thereto are independently formed into 3-8 members. An aromatic ring (carbocyclic or heterocyclic) which is optionally substituted by one or more JE. ® jlB, j2B, j7B and j9B are each independently a pendant oxy group or, optionally, a Cw aliphatic group substituted by one or more Q; or two jlB, two, two stern, two and two A 3-8 member non-aromatic ring (carbocyclic or heterocyclic ring) is optionally formed independently of the atom to which it is attached, and the non-aromatic ring is optionally substituted with one or more JE.

J1C, J2C, J7C, and J9C are each independently Q or a group of one or more Q-substituted groups, or two jic, two pcs, and two corpses. And two φ J, respectively, independently of the atoms to which they are attached, form a 3-8 member non-aromatic ring (carbocyclic or heterocyclic ring) independently, which is optionally substituted by one or more. Independently selected from the group consisting of: element, cyano, nitro, OR, _SR, -S(〇)Ra, _S〇2Ra, _NRRa, c(〇)Ra, c(〇)〇Ra, 〇C (0) R, _〇c(〇)〇Ra, _NRC(〇)Ra,. (〇), NRc(〇)NRRa, NRC(〇)〇r, -NRC(=NR)NRRa > -〇c〇NRRa' -C(0)NRC(0)0Ra ' 157033.doc •12- 201215604 -C(=NR)Ra, -C(=NOR)Ra, -S02NRRa, -NRS02Ra, -NRS〇2NRRa, -0P(0)(0Ra)0Ra, optionally replaced by one or more jE Ring, optionally substituted 4-8 membered heterocyclic ring, optionally substituted by one or more jF, C6-1Q, and optionally substituted by one or more JF Or 'each Q is independently selected from the group consisting of dentate, cyano, nitro, -ORa, -SRa, -S(0)Ra, -S02Ra, -NRRa, _c(0)Ra, -C (0) 0Ra, -〇C(0)Ra, -NRC(0)Ra, -C(0)NRRa, -NRC(〇)NRRa, -NRC(0)0Ra, -NRC(=NR)NRRa, - OCONRR3, -C(〇)NRC(〇)〇Ra, -C(=NR)Ra, -C(=NOR)Ra, -S02NRRa, -NRS02Ra, -NRS〇2NRRa, -OP(0)(ORa)〇 Ra, a C3-8 carbon ring substituted by one or more jEs, optionally a 4-8 member heterocyclic ring substituted by one or more JEs, optionally replaced by one or more ^C. And optionally substituted by one or more JF, 5-1 〇 heteroaryl. Each ruler 3 is independently: i)-H; iOCw aliphatic group 'Substituting one or more substituents independently selected from the group consisting of: self, alkoxy, -CN, -OR, -NRR', -OCOR, -COR", -C02R, -CONRR ·, -NRC(0)R, optionally a C3 8 carbocyclic group substituted with one or more jE, optionally a 4-8 membered heterocyclic group substituted with one or more JE, optionally one or more jF substituted C: 6 · aryl and optionally substituted by one or more jF 5 丨〇 heteroaryl; iu) C3.8 carbocyclyl or 4-8 membered heterocyclyl, each depending on the case Substituted independently by one or more JE; or iv) (: 6.1Q aryl or 5-10 membered heteroaryl, each independently substituted with one or more JFs as appropriate; or

Ra, together with R and the nitrogen atom to which it is attached, optionally forms a 4-8 membered heterocyclic ring which is optionally substituted with one or more JE. 157033.doc •13· 201215604 Each R is independently a Cw aliphatic group substituted by one or more JDs. ' Each R' is independently -H or optionally substituted by one or more JDs (: 丨_6 aliphatic group; or R, together with R and the nitrogen atom to which it is attached, form 4-8 members The ring is optionally substituted with one or more jEs. Each R" is a Ck aliphatic group substituted with one or more JDs as appropriate. Each JD is independently selected from the group consisting of: halogen, pendant oxy, -CN, -OH, -NH2, -Nl^CVCe alkyl), -N(Ci-C6 alkyl)2, -0C0(Ci-C6 alkyl), -CCKCVC6 alkyl), -C02H, -cokcvc^ An alkyl group, -CKCVC6 alkyl), -CKCVC6 from an alkyl group, a C3-7 cycloalkyl group, a C3.7 ring (haloalkyl group), and a phenyl group. Each: ^ is independently selected from the group consisting of: halogen, pendant oxy, -CN, -OH, -NH2, -N^CVCe alkyl), -Ν((ν(:6 alkyl)2, -OCCKC !-c6 alkyl), -CCKCi-Ce alkyl), -co2h, -CCMCVC^alkyl), -0 (Ci-C6 alkyl), -〇 (Ci-C6 dentate), and optionally Or a plurality of JD substituted C 1 -C 6 aliphatic groups. Each JF is independently selected from the group consisting of halogen, -CN, -OH, -NH2, -NH (C "C6 alkyl", -N(c)-c6 alkyl) 2, -OCCHCi-Ce alkyl ), -C0 (C丨-C6 alkyl), -C02H, -C02 (Ci-C6 alkyl), -0 ((:!-C6 alkyl), and optionally substituted by one or more JDs An aliphatic group. η is 0 or 1. In another embodiment, the invention relates to a pharmaceutical composition comprising a compound of the invention as described herein (for example, selected from the scope of the patent application and illustrated in Figure 1-3) a compound of the compound, such as a compound represented by any one of the formula (Ι)-(ΧΙΙΙ), (XX) 157033.doc • 14-201215604 and (XXI), or a pharmaceutically acceptable salt thereof) And a pharmaceutically acceptable carrier or excipient. In another embodiment, the invention provides a method of treating an HCV infection in an individual comprising administering to the individual a therapeutically effective amount of a text as described herein 1 A compound of the invention (for example, a compound selected from the group consisting of the compounds described in the patent application and in Figures 1-3, such as a compound represented by any one of the formulae (I)-(XIII), (XX) and (XXI) , A pharmaceutically acceptable salt thereof. In another embodiment, the invention relates to a method of inhibiting or reducing HCV polymerase activity in an individual comprising administering to the individual a therapeutically effective amount as described herein a compound of the invention (e.g., a compound selected from the group consisting of the compounds described in the patent application and Figures 1-3, such as those represented by any one of Structural Formulas (I)-(XIII), (XX), and (XXI) a compound, or a pharmaceutically acceptable salt thereof. In another embodiment, the invention relates to a method of inhibiting or reducing HCV polymerase activity in an in vitro biological sample, comprising administering to the sample a therapeutically effective amount A compound of the invention as described herein (for example, a compound selected from the group consisting of the compounds described in the patent application and in Figures 1-3, such as from Structural Formulas (I)-(XIII), (XX) and (XXI) a compound of any of the compounds, or a pharmaceutically acceptable salt thereof. The present invention also provides a compound of the invention as described herein (for example, the scope of the patent application and the compound described in Figure 1-3, such as by the structural formula (I)-(XIII), (XX) and (XXI) The use of a compound, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating an HCV infection in a subject or inhibiting or reducing the activity of HCV polymerase in an individual. 157033.doc -15- 201215604 Providing the compounds of the invention as described herein (for example, the scope of the patent application and the compounds described in Figures 1-3, such as compounds represented by Structural Formulas (I)-(XIII), (XX) and (XXI), or pharmaceuticals thereof The use of a salt that is acceptable for use in treating an HCV infection in an individual or inhibiting or reducing HCV polymerase activity in an individual. Without being bound by a particular theory, the compounds of the invention are generally NS5B inhibitors. [Embodiment] The compound of the present invention is as described in the scope of the patent application. In some embodiments, the compound of the invention is represented by any one of the formulae (Ι)-(ΧΠΙ), (XX), and (XXI) or a pharmaceutically acceptable salt thereof, wherein the variables are each independently as claimed Said in any of the patent scope. In some embodiments, the compounds of the invention are represented by any of the formulas depicted in Figures 1, 2, and 3, or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds of the invention are represented by any one of the formulae (Ι)-(ΧΙΙΙ), (XX), and (XXI), or a pharmaceutically acceptable salt thereof, wherein the variables are each independently as illustrated The chemical formulas in 1, 2 and 3 are depicted. In one embodiment, the compound of the invention is represented by structural formula (I) or a pharmaceutically acceptable salt thereof:

The first group of variables of structural formula (I) has the following meaning: 157033.doc -16- 201215604 Ring A depends on the situation - step by step - or multiple selected from _β, _ 素, ❿,

Substituent substitution of a group consisting of Ct.6 alkyl and C.6. In one aspect, 'ring A is further replaced by _? depending on the situation. Alternatively, Ring A is not further substituted. YM dicarbocyclic ring, 5-8 membered heterocyclic ring, also aliphatic group)_R, C6i〇 aryl group or 5 10 membered heteroaryl group, wherein the carbocyclic ring, heterocyclic ring, aryl group and heteroaryl group are each independently independently - ❹] γ substitution and wherein the Q aliphatic group is optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, Cu alkyl, CClyl, hydroxy and methoxy . In general, Y is a condition, a star-substituted C3·6 cycloalkyl group, optionally substituted C4 6 cycloalkenyl, -(C2 aliphatic)_R1, optionally substituted phenyl or A 56-membered heteroaryl group is substituted, and wherein the q-aliphatic group is optionally substituted. In the aspect, Y is _(匚2 aliphatic group)-111 or optionally substituted phenyl group, wherein the C2 aliphatic group is optionally substituted. In another aspect, γ is optionally substituted phenyl, optionally substituted thienyl or, optionally substituted, and 5'Y is a stupid group. In another aspect, γ is optionally substituted C3-6 cycloalkyl or optionally substituted 6-cycloalkenyl. In another aspect, Y is optionally substituted c4 6 cycloalkenyl. In another aspect, γ is optionally substituted cyclohexenyl. In another aspect, ¥ is -(C:2 aliphatic)-Ri, and wherein the Q aliphatic group is optionally substituted. In another aspect, Y is -CH2-CH2-R1, -CtKH-R1 or CsCR1. R is: i)-H; ii) CN6 alkyl, optionally substituted by one or more jlA; iii) C3.1Q carbocyclic or 4-10 membered heterocyclic ring, each independently passing one or more J1B substituted; or iv) C6.1 () aryl or 5_1 杂 heteroaryl, each of which is independently substituted by - or a plurality of γ, depending on the case 157033.doc • 17- 201215604. In the aspect, r1 is substituted by the condition c, the ring group, the C38 carbocyclic ring as the case may be taken, the phenyl group substituted by the visual material or the 5_6 member base which is optionally substituted. In another example, Ri is a group substituted with an It H or a optionally substituted Ch carbocyclic group. In another aspect, 'R1 is an optionally substituted Ci6 alkyl group or a Ch ring-based H-state t, and R1 is an optionally substituted Ci6 building. In another embodiment, 'R1 is a third butyl or isopropyl group which is optionally substituted. In another aspect, R1 is optionally substituted cyclopropyl. R is · OC -6 aliphatic group, optionally substituted by one or more jZA; (1) q carbocyclic or 4-H) heterocyclic ring, each of which is optionally substituted by one or more j2B; or iii) C6_丨. Aryl or 5_1 member heteroaryl, each of which is optionally independently - or multiple generations. In the aspect, 'r2 is an optionally substituted &aliphatic group, optionally substituted C38 carbocyclic group, optionally substituted 4-8 membered heterocyclic group m-substituted phenyl or substituted as appropriate 5_6 member heteroaryl. In another aspect, r2 is optionally substituted c5_c8 or a optionally substituted phenyl group. In the other aspect, the cwt base is replaced by the case. In another embodiment, r2 is a cyclohexyl group which is optionally substituted. R R and R are each independently _H, _D, or, optionally, one or more 7 JD-substituted Cl-6 aliphatic groups. When hydrazine is also an aliphatic group, r1, ampules 3 and R and the atom to which they are attached form a 4-(tetra)heterocycle, which is optionally substituted by one or more jE. In one aspect, R3 substituted Cm alkyl, R, R5 and R6 are each independently seven or as appropriate or 菖丫 is -((^2 aliphatic)-Rl, R3 and R7 and 157033. Doc 201215604 The atoms to which they are attached form, as appropriate, a 4_丨0 member heterocyclic ring which is optionally substituted. In another aspect, 'R3, R4, R5 and R6 are each independently _H or optionally a plurality of c丨6 alkyl groups substituted with a substituent selected from the group consisting of: _, oxa, _CN, -OH, -ΝΗ2, -ΝΗ (〇ν(:6& base), -NiCVCe alkyl 2, _OCO (Cl_C6 alkyl), yl), -C02H, -COKCrC^alkyl), -OCCi-G alkyl), haloalkyl), C:3·7 cycloalkyl, (:3_7 ring ( Haloalkyl) and phenyl; or when γ is -(C2 aliphatic)-111, R3 together with R7 and the atom to which it is attached, as the case may be, forming a 4_1 member heterocyclic ring, which may be A plurality of substituents selected from the group consisting of halogen, pendant oxy, -CN, 〇Η, -ΝΗ:, -NH(Ci_C6 alkyl), -N(Ci-C6 炫)2, 〇CO(Ci_C6 alkyl), -CCKCi-Ce alkyl), -C02H, -COJC^Ce alkyl) - C (CV C6 alkyl), -0 (Ci-C6 calcinyl) and, optionally, C?-C6 alkyl substituted with one or more substituents selected from the group consisting of: halogen, pendant oxy , -CN, -OH, -ΝΗ2, -ΝΗ((ν(:6 alkyl), -NCCVCe alkyl)2, -Ο C Ο (C1 - C 6 alkyl), _ c O (C1 - C 6 Burning base), -C Ο 2 Η, - C Ο 2 (C1 - C 6 ® alkyl), -〇 (Ci-C6 pit base), -◦ (Ci-Csii alkyl), c3.7 cycloalkyl And a C3-7 ring (dentate alkyl) and a phenyl group. In another aspect, R3, R4, R5 and R6 are each independently -Η or optionally substituted with one or more groups selected from the group consisting of Substituted C!-6 alkyl: halogen, -CN, -OH, -ΝΗ2, -NHCCu alkyl), -Νπκ alkyl)2, -CKCw alkyl) and -CHCkhaloalkyl); or when Y When (C2 aliphatic group)-111, R3, together with R7 and the atom to which it is attached, form a 4-10 membered heterocyclic ring as appropriate, optionally substituted with one or more substituents selected from the group consisting of: Halogen, -CN, -OH, -NH2, 157033.doc •19- 201215604 -NHCC]^ burnt base, burnt base) 2, -〇 (Ci-6 炫) and -〇 (Cl-6 halogen burn) ). Examples of heterocycles formed by R3 and R7 include:

Wherein the rings D1-D7 are each independently substituted as appropriate. R7 and R8 are each independently i)-H; iDC!·6 aliphatic group, optionally substituted by one or more J; iii) C3_10 carbocyclic ring or 4-10 membered heterocyclic ring, each of which is independently One or more J7B substitutions; or iv) a C6iQ aryl group or a 5_1 member heteroaryl group which are each independently substituted with one or more J7Cs; or R7 and R8 together with the nitrogen atom to which they are attached form a 4-1 0 member heterocyclic ring, as the case may be replaced by one or more JE. In one aspect, R7 and R8 are each independently an optionally substituted Gw aliphatic, optionally substituted C3.8 carbocyclyl or, optionally substituted heterocyclyl' or R7 and R8, The nitrogen atom to which it is attached - forms a 4-10 membered heterocyclic ring which is replaced by 157033.doc •20·201215604 as appropriate. In another aspect, R7 and r8 are each independently -H or optionally substituted C1-6 alkyl, optionally substituted C38 carbocycle, or optionally substituted 4-8 membered heterocyclyl; R7 and R8, together with the atom to which they are attached, form, as appropriate, a 4_ 〇 member heterocyclic ring which is optionally substituted. In another aspect, R7 and R8 are each independently -H; optionally substituted with one or more substituents selected from the group consisting of: dentate, pendant oxy, - CN, -OH, ·ΝΗ2, -NH(CVC6 alkyl), ...((:^匕alkyl)2, -OCCHC^-Ce Institute base), -CC^CrCe burn base), _c〇2H, ® _C 〇2 (Cl_C6 alkyl), -〇 (c "c6 alkyl", -0 (Ci-C6_ alkyl), C3.7 decyl, C3·7 (haloalkyl) and phenyl; or c38 Carbocyclyl or 4-8 membered heterocyclyl' are each optionally substituted with one or more substituents selected from the group consisting of halogen, pendant oxy, _CN, _0H, _NH2, -NH (CVC6 alkyl) ), -NCCVQ alkyl), _OCO (Cl_C6 alkyl), -CCKCi-Cfi alkyl), -C02H, -COdCrCe alkyl), alkyl), -0 (C1 - C6 self-burning) and, as appropriate By the substitution of one or more substituents selected from the group consisting of: 1_(::6 alkyl: halogen, pendant oxy, _-CN, -0Ή, -NH2, -NHCCi-Ce alkyl ), -NCCrC^ alkyl), 〇CO (Ci-C6 alkyl), _C0 (C!-C6 alkyl), -co2h, -COJCVC^ alkyl) - hydrazine (Ci-C6 alkyl), -◎ (Ci-Cj alkyl), c3.7 cycloalkyl, 匸 3.7 ring (haloalkyl) and phenyl; or R7 and R8 together with the atom to which they are attached The case of forming a 4-10 membered heterocyclic ring 'optionally substituted with one or more substituents selected from the group consisting of: a functional element, a pendant oxy group, -CN, -OH, -NH2, an alkyl group), -NCCrC^ Alkyl)2, -OCCHCrC^alkyl), -COCCVCs alkyl), -C02H, -COKCi-Cs alkyl), -CHCrCs alkene i57033.doc •21- 201215604 base), -CKCrQ haloalkyl) The case is substituted by one or more substituents selected from the group consisting of: 1-(:6 alkyl: halogen, pendant oxy, -CN, -OH, ΝΗ2, -NH(C 丨-(: 6 alkyl), -N(Ci-C6 alkyl) 2, -OCCKCV c6 alkyl), -CCKh-C^alkyl), -C02H, -C02(Ci-C6 alkyl), -◦(CVC6 alkane) (), -CKCrCeii alkyl), (: 3.7 cycloalkyl, C3-7 ring (dentate alkyl), and phenyl. In another aspect, R7 and R8 are each independently _H or optionally Or a plurality of Ci-6 alkyl groups substituted with a substituent selected from the group consisting of: a functional element, _CN, -OH, -NH2, -NHiCu Base, -N (Ci.6 alkyl) 2, -0 (Ci.6) and -〇 (Ci-6_ alkyl); or R7 and R8 together with the atom to which they are attached form 4-10 a heterocyclic ring, optionally substituted with one or more substituents selected from the group consisting of dentate, CN, -OH, -NH2, -NH(Ci_6 alkyl), -N(C 丨·6 alkyl 2, -CKCw alkyl) and -CKCw haloalkyl). In another aspect, R7 and R8 together with the atom to which they are attached form an optionally substituted heterocyclic ring. The heterocyclic ring formed by R7 and R8 may be a bridged ring or a spiro ring. R9 is: i)-H; ii) C丨·6 aliphatic group, optionally substituted by one or more j9A; iii) C3.1Q carbocyclic ring or 4-10 membered heterocyclic ring, each of which is independently One or more J9B substitutions; or iv) C6 1 aryl or 5-10 membered heteroaryl, each independently substituted with one or more j9c, as appropriate. In one aspect, the ruler 9 is _H or, as the case may be, a Cu alkyl group substituted with one or more substituents selected from the group consisting of: _ 素, pendant oxy, -CN, -OH, -NH2 -Nl^CrC^alkyl), alkyl)2,_0C0(Cl-C6 alkyl), -(^((^(alkyl), -C02H, -CC^CVC^alkyl), -CHCVCe Base), -〇(C 丨-C6 dentate), C3·7 cycloalkyl, c3_7 ring (haloalkyl) and phenyl. In another state 157033.doc -22· 201215604 sample 'R9 士士Or 匚^alkyl. In another aspect, R9 is -Η. Each JY is independently selected from the group consisting of halogen, _CN, nitro, azide, Ra, -S02Ra, -ORa, -CORa , -NRRa, -C(0)0Ra, -0C(0)Ra, -NRC(0)Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0)0Ra, -0C0NRR3, - S〇2NRRa, -NRS02Ra, -NRS02NRIH-NRC(=NR)NRRa. Typical examples of JY include halogen, -cn, nitro, Ra, -ORa, -CORa, and -NRRa. More typical examples of JY include halogen,

-CN, Shishaoji, Ci_6 alkyl, Cu-halogen, -〇H, alkyl), -0 (phenyl), -0 (5-6 membered heteroaryl), -NH2, -NHd-e ), -N (C!.6 alkyl) 2 and -C(0) (Ci.6 alkyl). More typical examples include halogen, -CN, schlossyl, Ci-6 alkyl, C1-6 halogen, hydrazine, -hydrazine (〇1.6 alkyl), -NH2, -NHCCm alkyl), -Νπυ Alkyl) 2 and -C(0) (CBu 6 alkyl). More typical examples of J include halogen, _cn, schlossyl, fluorenyl, ethyl, -CF3, -OH, -OMe, -NH2, and -C(0)Me. J, j2A, 7-8 and J9Ag are independently independently a pendant oxy group or Q; or two J1A, two J2A, two J7A and two atoms respectively associated with the atom to which they are attached, independently form a 3-8 member Non-aromatic ring, the non-aromatic ring is replaced by one or more JEs as a case of "J1A", and "Typical examples of the factory eight independently include halogen, pendant oxy, _CN, -ORa, _NRRa, _〇c (〇) Ra, -〇C(0)〇Ra, -CORa, -C〇2Ra, -NRC(〇)Ra, _c(〇)NRRa, -JNKC(0)NRRa ' -NRC(0)0Ra w J -β A few times difficult C8 ring (toothed base), 5_6 member heterocyclic group and optionally substituted phenyl group as appropriate.] 丨, and more typical examples of the wide package (four), side oxygen Base, -CN, -〇Ra, -NRRa, -〇c(〇)Ra, _c〇Ra, 157033.doc -23- 201215604 -C02Ra, -NRC(0)Ra, -C(0)NRRa, -NRC (0) NRRa, -NRC(0)0Ra, -OCONRRa, (:3_8 cycloalkyl, C3.8 ring (haloalkyl), and phenyl. Typical examples of J9A include halogen, pendant oxy, -CN, - ORa, -NRRa, -0C(0)Ra, -OC(0)ORa, -CORa, -C02Ra, -NRC(0)Ra ' -C(0)NRRa, -NRC(0)NRRa, -NRC(0 ) 0Ra, -OCONRRa, C3.8 ring An alkyl group, (: 3.8 ring (haloalkyl), phenyl, and optionally a 5-6 membered heterocyclic ring substituted with one or more substituents selected from the group consisting of a pendant oxy group and a C i -6 alkyl group. J9A More typical examples include -0C(0)Ra, -OC(0)ORa, phenyl, and optionally a 5-6 membered heterocyclic ring substituted with one or more substituents selected from the group consisting of pendant and Cm alkyl groups. More typical examples of J9A2 include dentate, pendant oxy, -CN, -ORa, -NRRa, -0C(0)Ra, -CORa, -C02Ra, -NRC(0)Ra, -C(0)NRRa, -NRC (0) NRRa, -NRC(0)0Ra, -OCONRRa, C3_8 cycloalkyl, C3-8 ring (haloalkyl) and phenyl. JIB, J2B, J7B and J9B are each independently a pendant oxy group, Q, Or optionally substituted by one or more Q (^_6 aliphatic groups; or two J1B, two J2B, two J3B, two J7B and two J9B, respectively, independently formed with the atoms to which they are attached 3-8 member non-aromatic ring, the non-aromatic ring is replaced by one or more JEs. Typical examples of J1B, J2B, J7B & J9B independently include halogen, pendant oxy, -CN, -ORa, -NRRa, -OCORa, -CORa, -C02Ra, -NRC(0)Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0)0Ra, -OCONRRa, and The C^-Ce aliphatic group substituted by one or more substituents selected from the group consisting of halogen, pendant oxy, -CN, -ORa, -NRRa, -OCORa, -CORa, -C02Ra, - NRC(0)Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0)0Ra, 157033.doc -24- 201215604 -OCONRRa, (:3.8 cycloalkyl, (:3.8 ring (halogen) Alkyl) and phenyl. More typical examples of J1B, J2B, J7B and J9B independently include halogen, -CN, -OH, -NH2, -NHCCk alkyl), -NCCw alkyl)2, -0((:, .6 alkyl), And optionally, Cu alkyl substituted with one or more substituents selected from the group consisting of: a functional element, -CN, -OH, -NH2, -NHCCw alkyl), an alkyl group 2, a -CKCw alkyl group ) and -CKCkiI alkyl). J1C, J2C, J7C and J9C are each independently a Q or a Ci_6 aliphatic group substituted by one or more Qs; or two J1C, two J2C, two J7C and two J9e respectively connected to the atom The 3-8 member non-aromatic ring is formed independently as appropriate, and the non-aromatic ring is replaced by one or more JEs as appropriate. Typical examples of J2C, J7e, and J9C independently include _-, side-oxy, -CN, -ORa, -NRRa, -OCORa, -CORa, -C02Ra, -NRC(0)Ra, -C(0)NRRa , -NRC(0)NRRa, -NRC(0)0Ra, -OCONRRa, and optionally a CJ-C6 aliphatic group substituted with one or more substituents selected from the group consisting of halogen, pendant oxy, -CN, -ORa, -NRRa, OCORa, -CORa, -C02Ra, -NRC(0)Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0)0Ra, -OCONRRa, C3- 8-cycloalkyl, C3-8 ring (haloalkyl) and phenyl. Each Q is independently selected from the group consisting of li, cyano, nitro, -ORa, -SRa, -S(0)Ra, -S02Ra, -NRRa, -C(0)Ra, -C(0 ) 0Ra, -0C(0)Ra, -0C(0)0Ra, -NRC(0)Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0)0Ra, -NRC(=NR NRRa, -OCONRRa, -C(0)NRC(0)0Ra, -C(=NR)Ra, -C(=NOR)Ra, -S02NRRa, -NRS02Ra, -NRS02NRRa, -OP(0)(ORa) ORa, C3_8 carbocyclic ring substituted by one or more JE, as appropriate 157033.doc -25- 201215604 Conditioned 4-8 member heterocyclic ring substituted by one or more JE, as appropriate by one or more ^ A C6-1() aryl group and a 5-10 membered heteroaryl group optionally substituted with one or more JF groups. Alternatively, each Q is independently selected from the group consisting of halogen, cyano, nitro, -ORa, -SRa, -S(0)Ra, -S02Ra, -NRRa, -C(0)Ra, -C( 0) 0Ra, -0C(0)Ra, -NRC(0)Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0)0Ra, -NRC(=NR)NRRa, -OCONRRa, -C(0)NRC(0)0Ra, -C(=NR)Ra, -C(=NOR)Ra, -S02NRRa, -NRS02Ra, -NRS02NRRa, -OP(0)(ORa)ORa, as appropriate Or a plurality of JE substituted C3_8 carbocyclic rings, optionally a 4-8 membered heterocyclic ring substituted by one or more JE, optionally substituted by one or more C6-1() aryl groups, and optionally A plurality of JF substituted 5-10 membered heteroaryl groups. Typical examples of Q include halogen; cyano; nitro; - 〇Ra; -SRa; S(0)Ra; -S02Ra; -NRRa; -C(0)Ra; -C(0)ORa; -OC(0 Ra; -0C(0)0Ra; -NRC(0)Ra; -C(0)NRRa; -NRC(0)NRRa; -NRC(0)ORa; -NRC(=NR)NRRa ; -OCONRR3 ; C(0)NRC(0)0Ra; -C(=NR)Ra ; -C( = NOR)Ra ; -S02NRRa ; -NRS02Ra ; -NRS02NRRa ; -0P(0)(0Ra)0Ra ; C3_8 carbocyclic ring; optionally substituted 4-8 membered heterocyclic group; optionally substituted phenyl; and optionally substituted 5-6 membered heteroaryl. Alternatively, typical examples of Q include a pheromone; a cyano group; a nitro group; -1Ra; -SRa; -S(0)Ra; -S02Ra; -NRRa; -C(0)Ra; -C(0)0Ra; 0C(0)Ra ; NRC(0)Ra ; -C(0)NRRa ; -NRC(0)NRRa ; NRC(0)0Ra ; -NRC(=NR)NRRa ; -OCONRRa ; -C(0)NRC( 0) 0Ra; -C(=NR)Ra; -C(=NOR)Ra; -S02NRRa; -NRS02Ra; -NRS02NRRa; -0P(0)(0Ra)0Ra; optionally substituted C3.8 carbocycle; a 4-8 membered heterocyclic group substituted as appropriate; optionally substituted phenyl; and optionally substituted 157033.doc •26·201215604 5.6 member heteroaryl. Each Ra is independently: i)-H; ii) Ci.6 aliphatic group, optionally substituted with one or more substituents independently selected from the group consisting of dentate, sideoxy CN, _〇 R, -NRR', -OCOR, -COR", -C02R, -CONRR,, nrc(o)r, q.8 carbocyclic groups substituted by one or more jE, as appropriate, one or more a JE-substituted 4-8 membered heterocyclic group, optionally substituted by one or more jFs (: 6·1 aryl and optionally substituted by one or more JF, 5_1 杂 heteroaryl, 111) C3_8 carbon a cyclic group or a 4-8 membered heterocyclic group, each of which is optionally substituted independently by one or more JE; or ") (: 6_1 () aryl or 5 - 1 member heteroaryl, each independently as appropriate One or more jF substitutions; or Rule 3, together with R and the nitrogen atom to which it is attached, form a 4-8 member heterocycle, optionally substituted by one or more jE. In one aspect, 1^ is _H, Optionally substituted q 6 aliphatic, optionally substituted CM carbocyclyl, optionally substituted 4-8 heterocyclyl, optionally substituted phenyl or optionally substituted 5-6 heteroaryl ; or... together with R and the nitrogen atom to which it is attached a 5-8 membered heterocyclic ring which is optionally substituted. In another aspect, the ruler & is _H, optionally substituted c!·6 alkyl, optionally substituted C3 6 carbocyclic group a 4-8 membered heterocyclic group, optionally substituted phenyl or optionally substituted 5-6 membered heteroaryl; or optionally formed with the ruler and the nitrogen atom to which it is attached, as appropriate 5-8 membered heterocyclic ring as appropriate. Each R is independently _H or a Ci 6 aliphatic group substituted with one or more jD, as appropriate. Each R' is independently _H or optionally Multiple jD substituted ci 6 aliphatic groups; or R' together with R and the nitrogen atom to which they are attached form a 4-8 member heterogeneous 157033.doc •27·201215604 ring 'this heterocyclic ring is replaced by one or more as appropriate Each R" is a Ci-6 aliphatic group substituted by one or more JDs as appropriate. Each JD is independently selected from the group consisting of halogen, pendant oxy, CN, 〇Η, -NH2, -NHCC ^-Ce alkyl), _N(Ci_C6 alkyl) 2, -OCO(C 丨-c6 alkyl), -CO(C 丨-C6 alkyl), -C02H, -C02(CrC6 alkyl), -CKCrC ^Alkyl), -OCC^Ce ialkyl), C3.7 cycloalkyl, C3 -7 ring (haloalkyl) and phenyl. Each JE is independently selected from the group consisting of: halogen, pendant oxy, -CN, -OH, -NH2, -NP^Ci-Ce alkyl), -NCCrCe alkyl)2, -OCCKCVCe alkyl), - CO(C 丨-c6 alkyl), -co2h, -co2(c 丨-c6 alkyl), -CKCrCe alkyl), -CHCrCe haloalkyl, and optionally CrCe aliphatic substituted by one or more JD base. Each JF is independently selected from the group consisting of: halogen, -CN, -OH, -NH2, -NHiCi-Q alkyl, -N(C)-C6 alkyl)2, -(^.((^- (^alkyl), -CCKCi-C^alkyl), -C02H, -C〇2 (Ci-C6 alkyl), -CKCi-C:6 alkyl), and optionally substituted by one or more jD (^-〇: 6 aliphatic group. The value of η is 0 or 1. n is usually 〇. The second group of the variables of the formula (I) has the following meaning: The ring Α is further substituted by -F. The remaining variables of (I) are each independently as described above in the first set of meanings of the variables of Structural Formula (j). The third set of variables of Structural Formula (I) has the following meaning: R1 is optionally substituted C a 6-alkyl or optionally substituted Cw carbocyclic group. Suitable substituents for R1 are as described above in the first set of variables of formula (1) 157033.doc • 28· 201215604. In one aspect And Ri is optionally substituted Ci 6 alkyl or c 3 8 cycloalkyl, which are each optionally substituted with one or more substituents selected from the group consisting of halogen, pendant oxy, _CN, - OH, -NH2, -NH(Ci-C6 alkyl), -N(C 丨-C6 alkyl) 2, -〇c〇(C 丨-C6 alkyl), -(^((^-(^alkyl), -C02H, -COJC^Ce alkyl), -〇(Ci-C6 alkyl), - CKCrCe haloalkyl), c3.7 cycloalkyl, C3_7 cyclo(haloalkyl) and phenyl. In another aspect, R1 is, as the case may be, one or more substituents selected from the group consisting of _ Substituted C!-6 yard base: halogen, pendant oxy, _cn, -OH, -NH2, -NH^-Cs alkyl), ·NA-Cfi alkyl), -OCCKC!-C6 alkyl), -CCKCVCe alkyl), -C02H, -COJCVC^alkyl), -CHCVQ alkyl), -CKCVCeii alkyl), c3-7 cycloalkyl, C3-7 cyclo(haloalkyl) and phenyl. In another aspect, R1 is Ci6 alkyl, optionally substituted with one or more substituents selected from the group consisting of _, -CN, -OH and alkyl. The remaining variables of Structural Formula (1) are each independently as described above in the first set of variables of Structural Formula (I). The fourth group of the variables of Structural Formula (I) has the following meanings: R1 is as described above in the meaning of any of the first to third groups of the variables of Structural Formula (I). Each Q is independently selected from the group consisting of: halogen; cyano; nitro; -0Ra; -SRa; -S(0)Ra; -S02Ra; -NRRa; -C(0)Ra; -C(0) 〇Ra ; 〇C(0)Ra ; -0C(0)Ra ; -NRC(0)Ra ; -C(〇)NRRa ; -NRC(0)NRRa ; -NRC(0)〇Ra ; -NRC(= NR)NRRa; -〇C〇NRRa; -C(0)NRC(0)0Ra; 157033.doc -29· 201215604 -C(=NR)Ra ; -C(=NOR)Ra ; -S02NRRa ; -NRS02Ra ; -NP02NRRa; -0P(0)(0Ra)0Ra; optionally substituted C3-8 carbocyclic ring; optionally substituted 4-8 membered heterocyclic group; optionally substituted phenyl; and optionally substituted 5-6 members of heteroaryl. Alternatively, each Q is independently selected from the group consisting of: halogen; cyano; nitro; -ORa; -SRa; -S(0)Ra; -S02Ra; -NRRa; -C(0)Ra; -C( 0) 0Ra; -0C(0)Ra; -NRC(0)Ra; -C(0)NRRa; -NRC(0)NRRa; -NRC(0)0Ra; -NRC(=NR)NRRa; -OCONRRa; -C(0)NRC(0)0Ra; -C(=NR)Ra ; -C(=NOR)Ra ; -S02NRRa ; -NRS02Ra ; -NRS02NRRa ; -0P(0)(0Ra)0Ra ;Substitution a C3.8 carbocyclic ring; optionally substituted 4-8 membered heterocyclic group; optionally substituted phenyl; and optionally substituted 5-6 membered heteroaryl. Suitable substituents for the C3.8 carbocyclyl, heterocyclyl, phenyl and heteroaryl groups are each independently as described above in the first group of the variables of structural formula (I). The remaining variables of Structural Formula (I) are each independently as described above in the first set of meanings of the variables of Structural Formula (I). The fifth group of the variables of the structural formula (I) has the following meanings: R1 is as described above in the meaning of any one of the first group to the third group of the variables of the structural formula (I). Each Q is independently as described above in the meaning of any of the first to fourth groups of the variables of Structural Formula (I).

Ra is -H, optionally substituted Cw aliphatic, optionally substituted C3-6 carbocyclyl, optionally substituted 4-8 membered heterocyclyl, optionally substituted phenyl or, as appropriate, substituted 5-6 membered heteroaryl; or 1^ together with R and the nitrogen atom to which it is attached, optionally form a substituted 5-8 membered heterocyclic ring. 157033.doc • 30· 201215604 The remaining variables of structural formula (i) are each independently as described above in the first set of meanings of the variables of structural formula (i). The sixth group of the variables of the structural formula (I) has the following meanings: R1 is as described above in the meaning of any one of the first group to the third group of the variables of the structural formula (I). Each Q is independently as described above in the meaning of any of the first to fourth groups of the variables of Structural Formula (I). 113 as described above in the meaning of any one of the first to fifth groups of the variables of the structural formula (I), *jlA, j2A, j7A and j9A are each independently halogen, pendant oxy, _CN, -ORa, - NRRa, -0C(0)Ra, -0C(0)0Ra, -CORa, -C02Ra, -NRC(0)Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0)ORa, -OCONRRa, C3.8 cycloalkyl, C3-8 ring (haloalkyl), optionally substituted 5-6 membered heterocyclic group or optionally substituted phenyl β or J1A, J2A, J7A & J9A Each independently is halogen, pendant oxy, -CN, -ORa, -NRRa, -0C(0)Ra, -CORa, -C02Ra, -NRC(0)Ra, -C(0)NRRa, -NRC(0 NRRa, -NRC(0)0Ra, -OCONRRa, C3.8 cycloalkyl, (: 3-8 ring (haloalkyl) or phenyl. jlB, j7B and j9B are each independently halogen, pendant oxy, _CN , -ORa, -NRRa, -OCORa, -CORa, -C02Ra, -NRC(0)Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0)0Ra, -OCONRRa, or as appropriate a CJ-C6 aliphatic group substituted with one or more substituents selected from the group consisting of halogen, pendant oxy, -CN, -ORa, -NRRa, -OCORa, -CORa, -C02Ra, -NRC ( 0) Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC (0) 0Ra, -OCONRRa, C3-8 cycloalkyl, 157033.doc • 31 · 201215604 c3-8 ring (haloalkyl) and phenyl. jlc, j2C, j7C and j9C are each independently halogen, side oxygen Base, _CN, -ORa, -NRRa, -OCORa, -C〇Ra, _c〇2Ra, _NRC(0)Ra, -C(0)NRRa, _NRC(0)NRRa, -NRc(0)0Ra, -〇 CONRAr, or optionally a C i -C 6 aliphatic group substituted with a substituent selected from the group consisting of halogen, pendant oxy, -c N, -Ο Ra, -NR Ra, -OCORa , -CORa, -C〇2Ra, _NRC(0)Ra, _C(0)NRRa, -NRC(0)NRRa, -NRC(0)0Ra, -0C0NRRa, (:3_8 cycloalkyl, C3-8 ring ( The haloalkyl group and the phenyl group. The remaining variables of the formula (I) are each independently as described above in the first group of the variables of the formula (1). The seventh group of the variables of the formula (I) has the following meanings: R] as described above in the meaning of any of the first group to the third group of the variables of the structural formula (I). Each Q is independently as in the first group to the fourth group of the variables of the structural formula (I) As stated in any group of meanings.

RaW is as described above in the meaning of any of the first to fifth groups of the variables of Structural Formula (I).

J1A , J2A , j7A , j9A , jlB , j2B , J7B , j9B , Jlc , j2C , j7C and J9C are each independently as defined above in the meaning of any of the first group to the sixth group of the variables of the structural formula (I) Said. R is optionally substituted c. .6 aliphatic group, optionally substituted c3.8 carbocyclic group, optionally substituted 4-8 membered heterocyclic group, optionally substituted stupid base or as appropriate Substituted 5-6 membered heteroaryl. In one aspect, R2 is 157033.doc -32- 201215604 optionally substituted c5-c8 cycloalkyl or optionally substituted phenyl. Suitable substituents for the Cl_6 aliphatic group, the C3.8 carbocyclic group, the heterocyclic group, the phenyl group and the heteroaryl group are each independently as described above in the first group of the variables of the structural formula (1). In another aspect, 'R2 is cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of: a hydroxyl group; a pendant oxy group; -CN; -OH; -NH2; -NHCCi- Ce alkyl); - NXCrCe alkyl) 2 ; -OCO (Ci-C6 alkyl); -CCKCi-Q alkyl); -C02H ; -CCMCVC^ alkyl), -◦ (CrC6 alkyl); ((^-(^6 haloalkyl); and optionally substituted by one or more substituents selected from the group consisting of: ^-(:6 aliphatic: halogen, pendant oxy, -CN, -OH, -NH2, yl), alkyl) 2, -OCO (Ci-C6 alkyl), -CCKCVCe alkyl), -C02H, -CO/CrCe alkyl), -0 (C丨-C6 alkyl) ), - ((ν〇: 6 haloalkyl), (: 3.7 cycloalkyl, C3.7 cyclo(haloalkyl) and phenyl. In another aspect, R2 is cyclohexyl, as the case may be One or more substituents selected from the group consisting of: halogen; pendant oxy; -CN; -OH; -NH2; -NH(C)-C6 alkyl); alkyl)2; -OCCKCVCe alkyl -CCKCVC6 alkyl); -C02H; -COJCi-C^alkyl); -◎((^-(^alkyl); haloalkyl); and optionally one or more selected from the following a group of substituted CrCe aliphatic groups: halogen, pendant oxy, -CN, -OH, -NH2, -NHCCrCe alkyl), -NCCVC6 alkyl)2, -0CCKCVC6 alkyl), -cckcvc^ Alkyl), -co2h, -ccmcvq alkyl), -OCCVCealkyl), -CKCVCealkyl), C3_7 cycloalkyl, c3-7 (haloalkyl) and phenyl. In another aspect, r2 is cyclohexyl, optionally substituted with one or more substituents selected from the group consisting of: 157033.doc -33- 201215604, -CN, -OH, -NH2, - NH(C,-6 alkyl), -NCCu alkyl) 2, -0 ((:!_6 alkyl) and, optionally, Cj.6 alkane substituted with one or more substituents selected from the group consisting of Base: halogen, -CN, -OH, -NH2, -NH (C!.6 alkyl), -N (Ci.6 thiol) 2, -〇 (Ci.6 alkyl) and -〇 (Ci. 6_ 烧基) The remaining variables of the structural formula (I) are each independently as described above in the first group of the variables of the structural formula (1). The eighth group of the variables of the structural formula (I) has the following meanings: The variables of the structural formula (I) are as described in the meaning of any one of the first group to the third group. Each Q is independently as in the meaning of any one of the first group to the fourth group of the variables of the structural formula (I). The above R is as described above in the meaning of any one of the first group to the fifth group of the variables of the structural formula (I): J1A, J2A, j7A, Yan, j丨B, j2B, j7B, Yan, 丨c, j2c, π and J9c are each independently as defined above in the structural formula (I The variables of the first group to the sixth group are as described in the meaning of any one of the first group to the seventh group of the variables of the structural formula (1). The group consisting of the following components: dentate, _cn'nitro, ^, -〇1^, -〇31^, and 氺111^. In one aspect, each of the groups consisting of 2 free radicals: fangs , -TM, nitro, c丨·6, K1, alkyl, 〇H, -CKCu alkyl, 〇(phenyl), 〇(5 6 heteroaryl), ΝΗ2, _NH (Cl·6 alkyl), _N(Ci·6 alkyl) 2 and 弋(〇) (〇1.6 alkane 157033.doc 201215604 base) In another aspect, each jY is independently selected from the group consisting of : halogen, -CN, nitro, Ci-6 alkyl, c!.6 _ alkyl, -OH, -0 ((:, .6 alkyl), -NH2, -NHCCu alkyl), Ν ( (:1 6 alkyl) 2 and 6 dazzle • base). In another cancer sample, 'each JY is independently selected from the group consisting of: halogen, -CN, nitro, thiol, ethyl, _Cf3, _〇h, _〇Me, _NH2, and -C(0)Me . The remaining variables of Structural Formula (I) are each independently as described above in the first set of meanings of the variables of Structural Formula (1).

The ninth group of the variables of the structural formula (I) has the following meanings: R1 is as described above in the meaning of any one of the first to third groups of the variables of the structural formula (I). Each Q is independently as described above in the meaning of any one of the first to fourth groups of the variables of the structural formula (Ϊ). 1^ is as described above in the first to fifth groups of the variables of the structural formula (I). J1A, J2A, J7A, J9A, JIB, j2B, j7B, j9B, jlc, j2c, and J9C are each independently as described above in the meaning of any of the first group to the sixth group of the variables of the structural formula (1). R2 is as described above in the first to seventh groups of the variables of the structural formula (1), and is defined in the meaning. Each of the broadly independent as described above in the meaning of any one of the first group to the eighth group of the variables of the structural formula (I). , γ is a C3-6 cycloalkyl group which is optionally substituted, optionally a dilute group, - (C2 aliphatic group, as appropriate, substituted base or as appropriate; ^ 157033.doc -35- 201215604 Substituted 5-6 membered heteroaryl, and wherein the oxime 2 aliphatic group is optionally substituted. In one aspect, Y is -(C2 aliphatic)-111 or optionally substituted phenyl, wherein The C2 aliphatic group is optionally substituted. In another aspect, γ is optionally substituted phenyl, optionally substituted thienyl or, as the case may be, substituted. Wherein 'γ is an optionally substituted phenyl group. Substituents suitable for the meaning of Y are as described above in the first group of the variables of structural formula (1). The remaining variables of structural formula (I) are each independently as above The text is described in the first group of the variables of the structural formula (1). The tenth group of the variables of the structural formula (I) has the following meanings: · R1 as in the first to third groups of the variables of the structural formula (I) above Each of the meanings of the group is as described above. Each Q is independently as described above in the meaning of any one of the first to fourth groups of the variables of the structural formula (I).

Ra is as described above in the meaning of any of the first to fifth groups of the variables of the structural formula (I).

jlA , j2A , j7A , j9A , jlB , j2B , j7B , j9B , jlC , j2C , j7C and J9C are each independently as defined in any one of the first group to the sixth group of the variables of the structural formula (I). Said. R2 is as described above in the meaning of any of the first to seventh groups of the variables of the structural formula (I). Each JY is independently as in the first to eighth groups of the variables of the structural formula (I) As stated in a set of meanings. Y is optionally substituted c3-6 cycloalkyl or optionally substituted c4.6 ring 157033.doc -36- 201215604 alkenyl. In one aspect, γ is optionally substituted c4-6 cycloalkenyl. In another aspect, hydrazine is a cyclohexenyl group which is optionally substituted. Substituents suitable for gamma meanings as described above in the first set of meanings of the variables of structural formula (I) 0 The remaining variables of structural formula (I) are each independently as defined above in the first group of variables of structural formula (1) Said in the middle. The eleventh group of the variables of the structural formula (I) has the following meanings: R is as described above in the meaning of any one of the first to third groups of the variables of the structural formula (I). Each Q is independently as described above in the meaning of any of the first to fourth groups of the variables of Structural Formula (I). Rule 3 is as described above in the meaning of any of the first to fifth groups of the variables of Structural Formula (I). J1A, J2A, 广A, J9A, JIB, j2B, j7B, j9B, jlc, j2c, 广c, and J are each independently of the meaning of any of the first group to the sixth group of the variables of the structural formula (I) Said in the middle. R2 is as described above in the meaning of any one of the first group to the seventh group of the variables of the structural formula (I), such as the first group, the ninth group and the tenth in the side of the structural formula (I) The meaning of any group of meanings in the group. Each JY is independently selected from the group consisting of halogen, _CN, nitro, R, -〇Ra, -COR2^-NRRa. In one aspect, each is independently selected from the group consisting of: halogen, -CN, nitro, c丨·6 alkyl, Ci6 dentate alkyl, -〇 (Ci-6 alkyl), -〇 (benzene) Base), _〇 (5·6 members heteroaryl 157033.doc • 37- 201215604 base), -NH2, -NH^.6 alkyl), -N(Ci.6 alkyl)2 and {(OXCu alkyl) ). In another aspect, each JY is independently selected from the group consisting of: halogen, -CN, nitro, Ck alkyl, Cuil alkyl, -OH, -ογυ alkyl, -NH2, -ΝΗβυ alkyl ), -Νβκ alkyl)2 and alkyl). In another aspect, each JY is independently selected from the group consisting of: halogen, _CN, schlossyl, fluorenyl, ethyl, _CF3, -OH, -OMe, -NH2, and -C(0)Me. The remaining variables of Structural Formula (I) are each independently as described above in the first set of meanings of the variables of Structural Formula (1). The twelfth group of the variables of the structural formula (I) has the following meanings: R1 is as described above in the dance of any of the first to third groups of the variables of the structural formula (I). Each Q is independently as described above in the meaning of any of the first to fourth groups of the variables of Structural Formula (I).

RaW is as described above in the meaning of any of the first to fifth groups of the variables of Structural Formula (I).

J1A , J2A , J7A , j9A , jlB , j2B , j7B , j9B , jlC , j2C , j7C and J are each independently as in the meaning of any of the first group to the sixth group of the variables of the structural formula (I). Said. R2 is as described above in the meaning of any one of the first to seventh groups of the variables of Structural Formula (1). Y is -(C2 aliphatic)_Ri, and wherein the c2 aliphatic group is optionally substituted. In one aspect, 'Y is -CH2-CH2-R1, -CH^CH-R1 or. Typical examples of substituents suitable for the group of -(C2 aliphatic)-Ri 157033.doc -38· 201215604 include halogen, -CN, C, ·2 alkyl, C!.2 halogen base, The remaining variables of the formula (I) are independently as described above in the first group of the variables of the formula (1). The thirteenth group of the variables of Structural Formula (I) has the following meanings:

R1, R2, Q, Υ, JY, Ra, jlA, j2A, j7A, j9A, ιβ, J2B, J7B, j9B, jlC, j2C, j7C and j9c are each independently as defined above in the variables of structural formula (I) The meaning of any one of the first group to the thirteenth group. R3, R4, R5 and R6 are each independently _H or optionally substituted 6-alkyl; or R3 and R7 and the atom to which they are attached, as the case may be, the optionally substituted 4-10 membered heterocyclic ring. The substituents applicable to the meanings of Rule 3, R4, Ruler 5 and Ruler 6 are each independently as described above in the first group of the variables of Structural Formula (1). The remaining variables of Structural Formula (1) are each independently as described above in the first set of meanings of the variables of Structural Formula (1). The fourteenth group of the variables of the structural formula (I) has the following meanings: R1, R2, Q, γ, jY, Ra, jlA, j2A, j7A, j9A, jlB, j2B, j7B, j9B, Jlc 2C, J and J, respectively Independently as described above in the meaning of the first to the thirteenth groups of the variables of the structural formula (1). R 3 , R 4 , R 5 and R 6 are each independently 7 or an optionally substituted alkyl group, and R and R | are independently independently substituted c] a aliphatic group, optionally substituted C 3 ·8 Carbocyclyl or optionally substituted 4-8 membered heterocyclic group, or RW and the nitrogen atom to which it is attached, form an optionally substituted 4-anthracene heterocyclic ring. The substituents which are applicable to the meanings of r3, r4, r5ar & are each independently as described above in the meaning of the first group of the variables of the structural formula (1) 157033.doc -39-201215604. The remaining variables of structural formula (i) are each independently as described above in the first set of meanings of the variables of structural formula (1). The fifteenth group of the variables of Structural Formula (I) has the following meanings:

R1, R2, Q, Y, JY, Ra, jlA, J2A, J7A, J9A, J1B, J2B, J7B, J9B, J1C, J2C, J7C and Yan are each independently as described above in the variables of structural formula (I) · ~ group to the meaning of any group of the thirteenth group. R 3 , R 4 , R 5 and R 6 are each independently # or, optionally, a C 6 alkyl group substituted with one or more substituents selected from the group consisting of halogen, pendant oxy, -CN, -OH, -NH 2 . -NHA-Ce alkyl), -NCCVC6 alkyl)2, -OCCKCi-Cs alkyl), -CCKCVCs alkyl), -C02H, -CC^CVC^alkyl), -CKCVC6 alkyl), -CKCi- Cealkyl), C3.7 cycloalkyl, C3.7 cyclo(haloalkyl) and phenyl·, and R7 and R8 are each independently -H; Cw alkyl, optionally selected by one or more Substituted by a substituent of the following group: halogen, pendant oxy, halogen, pendant oxy, -CN, -OH, -NH2, -Ni^C^-Ce alkyl), -Ν((ν C6 alkyl) 2, -OCCHCVCe alkyl), -CCHCi-Ce alkyl), -C02H, -COXCVCe alkyl), -CKCVC6 alkyl), -CHCVC^haloalkyl), C3.7 cycloalkyl, C3-7 a cyclo(haloalkyl) group and a phenyl group; or a C3.8 carbocyclic group or a 4-8 membered heterocyclic group, each of which is optionally substituted with one or more substituents selected from the group consisting of halogens, Side oxy, -CN, -OH, -NH2, -NH(C 丨-C6 alkyl), alkyl) 2, -OCCKCVCe alkyl) -C0(C 丨-C6 alkyl), -co2h, -COdCVC^alkyl), -0(C 丨-C6 alkyl), -CKCi-Ce haloalkyl) and optionally one or more selected from The following group 157033.doc -40- 201215604 substituted groups of substituted C!-C 6 alkyl groups: _, side oxy, -CN, -OH, -NH2, alkyl), -NCCVC^ alkyl 2, -OCCKCi-Ce alkyl), -CCKCrCe alkyl), -C02H, -COKCVCe alkyl), -0 ((^-(^6 alkyl), -CKCVC6 haloalkyl), c3.7 ring An alkyl group, a c3_7 ring (haloalkyl group) and a phenyl group; or alternatively, R7 and R8, together with the atom to which they are attached, form a 4-10 membered heterocyclic ring, optionally substituted with one or more groups selected from the group consisting of: Base substitution: halogen, pendant oxy, -CN, -OH, -NH2, yl), -Ν(ίν(:6 alkyl)2, -OCCKCVCe alkyl), -(^((^-(^) ), -CO2H, -C〇2 (Ci-C6 alkyl), -0 (Ci-C6 alkyl), -〇 (Ci-C6 haloalkyl) and optionally one or more selected from the group consisting of Group of substituents substituted CVC6 alkyl: _, side, oxy, -CN, -OH, -NH2, -Ni^Ci-Ce alkyl), -N(C)-C6 alkyl)2, -OCCKQ -C^ alkyl) , -CCKCVCe alkyl), -C02H, -COdCKC^alkyl), -0((:,-(:6 alkyl), -CHCVCeialkyl), C3-7 cycloalkyl, c3-7 ring (halogen Alkyl) and phenyl; or R3 and R7, together with the atom to which they are attached, form a 4-10 membered heterocyclic ring, optionally substituted with one or more substituents selected from the group consisting of halogens and pendant oxy groups. , -CN, -OH, -NH2, -NH((VC6 alkyl), -NA-C6 alkyl)2, -OCCKCi-Ce alkyl), -CCHCi-Ce alkyl), -C02H, -COJCVC^ An alkyl group, an alkyl group, a haloalkyl group, and optionally a C!-c6 alkyl group substituted with one or more substituents selected from the group consisting of dentate, pendant oxy, -CN, -OH , _NH2, -NHCCVCe alkyl), -NiCi-Ce alkyl)2, -OCOCCVC^alkyl), -C0 (Ci-C6 alkane 157033.doc •41 - 201215604 base), -C02H, -C〇2 ( Ci-C6 alkyl), -0(c 丨-C6 alkyl), haloalkyl), (: 3-7 cycloalkyl, C3-7 cyclo(haloalkyl) and phenyl. The remaining variables of Structural Formula (I) are each independently as described above in the first set of meanings of the variables of Structural Formula (1). The sixteenth group of the variables of Structural Formula (I) has the following meanings:

R1, R2, Q, Y, jY, Ra, jlA, j2A, J7A, j9A, jlB, J2B, J7B, J9B, J1C, j2C, j7C and f are each independently as described above in the variation of the structural formula (I) One group is as described in the meaning of any of the thirteenth groups. R3, R4, R^R6 are each independently _H or optionally substituted benzyl group; and R7 and R8 are each independently -H or optionally substituted Cu alkyl, optionally substituted A C3·8 carbocyclyl or an optionally substituted 4.8 heterocyclic group; or R7 and R8, optionally together with the atom to which they are attached, form a optionally substituted 4-10 membered heterocyclic ring. Substituents suitable for the meaning of R3 'R4, r5, r6, "and" are each independently as described above in the fifteenth group of the variables of structural formula (1).

The remaining variables of Structural Formula (I) are each independently as described above in the first set of meanings of the variables of Structural Formula (1). The seventeenth group of the variables of Structural Formula (I) has the following meanings:

Ri, R2, Q, γ, jY, J2B, J7B, j9B, Jlc, j2C,

Ra, jlA, j2A, j7A, j9A, jlB, J7C: and J9C are each independently as described above in the meaning of any of the first to thirteenth groups of the formula (I). RR, R and R6 are each independently -Η or optionally substituted by one or more substituents selected from the group consisting of: halogen, _cn, 157033.doc • 42· 201215604 -OH, -NH2, -NH(C丨_6 alkyl), -Nfw alkyl)2, -0((^.6 alkyl) and -〇(Ci_6iii alkyl); and R7 and R8 are each independently -H Or, optionally, a Cu alkyl group substituted with one or more substituents selected from the group consisting of: halogen, -CN, -OH, -NH2, -NHCCw alkyl), -ββυalkyl)2, -〇( C. .6 alkyl) and -0 (Ci_6 haloalkyl); or R7 and R8, together with the atom to which they are attached, form a 4-1 member heterocyclic ring, optionally comprising one or more selected from the group consisting of Substituent substituents of the group: halogen, -CN, -OH, -2, -NHiCw alkyl), -Nfw alkyl) 2, -0 (C丨_6 alkyl) and -CKCu haloalkyl). The remaining variables of Structural Formula (I) are each independently as described above in the first set of meanings of the variables of Structural Formula (1). The eighteenth group of the variables of Structural Formula (I) has the following meanings:

R1, R2, Q, Y, jY, Ra, jlA, J2A, J7A, j9A, J1B, j2B, j7B, j9B, jlC, cadaver C, j7C and j9C are each independently as described above in the variables of structural formula (I) The β R3, R4, R5 and R6 in the meaning of any one of the first group to the thirteenth group are each independently as defined in any one of the thirteenth to seventeenth groups of the variables of the structural formula (1). Said. R7 and R8, together with the atom to which they are attached, form a 4-10 membered heterocyclic ring, such as a bridged or spiro ring, optionally substituted with one or more substituents selected from the group consisting of: -, -, -OH, -NH2, -NH^Cu alkyl), -Nfu alkyl) 2...cKCu alkyl) and _〇((.6 haloalkyl). The remaining variables of structural formula (I) are each independently as above The text is described in the first group of variables of the structural formula (1). 157033.doc •43· 201215604 The nineteenth group of the variables of the structural formula (i) has the following meanings:

R1, R2, Q, Y, 广, Ra, jlA, J2A, j7A, j9a, J1B j2B, J7B, j9B, yc, j2C, j7C and j9C are each independently as described above in the first variation of the structural formula (I) The group is as described in the meaning of any of the thirteenth groups. R4, R5, R6 and R8 are each independently _H or optionally substituted by a plurality of Cl6 alkyl groups selected from the group consisting of halogen, _CN, -OH, -NH2, -NI^Cu Alkyl), _N(C)6 alkyl)2, _〇(Ci 6 alkyl) and -〇((^.6 haloalkyl); and r3&r7 and the atoms to which they are attached form 4_ 1 〇 a heterocyclic ring, optionally substituted with one or more substituents selected from the group consisting of: dentate, -CN, -OH, -NH2, -NHCCu alkyl), -NCCu alkyl) 2, -0 ( C丨_6 alkyl) and _〇(c丨·6卣 alkyl). Examples of heterocycles formed by R3 & R7 include: 4 s/wvr k^NR8,

7^ f NR8

D5 NR8

D6 NR8

And step substitution wherein ring m-D7 is independently independent of the case 157033.doc 201215604 The remaining variables of structural formula (i) are each independently as described above in the first set of meanings of the variables of structural formula (1). The twentieth group of the variables of structural formula (I) has the following meanings: R is a C.6 alkyl group, optionally consisting of one or more groups selected from the group consisting of halogen, _CN, -OH and -CKCi-C6 alkyl) The substituent is substituted. R2 is optionally substituted Cw aliphatic, optionally substituted c3 8 carbocyclyl, optionally substituted 4-8 membered heterocyclyl, optionally substituted phenyl or, as appropriate, substituted 5 -6 members of heteroaryl. R, R4, R5 and R6 are each independently _H or an optionally substituted Ci 6 alkyl group, and R 7 and R 8 are each independently _H, optionally substituted CM aliphatic group, optionally substituted a C3·8 carbocyclic group; or ... and a uldent 7 together with the nitrogen atom to which it is attached, optionally form a 4_1 杂环 member heterocyclic ring; or R and R8 together with the nitrogen atom to which they are attached, as the case may be, Replace the 4-10 member heterocycle. Substituents suitable for the meaning of R2, R3, R4, R5' R, r7 & r8 are each independently as described above in the first group of the variables of structural formula (I). In the twenty-first group of the variables of the structural formula (I), η is 〇, and the meanings of the remaining variables of the structural formula (1) are each independently as described above in any one of the variables of the variables of the structural formula (1). In another embodiment, the compounds of the invention are represented by the structural formula (π):

157033.doc •45- 201215604 or its pharmaceutically acceptable salts. The meanings of the variables of the structural formula (II) are each independently as described above in the meaning of any one of the first group to the twenty-first group of the variables of the structural formula (I). In the twenty-second group of the variables of the formula (II), n is 0, and the meanings of the remaining variables of the formula (II) are each independently as defined in any one of the variables of the formula (I) above. Said in the middle. In the meaning of the twenty-third group of the variables of structural formula (II), R3 and R7 do not form a 4-10 membered heterocyclic ring which is optionally substituted by one or more JE as the case may be, and the remaining variables of the structural formula (Π) The meanings are each independently as described above in any one of the meanings of the variables of Structural Formula (I). In another embodiment, the compounds of the invention are represented by structural formulae (III) and (VIII): R1 R, 7-Re (III), or

(VIII), or a pharmaceutically acceptable salt thereof. Where applicable, the meanings of the first to the eleventh groups of the variables of the structural formulae (III) and (VIII) are each independently from the first to the eighteenth groups of the variables of the structural formula (I), respectively. Said in the meaning. The circumstance of the ring was replaced. Substituents suitable for the cyclic oxime are as described above for JY in the first set of meanings of the variables of Structural Formula (I). In the twenty-second group of the variables of the structural formulae (III) and (VIII), n is 〇, and the meanings of the remaining variables of the structural formulae (III) and (VIII) are each independently as 157033.doc -46- 201215604 Above is described in any of the meanings of the variables of Structural Formula (i). In the meaning of the twenty-third group of the variables of the formula (III), R3 and R7 do not form, as the case may be, a 4-1 member heterocyclic ring substituted by one or more JE, and the rest of the structural formula (ΠΙ) The meanings of the variables are each independently as described above in any one of the meanings of the variables of the structural formula (丨). The twenty-fourth group of the variables of structural formulae (III) and (VIII) have the following meanings: R is optionally substituted C1·6 leukoxyl or optionally substituted c 3 -8 carbon ring group. The substituents which are suitable for the meaning of R1 are each independently as described above in the first group of the variables of the formula (I). In one aspect, Ri is Ci 6 alkyl or C 3 .8 cycloalkyl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, pendant oxy, _CN, -OH, -NH2, -NHCCVCe alkyl), -NCCi-Ce alkyl)2, -OCOCCV C6 alkyl), -COCCVCe alkyl), -C02H, -COKCVCe alkyl), -OCCrQ alkyl), - 〇 (Cl-c6_alkyl), c3.7 cycloalkyl, c3_7 ring (haloalkyl) and phenyl. In another aspect, 'R1 is a C 6 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, pendant oxy, -CN, -OH, -NH2, -NH ( C 丨-C6 alkyl), -1^((:1-(:6 alkyl)2, -OCCKCVCe alkyl), -CC^Ci-C^alkyl)'-C02H, -CCMCVC6 alkyl), _0 (Cl_C6 alkyl), _0 (Ci_c6i alkyl), c3.7 cycloalkyl, C3_7 ring (haloalkyl) and phenyl. In another aspect, the ruler 1 is a (::16 alkyl group) substituted by one or more groups selected from the group consisting of a pheromone, _CN, -0H, and -〇 (0:!-C6 alkyl). Substituent. In another aspect, R1 is a third butyl or isopropyl group, optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, -OH, and -CKCrC6 alkyl) . I57033.doc -47· 201215604 Each Q is independently selected from the group consisting of: halogen; cyano; nitro; -ORa; -SRa; -S(0)Ra; -S02Ra; -NRRa; -C(0) Ra ; -C(0)0Ra ; -OC(0)Ra ; -0C(0)0Ra ; -NRC(0)Ra ; -C(0)NRRa ; -NRC(0)NRRa ; -NRC(0)ORa ; -NRC(=NR)NRRa ; -OCONRR3 ; -C(0)NRC(0)0Ra ; -C(=NR)Ra ; -C(=NOR)Ra ; -S02NRRa ; -NRS02Ra ; -NRS02NRRa ; -OP (0) (ORa)ORa; optionally substituted C3.8 carbocyclic group; optionally substituted 4-8 membered heterocyclic group; optionally substituted phenyl; and optionally substituted 5·6 Heteroaryl. Alternatively, each Q is independently selected from the group consisting of: halogen; cyano; nitro; -〇Ra; -SRa; -S(0)Ra; -S02Ra; -NRRa; -C(0)Ra; (0)0Ra; -0C(0)Ra; -NRC(0)Ra; -C(0)NRRa; -NRC(0)NRRa; -NRC(0)0Ra; -NRC(=NR)NRRa ; -OCONRR3 ; -C(O)NRC(0)0Ra ; -C(=NR)Ra ; -C(=NOR)Ra ; -S02NRRa ; -NRS02Ra ; -NRS02NRRa ; -0P(0)(0Ra)0Ra ; Substituted C3-8 carbocyclyl; optionally substituted 4-8 membered heterocyclyl; optionally substituted phenyl; and optionally substituted 5-6 membered heteroaryl. The substituents applicable to the meaning of Q are each independently as described above in the first set of meanings of the variables of structural formula (I). The remaining variables of Structural Formula (I) are each independently as described above in the first set of meanings of the variables of Structural Formula (I). The twenty-fifth group of the variables of the formulae (III) and (VIII) have the following meanings: R1 and Q are each independently as described above in the meaning of the twenty-fourth group of the variables of the structural formulae (III) and (VIII). .

Ra is -H, optionally substituted Cm aliphatic, optionally substituted C3-6 carbocyclyl, optionally substituted 4-8 membered heterocyclyl, optionally substituted 157033.doc -48- The base of 201215604 or a optionally substituted 5-6 membered heteroaryl; or Ra, optionally together with the nitrogen atom to which it is attached, form a 5-8 membered heterocyclic ring which is optionally substituted. The substituents which are applicable to the meaning of Ra are each independently as described above in the first group of the variables of the structural formula (j). The remaining variables of Structural Formula (I) are each independently as described above in the first set of meanings of the variables of Structural Formula (j). The twenty-sixth group of the variables of the structural formulas (in) and (vm) have the following meanings: R1 and Q are each independently as defined above in the meaning of the twenty-fourth group of the variables of the structural formulae (IH) and (VIII). Said.

Ra is -H, optionally substituted C丨_6 aliphatic, optionally substituted C: 3·6 carbocyclyl, optionally substituted 4-8 membered heterocyclyl, optionally substituted Phenyl or optionally substituted 5-6 membered heteroaryl; or Ra, optionally together with R and the nitrogen atom to which it is attached, form a optionally substituted 5-8 membered heterocyclic ring. The substituents which are suitable for the meaning of Ra are each independently as described above in the first group of the variables of the structural formula (1). J1A, J2A, J7A and J9A are each independently halogen, pendant oxy, _CN, _ _0Ra, -NRRa, -0C(0)Ra, -OC(0)ORa, -CORa, -C02Ra, -NRC(0) Ra, •C(0)NRRa, -NRCXCONRRa, -NRC(0)0Ra, -〇CONRRa, (:3-8 cycloalkyl, Cm ring (haloalkyl), optionally substituted 5-6 heterocyclyl Or a substituted phenyl group. Alternatively, J1A, J2A, j7a and j9A are each independently halogen, pendant oxy, _CN, -ORa, -NRRa, -〇C(0)Ra, -CORa, -CC^ R3, -NRC(0)Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0)0Ra, -OCONRRa, 匸3-8 Bad Hyun! Base, ¢3.83⁄4 (tooth base) Or phenyl. jlB, j2B, j7B and j9B are each independently halogen, pendant oxy, _CN, 157033.doc • 49- 201215604 -ORa, -NRRa, -OCORa, -CORa, -C02Ra, -NRC(0) Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0)ORa, -OCONRRa, or, optionally, a CrCfi aliphatic group substituted with one or more substituents selected from the group consisting of: Halogen, pendant oxy, -CN, -ORa, -NRRa, -OCORa, -CORa, -C02Ra, -NRC(0)Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0) 0Ra, -OCONRRa, C3-8 cycloalkyl, C3-8 ring (halogen And phenyl. jlC, j2C, j7C and j9C are each independently halogen, pendant oxy, _CN, -ORa, -NRRa, -OCORa, -CORa, -C02Ra, -NRC(0)Ra, -C( 0) NRRa, -NRC(0)NRRa, -NRC(0)0Ra, -OCONRRa' or, optionally, Ci-Cs aliphatic group substituted with one or more substituents selected from the group consisting of dentate, Sideoxy, -CN, -ORa, -NRRa, -OCORa, -CORa, -C02Ra, -NRC(0)Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0)0Ra, -OCONRRa, C3_8 cycloalkyl, (: 3.8 ring (functional alkyl) and phenyl. The remaining variables of structural formula (I) are each independently as described above in the first set of meanings of the variables of structural formula (I) The twenty-seventh group of the variables of the structural formulae (III) and (VIII) have the following meanings: R1 and Q are each independently as defined above in the meaning of the twenty-fourth group of the variables of the structural formulae (ΠΙ) and (VIII). Said.

Ra is as described above in the twenty-fifth group of the variables of structural formulae (III) and (VIII).

jlA , j2A , j7A , j9A , jlB , j2B , j7B , j9B , jlC , j2C , j7C and J9C are each independently as described above in the structural formula (ΠΙ) and (VIII) of the variable 157033.doc -50- 201215604 The meaning of the sixteen groups is defined. R is optionally substituted Cu aliphatic, optionally substituted C3 8 carbocyclyl, optionally substituted 4-8 heterocyclyl, optionally substituted phenyl or optionally substituted 5-6 Heteroaryl. In one aspect, "Cs-Cs cycloalkyl or optionally substituted phenyl substituted as appropriate. Substituents suitable for the meaning of R are each independently as defined above in the formula (I) The rest of the variables of Structural Formula (I) are each independently as described above in the first set of meanings of the variables of Structural Formula (j). The variables of Structural Formulas (III) and (VIII) The meaning of the twenty-eighth group is as follows:

Rl and Q are each independently as described above in the twenty-fourth group of the variables of the structural formulae (πι) and (viii).

Ra is as described above in the twenty-fifth group of the variables of structural formulae (III) and (VIII).

J1A , J2A , j7A , j9A , J丨B , j2B , j7B , j9B , jlc , j2C , j7C and J9C are each independently as in the first sixteen meanings of the variables of the structural formulas (in) and (VIII) above. Said. R2 is C5-c8 cycloalkyl, optionally substituted by one or more substituents selected from the group consisting of: halogen; pendant oxy; -CN; -OH; -NH2; -NHd-Q alkyl); -NCCVC^alkyl)2; -OCCKCVC^alkyl); -COCCVC6 alkyl); -C02H; -CO/CrC^alkyl);-0((:1-(:6)); haloalkyl And C + -C6 aliphatic groups substituted by one or more substituents selected from the group consisting of halogen, pendant oxy, -CN, -OH, -NH2, -NH(C丨- C6 alkyl), -NCCi-C^ alkyl) 2 ' 157033.doc -51 - 201215604 -OCO(C!-C6 alkyl), _CO (Ci_C6 hospital base), -C〇2H, -C〇2 ( Ci_C6 alkyl), -ckcvc^alkyl), -CKC^-Cei alkyl), (: 3.7 cycloalkyl, C3_7 ring (haloalkyl) and phenyl. In one aspect, R2 is cyclohexyl, Substituting one or more substituents selected from the group consisting of: ii; sideoxy; -CN; -OH; -NH2; -NH(Ci-C6 alkyl); alkyl)2; OCCKC^-Ce alkyl); -CCHCi-Ce alkyl); ·<:02Η; -COJCrCe alkyl);alkyl);-CHCrCe haloalkyl); and optionally Ci-C6 aliphatic group substituted with a substituent consisting of a group consisting of: a side group, a side oxy group, -CN, -OH, -NH2, -NH (C!-C6 alkyl group), -N (Ci_C6) Burning base) 2, -〇CO (C!-C6 alkyl), -C0 (Ci_C6 alkyl), -CO2H, -C〇2 (Ci_C6 alkyl), -0 (Ci_C6 alkyl), -0 (C) !-C6lS alkyl), C3-7 cycloalkyl, C3-7 (self-burning) and phenyl. In another aspect, 'R is a singularity' is optionally substituted with one or more J2Bs independently selected from the group consisting of: halogen, -CN, _〇Η, -NH2, alkyl), -N (C) _6 alkyl) 2, -CKCu alkyl) and, optionally, a Cl-6 succinyl group substituted with one or more substituents selected from the group consisting of halogen, -CN, -OH, -2 - ΝΗ ((^·6 alkyl), _n(Ci.6 alkyl) 2, -CKCm alkyl) and -CHCwiialkyl). The remaining variables of Structural Formula (I) are each independently as described above in the first set of meanings of the variables of Structural Formula (1). The twenty-ninth group of the variables of the structural formulae (III) and (VIII) have the following meanings: R1 and Q are each independently as described above in the meaning of the twenty-fourth group of the variables of the structural formulae (III) and (VIII). . Rule 3 is as described above in the twenty-fifth group of the variables of Structural Formulas (III) and (VIII) 157033.doc • 52· 201215604. 1 A %

j9A , jlB , j2B , j7B , j9B , jlC , j2C

And J9C are each independently as described above in the meaning of the twenty-sixth group of the variables of structural formulae (III) and (VIII). R2 is a cyclohexyl group, optionally substituted with one or more substituents selected from the group consisting of: ||, -CN, -OH, -NH2, -NHCCw alkyl), -NiCw alkyl)2, a CKCu alkyl group) and, optionally, a Cu alkyl group substituted with one or more substituents selected from the group consisting of halogen, -CN, -OH,

-NH2, -NHCCu alkyl), -NCCu alkyl) 2, -CKCu alkyl) and -CKCk alkyl. R3, R4, R5 and R6 are each independently -H or an optionally substituted Cl6 alkyl group; or R3, together with R7 and the atom to which it is attached, optionally forms a 4-10 membered heterocyclic ring which is optionally substituted. The remaining variables of Structural Formula (I) are each independently as described above in the first set of meanings of the variables of Structural Formula (1). The thirtieth group of the variables of the formulae (III) and (VIII) have the following meanings: R1 and Q are each independently as described above in the twenty-fourth group of the variables of the structural formulae (ΠΙ) and (VIH). Rule 3 is as described above in the twenty-fifth group of the variables of Structural Formulas (III) and (VIII).

J1A , j2A , j7A , j9A , jlB , j2B , j7B , j9B , jlc , j2C , j7C and ] are each independently as described above in the first sixteenth meaning of the variables of structural formulae (III) and (Vlii) . R2 is as described above in the twenty-ninth group of the variables of Structural Formulas (III) and (VIII) 157033.doc-53-201215604. R, R, R5 and R6 are each independently _H or optionally substituted C16 alkyl; and R7 and R8 are each independently optionally substituted Cw aliphatic, optionally substituted C3.8 carbon. A cyclic or substituted 4-8 membered heterocyclic group, or R7 and R8 together with the nitrogen atom to which they are attached form a optionally substituted 4-10 membered heterocyclic ring. The remaining variables of Structural Formula (I) are each independently as described above in the first set of meanings of the variables of Structural Formula (1). The thirty-first group of the variables of the structural formulae (III) and (VIII) have the following meanings: R1 and Q are each independently as described above in the meaning of the twenty-fourth group of the variables of the structural formulae (III) and (VIII). .

Raw is as described above in the twenty-fifth group of the variables of structural formulae (III) and (VIII). jlA, J2A, j7A, j9A, jlB, j2B, j7B, j9B, jlc, j2c, guangc and J9C are each independently as in the twenty-sixth group meaning of the variables of structural formulae (III) and (VIII) above. Said. R2 is as described above in the twenty-ninth group of the variables of structural formulae (III) and (VIII). R 3 , R 4 , R 5 and R 6 are each independently -H or optionally substituted by one or more substituents selected from the group consisting of: halogen, pendant oxy, -CN, -OH , -NH2, -NHd-Ce alkyl), -N(Ci-C6^)2, -OCCKC^-Ce alkyl), -CCHCrCe alkyl), -C02H, -C Ο 2 (C 1 - C 6 alkyl), _ 〇 (C 1 - C 6 building base), - 〇 (c 1 - C 6 dentate), C 3 _ 7 cycloalkyl, c3_7 ring (haloalkyl) and phenyl; 157033.doc • 54· 201215604 R7 and R8 are each independently -Η; CN6 alkyl, optionally substituted with one or more substituents selected from the group consisting of dentate, pendant oxy, halogen, side oxygen Base, -CN, -OH, -NH2, -NHCCi-C^alkyl), -NCC, -C6 alkyl)2, -OCCKCVCe alkyl), -CCHCVCe alkyl), -C02H, -C02 (C" C6 alkyl), -CKCVC6 alkyl), -CHCVCe from alkyl), C3.7 cycloalkyl' (: 3-7 cyclo(haloalkyl) and phenyl; or (:3-8 carbocyclyl or 4- An 8-membered heterocyclic group, each optionally substituted with one or more substituents selected from the group consisting of halogen, pendant oxy, -CN, -OH -NH2, alkyl), -N(C,-C6 alkyl)2, -OCCKCVCe alkyl), -CCHCVC^alkyl), -C02H, -COdCVQ alkyl), -CKCVC6 alkyl), -0 ( (^-(36 haloalkyl) and optionally substituted by one or more substituents selected from the group consisting of: 丨-(:6 alkyl: halogen, pendant oxy, CN, -OH, - NH2, -Ni^C^-Ce alkyl), alkyl)2, -OCCHCVCe alkyl), -COCCVCe alkyl), -C02H, -CO/CVC^alkyl), -CKCVC6 alkyl), -CKCVC6 Alkyl), C3-7 cycloalkyl, <:3-7 cyclo(haloalkyl) and phenyl; or R7 and R8 together with the atom to which they are attached form a 4-10 membered heterocyclic ring, The case is substituted by one or more substituents selected from the group consisting of halogen, pendant oxy, -CN, -OH, -NH2, -1^11 ((:1-0:6 alkyl), alkyl 2, -OCCKCi-Ce alkyl), -CCKCVC^alkyl), -C02H, -COJCVCe alkyl), -CKCVC6 alkyl), -OCCVCe haloalkyl, and optionally one or more selected from the following a group of substituted CVC6 alkyl groups: halogen, pendant oxy, -CN, -OH, -NH2, -NHd-Ce alkyl)' -^[((:丨-匕alkyl) 2, -OCOCCVCe alkyl), 157033.doc •55· 201215604 -CO (Ci-C6 alkyl), -C02H, -C02 (Ci_C6 alkyl), alkyl), -〇 (Ci -C6 haloalkyl), C3-7 ring, C3-7 (halogen) and phenyl; or in the formula (III), R3 and R7 together with the atom to which they are attached form 4 a 10-membered heterocyclic ring which is optionally substituted with one or more substituents selected from the group consisting of halogen, pendant oxy, -CN, -OH, -NH2, -NH(C 丨-C6 alkyl ), -N(C "C6 alkyl" 2, -〇CO(Ci-C6 alkyl), -CO(C 丨-C6 alkyl), -C02H, -CCMC^-Ce alkyl), -0 ( (^-C6 alkyl), -〇(Ci-C6_院), and optionally a Ci-Ce alkyl substituted with one or more substituents selected from the group consisting of halogen, pendant oxy, CN , -OH, -NH2, -NI^CVC^alkyl), -NWrCe alkyl)2, -OCCHCVCe alkyl), -CCKQ-Ce alkyl), -C02H, -COdCi-Ce alkyl), -0 (Ci_C6 alkyl), -0 (Ci_C6 calcinyl), C3-7 cycloalkyl, C3-7 (haloalkyl) and phenyl. Examples of heterocycles formed from R3 and R7 are as described above. The remaining variables of Structural Formula (I) are each independently as described above in the first set of meanings of the variables of Structural Formula (I). The thirty-second group of the variables of the formulae (III) and (VIII) have the following meanings: R1 and Q are each independently as described above in the meaning of the twenty-fourth group of the variables of the structural formulae (III) and (VIII). .

Ra is as described above in the twenty-fifth group of the variables of structural formulae (III) and (VIII).

jlA , J2A , j7A , j9A , jlB , j2B , j7B , j9B , jlc , j2C , j7C and J9C are each independently as described above in the variables of Structural Formulas (III) and (VIII) 157033.doc • 56- 201215604 The meaning of the sixteen groups is defined. R2 is as described above in the twenty-ninth group of the variables of the structural formulae (III) and (VIII). R3, R4, R5 and R6 are each independently _ti or, as the case may be, Ci-6 alkyl substituted with one or more substituents selected from the group consisting of halogen, pendant oxy, -CN, -OH, -NH2, -NHCCrCe alkyl), -Nd-Ce alkyl)2, -OCCKCrCe alkyl), alkyl), -C02H, -CCMCVCe alkyl), -CKC^-Ce alkyl), -CKCVCei alkyl ), C3.7 cycloalkyl, C3_7 ring (haloalkyl) and phenyl. R7 and R8 are each independently -H; C, _6 alkyl, optionally substituted by one or more substituents selected from the group consisting of halogen, pendant oxy, halogen, pendant oxy, -CN, -OH, -NH2, -NHCCi-C^alkyl), -NCC, -C6 alkyl)2, -OCCKCi-Ce alkyl), -CCKCVCe alkyl), -C02H, -COKCVC^alkyl), CKCVCe alkyl), -CKC^-Cei alkyl), C3.7 cycloalkyl, C3.7 cyclo(haloalkyl) and phenyl; or (: 3-8 carbocyclyl or 4-8 membered heterocyclyl, Each of them is optionally substituted independently with one or more substituents selected from the group consisting of: halogen, pendant oxy, -CN '-OH, -NH 2 -Nl^CVCe alkyl), -NiCVCe alkyl) 2, -OCCKC^-Ce alkyl), -ccKq-c^alkyl), -co2h, -cokcvc^alkyl), alkyl), -CKCrCe haloalkyl) and optionally selected from one or more C 1 -C 6 alkyl substituted with a substituent of the following group: halogen, pendant oxy, -CN, ·0Η, -NH2, -NH(Ci-C6 alkyl), -NCCrCs alkyl) 2, OCCHCVC^alkyl), -CCKCrQ alkyl), -C02H, -CCMCVCe alkyl), -0(Ci-C6 alkyl), -CKCi-Ceii alkyl , C3_7 cycloalkyl, 157033.doc -57- 201215604 c3-7 cycloalkyl (haloalkyl) and phenyl. The remaining variables of Structural Formula (I) are each independently as described above in the first set of meanings of the variables of Structural Formula (I). The thirty-third group of the variables of the structural formulae (III) and (VIII) have the following meanings: R1 and Q are each independently as described above in the meaning of the twenty-fourth group of the variables of the structural formulae (III) and (VIII). . 113 is as described above in the twenty-fifth group of the variables of structural formulae (III) and (VIII).

J1A , J2A , j7A , J9A , jIB , J2B , J7B , J9B , jic , j2C , j7C and J9C are each independently as described above in the twenty-sixth group meaning of the variables of structural formulae (III) and (VIII) . R2 is as described above in the twenty-ninth group of the variables of structural formulae (III) and (VIII). R3, R4, R5 and R6 are each independently -H or optionally substituted by one or more substituents selected from the group consisting of: halogen, -CN, -OH, _ΝΗ2, -ΝΗγκ Alkyl), _ Ν ((^_6 alkyl) 2, -CKCw alkyl) and -CHCuii alkyl). R7 and R8 are independently -H or optionally substituted by one or more substituents selected from the group consisting of halogen, -CN, -OH, -NH2, -NI^Cu alkyl), -NCCu alkyl)2, -CHCu alkyl) and -CKCkhaloalkyl); or R7 and R8, together with the atom to which they are attached, form a 4-10 membered heterocyclic ring, as the case may be selected from one or more The substituents of the constituent group are substituted: halogen, -CN, -OH, -NH2, -NHCCu, and -N(C丨-6 alkyl)2, -CKCu alkyl) and -CKCu are alkyl. 157033.doc -58 · 201215604 The remaining variables of structural formula (i) are each independently as described above in the first set of meanings of the variables of structural formula (i). The thirty-fourth group of the variables of the structural formulae (III) and (VIII) have the following meanings: R1 and Q are each independently as defined above in the meaning of the fourteenth group of the variables of the structural formulas (in) and (viii). Said.

Ra is as described above in the twenty-fifth group of the variables of the structural formulae (ΠΙ) and (VIII).

jlA , J2A , j7A , j9A , jlB , j2B , j7B , j9B , jlC , j2c , j7C and J9C are each independently as described above in the first sixteenth meaning of the variables of structural formulas (in) and (VIII) . R2 is as described above in the twenty-ninth group of the variables of the structural formulae (III) and (VIII), wherein β r3, r4, r5 and r6 are each independently as defined above in the structural formulae (m) and (VIII) The meaning of the thirty-third group of meanings. R and R are independently _ Η or optionally substituted by one or more substituents selected from the group consisting of: halogen, -CN, -ΟΗ, -NH2, -NHCCu alkyl), -Νβυ Alkyl) 2, -CHCu alkyl) and -〇 (Ci.6 halogen); or R7 and R8 together with the atom to which they are attached form a 4-10 membered heterocyclic ring as appropriate. Substituted by a substituent of the group consisting of: ||素, -CN, -OH, -NH2, -NHCC, 6 alkyl), -N(Cb6 alkyl)2, -CKCu alkyl) and -CKCu base). The remaining variables of Structural Formula (I) are each independently as described above in the first set of meanings of the variables of Structural Formula (1). The thirty-fifth group of the variables of the structural formulae (III) and (VIII) have the following meanings: 157033.doc • 59· 201215604 R1 and Q are each independently as in the second variation of the structural formulae (III) and (VIII) above. The meaning of the fourteen groups is defined. ... as described above in the twenty-fifth group of the variables of Structural Formulas (III) and (VIII).

jlA , J2A , j7A , j9A , jlB , j2B , J7B , J9B , jic , J2C , J7C and J9C are each independently as described above in the twenty-sixth group meaning of the variables of structural formulae (III) and (VIII) . R2 is as described above in the twenty-ninth group of the variables of structural formulae (III) and (VIII). R3, R4, R5 and R6 are each independently as described above in the thirty-third group of the variables of structural formulae (III) and (VIII). R7 and R8, together with the atom to which they are attached, form a 4-1 member heterocyclic ring, optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, -OH, -NH2, - NH(Ci.6 alkyl), -Νβυalkyl)2, -〇(Ci.6 alkyl) and -CKCuialkyl). The heterocyclic ring formed by R7 and R8 may be a bridged ring or a spiro ring. Examples of heterocycles formed from R3 and R7 are as described above. The remaining variables of Structural Formula (I) are each independently as described above in the first set of meanings of the variables of Structural Formula (1). The thirty-sixth group of the variables of the formulae (III) and (VIII) have the following meanings: R1 and Q are each independently as described above in the meaning of the twenty-fourth group of the variables of the structural formulae (III) and (VIH). .

Ra is as described above in the twenty-fifth group of the variables of structural formulae (III) and (VIII).

jlA , j2A , j7A , j9A , jlB , j2B , j7B , j9B , jic 2C 7C 157033.doc • 60- 201215604 and J9c are each independently the twenty-sixth of the variables of structural formulae (III) and (VIII) above. As stated in the meaning of the group. R2 is as described above in the twenty-ninth group of the variables of structural formulae (III) and (VIII). R4, R5, R6&R8 are each independently seven or optionally substituted by one or more substituents selected from the group consisting of halogen, pendant oxy, _CN, -oh, -NH2, - Nl^CrCe alkyl), -^(^-(^alkyl)2, -OCOCCVCe alkyl), -COCCrCe alkyl), -C02H, -CCMCi-C^alkyl), -CKCVCe alkyl), CKCVC^ alkyl), c3_7 cycloalkyl, C3-7 (haloalkyl) and phenyl. In the formula (III), R3 and R7 and the atom to which they are attached, optionally form a 4- to 10-membered heterocyclic ring, which is optionally substituted with one or more substituents selected from the group consisting of halogens, Side oxy, -CN, - Ο Η, • ΜΗ:, alkyl), ^((^-(^, base, -OCCHC^-C^), -CCKCi-Ce), -C02H , -COXC^-Cs alkyl), -0 ((^-C6 alkyl), -0 (C "C6ii alkyl") and optionally substituted by one or more substituents selected from the group consisting of: -Cg alkyl group: a hydroxyl group, a pendant oxy group, -CN, -OH, -NH2, -NH(C)-C6 alkyl group, an alkyl group) 2, -OCO (Ci-C6 alkyl group), -CCHCVC^ Anthracene), -C02H, -C02 (Ci-C6 alkyl), -ckcvc^alkyl), -o(Ci-c6ialkyl)' c3-7 cycloalkyl, C3·7 ring (haloalkyl) And a phenyl group. In one aspect, R3 and R7 together with the atom to which they are attached form a 4-10 membered heterocyclic ring which is optionally substituted with one or more substituents selected from the group consisting of halogen, _CN , -OH, -NH2, -Ni^Cu alkyl), -NCCu alkyl), 〇 ((: ι_6 alkyl) and 157033.doc •61 · 201215604 -CKC,· 6Cyl radicals. Examples of heterocycles formed from R3 and R7 are as described above. The remaining variables of Structural Formula (I) are each independently as described above in the first set of meanings of the variables of Structural Formula (I). The thirty-seventh group of the variables of the formulae (III) and (VIII) have the following meanings: R1 and Q are each independently as described above in the meaning of the twenty-fourth group of the variables of the structural formulae (III) and (VIII). .

Ra is as described above in the twenty-fifth meaning of the variables of structural formulae (III) and (VIII)

1 A

j2A, j7A Γ9Α

IB Γ2Β

"7Β, j9B

1C

r2C

r7C and J9C are each independently as described above in the meaning of the twenty-sixth group of the variables of structural formulae (III) and (VIII). R2 is as described above in the twenty-ninth group of the variables of structural formulae (III) and (VIII). R4, R5, R6 and R8 are each independently _H or optionally substituted by one or more substituents selected from the group consisting of halogen, -CN, -OH, -NH2, -NK^ Cw alkyl), -N(Ci_6 alkyl) 2, -〇(Ci.6 alkyl) and -〇((^_6 from alkyl). In the formula (III), R3 and R7 are attached thereto The atoms together form a 4-10 membered heterocyclic ring which is optionally substituted with one or more substituents selected from the group consisting of: dentate, -CN, -OH, -ΝΗ2, -ΝΗγΜ), -N (Ci_6 alkyl) 2, -0 (Ci_6 alkyl) and -〇 (Ci_6 halogenated base). Examples of heterocycles formed from r3 and R7 are as described above. The remaining variables of Structural Formula (I) are each independently as described above in the first set of meanings of the variables of Structural Formula (I). 157033.doc •62- 201215604 The thirty-eighth group of the variables of Structural Formulas (III) and (VIII) have the following meanings: · Q The meaning of the twenty-fourth group of the variables in Structural Formulas (III) and (VIII) above Said in the middle. 1^ is as described above in the twenty-fifth group of the variables of structural formulae (III) and (VIII).

J1A, J2A, j7A, J9A, jlB

J2B, J7B, j9B, jic, J2C, j7C and J9C are each independently as described above in the twenty-sixth group of the variables of structural formulae (III) and (VIII).

... is an anthracene-6 alkyl group, optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, -OH and -0 (CN6 alkyl). R2 is optionally substituted cN6 aliphatic, optionally substituted c3_8 carbocyclyl, optionally substituted 4-8 membered heterocyclyl, optionally substituted, or optionally substituted 5- 6 members of heteroaryl. R, R, R5 and R6 are each independently or optionally substituted Ci6 alkyl. R and R8 are each independently _H, optionally substituted Cw aliphatic, optionally substituted CM carbocyclyl; or in the formula, r3 and r7 together with the atom to which they are attached, as appropriate The substituted 4_1〇%, or r and r8 and the nitrogen atom to which they are attached, form a 4-1 member heterocyclic ring which is optionally substituted. The substituents which are applicable to the meanings of R2, R4, R5, R6, r7 and r8 are each independently as described above in the meaning of the first group of the variables of the structural formula (1). The remaining variables of the construction are each independently as described above in the first set of meanings of the number of crosses of the structural formula (1). 157033.doc •63· 201215604 In another embodiment, the compounds of the invention are represented by structural formulae (IV) and (IX).

Or a pharmaceutically acceptable salt thereof. The meanings of the variables of the structural formulae (IV) and (IX) are each independently as described above in the meaning of any of the first to thirty-eighth groups of the variables of the structural formulae (III) and (VIII). In another embodiment, the compounds of the invention are represented by structural formulae (V), (X) and (XI):

Or a pharmaceutically acceptable salt thereof. The meanings of the variables of the structural formulas (v), (X) and (XI) are each independently as defined above in the meaning of any of the first to the thirty-eighth groups of the variables of the structural formulas (111) and (VIII). Said. In another embodiment, the compounds of the invention are represented by structural formulas (VI) and (XII): 157033.doc • 64 · 201215604

Or a pharmaceutically acceptable salt thereof, wherein Ring B is substituted with one or more J2B as appropriate. The meanings of the variables of the formulae (VI) and (XII) are each independently as described above in the meaning of any of the first to the thirty-eighth groups of the variables of the structural formulae (III) and (VIII). In another set of variables of the formulae (VI) and (XII), J2B is halogen, -CN, -OH, -NH2, -NHCCu alkyl), -N(Ci.6 alkyl) 2, CKCw alkyl), or optionally C 丨 6 alkyl substituted with one or more substituents selected from the group consisting of halogen, -CN, -OH, -NH2, -NH (Ci.6 alkyl) ), -N (Ci-6 alkyl) 2, -0 (Ci.6 alkyl) and -〇 (Ci.6 halogen); and the meanings of the remaining variables of structural formulae (VI) and (XII) Independently as described above in the meaning of any of the first to thirty-eighth groups of the variables of the structural formulae (III) and (VIII). In another set of variations of the variables of structural formula (VI) and (XII), 128 is (: 1-6 alkyl or -OCCk alkyl); and the meanings of the remaining variables of structural formulae (VI) and (XII) Each is independently as described above in the meaning of any one of the first to thirty-eighth groups of the variables of the structural formulae (III) and (VIII). In another embodiment, the compounds of the invention are represented by structural formulae (VII) and (XIII): 157033.doc • 65- 201215604

Or a pharmaceutically acceptable salt thereof. The meanings of the variables of the formulae (VII) and (XIII) are each independently as described above in the meaning of any one of the first to thirty-eighth groups of the variables of the structural formulae (III) and (VIII). In another set of variables of the formulae (VII) and (XIII), J2B is halogen, -CN, -OH, _NH2, -N^Cw alkyl), -NCCw alkyl)2, -Ο (C1 _6院基), or optionally C丨_6 alkyl substituted with one or more substituents selected from the group consisting of: halogen, .-CN, -OH, -NH2, -NHCCw alkyl), - Nfu alkyl) 2, -CKCw alkyl) and -0 (Ci.6 haloalkyl); and the remaining variables of structural formulae (VII) and (XIII) are each independently as defined above in formula (III) and The variables of (VIII) are as described in the meaning of any of the first to thirty-eighth groups. In another set of meanings of the variables of the formulae (VII) and (XIII), J2Bg Cu alkyl or -o(cN6 alkyl); and the remaining variables of the structural formula (VI) are each independently as defined above in the structure The variables of the first to the thirty-eighth groups of the variables of the formulae (III) and (VIII) are as described in the meaning of any one of the groups. In another set of variables of the formulae (VII) and (XIII), J2Bg Cu alkyl, such as fluorenyl; and the rest of the variables of structural formulae (VII) and (XIII) are each independently as defined above. The variables of the first to the thirty-eighth groups of the variables of the formulae (III) and (VIII) are as described in the meaning of any one of the groups. 157033.doc •66- 201215604 In another set of variables of the formulae (VII) and (XIII), j2b is Ci-6 alkyl or -0 ((^.6 alkyl); ^ is ^6 a base such as a tributyl or isopropyl group; and the remaining variables of the formulae (VII) and (XIII) are each independently as defined above in the group of the variables of the formulae (III) and (VIII). In the meaning of any one of the variables of the thirty-eighth group, in another set of the variables of the structural formulae (VII) and (XIII), J2B is a Cl-6 alkyl group; an alkyl group such as a tert-butyl group or a different group a propyl group; R3, R4, R5 and R6 are each independently -H or optionally a Cw alkyl group substituted with a substituent selected from the group consisting of halogen, _CN, -OH, -NH2, - NHCCw alkyl), alkyl) 2, -〇 (Cl. 6 alkyl) and -CKCu haloalkyl); and the meanings of the remaining variables of structural formulae (VII) and (XIII) are each independently as defined above in the structural formula The variables of (III) and (VIII) are as described in the meaning of any of the first to thirty-eighth groups. In another set of variations of the variables of structural formula (VII) and (XIII), J is Ci_6 alkyl, R1 is Ci-6 alkyl, such as tert-butyl or isopropyl; R3, R4, R5 and R6 CN6 alkyl groups each independently substituted with -H or optionally with one or more -CKCu haloalkyl groups; and the rest of the variables of structural formulae (VII) and (XIII) are each independently as defined above in the structural formula ( The variables of III) and (VIII) are as described in the meaning of any of the first to thirty-eighth groups. In another set of variables of the formulae (VII) and (XIII), J is a Ci-6 building group, and R is a Cl.6 alkyl group such as a tert-butyl group or an isopropyl group 157033.doc-67-201215604 R3, R4, R5 and R6 are each independently -Η, -CH3, -CH2CH3, -CH2CH2CH3 > -CH2-OCH3 > -CH2CH2-OCH3 '-ch2ch2- 〇ch2ch3 or -ch2ch2-och2ch3; The meanings of the remaining variables of the formulae (VII) and (XIII) are each independently as described above in the meaning of any of the first to thirty-eighth groups of the variables of the structural formulae (III) and (VIII). In some embodiments, 'j2B is trans in position relative to the carbonyl group at position 1 of the cyclohexyl ring to which j2Bm is attached. In some embodiments, the compound of the invention is represented by any one of the formula (Ι)_(ΧΠΙ), wherein: R9 is -Η or optionally substituted with one or more substituents selected from the group consisting of 0··6 alkyl: _, side oxy, -CN, -OH, -ΝΗ2, -NHCCVCe alkyl), -N(C)-C6 alkyl)2, -OC^OXC^-Ce alkane Base), -00(0)0((^-(:6 alkyl), -CCHCi-C^ alkyl), -C02H, -COXC!·C6), alkyl), decyl) a c3_7 cyclohexyl group, a C3·7 ring (haloalkyl group), a phenyl group, and optionally a 5-6 membered heterocyclic ring substituted with one or more substituents selected from the group consisting of a pendant oxy group and a CN6 alkyl group; And the meaning of the remainder thereof are each independently as described above. In some embodiments, the compound of the invention is represented by any one of Formulas (I)-(XIII), wherein: R9 is -H or optionally substituted with one or more substituents selected from the group consisting of CN6 alkyl: _, side oxy, -CN, -OH, -NH2, alkyl), -N(C,-C6 alkyl) 2, -0(:(0)((:,-( :6 alkyl), 157033.doc •68· 201215604 -COCC^-Cs alkyl), -C02H, -CCMC^-C^ alkyl), -0((^-(:6 alkyl), -CKCVC6 Haloalkyl), C3_7 cycloalkyl, C3-7 cyclo(haloalkyl) and phenyl; and the meanings of the remaining variables are each independently as described above. In some embodiments, the compounds of the invention are structural formulas ( Any of I)-(XIII) wherein: R9 is -H or optionally substituted by -00(0)((^-(:6 alkyl)); and the meaning of the remainder thereof is independent In some embodiments, the compound of the invention is represented by any one of the structural formulae (Ι)_(ΧΙΠ), wherein: R9 is -Η or optionally -0(:(0)0 ((^-(^6 alkyl)-substituted Cw alkyl; and the meanings of the remaining variables are each independently as described above. In the embodiment, the compound of the present invention is represented by any one of the formulae (I)-(XIII), wherein: R9 is -H or a Cw alkyl group optionally substituted with a 5-6 membered heterocyclic ring, the 5-6 The heterocyclic ring is optionally substituted with one or more substituents selected from the group consisting of pendant oxy groups and Cl-6 alkyl groups; and the remainder of the variables are each independently as described above. In some embodiments, the compounds of the invention are Any one of the formula (Ι)_(χιπ) or a pharmaceutically acceptable salt thereof, wherein: R9 is an alkyl group; and the meanings of the remaining variables are each independently as described above. 157033.doc •69- 201215604 In some embodiments 'a compound of the invention is represented by any one of formulas (I)-(XIII) or a pharmaceutically acceptable salt thereof, wherein: R9 is -H; and the meanings of the remaining variables are independent As described above, in some embodiments, the compounds of the invention are represented by structural formula (XX) or (XXI) or a pharmaceutically acceptable salt thereof:

Wherein: R^C]·6 alkyl' is optionally substituted with one or more substituents selected from the group consisting of dentate, -CN, -OH and -O(Ci-C6 alkyl). R8 is -H or, as the case may be, substituted by one or more substituents selected from the group consisting of: ^4 alkyl: dentate, hydroxyl, -0 ((:, -4 alkyl), -NH2 Alkyl) and -ΝγΜalkyl)2; R9 is -Η or optionally substituted by one or more substituents selected from the group consisting of halogen, pendant oxy, -CN, -OH, -ΝΗ2, -Nl^CVCe alkyl), -NCCVC^alkyl)2, -OCCOKC^-C^ alkyl), -oc(o)o(c丨-C6 alkyl), -C0(c丨- C6 alkyl), -C02H, -COKCV c6 alkyl), -CKCVC6 alkyl), -CKCVCei alkyl)' (: 3.7 cycloalkyl, C3·7 ring (haloalkyl), phenyl, and optionally a 5-6 membered heterocyclic ring substituted with one or more substituents selected from the group consisting of a pendant oxy group and a C..6 alkyl group; I57033.doc -70· 201215604 Ring B is replaced by one or more J2Bs as appropriate Ring C is a 5-7 membered heterocyclic ring, optionally substituted with one or more substituents selected from the group consisting of: hydroxyl, hydroxyl '-0 ((:, -4 alkyl), -NH2, -NH) ^Cm alkyl) and alkyl) 2; and q is 0, 1, or 2. In some embodiments, the compound of the invention is represented by structural formula (XX) or (XXI) or a pharmaceutically acceptable salt thereof, wherein: R is a second butyl or isopropyl group; R is -H or The case is substituted by one or more substituents selected from the group consisting of Ck4 alkyl, hydroxy, _0(Ch3), -〇(C2H5), -NH2, -NH(CH3), and -N ( CH3)2; 】28 is _, -CN, -OH, -NH2, -NHCCu alkyl), -ISKCu, 2, -((^.6 alkyl), or as the case may be one or more Ci6 alkyl substituted with a substituent selected from the group consisting of: halogen '-CN, -oh, -nh2, -ni^Ch alkyl), _N(Cl 6 alkyl) 2, _0 (Ci 6 alkyl) And - oxime (Cw haloalkyl); and other meanings as described above for structural formulas (xx) and (χχι). In some embodiments, the compound of the invention is represented by the formula (χχ) or (XXI) or a pharmaceutically acceptable salt thereof, wherein a leuco group. In some embodiments, the compounds of the invention are represented by structural formula (XX) or (XXI) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present invention is represented by the structural formula (XX) or (XXI) or a pharmaceutically acceptable salt thereof, wherein j2B is · or 157033.doc -71. 201215604 o(ch3). In some embodiments, the compound of the invention is represented by structural formula (xx) or (XXI) or a pharmaceutically acceptable salt thereof, wherein the variables of structural formulas (XX) and (XXI) are each independently as defined above. For any of the structural formulas (1). In some embodiments, the compound of the invention is a pharmaceutically acceptable salt represented by any one of Structural Formulas (I) (XIII), wherein the remainder of the variables are each independently as described above. In some embodiments, the compound of the invention is a pharmaceutically acceptable salt represented by any one of Structural Formulas (xx) and (XXI), wherein the remainder of the variables are each independently as described above. In some embodiments, the compound of the invention is represented by any one of the formula (Ι)_(ΧΠΙ) or a pharmaceutically acceptable salt thereof, wherein: η is 0; and the meanings of the remaining variables are each independently as above As stated in the article. In some embodiments 'the compound of the invention is represented by the formula (χχ) or (XXI) or a pharmaceutically acceptable salt thereof, wherein ... is or optionally substituted by C丨·6 alkyl:- 〇C(〇)(Ci_C6 alkyl), -〇〇(〇)〇((ν(:6 alkyl) or 5.6-membered heterocyclic ring, the 5-6 member heterocyclic ring is optionally selected from side oxygen by one or more And a pharmaceutically acceptable salt of the compound of the formula (^ (V), wherein: Substituted Cs-c: 8 cycloalkenyl. Suitable substituents are as described above for structural formula (I). 157033.doc •72· 201215604 Other variables have the meanings as defined above in the structural formula (ι)-(ν) In any of the embodiments, the compounds of the invention are represented by any of the structural formulae depicted in Figure 1. or a pharmaceutically acceptable salt thereof. In other embodiments, the compounds of the invention are It is represented by any of the structural formulae depicted in Figure 2 or a pharmaceutically acceptable salt thereof. In other embodiments, the compounds of the invention are as depicted in Figure 3. Any of the structural formulae depicted or pharmaceutically acceptable salts thereof. In other embodiments, the compounds of the invention are from the compounds 1-120, 121-154, 156-173, and 174-191 or in their medicinal Acceptable salts are indicated. As used herein, reference to a compound of the invention (e.g., a compound of formula (I), or a compound of claim 1) will include a pharmaceutically acceptable salt thereof. The compounds of the invention may be prepared by any suitable method known in the art. For example, such compounds may be used in accordance with US 6,881,741 'US 2005/0009804, US 2006/0276533, WO 2002/100851 and WO 08/58393 The procedures described in the preparations are herein incorporated by reference. The compounds of the invention (e.g., compounds of formula (I)-(VII)) can be prepared as outlined in General Schemes 1-7. The compounds of the formulae (I)-(V) can be prepared as shown in the general schemes 1-5; the compounds of the formula (VI) can be prepared as shown in the general schemes 6A and 6B; and the formula (VII) The compound can be as shown in general procedures 7A and 7B The compound of the formula (νΐΙΙ)-(ΧΠΙ) can be prepared as shown in the general scheme 1 and as shown in General Scheme 8-13, 157033.doc -73-201215604. The compound of the formula (xx) can be as a general scheme. Prepared as shown in 1 and as shown in General Schemes 20A-20B. Compounds depicted in these schemes (eg, compounds (la)-(lp), (2a)-(2p), (3a)-(3p) , (4a)_(4p), (5a)-(5p), (6a)-(6p), (7a)-(7p), (8a)-(8p), (9a)-(9p), ( L〇a)-(l〇p) '(iia)-(ilp), (12a)_(12p), (13a) (13p) and (20a)-(20p)) are known in the art Prepare any suitable method. Each of the steps depicted in the flow of the invention may employ any suitable conditions known in the art. In one embodiment, the invention provides a method of making a compound represented by the structural formula. In a particular embodiment, as shown in the general scheme, the method comprises reacting compound (lg) with compound (lh) (R8R7N) C(0)(;CR5R_6)n C(R3R4)-X (where X is as above Suitable for leaving the base, such as F,

Reactions of Cl, Br, I, OMs, OTs, OTf, 〇Ns, OBs, OR, 0C(0)R, 〇C(=NR)NR, 〇Bt, OAt, etc. (eg Han et al., 2004, 2447) The step of forming a compound (li) wherein the rule 9 is a compound of the formula (I) of -Me. In another specific embodiment, as shown in General Scheme 1, the method comprises reacting a compound (lp) with a compound (lf) XC(0)R2 (wherein X is a suitable leaving group as described above) to form The step of the compound (li) wherein R9 is a compound of the formula (1) of -Me. If desired, the compound (1 i) can be further hydrolyzed as appropriate to form a compound of the formula (I) wherein R9 is -H, that is, the c(〇)〇Me group on the ring a is suitable for the condition (for example, a base) Hydrolysis under conditions such as the presence of Li 〇 H) forms -C(0)0H. If desired, the -C(〇)〇H group can be further reacted with suitable reagents known in the art to form a compound of the formula 157033.doc-74·201215604 (i) which is different from hydrazine. Each of the steps described in i can use any suitable conditions known in the art. Specific example transition conditions are described in the wire. An exemplary detailed procedure is described in the example section below. Compounds (lg) and (1P) can be prepared by any suitable method known in the art. In some particular embodiments, the method further comprises the step of preparing compound (lg) or (lp) as shown in General Procedure 1. For example, the compound L (lg) can be prepared by reacting the compound (le) with the compound (lf) xc(〇)R2 (wherein X is a suitable leaving group as described above). Compound (lb) can be produced by treating compound (1) with sulphonic acid; then hydrazine can be introduced into ring VIII by reacting the compound with 12 under suitable conditions; then treating the compound with a base such as κπ〇3 (lc) can produce compound (id); compound (id) and YH (if Y = (c2 aliphatic) - Rl) or with YB (〇Rk) 2 (where "d alkyl, phenyl fluorenyl, etc." Compound (le) can be produced if γ = aryl, heteroaryl, carbocyclic or heterocyclic) under suitable coupling conditions (for example, as shown in general scheme i). For example, compound (lp) can be compounded ...) is prepared with compound (l〇)(R8R7N)C(9)[(c(R5R6)]nC(R3R4)_NH2m. The sigma (1|1) can be compound (1丨) or compound with γ_Η (if Y = aliphatic Base) -111) or with YB(0Rk)2 (wherein 妒 is 汨, Ci0 炫, 甲基 methyl, etc.) (if Y = aryl 'heteroaryl, carbocyclic or heterocyclic) reacts under suitable coupling conditions (Prepared as described in General Procedure 1) Compound (1) can be prepared by reacting compound (1)) with 12 under the conditions of the compound (example b, as shown in general scheme i). Compound (lm) can be Compound (lk) is prepared by carboxylation under suitable conditions (for example, as shown in General Scheme 1). In another embodiment, the 'S method is as described in General Procedure 2, General Procedure 2 157033.doc -75 · 201215604 shows the general synthetic scheme for the compounds of formula (II). The synthesis details are each independently as described above for general scheme 1. For example, compounds (2a) - (2p) are each independently as specified in general scheme 1 Compounds (la)-(lp) are described. In another embodiment, the process is as described in General Scheme 3. General Scheme 3 shows the general synthetic scheme for compounds of structural formula (III). The synthesis details are each independently as above For the general scheme 1, for example, the compounds (3a) to (3p) are each independently as described for the compounds (la)-(ip) in the general scheme 1. In another embodiment, the method is as a general procedure General procedure 4 shows a general synthetic scheme for compounds of formula (IV). The synthesis details are each independently as described above for general scheme 1. For example, compounds (4a)-(4p) are each independently As described in general procedure i for compounds In another embodiment, the method is as described in General Scheme 5. General Scheme 5 shows the general synthetic scheme for compounds of Structural Formula (V). The synthesis details are each independently as described above for General Scheme 1. For example, compounds (5a)-(5p) are each independently as described in general scheme 1 for compound (la)-(lp). In another embodiment, the method is as described in general scheme 6A or 6B. General Schemes 6A and 6B A general synthetic scheme for the compounds of structural formula (VI) is shown. The synthesis details are each independently as described above for General Scheme 1. The compounds (6a) to (6p) are each independently as described in the general scheme for the compound (ia)_(lp). 157033.doc -76- 201215604 In another embodiment, the method is as described in general procedure 7 A or 7B. General Schemes 7A and 7B show the general synthetic scheme of the compounds of formula (νπ). The synthesis details are each independently as described above for General Scheme 1. The compounds (7a) to (7p) are each independently as described in the general scheme 1 for the compounds (la)-(lp), respectively. In other embodiments, the method is as described in general procedures 8-13. General Processes 8-13 show the general synthetic schemes for compounds of Structural Formulae (VIII)-(XIII), respectively. The synthesis details are each independently as described above for General Scheme 1. Compounds (8a)-(8p), (9a)-(9p), (10a)-(10p), (lla)-(llp), (12a)-(12p) and (13a)_(13p) are each independently The conditions are as described in general scheme 1 for compounds (la)-(lp), respectively. In another embodiment, the method is as described in general procedures 2 and 21. General Schemes 20 and 21 show the general synthetic scheme for compounds of structural formula (XX)-(XXI), respectively. The synthesis details are each independently as described above for General Process 1. The compounds depicted in the scheme can be prepared by any suitable method known in the art. For example, the reaction between the compound (20n) and (20〇) can produce the compound (20a), and then reacting with the compound (20f) to produce the compound (20i). If necessary, the compound (20i) may be further hydrolyzed as appropriate to form a compound of the formula (χχ) wherein R9 is 4, that is, the _C(0)〇Me group is in a suitable condition (for example, basic conditions such as the presence of Li0H). Hydrolysis to form -C(0)0H. When desired, the -C(0)0H group can be further reacted with a suitable reagent known in the art to form a compound of formula (XX) wherein R9 is different from -H. The various steps described in the general scheme 2 can employ any suitable conditions known in the art. In General Procedure 21, 157033.doc • 77- 201215604 are each independently as exemplified above for general flow conditions. The exemplary detailed procedure is described in the synthetic procedure 20 of the various steps depicted. The process _ description is described in the example section below. Compounds (20j), (2〇k), (2〇) (2〇m), (20η), (20〇), 叫(21丨), (2lm), are known to be known in the art. Prepare any suitable method. For example, the compound (20A) can be prepared as described in General Scheme 23, for example, using Compound (23a) or (23e) as shown in the scheme. A similar combination can be prepared as depicted in General Scheme 22, for example, ^1〇) (22e). Each of the steps described in the general schemes 22 and 23, or any suitable conditions known in the art. In the process, the description of the particle a technique will be described. The exemplary detailed procedure is described in the example section below. β, τ ° 157033.doc 78- 201215604 General Process 1

Substituting conditions: (4) trifluoroacetic anhydride (TFAA), Et2〇; (b pity Γ2ΝΗ, n_BuLi, 2_MeTHF,

78 c ' I2 ; (c) 2-MeTHF ' MeOH, H 2 O, K 2 C 〇 3 ; (d) Y = (C 2 aliphatic group VR1: HY, Cul, 1,4-dioxane, Pd(PPh3) 2Cl2 ' i-Pr2NH ; Y = aryl, heteroaryl, carbocyclic, heterocyclic: YB(〇Rk)2, Pd(OAc)2, Κ3Ρ04, benzene, heating; (e)i. R2C02H, SOCl2, DCM,cat. D〇MF, or R2c〇a, ii.pyridine, DCE, DCM; (f) LiHMDS, THF, (X=a, Br, I, etc.), 〇 °C to room temperature; (g) R9 =H: THF, H20, LiOH; (h) i-Pr2NH, n-BuLi, 2-MeTHF, -78 ° C, I2; (i) i. LDA, THF, -78., C02, ii. (COCl) 2, DCM, DMF, MeOH; 0) 1,4-dioxane, hydrazine (12 (North 3) 3, € 32 (: 〇 3, 〇 -8 -8), 90. (:; (Noisy. 112 (: 〇汨, 3 〇 (: 12, DCM, cat. DMF, or R2COCl, ii. pyridine, A stupid, DCE 157033.doe -79· ttn; ««»r 201215604 General Process 2

Detergent conditions: (a) trifluoroacetic anhydride (TFAA) ' Et20; (b) z_-Pr2NH, n-BuLi, 2-MeTHF, -78 ° C, I2; (c) 2, MeTHF, MeOH, H20 , K2C03; (d) Y = (C2 aliphatic group) - Ri: HY,

Cul '1,4-dioxane, pd(PPh3)2Cl2, i-Pr2NH; Y=aryl, heteroaryl, carbocyclic, heterocyclic: YB(ORk)2, Pd(〇Ac)2, K3P 〇4, benzene, benzene heat; (e) i. R2C02H, SOCl2, DCM, cat. DMF, or R2C〇cn, ii. pyridine, DCE, DCM; (f) LiHMDS, THF, "RX" (X =Q, Br, I, etc.) ' 〇 °C to room temperature; (g) R9=H: Ding 1^, 0, 1^0^1; (Noisy -? 1^11, 11-8111^, 2-MeTHF, -78. (:, I2; (i) i. LDA, THF, -78 ° C, C02, ii. (COCl) 2, DCM, DMF,

MeOH; (j) 1,4-dioxane, Pd2(dba)3, Cs2CO3, mc-BINAP, 90 °C; (k)i.R2CO2H, SOCl2, DCM, cat. DMF, or R2COC ii. ArNHR","Bite, Benzene, DCE 157033.doc • 80 · 201215604 General Process 3

Representative conditions: (a) tri-I acetate needle (TFAA) ' Et2〇; (b) i'-Pr2NH, n-BuLi, 2-MeTHF, _78eC, I2; (c) 2-MeTHF, MeOH, H20, K2C03 (d) CuI, 1,4-dioxane, Pd(PPh3)2Cl2^i-Pr2NH; (e)i. R2C02H » SOCl2 > DCM « cat. DMF > ^R2COCl > ii. »tt acridine , DCE, DCM; (f) LiHMDS, THF, (X = a, Br, I, etc.), 0 ° C to room temperature; (g) R9 = H: THF, H20, LiOH; (h) i-Pr2NH , n-BuLi, 2-MeTHF, -78. . , I2; (i) i. LDA, THF, -78 ° C, C02, ii. (COCl) 2, DCM, DMF, MeOH; 〇) 1,4-dioxane, Pd2(dba)3, Cs2C03, rac-BINAP, 90〇C; (k)i. R2C02H, SOCl2, DCM, cat. DMF, or R2COCl, ii. "ArNHRj, pyridine, stupid, DCE 157033.doc -81 · 201215604 General Process 4

Representative conditions: (a) trifluoroacetic anhydride (TFAA), Et20; (b) i-Pr2NH, n-BuLi, 2-MeTHF, -78 ° C, I2; (c) 2-MeTHF, MeOH, H2O, K2C03; (d) CuI, 1,4-dioxane, Pd(PPh3)2Cl2, i-Pr2NH; (e)i. R2C02H, SOCl2, DCM, cat. DMF, or R2COCl, ii. Pyridine, DCE, DCM (f) LiHMDS, THF, (X = C, Br, I, etc.), 0 ° C to room temperature; (g) R9 = H: THF, H20, LiOH; (h) / -Pr2NH, n-BuLi , 2-MeTHF, -78 ° C, I2; (i) i. LDA, THF, 78 ° C, CO 2 , ii · (COCl) 2 , DCM, DMF, MeOH ; (j) l, 4- dioxole Alkane, Pd2(dba)3, Cs2C03, rac-BINAP, 90°C; (k)i. R2C02H, SOCl2, DCM, cat. DMF, or R2C〇a, ii. Pyridine, toluene, DCE 157033.doc -82 - 201215604 General Process 5

Sub-heterogeneous conditions: (a) trifluoroacetic anhydride (TFAA), Et20; (b) z-Pr2NH, n-BuLi, 2-MeTHF, _78 ° C, I2; (c) 2-MeTHF, MeOH, H20, K2C03; (d) CuI, 1,4-dioxane, Pd(PPh3)2Cl2, i-Pr2NH; (e) i. R2C02H, SOCl2, DCM, cat. DMF, or R2C〇a, ii. Pyridine' DCE , DCM; (f) LiHMDS, THF, (Χ = α, Br, I, etc.), (TC to room temperature; (g) R9 = H: THF, H20, LiOH; (h) i-Pr2NH, n- BuLi, 2-MeTHF, -78t, I2; (i) i. LDA, THF, -78 ° C, C02, ii_ (COCl) 2, DCM, DMF, MeOH; (j) 1,4-dioxane Pd2(dba)3, Cs2C03, rac-BINAP, 90〇C; (k)i. R2C02H, SOCl2, DCM, cat. DMF, or R2C〇a, ii·0 ratio bite, toluene, DCE-83- 157033. Doc 201215604

General Process 6A

Chiral conditions: (a) trifluoroacetic anhydride (TFAA), Et20; (b) i-Pr2NH, n-BuLi, 2-MeTHF, • 78 ° C, I2; (c) 2-MeTHF, MeOH, H20 , K2C03; (d) CuI, 1,4-dioxane, Pd(PPh3)2Cl2, i-Pr2NH; (e) i· X=OH: SOCl2, DCM, cat. DMF, or Χ=α, ii .pyridine, DCE, DCM; (f) LiHMDS, THF, (Χ=α, Br, I, etc.), 0 ° C to room temperature; (g) R9 = H: THF, H20, LiOH 157033.doc -84 - 201215604

General Process 6B

Representative conditions: (d) CuI, 1,4-dioxane, Pd(PPh3)2Cl2, i-Pr2NH; (g) R9=H··THF, H20, LiOH; (h)/-Pr2NH,n -BuLi, 2-MeTHF, -78 ° C, I2; (i) i. LDA, THF, -78 ° C, C02, ii. (C0C1) 2, DCM, DMF, MeOH; 1 1,4-dioxane ,卩(12(£«^)3,〇32(:03,^〇BINAP,90t ; (k)i. R2C02H,SOCl2,DCM,cat. DMF, or R2C〇a,ii. «比啶,曱Stupid, DCE 85-157033.doc 201215604

Representative conditions: (a) trifluoroacetic anhydride (TFAA), Et20; (b) /-Pr2NH, n-BuLi, 2-MeTHF, -78. (:, I2; (c) 2-MeTHF, MeOH, H20, K2C03; (d) CuI, 1,4-dioxane, Pd(PPh3)2Cl2, i-Pr2NH; (e)i. X=OH Day Capture: S0C12, DCM, cat. DMF, or X=C1, ii. pyridine, DCE, DCM; (f) LiHMDS, THF '"RX" (Χ=α, Br, I, etc.), 0〇C to Room temperature; (g) when R9=H: THF, H20, LiOH 157033.doc 86 201215604

General Process 7B

Representative conditions: (d) CuI, 1,4-dioxane, Pd(PPh3)2Cl2, i-Pr2NH; (g) R9=H: THF, H2O, LiOH; (h)i-Pr2NH, n- BuLi, 2-MeTHF, -78 ° C, I2; (i) i. LDA, THF, -78 ° C, C02, ii. (C0C1) 2, DCM, DMF, MeOH; (j) l, 4- Oxane, oxime (12((^)3, €52(:03, which-BINAP, 9(TC; (k)i. R2C02H, S0C12, DCM, cat. DMF, or R2C0C1, ii. Toluene, DCE 157033.doc 87- 201215604 General Process 8

Representative conditions: (a) tris-acetic anhydride (TFAA), Et2〇; (b) z_-Pr2NH, n-BuLi, 2-MeTHF, -78〇C, I2; (6) 2-MeTHF, MeOH, H2O, K2C03; (d) Ar "P"-B(ORk)2, Pd(OAc)2, K3P04, toluene, heat of mouth; (e)i. R2C02H, S0C12, DCM, cat·DMF, or R2C〇a, ii. Pyridine, DCE, DCM; (f) LiHMDS, THF, "RX" (Χ = α, Br, I, etc.), Ot to room temperature; (g) R9 = H: THF, H20, LiOH; (h>- Pr2NH, n-BuLi, 2-MeTHF, -78 ° C, I2; (i) i. LDA, THF, -78 ° C, CO2, ii· (COCl) 2, DCM, DMF, MeOH; (j)l , 4-dioxane, Pd2(dba)3, Cs2C03, rac-BINAP, 90°C; (k)i. R2C02H, SOCl2, DCM, cat. DMF, or R2COCl, ii. “ArNHR”, pyridine, toluene ,DCE 157033.doc -88- 201215604 General Process 9

Substituting conditions: (a) trifluoroacetic anhydride (TFAA), Et20; (b) /-Pr2NH, n-BuLi, 2-MeTHF, -78 ° C, I2; (c) 2-MeTHF 'MeOH, H20 , K2C03; (d) Ar "P"-B(ORk)2, Pd(OAc)2 'K3P04, benzene, heating; (e)i. R2c〇2h, S0C12, DCM, cat. DMF, or R2COC Ii. pyridine 'DCE, DCM; (f) LiHMDS, THF, "RX" (X=Q, Br, I, etc.), 0 ° C to room temperature; (g) R9 = H: Occasionally, 0, [ Gaya; the teacher runs Yang, 11 in 1^, 2 she 1' book, -78. (:, 12; egg · LDA, THF, -78〇C, C02, ii. (COCl) 2, DCM, DMF, MeOH; (j) 1,4-dioxane, Pd2(dba)3, Cs2C03, rac-BINAP, 90°C; (k)i. R2C02H, SOCl2, DCM, cat. DMF, or R2COCl, ii. “ArNHR”, pyridine, toluene, DCE 157033.doc •89· 201215604 General procedure ίο

Representative conditions: (4) trifluoroacetic anhydride (TFAA) ' Et20; (b&gt;_-Pr2NH, n-BuLi, 2_MeTHF, -78 ° C, I2; (c) 2-MeTHF, MeOH, H20, K2C03; Ar "P"-B(ORk)2, Pd(OAc)2, K3PO4, abbreviated, heated; (e)i. R2C02H, SOCl2, DCM, cat. DMF, or R2COC ii.. Bisidine, DCE , DCM; (f) LiHMDS, THF, "RX" (X=C Bra, I, etc.), 〇t to room temperature; (g) R9=HB^: T HF Ή20 &gt;LiOH; (h)/- </ RTI> </ RTI> <RTIgt; 11,4-dioxane, Pd2(dba)3, Cs2C03, rac-BINAP, 90〇C; (k)i. R2C02H, SOCl2 'DCM, cat. DMF, or R2COCl, ii. "ArNHR", pyridine, Toluene, DCE 157033.doc -90- 201215604 General Process 11

Chiral conditions: (a) trifluoroacetic anhydride (TFAA), Et20; (b) z-Pr2NH, n-BuLi, 2-MeTHF, -78 °C 'I2; (4) 2-MeTHF, MeOH, H20, K2C03; (d) PhB(ORk)2, Pd(OAc)2, K3PO4' 甲笨, heating; (e)i·r2c〇2H, SOCI2, DCM, cat. DMF, or R2COC ii. »Bipyridine, DCE, DCM; (f) LiHMDS, THF, "RX" (Χ=α, Br, I, etc.), 0〇C to room temperature; (g) R9=H: THF, H20, LiOH; (h&gt;-Pr2NH, n-BuLi, 2-MeTHF, -78 ° C, I2; (i) i. LDA, TH F, -78. (:, C02, ii. (COCl) 2, DCM, DMF, MeOH; (j)l , 4-dioxane, Pd2(dba)3, Cs2C03 ' rac-BINAP, 90〇C ; (k)i. R2C02H, SOCl2, DCM, cat. DMF, or R2C〇a, ii. "ArNHR", pyridine , Benzene, DCE 157033.doc -91 - 201215604

General Process 12A

Representative conditions: (a) trifluoroacetic anhydride (TFAA), Et20; (b) /-Pr2NH, n-BuLi, 2-MeTHF, -78 ° C, I2; (c) 2-MeTHF, MeOH, H20, K2C03; (d) PhB(ORk)2, Pd(OAc)2, K3P04, benzene, heating; (e)i. X=OH: SOCl2, DCM, cat. DMF, or X=Cn, ii. , DCE, DCM; (f) LiHMDS, THF, "RX" (X = C1, Br, I, etc.), 0 ° C to room temperature; (g) R9 = H: THF, H20, LiOH 157033.doc • 92· 201215604

General Process 12B

Representative conditions: (d) PhB(ORk)2, Pd(OAc)2, Κ3Ρ04, benzene, heating; (g) R9=H: THF, H20, LiOH; (h)/-Pr2NH, n-BuLi , 2-MeTHF, -78 ° C, 12 ; (i) i. LDA, THF, -78 ° C '

C02, ii. (COCl) 2, DCM, DMF, MeOH; (j) 1,4-dioxane, hydrazine (12 (North 3) 3, 匚32 (:03, 〇 BINAP, 90 ° C; k)i. R2C02H, SOCl2, DCM, cat. DMF, or R2C〇a, ii. Pyridine, toluene, DCE 93-157033.doc 201215604

General Process 13A

Representative conditions: (a) trifluoroacetic anhydride (TFAA), Et20; (b) i-Pr2NH, n-BuLi, 2-MeTHF, -78 ° C, I2; (c) 2-MeTHF, MeOH, H20, K2C03; (d) PhB(ORk)2, Pd(OAc)2, K3P04, toluene, heating; (e)i. X=OH: SOCl2, DCM, cat. DMF, or X=a, ii. pyridine, DCE, DCM; (f) LiHMDS, THF, "RX" (X=C Bra, I, etc.), 0 ° C to room temperature; (g) R9 = H: THF, H20, LiOH 157033.doc -94 · 201215604

General Process 13B

Representative conditions: (d) PhB(ORk)2, Pd(OAc)2, Κ3Ρ04, benzene, heating; (g) R9=H: THF, H20, LiOH; (h) z-Pr2NH, n-BuLi , 2-MeTHF, -78〇C, I2; (i) i. LDA, THF, -78. . , C02, ii. (COCl) 2, DCM, DMF, MeOH; (j) 1,4-dioxane, 卩〇12 ({«^)3, €32 (:03, goods (;-BINAP, 9 (TC; (k)i. R2C02H, SOCl2, DCM, cat. DMF, or R2COC ii.&quot;Bipyridine, toluene, DCE 157033.doc 95- 201215604 General Process 20

Representative conditions: (d) CuI, 1,4-dioxane, Pd(PPh3)2Cl2, i-Pr2NH; (g) R9=H: THF, H20, LiOH; (h&gt;-Pr2NH, n-BuLi , 2-MeTHF, -78 ° C, I2; (i) i. LDA, THF, -78 ° C, C02, ii. (COCl) 2, DCM, DMF, MeOH; (j) l, 4- dioxin Alkane, anthracene (12 (North 3) 3, 〇52 (:03, melon BINAP, 9 (TC; (k)i. R2C02H, SOCl2, DCM, cat. DMF, or R2COCl, ii.-specific bite, toluene ,DCE 157033.doc 96- 201215604 General flooding 21

(XXI)

Representative conditions: (d) CuI, 1,4-dioxane, Pd(PPh3)2Cl2, i-Pr2NH; (g) when R9=H: THF, H20 'Li〇H; (h)/-pr2NH, n-BuLi, 2-MeTHF, -78 ° C, I2; (i) i. LDA, THF, -78 ° C, C 〇 2, ii. (C0C1) 2, DCM, DMF, MeOH; (j)l , 4-dioxane,? (12(^^)3, €320)3, Nor-BINAP, 90〇C; (k)i. R2C02H, S0C12, DCM, cat. DMF, or R2COC ii. »Bipyridine, toluene, DCE 157033. Doc 97- 201215604 General Process 22

Representative conditions: (1) HN(TMS)2, MeCN, reflux; (m) "PG-X" (X = LG, Cb Br, I), such as Boc20, Et3N, DCM, RT; (8) R8-X ( X = LG, C, Br, I), NaH, THF, DMF, 0 ° C to room temperature; (6) removal of protecting groups (for example, PG = Boc: HC1, Et20); (p) R8-NH2, Me3Al, DCM, 〇°C ; (q)t-Bu0C(0)N=NC(0)0Bu-t,Bu3P,THF General Process 23

Representative conditions: 1HN(TMS)2, MeCN, reflux; (m) "PG-X" (X = LG, Cl, Br, I), such as Boc20, Et3N, DCM, RT; (n) R8-X ( X = LG, Cl, Br, I), NaH, THF, DMF, 0 ° C to room temperature; (〇) removal of protecting groups (eg PG = Boc: HQ, Et20); (p) R8-NH2, Me3Al, DCM, 〇〇C; (q)t-Bu0C(0)N=NC(0)0Bu-t,Bu3P, THF Those skilled in the art will appreciate that in the process of the present invention, the starting reagent or intermediate Certain functional groups in the compound, such as hydroxyl or amine groups, may require -98 - 157033.doc 201215604 is protected by a protecting group. Thus, the preparation of the above compounds can include the addition and removal of one or more protecting groups at various stages. Functional group protection and removal of protecting groups are described in "Protective Groups in Organic Chemistry", edited by JWF McOmie, Plenum Press (1973) and "Protective Groups in Organic Synthesis," 3rd edition, TW Greene and PGM Wuts Wiley Interscience, and "Protecting Groups," 3rd edition, PJ Kocienski, Thieme (2005). For the purposes of the present invention, chemical elements are identified in accordance with the Periodic Table of the Elements (CAS version) of Handbook of Chemistry and Physics 75th Edition. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausolito: 1999, and "March's Advanced Organic Chemistry", 5th edition, Smith, MB and March, J., John Wiley &amp; Sons, New York: 2001, the entire contents of which are incorporated herein by reference. As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, as exemplified below, or by specific classes, subclasses, and materials of the above compounds. It should be understood that the phrase "replaced as appropriate" may be used interchangeably with the phrase "substituted or unsubstituted". In general, the term "substituted", whether preceded by the term "optionally" or not, refers to the replacement of one or more hydrogen groups in a given structure by a group of a given substituent. Unless otherwise stated, a substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure may be substituted with more than one substituent selected from the specified group, the substituents at each position may be the same or different. When the term "as appropriate" is placed before a list 157033.doc -99- 201215604, the term means that all subsequent groups in the list are supersedable. If a substituent group or structure is not identified or defined as "optionally substituted", the substituent group or structure is unsubstituted. For example, if X is optionally substituted C^-C:3 alkyl or phenyl, then x may be optionally substituted Ci_C3 alkyl or optionally substituted phenyl. Similarly, if the term "optionally placed after m" is used, then the term also refers to all groups in the pre-list that can be substituted unless otherwise stated. For example, if XgCi_c3 alkyl or phenyl, wherein X is independently substituted by JX, the Ci_C3 alkyl group and the phenyl group may be replaced by Jx as appropriate, as is apparent to those skilled in the art, such as H, halogen, The group of N02, CN, NH2, OH or OCF3 is not a substitutable group. The phrase "up to" as used herein refers to any integer that is zero or equal to or less than the number after the phrase. For example, "up to 3" means any of 〇, i, 2, and 3. As specified herein, the specified range of atoms includes any integer therein. For example, a group having 丨_4 atoms may have 1, 2, 3 or 4 atoms. The substituents and substituent combinations contemplated by the present invention are selected to form stable or chemically feasible compounds. The term "stable" as used herein refers to a compound that does not substantially change when subjected to conditions of preparation, detection, and in particular, recovery, purification, and use in one or more of the purposes disclosed herein. In some embodiments, the stabilizing compound or chemically feasible compound is a compound that does not substantially change at least 4 weeks or less than 40 ° C in the absence of moisture or other chemically reactive conditions for at least one week. The present invention covers only those alternatives and combinations of substituents that produce stable structures. These selections and combinations are 157033.doc -100· 201215604 and are readily known to the general practitioner and can be determined without undue experimentation. As used herein, the term "aliphatic" or "aliphatic" means a straight chain (ie, no branching) or branch that is fully saturated or contains one or more unsaturated units but is non-aromatic. Chain, hydrocarbon chain. Unless otherwise stated, the aliphatic group contains 1 to 10 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1-6 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 丨4 aliphatic carbon atoms. The aliphatic group may be a linear or branched alkyl group, an alkenyl group or an alkynyl group. Specific examples include, but are not limited to, methyl, ethyl, isopropyl, n-propyl, t-butyl, vinyl, n-butenyl, ethynyl, and tert-butyl and acetylene. The term "alkyl" as used herein means saturated straight or branched chain smoke. The term "r-thyl" as used herein means a straight or branched chain hydrocarbon comprising one or more double bonds. The term "alkynyl" as used herein means a straight or branched chain hydrocarbon containing one or more reference bonds. As used herein, "alkyl", "alkenyl" or "alkynyl" may each be substituted as described below. In some embodiments, "alkyl" is €1_〇6 alkyl or hydrazine: 1_decyl. In some embodiments, "alkenyl" is C2_C6 alkenyl or C2_c4 alkenyl. In some embodiments, "alkynyl" is CrC6 alkynyl or C2_C4 alkynyl. The term "cycloaliphatic" (or "carbocyclic" or "carbocyclyl") refers to a non-aromatic hydrocarbon containing only a ring system having three to fourteen ring carbon atoms, which ring system may be saturated or contain one Or multiple unsaturated units. In some embodiments, the number of carbon atoms is from 3 to 10[0]. In other embodiments, the number of carbon atoms is from 4 to gamma. In other embodiments, the number of carbon atoms is 5 or 6. The term includes single ring, two 157033.doc -101 - 201215604 = screwed or bridged carbon ring system. The term also encompasses that the polycyclic ring may be "fused" to the carbocyclic ring with or - a plurality of non-aromatic carbocyclic or _ or ~ or squaring rings or combinations thereof. "Intrusion junction or attachment point... The bicyclic system consists of two rings sharing two adjacent ring rafts. The bridged bicyclic group contains two rings of atoms. 蟫-', with two or Examples of four adjacent ring atoms include, but are not limited to, tabs and ', 裒 裒 基 ) ... 环 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Alkyl and cyclobutyl. Not limited to the term "heterocyclic" (aromatic heterocyclic ring) or non-aromatic ring system as used herein, (iv) a plurality of ring carbons having tt t unsaturated units The substitution is made into four sub-subjects of the material, wherein one or 罝 is replaced by a hetero atom, such as N, :, and the ring containing the non-aromatic heterocyclic ring contains at most three selected from the two examples. In other embodiments, non### and 〇 Miscellaneous

Gamma, "a non-square heterocyclic ring system contains ? 夕 A selected from N, S, and 〇, at most two - ^ ^ In the eight-he embodiment, the non-aromatic 鞑 (4) contains at most three The non-aromatic heterocyclic oxime &amp; hetero atom selected from the N and non: heterogeneous soil examples. In other systems, the system contains at most two heteroatoms selected from the group consisting of ruthenium and osmium. Monocyclic, secondary, and sighed heterocyclic systems. The surgery &amp; also ~ ° °, screw or bridge or multiple non-including polycyclic system, where the heterocyclic ring *-#方族 &% Or a heterocyclic ring or - or more, wherein the linking group or point of attachment is on the heterocyclic ring. a combination of "rich (but not limited to) (four) groups, an example package of a pyridazine, azacycloheptyl, diazepine, diazepine, aza-aza Cycloheptane in the pit-based diaza-heterocyclic sulfonyl group, 157033.doc -102- 201215604 ° 恶 ° sitbit, different &quot; sinister bite, squirrel bite base, iso-neck bite base, oxygen-oxygen heterocycle Octyl, oxazepanyl, triazacycloheptyl, thiazepine, benzimidazolone, tetrahydrofuranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiophenyl, Morpholinyl (including, for example, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl), indole-purine group, 2-pyrrolidinyl, 3-pyrrolidinyl, indole-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, indole-piperidinyl '2-piperidinyl, 3_ Piperidinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, oxathiazolidinyl, 3-oxazolidinyl, 4-oxazolidinyl, oxime-oxazolidinyl, &amp; rice sulphate, 4-mi Benzoyl, 5-azazolidinyl, oxalinyl, tetrahydroquinolyl, tetrahydroisomeric, benzodisulfide, benzothiazepine, 3-(1-burning Base) _ benzo flavor. sit 2 ketone group and dichloro beer. sit _2_ steel base / used alone or as a larger group (such as "aromatic base", "aromatic alkoxy", "fang The term carbocyclic aromatic ring system is used in the _ moiety of oxynonyl or "four". The term "aryl" is used interchangeably with the terms "aryl ring"; "aryl group". "Carbocyclic (tetra) ring" groups have only carbon ring atoms (usually six to fourteen) and include a single) stalk early % ring (such as phenyl), and a fused polycyclic aromatic ring system, Two or more of the carbon ring aromatic garments are fused to each other. Examples include b-naphthyl, L丄 荣 荣, 蒽 and 2-indenyl. As used herein, the term "anti-clothing J-clothing" or "carbon-ringed genus" also includes the genus of one of the aromatics, P, "a fine person once a non-aromatic ring (carbon coat or a condensed group of condensed j, such as a bis-methane group, a phthalimido group, a xylylene group, a phenanthyl group or a tetrahydronaphthyl group, wherein 157033 .doc 201215604 The group or point of attachment is on the aromatic ring. The term ":: burnt its base" or "heteroaryl" used in the early part or as part of a larger group (such as alkoxy) Heteroaryl rings, "heteroaryl groups", "aromatic groups", heteroaromatics, and heterocyclic rings having five to fourteen members have been replaced by heteroatoms such as ruthenium. , = group 'where - or medium, the heteroaryl ring contains at most -. In: Some examples. In other embodiments, the heteroaryl ring is /8. The heterogene is selected from N, S and ring systems containing up to two sub-systems. In other embodiments, the ring system of the heteroaryl ring contains up to three heterogenes selected from the group consisting of phoenix quinones, and the ring system of the heteroaryl ring contains ^, and the yoke is exemplified by ', 円Packing 3 or more of two miscellaneous species selected from N and hydrazine. The aryl ring includes a monocyclic heteroaromatic ring and a polycyclic aromatic ring in which the monocyclic aromatic ring is fused to the or the aromatic ring. Also included within the scope of the term 'heteroaryl" as used herein is a group wherein the aromatic ring is "fused" to one or more non-aromatic rings (carbocyclic or heterocyclic), wherein the linking group The money contact is located in the aromatic ring. For example, the biguanide 6,5 hetero group, as used herein, is a six-membered heteroaromatic ring fused to a second five-membered ring, wherein the linking group or The connection point is on the six-member ring. Examples of heteroaryl groups include acridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadi Azolyl, thiophene. Sedentyl, isothiazolyl or thiadiazolyl, including, for example, 2-furyl, 3-propanyl, indole-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoindoline , 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-βoxadithiol, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-pyridyl Azolyl, 4-11 than spit 157033.doc -104· 201215604

Base, 1-D ratio, § base, 2 -α ratio, 3 - ° ratio, 2 - etb D group, 3 - π ratio, 4-pyridyl, 2-pyrimidinyl, 4- Pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl '2-triazolyl, 5-triazolyl, tetrad-spinyl, 2_ porphin , 3-D-sepeno, β-carbyl, benzo-m-saltyl, benzothienyl, benzofuranyl, fluorenyl, benzotriazolyl, benzopyrene, benzo . evil. Sodium, benzopyrene, isoindolyl, sulfhydryl, isodecyl, acridinyl, benzoisoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, ι,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadi Azyl, 1,2,5-thiadiinyl, fluorenyl. Biazinyl, 1,3,5-three. Qin, quinoline (eg 2-oxalidyl, 3-quinolinyl, 4-quinolinyl)' and isoquinolinyl (eg 丨_isoindolyl, 3-isoquinolinyl or 4- Isoquinolyl). As used herein, "ring", "ring", "ring group" or "ring moiety" includes monocyclic, bicyclic and tricyclic ring systems, including cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl. Bases, each of which has been previously defined. As used herein, a "bicyclic system" includes a 12 (eg, 9, 10, or 11) member structure that forms two rings, wherein the two rings have at least one shared atom (eg, two shared atoms, a bicyclic system, including a double ring) Aliphatic (e.g., bicycloalkyl or bicycloalkenyl), bicyclic heteroaliphatic, bicyclic aryl, and bicyclic hetero" as used herein, "bridged bicyclic system" refers to a bicyclic heterocyclic aliphatic ring system in which a ring is formed. Or a bicyclic cycloaliphatic ring system. Examples of bridged heterocyclic ring systems include, but are not limited to, adamantyl, sulphate, bis-I57033.doc-105-201215604 [3.2.3] fluorenyl, 2_ oxa-di Cyclo [2.2.2] octyl, 1-aza-bicyclo[2.2.2] octyl, 3·aza-bicyclo[3.2.1]octyl and 2,6-dioxatricyclo[ 3.3.1 _〇3,7] fluorenyl. Bridged bicyclic systems may be substituted by one or more substituents, such as a base (including a slow-base group, a base-based group, and a ii-based group, such as trifluoromethyl). , alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy Base, heterocycloalkane Oxyl, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkyloxy, arylsulfonyl, heteroarylalkyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy , aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamine , (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, decyl, decyl, alkylthio, thiol , urea, thiourea, amine sulfhydryl, decylamine, pendant oxy or carbamoyl. As used herein, "bridge" refers to a bond or atom or atom that connects two different parts of a molecule. Branching chain. Two atoms connected by a bridge (generally but not always two tertiary carbon atoms) are designated as "bridgeheads." As used herein, the term "spiral" refers to one of the atoms (generally four Carbon) is a ring system in which only two atoms share a common atom. The term "ring atom" is an aromatic group, a cycloalkyl group or a non-aromatic heterocyclic ring. An atom in the ring, such as C, N, hydrazine or S. The "substitutable ring atom" in the aromatic group is a ring carbon or a nitrogen atom bonded to a hydrogen atom. Hydrogen may be optionally substituted by a suitable substituent. The twisted "substitutable ring atom" does not include the ring nitrogen biting that is shared when the two rings are fused. 157033.doc •106· 201215604 Atom 3, "Can replace the earth atom" $includes when the structure shows that it is connected to different a ring carbon or nitrogen atom in the form of a hydrogen. The term "hetero atom" means one or more oxygen, sulfur, nitrogen, fill or rock (including any oxidized form of nitrogen, sulfur, phosphorus or shi shi; any test) a quaternized form of sexual gas; or a substitutable nitrogen in a heterocyclic ring, such as hydrazine (such as 3,4-dihydro-2-indole-pyrrolyl), hydrazine (such as pyrrolidinyl) or >^+ (such as Substituted pyrrolidinyl)). As used herein, an optionally substituted aralkyl group can be substituted on the alkyl and aryl moieties. As used herein, unless otherwise indicated, • An optionally substituted aralkyl group is optionally substituted on the aryl moiety. In some embodiments, the 'aliphatic group and the heterocyclic ring may independently contain one or more substituents. Suitable substituents on the saturated carbon of the aliphatic or non-aromatic heterocyclic ring are selected from the above four substituents. Other suitable substituents include the substituents listed above for the unsaturated carbon of the aryl or heteroaryl group and additionally include the following: =0, =S, =NNHR, =NN(R*)2, =NNHC(0 R·, =NNHC〇2 (hospital), =NNHS〇2(alkyl) or =NR·, wherein each r* is independently selected from hydrogen or optionally substituted Ci.6 aliphatic. The substituent present on the aliphatic group of r* is selected from the group consisting of NH2, aliphatic, n (CN4 aliphatic), halogen, CN4 aliphatic, 〇H, 0 (0^.4) An aliphatic group, N〇2, CN, CO2H, C 02 ((1^.4 aliphatic group), 0 (halo C!.4 aliphatic group), or a halogen group (Cm aliphatic group) The above respective Cw aliphatic groups of R* are unsubstituted. In some embodiments, the substituents which are optionally present on the nitrogen of the heterocyclic ring include the above substituents. Examples of such suitable substituents include -OH, - NH2, -NHCCVC^alkyl), -NiCVG alkyl)2, -CCKCVC^alkyl), -C02H, -CCMC^-C^alkyl), -CKCVC4 alkyl), and 157033.doc-107 - 201215604 A C-C4 aliphatic group independently substituted with a substituent selected from the group consisting of halogen, pendant oxy, -CN, 〇H, -NH2, -NH(C 丨-C4 alkyl), -N(C 丨-C4 alkyl) 2, _〇c〇(Ci_C4 alkyl), -CCHCVC^alkyl), -C02H, -COJCVCU alkyl), alkyl), 〇3_7 a cycloalkyl group and a C:3·7 ring (haloalkyl). Other suitable substituents include -R+ ' -N(R + ) 2 ' -C(0)R+ &gt; -C02R+ &gt; -C(0)C(0)R+ ' -C(0)CH2C(0)R+, -S02R+, -S02N(R+)2, -C(=S)N(R+)2, -C(=NH)-N(R+)2, or -NR+S〇2R+; where R+ is hydrogen, as appropriate Substituted C!·6 aliphatic group, optionally substituted stupid base, optionally substituted -O(Ph), optionally substituted _CH2(Ph), optionally substituted-(CH2) 2(Ph), optionally substituted _CH=CH(Ph), or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen or sulfur; Two R+ independently occurring on the same substituent or different substituents together with the atom to which each R+ group is bonded form a 5-8 membered heterocyclic group, an aryl or heteroaryl ring or a 3-8 membered cycloalkyl ring, wherein The heteroaryl or heterocyclyl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. The substituent which is optionally present on the aliphatic or phenyl ring of R+ is selected from the group consisting of NH2, NH(Ci_4 aliphatic group), &gt;! ((:,-4 aliphatic group) 2, halogen, Ci 4 fat Group, OH, 0 ((3,-4 aliphatic), N02, CN, C02H, COKCw aliphatic), hydrazine (functional C. 4 aliphatic), or halogen (Ci·4 aliphatic) a group in which each of the above C 1-4 aliphatic groups of R+ is unsubstituted. In some embodiments, an aryl group (including an aralkyl group, an aralkyloxy group, an aryloxyalkyl group, and the like) or Heteroaryl groups (including heteroarylalkyl and heteroarylalkoxy groups and the like) may contain one or more substituents. Aryl or heteroaryl 157033.doc • 108· 201215604 based on unsaturated carbon atoms Suitable substituents are selected from the above substituents. Specific examples include halogen, -CN, -OH, -NH2, -NHCCVC^alkyl, -NCCi-C* alkyl)2, -OCOd-G alkyl , -CCKCfC^alkyl), -C02H, -CCMCi-C^alkyl), -oxime (CVQ alkyl), and optionally C substituted by one or more substituents independently selected from the group consisting of ! - C 4 aliphatic group: halogen, pendant oxy group, -c N, - Ο Η, - N Η 2 , -NHd-CU alkyl), -NCCrC^ alkyl)2, -OCCKCVC^alkyl), -(30((1^-04 炫基), -C02H, -C02(Ci-C4 alkyl), -0 ((^-04 alkyl), C3_7 cycloalkyl and C3.7 ring (halogen). Other suitable substituents include: li; -R°; -OR°; -SR.; 1,2 - Methylenedioxy; 1,2-ethylenedioxy; phenyl (Ph) optionally substituted by R; optionally substituted by O. -O(Ph); optionally substituted by R. -(CH2)丨.2(Ph); as appropriate by R. Substituted -CH = CH(Ph) ; -N〇2 ; -CN ; -N(R°)2 ; -NR°C(0)R °; -NR°C(S)R° ; -NR°C(0)N(R°)2 ; -NR°C(S)N(R°)2 ; -NR°C02R° ; -NR°NR °C(0)R°; -NR°NR0C(0)N(R0)2; -NR°NRoC02Ro ; -C(0)C(0)R° ; -C(0)CH2C(0)R° ; -C02R° ; -C(0)R° ; -C(S)R° ; -C(0)N(R°)2 ; -C(S)N(R°)2 ; -0C(0)N (R°) 2 ; -0C(0)R° ; -C(0)N(OR°)R° ; -C(NOR°)R° ; -S(0)2R° ; -S(0)3R ° ; -S02N(R°) 2 ; -S(0)R° ; -NR°S02N(R0)2 ; -NR°S02R° ; -N(OR°)R° ; -C(=NH)-N (R°) 2 ; or -(CH2)0-2NHC(O)R°; wherein each independently occurring R° is selected from , optionally substituted C!-6 aliphatic, unsubstituted 5-6 membered heteroaryl or heterocyclic, phenyl, -O(Ph) or -CH2(Ph), or two independently present in The same substituent or a different substituent on the substituent forms a 5-8 membered heterocyclic group, an aryl group, or a heteroaryl ring or a 3-8 membered cycloalkyl ring together with an atom to which each R° group is bonded. 157033.doc • 109· 201215604 The heteroaryl or heterocyclyl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. Exists in R as appropriate. The substituent on the aliphatic group is selected from the group consisting of NH2, NH (Ci. 4 aliphatic group), N (Ci-4 aliphatic group) 2, halogen, 4 aliphatic group, OH, hydrazine ((: "aliphatic Base), n〇2, CN, C02H, COJCw aliphatic group), fluorene (halogen Cm aliphatic group), or halogen group (Cl.4 aliphatic group), CH〇, (7)-like "aliphatic group" , C(0)N (Cl 4 aliphatic), wherein R. Each of the above C 1-4 aliphatic groups is unsubstituted. The non-aromatic nitrogen-containing heterocycle substituted on the ring nitrogen and attached to the remainder of the molecule at the ring carbon atom is referred to as a N-substituted. For example, a 1 alkylpiperidinyl group is attached to the remainder of the molecule at the 2, 3 or 4 position of the piperidinyl ring and is alkyl substituted on the ring nitrogen. A non-aromatic nitrogen-containing heterocycle which is substituted on the ring nitrogen and which is bonded to the remainder of the molecule at the second ring nitrogen atom (such as a beta-pyrazine group) is referred to as a substituted Ν-heterocyclic ring on Ν'. For example, a Νι醯yl ν_pyrazinyl group is attached to the remainder of the molecule at the ring nitrogen atom and is awake-substituted at the second ring nitrogen atom. The term "unsaturated" as used herein means that the moiety has one or more units of unsaturation. + As detailed above, in some embodiments, two independently occurring Rs. (or R+ or any other variable similarly defined herein) may be combined with the atoms of the various variables to form a 5-8 membered heterocyclyl, aryl or heteroaryl ring or a 3-8 member: alkyl ring. Two independent Rs. Exemplary rings formed by (or R+' or any other variable similarly defined herein) and atoms associated with each variable include, but are not limited to, the following: a) two independently occurring rulers. (or r+, or any other variable similarly defined herein) binds to the same atom and forms an enthalpy with the original 157033.doc •110·201215604, such as N(R.)2, where the two Rs appear. Forming a small base, piperazin-1-yl or morpholin-4-yl with a nitrogen atom; and b) two independently occurring R. (or R+, or any other variable similarly defined herein). ^^ is the same atom and forms a ring with the two atoms, such as \/^^〇R. (where the stupid base is replaced by the two ORs present), the two oxygen atoms that are present together form a fused 6-membered oxygen ring. It should be understood that 'two independent R'. (or R+, or this

Any other variables similarly defined herein) may be combined with the atoms to which the variables are combined, and various other rings and the examples detailed above are not limiting. As used herein, "amino" refers to _Nh2. The term "hydroxy" or "alcohol moiety" means _〇H. As used herein, &quot;side oxy group&quot; refers to 〇. The term "alkoxy" or "alkylthio" as used herein, as used herein, refers to an alkyl group as defined previously via oxygen ("alkoxy", eg,-0-alkyl) or sulphur ( An "alkylthio" group, such as an _s_alkyl group, is attached to the molecule. As used herein, the terms "halogen", "halo" and "hal" mean F, CM, Br or I. As used herein, the term "cyano" or "nitrile" means _CN or -C^N 〇 the terms "alkoxyalkyl", "alkoxyalkenyl" and "alkoxy aliphatic". And "alkoxyalkoxy" means 157033.doc • 111·201215604 alkyl, alkenyl, aliphatic or alkoxy substituted by one or more alkoxy groups, as appropriate. The terms "alkenyl", "dental alkenyl", "aliphatic", "-alkoxy" and "cyclo" are meant to be alkyl, alkenyl, optionally substituted by one or more halogen atoms. An aliphatic group, an alkoxy group or a cycloalkyl group. This term includes perfluorinated yards such as -CF3 and -CF2CF3. The terms "cyanoalkyl", "cyanoalkenyl", "cyanoaliphatic" and "cyanooxy" mean alkyl, alkenyl, or aliphatic, optionally substituted by one or more cyano groups. Group or alkoxy. In some embodiments, the cyanoalkyl group is (NC)-alkyl-. The terms "aminoalkyl", "aminoalkenyl", "aminoaliphatic" and "aminoalkyloxy" mean alkyl, alkenyl, aliphatic, optionally substituted with one or more amine groups. Or an alkoxy group wherein the amine group is as defined above, the terms "hydroxyalkyl", "hydroxyaliphatic" and "hydroxyalkoxy" means an alkane substituted by one or more -OH groups, as appropriate. Base, aliphatic or alkoxy. The terms "oxyalkyl group", "based alicyclic group" and "base oxy group" mean an alkyl, aliphatic or alkoxy group optionally substituted with one or more alkoxy groups. For example, "alkoxyalkyl" means an alkyl group such as (alkyl fluorene)-alkyl, wherein alkyl is as defined above. Unless otherwise stated, the terms (eg, "aliphatic", "alkyl" (including, for example, "alkoxyalkyl", "hydroxyalkyl", "nanalkyl", "cyanoalkyl", "Aminoalkyl", etc., "alkenyl", "alkynyl", "cycloaliphatic group j, "heterocyclic group", "aryl", "heteroaryl", "carbocyclic group", etc.) When used without being superseded as appropriate, these terms mean that 157033.doc -112· 201215604 generation has not been taken. The terms "protecting group" and "protective group" as used herein are used interchangeably and refer to an agent used to temporarily block one or more predetermined functional groups in a compound having multiple active sites. In certain embodiments, the protecting group has one or more or in particular all of the following features: a selective yielding of the functional group with a good yield to obtain a protected substrate; the substrate... one or more other The reaction at the active site is stable; and c) the removal of the agent by chemical reaction with the functional group from which the protecting group is removed by regeneration is selected in good yield. As will be appreciated by those skilled in the art, in some cases, the reagent does not chemically react with other reactive groups in the compound. In other cases, the reagent may also react with other reactive groups in the compound. Examples of protecting groups are detailed in Greene, T. W" Wuts, P. G. rProtective G just ps in 〇rganic Synthesis", 3rd edition, J〇hn wiley &amp; Sons, New York: 1999 (and the book In other versions, the entire contents of which are incorporated herein by reference. The term "nitrogen protecting group" as used herein refers to an agent used to temporarily block one or more pre-nitrogen-reactive sites in a polyfunctional compound. Preferred nitrogen protecting groups also have the features described above for protecting groups, and certain exemplary nitrogen protecting groups are also described in detail in "Protective Groups in Organic Synthesis" 3rd edition by Greene, TW., Wuts, P. G. In Chapter 7, John Wiley &amp; Sons, New

York: 1999' is incorporated by reference herein in its entirety. As used herein, the term "substitutable moiety" or "leaving group" refers to a group that is associated with an aliphatic or aromatic group as defined herein and that is replaced by a nucleophile by a nucleophilic attack. 157033.doc 201215604 Unless otherwise indicated, structures depicted herein are also intended to include all isomers of the structure (eg, enantiomers, diastereomers, cis and trans isomers, conformational variants). Construct and rotamer) forms. For example, unless only one isomer is specifically drawn, the invention includes R and s configurations for each asymmetric center, (z) and (E) double bond isomers, and (2) and (complex configuration) Isomers. As is known to those skilled in the art, the substituted soil can be rotated around any rotatable bond. For example, a substituent having a fluorene bond is also represented.

Thus, single stereochemical isomers as well as enantiomers, diastereomers, cis/trans isomers, conformational isomers and rotamer mixtures of the compounds of the invention are within the scope of the invention . All of the tautomeric forms of the compounds of the invention are within the scope of the invention. Bar Dingmen ^ j and 1 { 羝 羝 亦

Compounds having one or more isotope quinone condensed atoms having the structure of the present invention, in addition to being replaced by carbon or carbon, such as concentrated carbon, are within the scope of the invention, such as 4 (4), for example, bioassay Compound _ is _ analog) in treatment:: probe. The terms "key" and "non-existent" are available. The term 1 is used to mean no group. Structure and/or chemical name The compound of the present invention utilizes its chemistry in this context. 157033.doc .114- 201215604

The compounds described herein may exist in free form or, where appropriate, in the form of a salt. Pharmaceutically acceptable salts are of particular interest because of their suitability for administration of the above compounds for medical purposes. Pharmaceutically unacceptable salts are suitable for use in the separation and purification of the manufacturing process, and in some cases may be used to isolate the stereoisomers of the compounds of the invention or their intermediates as used herein, the term "pharmaceutical "Acceptable salt" means a salt of a compound which, within the scope of correct medical judgment, is suitable for use in humans and lower animals without undue side effects such as poisoning, inflammation, allergic reactions and the like, and is reasonable The revenue/risk ratio is commensurate. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., ip??, 66 ι_19, describe pharmaceutically acceptable salts in detail, which is incorporated herein by reference. The pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. These salts can be prepared on the spot during the final separation and purification of the compound. In the case where the compounds described herein contain a basic group or a substantially basic bioisosteric acid, an acid addition salt can be prepared, for example: 丨) a purified compound in a free form and a suitable organic acid or inorganic Acid reaction; and 2) separation of the salt thus formed. In practice, acid addition salts may be a more convenient form of use and the use of a salt is equivalent to the use of the free base form. 157033.doc •115- 201215604 Examples of pharmaceutically acceptable non-toxic acid addition salts are amine and inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or organic acids (such as acetic acid, B). A salt formed by a diacid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or a salt formed by using other methods (such as ion exchange) used in the art. Other pharmaceutically acceptable salts include adipic acid salts, alginate, ascorbate, aspartate, besylate, benzoate, hydrogen sulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethane sulfonate, formate, fumarate, glucose Acid salt, glycerin phosphate, glycolate, gluconate, hydrazine acetate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy- Ethane sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonic acid Salt, nicotinic acid salt, nitrate, oleate 'oxalate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate , pivalate, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, Salts and the like. In the case where the compound described herein contains a carboxyl group or a sufficiently acidic bioisosteric object, a base addition salt such as hydrazine can be prepared as follows to react a purified compound in acid form with a suitable organic or inorganic base and 2) The salt thus formed is separated. In practice, it may be more convenient to use an additive salt and the use of a salt form is inherently equivalent to the use of the free acid form. Salts derived from appropriate bases include 157033.doc • 116· 201215604 metals (eg, sodium, lithium, and potassium), alkaline earth metals (eg, magnesium and calcium), ammonium, and N+ (C!·4). The present invention also contemplates any of the quaternary reactions of the nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products can be obtained by this quaternization reaction. The test addition salts include pharmaceutically acceptable metal salts and amine salts. Suitable metal salts include sodium, potassium, calcium, barium, zinc, magnesium and aluminum. Sodium and potassium salts are generally preferred. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and the use of relative ions (such as _ s, hydroxide, sulphate, sulphate, phosphate, nitrate, lower alkyl) An amine cation formed by a sulfonate and an aryl sulfonate. Suitable inorganic base addition salts are prepared from metal bases including sodium hydride, sodium hydroxide, potassium hydroxide, hydrazine, hydrazine, hydroquinone, magnesium hydroxide, zinc hydroxide and Its analogues. Suitable amine base addition salts are prepared from amines which are commonly used in pharmaceutical chemistry due to their low toxicity and acceptable for medical use. Ammonia, ethylenediamine, N-methyl-glucosamine, lysine, arginine, auramine, choline, N, N, _ a thioglycolide, chloroprocaine , diethanolamine, procaine, N-benzylphenytamine, diethylamine, piperazine, hydrazino-aminomethane, tetraammonium hydroxide, triethylamine, Diphenylmethylamine, ephenamine, dehydroabietylamine, N-ethyl 0 bottom bite, benzoguanamine, tetramethine, tetrahedral, methylamine, dimethylamine, Trimethylamine, ethylamine, basic amino acid, dicyclohexylamine, and the like. Other acids and bases, while inherently pharmaceutically unacceptable, can be used to prepare salts suitable as intermediates to obtain the compounds described herein and their pharmaceutically acceptable acid or test addition salts. 157033.doc -117· 201215604 It is to be understood that the invention encompasses mixtures/combinations of different pharmaceutically acceptable salts and also includes mixtures/combinations of the compounds in free form with pharmaceutically acceptable salts. Such solvates (e.g., hydrates) can also be prepared by the methods of the present invention and pharmaceutically acceptable in addition to the compounds described herein. As used herein, the term "pharmaceutically acceptable solvate"

M A f § ± acceptable solvent molecules and the solvates formed by the contents described herein. The term solvate includes water names (eg, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like). 0 As used herein, the term "hydrate" means further includes chemistry. A compound of the formula or a salt thereof, in a metered or non-stoichiometric amount of water, which is bound by non-covalent intermolecular forces. As used herein, the term "cage" means the form in the form of a lattice.

A sigma or a salt thereof containing a space (e.g., a channel) in which a guest molecule (e.g., a solvent or water) is trapped. In addition to the compounds described herein, pharmaceutically acceptable derivatives or prodrugs of such compounds can also be prepared by the methods of the invention. "Medically acceptable enchant or prodrug" includes any pharmaceutically acceptable vinegar, vinegar, or other derivative or salt thereof as described herein. It can be directly or indirectly when administered to a recipient. The compounds described herein or inhibitory active metabolites or residues thereof are provided. Particularly advantageous derivatives or prodrugs are those which enhance the compound when such compounds are administered to a patient, for example, to enable the orally administered compound to be more readily absorbed into the blood or In the case of the parent substance, it is possible to enhance the delivery of the parent compound to the biological metabolic zone (for example, the brain or lymphatic system). As used herein, unless otherwise indicated, the term "prodrug" means a compound derived from a compound which hydrolyzes, oxidizes or otherwise reacts under biological conditions (in vitro or in vivo) to provide a compound described herein. Things. Prodrugs may become active when subjected to this reaction under biological conditions, or their unreacted form may be active. Examples of prodrugs encompassed by the present invention include, but are not limited to, analogs or derivatives of the compounds of the invention comprising a biohydrolyzable moiety, such as biohydrolyzable guanamines, biohydrolyzable esters, biohydrolyzable amines, Sa, Biohydrolyzable carbonate, biohydrolyzed brewed urea, and biohydrolyzable phosphate analog. Other examples of prodrugs include derivatives of the compounds described herein that contain a portion of _n〇, -Ν〇2, -ΟΝΟ or -〇N〇2. Prodrugs can generally be prepared using well known methods, such as those described in the literature: BURGER'S MEDICINAL CHEMISTRY and DRUG DISCOVERY (1995) 172-178, 949-982 (edited by Manfred E. Wolff, 5th edition). &quot;Pharmaceutically acceptable derivatives&quot; are adducts or derivatives which, when administered to a patient in need thereof, are capable of providing, directly or indirectly, a compound or a metabolite or residue thereof otherwise described herein. Examples of pharmaceutically acceptable derivatives include, but are not limited to, esters and salts of such esters. Pharmaceutically acceptable prodrugs of the above compounds include, without limitation, esters, amino acid esters, acid esters, metal salts, and acid esters. Those skilled in the art will appreciate that the compounds of the invention may be stereoisomers (e.g., optical isomers (+ and ·), geometric isomers (cis and trans), and configurations 157033.doc -119-201215604 The conformation (axial and equatorial) forms exist. All such stereoisomers are included within the scope of the invention. It will be understood by those skilled in the art that the compounds of the invention may contain a palm center. It may exist in two different optical isomers (i.e., or as (-) enantiomers). All such enantiomers and mixtures thereof, including racemic mixtures, are included within the scope of the invention. -: Diisomers or enantiomers can be obtained by methods well known in the art, such as palmitic HPLC, enzymatic analysis, and palmitic adjuvants. In one embodiment, the compounds of the invention are at least 95%, at least 97%, and at least 99% of the single enantiomer form free of the corresponding enantiomer provides a beta. In another embodiment, the compound of the invention is at least 95% free of the corresponding ( -) The (+) enantiomeric form of the enantiomer. In another embodiment, the compounds of the invention are at least 97% «te /, ~ (+) enantiomers containing the corresponding (one) enantiomer. In another embodiment, the compounds of the invention are At least 99% of the (+) enantiomer form without the corresponding (i) enantiomer ❶ 3 In another embodiment, the compound of the invention is at least 95% free of the corresponding (+) enantiomer (-) enantiomeric form of the isomer. 3 Mesh In another embodiment, the compound of the invention is at least 97% uninvolved (+) enantiomer (·) enantiomer In another embodiment, the compound of the invention is at least 99% free of the (-) enantiomer form of the corresponding (+) enantiomer. The compound is available as a pharmaceutically acceptable 157033.doc -120· 201215604 melon (eg Handb〇〇k 〇f pharmaceutical Salts Properties, Selection, ^ Use, Wiley, 2002, (P. Heinrich Stahl, Camille G) Wermuth ed.). As noted above, these pharmaceutically acceptable salts can be derived from pharmaceutically acceptable inorganic and organic acids and Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, high gas, fumaric acid, maleic acid, acid, glycolic acid, lactic acid, hydrazine, succinic acid, Toluene to sulfonic acid, tartaric acid, acetic acid, trifluoroethylidene and &quot;citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid and stupid sulfonic acid. Other acids such as oxalic acid, although It is itself pharmaceutically unacceptable, but can be used as an intermediate to obtain the compounds of the invention and their pharmaceutically acceptable acid addition salts. Also included are salts derived from amino acids such as L-arginine, L-isoamine. Salts derived from appropriate bases include alkali metal salts (e.g., sodium, lithium, potassium salts), alkaline earth metal salts (e.g., calcium, magnesium salts), ammonium salts, NR4+ (wherein the ruthenium "alkyl" salt, choline and In the embodiment of the present invention, the pharmaceutically acceptable salt is a sodium salt. In the embodiment of the present invention, the pharmaceutically acceptable salt is an oblique salt. In the present invention, the pharmaceutically acceptable salt is a lithium salt. In the embodiment of the invention, the pharmaceutically acceptable salt is a tromethamine salt. In the embodiment of the invention, the pharmaceutically acceptable The acceptable salt is the salt of the present invention, which is acceptable for those skilled in the art. Those skilled in the art will appreciate that the compounds of the invention described herein may be 157033.doc • 121· 201215604 different polycrystals. The type is present. As is known in the art, the polymorphism is a phenomenon in which a compound can be crystallized in the form of a different crystal or a "polycrystalline" (four). The polymorph is a solid crystalline phase of the compound wherein the compound molecule in solid form has one less than two different arrangements or polycrystalline M. The polymorphic form of any given compound is defined by the same chemical formula or composition and the two different compounds are chemically different in structure, and their crystal structures are also different. It will be further appreciated by those skilled in the art that the compounds of the invention described herein can exist in different/solvent forms, such as hydrates. The compounds of the present invention may also form solvates when the solvent molecules are within the crystal lattice structure of the human compound molecules during crystallization. "Individual" or "patient" includes animals and humans (such as males or females, such as children, adolescents or adults), "individuals", "hosts" or "patients" are preferably humans. The invention provides a method of treating or preventing a Flaviviridae viral infection in a host comprising administering to the host a therapeutically effective amount of at least one compound of the invention as described herein. In one embodiment, the viral infection system Selected from a flavivirus infection. In one embodiment, the flavivirus infection is hepatitis C virus (HCV), bovine viral diarrhea virus (BVDV), porcine virus, dengue fever virus, sputum encephalitis virus or Yellow fever virus. In one embodiment, the Flaviviridae virus infection is hepatitis C virus infection (HCV). In one embodiment, the method of the invention is directed to a therapy for HCV genotype 1 infection. In another embodiment , HCV is genotype la or genotype lb. 157033.doc 201215604 In one embodiment 'the invention provides a method of treating or preventing a Flaviviridae viral infection of a host' which comprises Mainly administering a therapeutically effective amount of at least one compound of the invention as described herein, and further comprising administering at least one additional agent selected from the group consisting of a viral serine protease inhibitor, a viral polymerase inhibitor, a viral unwinding Enzyme inhibitors, immunomodulators, antioxidants, antibacterials, therapeutic vaccines, hepatoprotectants, antisense agents, HCV NS2/3 protease inhibitors, and internal ribosome entry site (IRES) inhibitors.

In one embodiment, a method of inhibiting or reducing viral polymerase in a host is provided which comprises administering a therapeutically effective amount of a compound of the invention as described herein. In one embodiment, a method of enzymatic activity, a compound of the present invention. Providing a method for inhibiting or reducing viral aggregation in a host comprising administering a therapeutically effective amount as described herein comprising administering one or more viral polymerase inhibitors, wherein the disease t polymerase is a Flaviviridae viral polymerase . In the case of f &amp;, the viral polymerase is an RNA-dependent RNA polymerase. In an embodiment, the viral polymerase is HCV polymerase. In the treatment or prevention of each of the above mentioned conditions/diseases, the above compounds may be formulated to be further packaged as appropriate, and the above-mentioned compounds, adjuvants, agents or adjuvants ^ Pharmaceutically acceptable formulations. In a consistent application, the present invention is as described herein, "the composition of the composition" which contains at least - the quinquin's Gongmao from the sputum sigma and at least one kind of medicinally acceptable carrier, An adjuvant, a formulation, and any other suitable dosage form and 157033.doc • 123· 201215604 U, a diluent or other liquid vehicle, a dispersion or suspension aid, a surface active agent I, Thickeners or emulsifiers, preservatives, solid adhesives, 'monthly agents and their analogues. Remington's Pharmaceutical nCeS, 16th edition 'EW Martin (Mack Publishing Co., Easton, pa., 198 〇) is disclosed for Formulating various carriers of pharmaceutically acceptable compositions and known techniques for their preparation, unless any conventional carrier medium is incompatible with the present compound, such as to produce any undesirable biological effects or in a deleterious manner Any other group of knives in a pharmaceutically acceptable composition that interacts, otherwise its use is encompassed within the scope of the invention. As used herein, "the side effect" covers treatment (eg, prophylactic or therapeutic agents). produced Effects and adverse effects desired. Side effects are always undesired, but the undesired effects are not necessarily bad. The adverse effects of treatment (e.g., prophylactic or therapeutic agents) can be deleterious or uncomfortable or dangerous. The pharmaceutically acceptable carrier can contain inert ingredients which do not unduly inhibit the biological activity of the compound. A pharmaceutically acceptable carrier should be biocompatible, e.g., t-free, non-inflammatory, non-immunogenic, or non-invasive when administered to an individual. Standard pharmaceutical blending techniques can be used. Examples of some materials that can be used as pharmaceutically acceptable carriers include (but) ion exchange agents, alumina, aluminum stearate, lecithin, serum: white (such as human serum albumin), buffering Substance (such as twin 80, glyceryl phosphate sorbate or potassium sorbate), saturated plant fatty acid = brewed mixture, water, salt or electrolyte (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, chlorination) Sodium or zinc salt), colloidal cerium oxide, 157033.doc •124· 201215604

Magnesium tricaprate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene block polymer, methyl cellulose, hydroxypropyl methylcellulose, lanolin, sugar (such as lactose , glucose and sugar), powder killing (such as corn starch and potato starch), cellulose and its derivatives (such as carboxymethyl Davisina ethyl cellulose and cellulose acetate)' powdered yellow gum, malt, Gelatin, talc, excipients (such as cocoa butter and suppository wax), oils (such as chemical oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), i alcohol (such as propylene glycol or poly Ethylene glycol), such as oleic acid and lauric acid, agar, buffer (such as magnesium hydroxide and aluminum oxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution (Rmger's s〇lution), ethanol and phosphate buffers, and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as color-sensitive J release agents & coatings, sweeteners, Flavoring and Fragrance, Preservatives and Antioxidants It may be present in the composition according to the judgment of the formulator. Depending on the severity of the infection to be treated, the above compounds and their pharmaceutically acceptable compositions can be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (eg as a powder, ointment or drip). In human form, intra-frequency (oral or nasal spray) or the like, it is administered to humans and other animals. As used herein, "parenteral" includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intra-, intra-hepatic, intralesional, and intracranial Injection or infusion techniques. The composition is administered, inter alia, orally, intraperitoneally or intravenously. Any orally acceptable dosage form (including but not limited to capsules, lozenges, aqueous suspensions or solutions) can be used for oral administration. In the case of 157033.doc -125-201215604 for oral use tablets, common carriers include, but are not limited to, lactose and corn starch. A lubricant such as magnesium stearate is also usually added. When administered orally in the form of a capsule, suitable diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with emulsifying and suspending agents. Some sweeteners, flavoring or coloring agents may also be added as needed. Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable

Emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound (the above compound), the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, Benzophenone, benzyl benzoate, propylene glycol, L3-butanediol, dimercaptocarmine-oil (specifically cottonseed oil, strontium oil, corn oil, germ oil, olive oil, castor oil And sesame oil), glycerin, tetrahydrofuranol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof. Besides the inert diluent, the oral compositions may also contain adjuvants such as moisturizing agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents.

The solid dosage forms of oysters include capsules, lozenges, pills, powders and granules. In such solid dosage forms, the active compound is in admixture with at least one pharmaceutically acceptable H-excipient or (iv) (such as lemon (10) or acid-dissolving 2 and/or 7: a) filler or increment Agents such as starch, lactose, grape #mannitol and ♦ acid; b-reading agents, such as betavirin, (tetra) acid salts, gelatin, polyethylene (tetra), and ala = (acacia); e) humectants , such as glycerin, .d) disintegrants, such as slow-acting fat, carbon _, horse yam or cassava powder, alginic acid, certain oxalic acid 157033.doc • 126-201215604 and sodium carbonate; e) dissolved a retarder such as paraffin; f) an absorption enhancer such as a quaternary compound; g) a humectant such as cetyl alcohol and glycerol monostearate; h) an absorbent such as kaolin and bentonite; Agents such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, lozenges and pills, such dosage forms may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft-filled gelatin capsules and hard-filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycols and the like. Solid dosage forms of lozenges, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. It may optionally contain an opacifying agent and may also have a composition such that it releases the active ingredient, if only in a certain portion of the intestinal tract, as appropriate, in a delayed manner. Examples of embedded compositions that can be used include polymers and waxes. Solid compositions of a similar type may also be employed as fillers in soft-filled gelatin capsules and hard-filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycols and the like. The active compound may also be in microencapsulated form with one or more excipients as described above. Solid dosage forms of lozenges, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release control coatings, and other coatings well known in the art. In such solid dosage forms, the active compound can be combined with at least one inert diluent such as sucrose, lactose or starch. In accordance with normal practice, such dosage forms may also contain materials other than inert diluents, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, lozenges and pills 157033.doc • 127· 201215604, these dosage forms may also contain buffers. It may optionally contain opacifying agents and may also be of a composition such that it only releases or preferentially releases the active ingredient in a portion of the intestinal tract, optionally in a delayed manner. Examples of embedded compositions that can be used include polymers and waxes. Injectable preparations (for example, sterile injectable aqueous or oily suspensions)

It is known to be formulated using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion, such as a solution in n-butanediol, in a non-toxic diluent or solvent for parenteral administration. The acceptable vehicles and solvents for the materials are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. Sterile, non-volatile oils are conventionally used as a solvent. For this purpose, any mild, fixed oil may be employed, including synthetic mono-glycol (tetra) or diglyceride. In addition, injectables can be prepared using fatty acids such as oleic acid. The injectable formulations may be sterilized, for example, by filtration through a bacteria-carrying sputum or by sterilizing in the form of a sterile solid composition!

The body composition can be dissolved or dispersed in sterile water or other sterile injectable medium prior to k. The sterile injectable form can be an aqueous or oily suspension. Such suspensions; :: according to techniques known in the art, using suitable dispersing agents or wetting agents 2 heart 1 #=. Sterile injectable preparations can also be: no release in the release agent or solvent or::: can be: if stored in 1,3-butyl-pro φ+, ~, 士' Μ acceptable media can be used and thought h Ringer's solution and isotonic gasification nano solution. In addition, hair oils are conventionally used as a solvent or suspending medium. For this purpose, use: (iv) 157033.doc •128- 201215604 mild fixed oils, including synthetic monoglycerides or diglycerides. Fatty acids (such as oleic acid) and their glycerol 8 derivatives are suitable for the preparation of a biocide, and pharmaceutically acceptable natural oils (such as olive oil or sesame oil: especially in its polyoxyethylated form) are also suitable for the preparation. Injectables. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersing agents, such as buffered cellulose, commonly used in the formulation of pharmaceutically acceptable dosage forms (including emulsions and suspensions). Surfactant (such as

Tween' Span and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms may also be used for formulation purposes. In order to prolong the action of the active compound administered, it is usually necessary to slow the absorption of the compound injected subcutaneously or intramuscularly. This can be accomplished by using a liquid suspension of crystalline or amorphous material that is poorly soluble in water. The rate of absorption of a compound depends on its rate of dissolution, which in turn depends on crystal size and crystalline form. Alternatively, the absorption delay in the form of a parenterally administered compound is achieved by dissolving or suspending the compound in an oil vehicle. Injectable reservoir forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. The rate of release of the compound can be controlled depending on the ratio of the compound to the polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Reservoir injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues. If desired, the above formulations may be formulated with a modified sustained release active ingredient. 0 157033.doc -129 - 201215604 A composition for rectal or vaginal administration, especially a suppository, which may be formulated with a non-irritating agent Prepared by mixing a vehicle or carrier such as cocoa butter, polyethylene glycol or suppository, which is solid at ambient temperature but liquid at body temperature and therefore in the rectum Or vaginal cavity melts and releases the active compound. Dosage forms for topical or transdermal administration include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. When desired, the active ingredient is placed under sterile conditions with a pharmaceutically acceptable carrier and any desired preservative or buffer. Ophthalmic formulations, ear drops, and eye drops are also contemplated as being within the scope of the invention. In addition, transdermal patches may be used with the added advantage of controlled release of the compound into the body. Such dosage forms can be prepared by dissolving or dispensing the compound in the appropriate medium. Absorption enhancers can also be used to enhance the flow of a compound across the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer based f or gel. Alternatively, the above compounds and their pharmaceutically acceptable compositions can also be administered by nasal aerosol or inhalation. These compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be used in physiological saline using benzyl alcohol or other suitable preservatives, absorption enhancers that enhance the strong bioavailability of peaks, fluorocarbons, and/or other conventional dissolutions. The agent or dispersant is prepared as a solution. The above compounds and their pharmaceutically acceptable compositions can be formulated into unit dosage forms. The term "unit dosage form" refers to a physical individual unit that is suitable for use as an early-type dose for an individual undergoing treatment. Each unit in # contains a predetermined amount of active substance calculated to produce the desired effect, as appropriate and suitable for the medical 157033. Doc 201215604 Drug carrier combination. The unit dosage form can be a single-day dose or multiple daily doses (e.g., about 1 to 4 times or more than 4 times daily). When multiple doses are used, the unit dosage form of each dose may be the same or different. The amount of active compound in a unit dosage form will vary depending, for example, on the host treated and the particular mode of administration, for example, from 0.01 mg to 100 mg per kilogram of parent weight. It will be appreciated that the amounts of the compounds of the invention described herein for use in therapy are not only dependent upon the particular compound selected, but also on the route of administration, requiring treatment

The nature of the condition, and the age and condition of the patient vary, and is ultimately determined by the attending physician or veterinarian. However, in general, the suitable dose will be in the range of from about 0.1 to about 750 mg per kilogram of body weight per day, for example, in the range of from 5 to mg per kilogram of body weight per day, or, for example, in the range of (9) mg per kilogram of body weight per day. Inside. The desired dose is provided in a single dose; £ or in divided doses administered at appropriate intervals, e.g., twice, three times, four times, or more than four doses per day. In an embodiment, the invention provides a pharmaceutical composition comprising at least one compound of the invention described herein and further comprising one or more additional agents selected from the group consisting of a viral serine protease inhibitor, a viral polymerase inhibitor , viral helicase inhibitors, immunomodulatory antioxidants, antibacterial agents, therapeutic vaccines, hepatoprotectants, antisense agents, HCv donation/3 protease inhibitors and internal ribosome entry sites (111 £ 8) inhibition Agent. In another embodiment, a combination therapy of at least one of the compounds of the present invention and/or a plurality of other agents selected from the group consisting of viral serine (IV), viral polymerase (IV), and viral solution is provided. Cyclonease inhibitors, immunomodulatory antioxidants, antibacterial agents, therapeutic vaccines, 157033.doc -131- 201215604 liver protectants, antisense agents, HCV NS2/3 protease inhibitors and internal ribosome entry sites (IRES) ) inhibitors. Other agents for use in compositions and combinations include, for example, ribavirin, amantadine, merimepodib, levovirin, Viramidine, and histamine dihydrochloride. (maxamine) In a combined embodiment, the compound and other pharmaceutical agents are administered sequentially. In another combined embodiment, the compound and other pharmaceutical agents are administered simultaneously. The combinations mentioned above are preferably provided in the form of a pharmaceutical formulation which can be used, and thus, a pharmaceutical formulation comprising a combination as defined above and a pharmaceutically acceptable carrier thus constitutes another aspect of the invention. .

The term "viral serine protease" as used herein means an agent effective to inhibit the function of viral serine proteases, including HCV serine proteases, in mammals. HCV serine protease inhibitors include, for example, those compounds described in WO 99/07733 (Boehringer Ingelheim) 'WO 99/07734 (Boehringer Ingelheim) 'WO 00/09558 (Boehringer Ingelheim), WO 00/09543 (Boehringer Ingelheim), WO 00/59929 (Boehringer Ingelheim) &gt; WO

02/060926 (BMS) 'WO 2006039488 (Vertex), WO 2005077969 (Vertex), WO 2005035525 (Vertex), WO 2005028502 (Vertex) WO 2005007681 (Vertex), WO 2004092162 (Vertex), WO 2004092161 (Vertex), WO 2003035060 (Vertex), WO 03/087092 (Vertex), WO 02/18369 (Vertex), or W098/17679 (Vertex). 157033.doc -132- 201215604 The term "viral polymerase" as used herein means an agent that is effective in inhibiting the function of a viral polymerase (including HCV polymerase) in a mammal. HCV polymerase inhibitors include non-nucleosides such as those described in the following documents: WO 03/010140 (Boehringer Ingelheim), WO 03/026587 (Bristol Myers Squibb); WO 02/100846 A1 'WO 02/100851 A2 , WO 01/85172 AI (GSK), WO 02/098424 Al (GSK), WO 00/06529 (Merck), WO 02/06246

Al (Merck), WO 01/47883 (Japan Tobacco), WO 03/000254 (Japan Tobacco) and EP 1 256 628 A2 (Agouron). In addition, other inhibitors of HCV polymerase also include nucleoside analogs such as those described in the following documents: WO 01/90121 A2 (Idenix) 'WO 02/069903 A2 (Biocryst Pharmaceuticals Inc), and WO 02 /057287 A2 (Merck/Isis) and WO 02/057425 A2 (Merck71sis). Specific examples of nucleoside inhibitors of HCV polymerase include R1626, R1479 (Roche), R7128 (Roche), MK-0608 (Merck), R1656 (Roche-Pharmasset), and Valopicitabine (Idenix). Specific examples of HCV polymerase inhibitors include JTK-002/003 &amp; JTK-109 (Japan Tobacco), HCV-796 (Viropharma), GS-9190 (Gilead), and PF-868, 554 (PHzer). The term "viral NS5 A inhibitor" as used herein means an agent effective to inhibit the function of the viral NS5A protease in a mammal. HCV NS5A inhibitors include, for example, those compounds described in the following literature: W02010/117635, W02010/117977, W02010/117704, 157033.doc-133-201215604 W02010/1200621, W02010/096302, W02009/102633 'W02009/102318 , W02008144380, W02008/021927, W02004/014313, W02010/065668, W02010/099527 &gt; W02010/094077, W02009/102568, W02009020828, W02008/021936 'WO2006/133326 'W02010/096777, W02010/065674, W02010/096462, W02010/111483, W02010/017401, W02009/102325, W02009020825, W02008/021928, W02004/014852, W02010/065681, W02010/062821, W02010/091413 'W02010/120935,

WO2010/126967, WO2010/132538, and WO201 (V122162. Specific examples of HCV NS5A inhibitors include: EDP-239 (developed by Enanta); ACH-2928 (developed by Achillion); PPI-1301 (developed by Presido Pharmaceuticals); PPI-461 (developed by Presido Pharmaceuticals); AZD-7295 (developed by AstraZeneca); GS-5885 (developed by Gilead); BMS-824393 (developed by Bristol-Myers Squibb); BMS-790052 (developed by Bristol-Myers Squibb) )

BMS-790052

3 (Gao M. et al., Nature, 465, 96-100 (2010); nucleoside or nucleotide polymerase inhibitors such as PSI-661 (developed by Pharmasset), PSI-938 (developed by Pharmasset), PSI -7977 (developed by Pharmasset), INX-1 89 (developed by Inhibitex), JTK-853 (developed by Japan Tobacco), TMC-647055 (Tibotec Pharmaceuticals), RO-5303253 (by 157033.doc -134- 201215604

Developed by Hoffmann-La Roche), and IDX-184 (developed by Idenix Pharmaceuticals). The term "viral helicase inhibitor" as used herein means an agent which is effective for inhibiting the function of a viral helicase (including a Flaviviridae helicase) in a mammal.

As used herein, &quot;immunomodulatory agent&quot; means an agent that is effective to increase or enhance the immune system response of a mammal. Immunomodulators include, for example, class I interferons (such as alpha-interferon, beta-interferon, Δ-interferon and ω-interferon, X-interferon, complex interferon and asialo-interferon), and sputum interference (such as γ-interferon) and pegylated interferon. Exemplary immunomodulatory agents include, but are not limited to, thalidomide, IL-2, hematopoietin; IMPDH inhibitors, such as Vertex Pharmaceuticals Inc; interferons, including natural interference (such as OMNIFERON, Viragen and SUMIFERON, Sumitomo, blend of natural interferon), natural interferon a (ALFERON, Hemispherx Biopharma, Inc), interferon-an derived from lymphoblastoids (WELLFERON, Glaxo Wellcome), Oral cx interferon, pegylated interferon, pegylated interferon a2a (PEGASYS, Roche), recombinant interferon a2a (ROFERON, Roche), inhaled interferon a2b (AERX, Aradigm), PEGylation Interferon a2b (ALBUFERON, Human Genome Sciences/Novartis, PEGINTRON, Schering), recombinant interferon a2b (INTRON A, Schering), pegylated interferon a2b (PEG-INTRON, Schering, VIRAFERONPEG, Schering), interferon p -la(REBIF,Serono, 157033.doc -135- 201215604

Inc. and Pfizer), interferon a (INFERGEN, Valeant Pharmaceutical), interferon y-lb (ACTIMMUNE, Intermune, Inc.), unpegylated interferon alpha, alpha interferon and its analogs, and synthesis Thymosin al (ZADAXIN, . SciClone Pharmaceuticals Inc.). The term "class I interferon" as used herein means an interferon selected from the group of interferons that bind to a type 1 receptor. It includes naturally occurring class I interferons and synthetically produced class I interferons. Examples of class I interferons include alpha-interferon, beta-interferon, delta interferon and omega-interferon, tau-interferon, complex interferon, and asialo interferon. The term "interferon type II" as used herein means an interferon selected from the group of interferons that bind to a type II receptor. Examples of class II interferons include gamma-interferon. Antisense agents include, for example, ISIS-14803. Specific examples of HCV NS3 protease inhibitors include BILN-2061 (Boehringer Ingelheim), SCH-6 and SCH-503034/Boceprevi-r (Schering-Plough), VX-950/telaprevir (Vertex), and ITMN-B (InterMune), GS9132 (Gilead) 'TMC-435350 (Tibotec/Medivir) &gt; ITMN-191 (InterMune), MK-7009 (Merck) o Internal ribosome entry site (IRES) inhibitors including ISIS-14803 (ISIS Pharmaceuticals) and WO Their compounds (PTC therapeutics) as described in 2006019831. In one embodiment, the other agent is interferon alpha, viral saliva, silybum marianum, interleukin-12, amantadine, ribozyme, thymosin, N-acetylcysteine or circumcision Cyclosporin. In one embodiment, the other agent is interferon otlA, interferon alpha ΙΒ, 157033.doc-136-201215604 interferon alpha 2 A or interferon alpha 2 Β. Interferons can be used in both PEGylated and non-PEGylated forms. Pegylated interferons include PEGASYSTM &amp; Peg-intronTM. The recommended dose for one of the treatments for chronic hepatitis C is 180 mg (l_0 mL vials or 0.5 mL prefilled syringes), once a week for 48 weeks, subcutaneously in the abdomen or thigh. When used in combination with viral sputum for chronic hepatitis C, the recommended dose for pegasystm is 180 mg (1. 〇 mL vial or 0.5 mL syringe with pre-filled drug), mother-week-time. —The points a~% are used for the purchase of the eight-day mouth. A typical standard daily dose of ribavirin (for example, about 200 mg of tablet) is mg to 12 mg. For example, a viral wort agent is administered to an individual having a body weight of less than 75 kg at about _mg, or an individual having a weight of more than or equal to 75 kg at about 12 (9). However, in the present invention, the present invention

== is not subject to any specific dosage form or therapy. Typically, the dosing regimen described in the virus is administered. ’-, the dose should be administered on the same day of the week. When administered with the virus, pE (Mrm kg/week. Heart recommender 1 is 1.5 μg / in the example, the viral serine methionine protease inhibitor. The agent is more viral.) Example Φ, β-toxic polymerase inhibits Sword-Dragon 10* preparation. 』 is a Virgoviral polymerase 157033.doc • 137- 201215604 In one embodiment, the viral helicase inhibitor is a Flaviviridae helicase In other embodiments, the viral serine protease inhibitor is an HCV serine protease inhibitor; the viral polymerase inhibitor is an HCV polymerase inhibitor; the viral helicase inhibitor is an HCV helicase inhibitor In one embodiment, the invention provides a pharmaceutical composition comprising at least one compound of the invention described herein; or a plurality of other agents selected from the group consisting of non-nucleoside HCV polymerase inhibitors (eg, Hcv_796), nucleoside HCV polymerization Enzyme inhibitors (eg R7128, R1626, R1479), HCV NS3 protease inhibitors (eg VX-950/teiaprevir &amp; ITMN191), interferon and ribavirin; and at least one pharmaceutically acceptable Carrier or shape The combinations mentioned above are preferably provided in the form of a pharmaceutical formulation that can be used, and thus, a pharmaceutical formulation comprising a combination as defined above and a pharmaceutically acceptable carrier thus constitutes another aspect of the invention. The individual components used in the methods of the invention or in the combinations of the invention may be administered sequentially or simultaneously in separate or combined pharmaceutical formulations. In one embodiment, the invention provides a compound of the invention as described herein. Use in the treatment or prevention of a Flaviviridae viral infection in a host. In an embodiment, the invention provides the use of a compound of the invention as described herein for the manufacture of a medicament for the treatment or prevention of a Flaviviridae viral infection in a host. - In the examples, the use of a compound of the invention as described herein for inhibiting or reducing viral polymerase activity in a host. 157033.doc 201215604 In another embodiment, the composition or combination of the invention further comprises At least one compound of the invention described herein; one or more additional agents selected from the group consisting of non-nucleoside HCV polymerase inhibitors (eg, HCV-796), nuclear HCV polymerase inhibitors (eg, R7128, R1626, R1479) and HCV NS3 protease inhibitors (eg, VX-950/Trappy and ITMN-191); and interferon and/or virus alpha sit. In one embodiment The other agent is interferon alpha, interferon alpha, interferon alpha 2 or interferon alpha 2, and optionally ribavirin. In one embodiment, the invention provides a method of treating or preventing HCV viral infection in a host, A combination comprising at least one compound of the invention as described herein and one or more other agents selected from the group consisting of a non-nucleoside HCV polymerase inhibitor (eg, HCV-796), a nucleoside HCV, comprising administering to the host a therapeutically effective amount. Polymerase inhibitors (eg, R7 128, R1626, R1479), HCV NS3 protease inhibitors (eg, VX-950/tratopril and ITMN-191), interferons, and ribavirin. In a combined embodiment, the compound and other pharmaceutical agents are administered sequentially. In another combined embodiment, the compound and other pharmaceutical agents are administered simultaneously. In one embodiment, a method of inhibiting or reducing HCV viral polymerase activity in a host comprising administering to the host a therapeutically effective amount of at least one compound of the invention in combination with one or more other agents selected from the group consisting of: : non-nucleoside HCV polymerase inhibitors (eg HCV-796) and nucleoside HCV polymerase inhibitors (eg R7128, R1626, R1479), interferons and viruses. The combinations mentioned above are preferably provided in the form of a pharmaceutically acceptable pharmaceutical formulation, 157033.doc - 139 - 201215604 and, thus, a pharmaceutical formulation or combination comprising a combination as defined above and a pharmaceutically acceptable carrier The article thus constitutes another aspect of the invention. The individual components used in the methods of the invention or in the combinations of the invention may be administered sequentially or simultaneously in separate or combined pharmaceutical formulations. In one embodiment, the invention provides the use of at least one compound of the invention in combination with one or more other agents selected from the group consisting of: for the manufacture of a medicament for the treatment or prevention of HCV infection in a host: a non-nuclear HCV polymerase inhibitor (eg, : δ HCV 796), nucleoside HCV polymerase inhibitors (eg R7128, IU626, R1479), HCV NS3 protease inhibitors (eg νχ_95〇/特#Lapvi and ΙΤΜΝ-191), interferon and ribavirin. When a compound of the invention as described herein is used in combination with at least one second therapeutic agent having activity against the same virus, the dose of each compound may be the same as or different from the dose when the compound is used alone. Those skilled in the art will readily be able to identify the appropriate dosage. The administration amount of the compound of the present invention described herein is relative to other agents (non-nuclear bud HCV polymerase inhibitor (eg, Hcv_796), nuclear hcv polymerase inhibitor (eg, R7128, Rl626, R1479), (iv) (d) protease inhibitor # preparation ( For example, the dose ratio of VX-950/Trapov and ΙΤΜΝ_ΐ9ι), +Interferon or viral saliva will vary depending on the choice of compound and other agents. In addition, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art. All publications, patent applications, patents, and other references mentioned herein are hereby incorporated by reference in their entirety. The present specification, including definitions, is subject to inconsistency. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. EXAMPLES Example 1 : Synthesis of Compounds of the Invention Any of the compounds of the invention described herein may utilize any of the techniques known in the art (e.g., US 6,881,741, US 2005/0009804, US 2006/0276533, WO 2002/100851, and WO 08/58393). Suitable for method preparation. The preparation of some exemplary compounds is detailed below. The synthesis of certain exemplary compounds of the invention is described below. In general, the compounds of the invention can be prepared as shown in the synthesis of the invention, as appropriate, with any modifications as appropriate. General Methods of Analysis and Methods for Synthesizing and Characterizing Compounds As used herein, the term RT (min) refers to the LCMS residence time (minutes) associated with a compound. The NMR and mass spectral data for some specific compounds are summarized in Tables 1 and 2. Preparation of compound 5

Step I: Trans-4-methylcyclohexylcarboxylic acid chloride. To the suspension of trans-4-methylcyclohexylcarboxylic acid (2.3 g, 16 mmol) in dichloromethane (5 mL) and DMF (0.1 mL) 157033.doc -141 - 201215604 Gas (2 M, contained in dichloromethane, 丄 7 mL). The reaction mixture was stirred at room temperature for 3 hours. The volatiles were removed under reduced pressure to give a crude acid gas which was used directly in the next reaction. 5-(3,3-Dimethyl-butynyl)_3_[(trans-4-methyl-cyclohexylcarbonyl)amino]-thiophene-2-carboxylic acid methyl ester. To 3-amino-amino-5-(3,3-diindenyl-tau- 1 -alkynyl)-thiophene-2-decanoate (2.5 g, 1 〇mm〇l) in di-ethane The solution in mL) was added with trans-4-mercaptocyclohexyldecanoic acid vapor (2 54 g, 15 8 mmol). The resulting mixture was stirred at 8 (TC for 16 hours. The reaction mixture was diluted with chloroform) and then water was added. The organic layer was separated, dried (Na.sub.4) and concentrated. 20% EtOAc. Purification of solids by Shixi gum column chromatography to obtain 5-(3,3-dimethyl-but-1-ynyl)_3_[(trans-4-indolyl-cyclohexylcarbonyl)-amino]-thiophene 2_Methyl decanoate (3.37 g) Step II: 5-(3,3-Dimethyl-but-1-ynyl)_3_[dimethylaminecarbamimidylmethyl-trans-4-methyl-ring Ethylene)-Amino]·Fan-2-methyl formate. '5-(3,3-Dimercapto-but-1-ynyl)-3-[(trans-4-methylcyclohexylcarbonyl)-amino]-° thiophene in a 1 mL flask Ethyl 2-formate (100 mg, 0.277 mmol) was dissolved in DMF (1 mL) and cooled to EtOAc EtOAc. 2-Gas-N,N-dimethyl-acetamide (50 mg, 0-41 mmol) was added to the mixture and stirred at room temperature overnight. The reaction mixture was cooled to 〇 ° C and water (0.5 mL) was added and extracted between water and ethyl acetate. The organic layer was separated and dried (Na2SO4). Evaporation of the solvent gave 5-(3,3-dimercapto-but-1-ynyl)-3-[dimethylaminoindolyl-(trans-4-methyl-cyclohexylcarbonyl)-amine Ethyl]-thiophene-2-carboxylate (49 mg, 42% yield). 157033.doc -142· 201215604 Step III: 5-(3,3-Dimethyl-but-1-ynyl)-3-[dimethylaminecarbamimidomethyl-(anti-4-methyl-ring Retardyl)-amino]-porphin-2-carboxylic acid. To 5-(3,3-dimercapto-but-1-ynyl)-3-[dimethylaminecarbamimidyl-(trans-4-fluorenyl-cyclohexylcarbonyl)-amino]- Methyl thiophene-2-carboxylate (52 mg, 0.12 mmol) was added to a solution of THF, methanol, water (1 mL). The resulting mixture was stirred at room temperature overnight. The solvent was removed and purified by preparative HPLC using a Phenomenex AXIA Gemini 5u C18 110A 100 mm x 30 mm column (gradient 39% to 69% acetonitrile: 3 mM HCl in water < 90 min and flow rate 12 mL/min) substance. Thus, 5-(3,3-dimercapto-but-1-ynyl)_3_[didecylaminecarbazinyl-(trans-4-indolyl-cyclohexylcarbonyl)amino group]- Thiophene-2-carboxylic acid 5 (38 mg, 76% yield). LCMS [M+H]+: 433.05. Preparation of compound 6

5-(3,3-dimethyl-but-1-ynyl)_3_[(trans-4-indolyl-cyclohexylcarbonyl)-(2_f-oxy-2-pyrrolidin-1-yl-B Amino]-thiophene-2-carboxylic acid. Compound 6 was prepared using a procedure similar to that described above for the preparation of compound 5: LCMS [M+H] + : 459.01 〇 Preparation of compound 4 157033.doc • 143- 201215604

3-[(2,4-dioxa-benzylidenyl)-dimethylamine-methylmethyl-amino]-5-(3,3-dimethyl-but-1-ynyl)- Thiophene-2-carboxylic acid. Compound 4 was prepared using a procedure similar to that described above for the preparation of compound 5: LCMS [M+H] + : 480.93. Preparation of Compound 1

5-(3,3-dimethylbut-1-ynyl)-3-[[2-(methylamino)-2-oxo-ethyl]-(trans-4-methylcyclohexane Carbonyl)amino]thiophene-2-carboxylic acid. Compound 1 was prepared using a procedure similar to that described above for the preparation of compound 5: LCMS [M+H] + : 419.60. Preparation of Compound 2 157033.doc -144- 201215604

Step i: φ Cool the 'smelting copper (II) (1.74 g ' 7.78 mmol} suspension in acetonitrile to 〇 °c' followed by the addition of tribasic vinegar (14 mL, 1〇4匪〇) 1), and the mixture is stirred for 15 minutes. After 5 minutes, 5_(3,3 dimethylbutanyl)-3-amino-porphin-2-carboxylic acid methyl acetate 〇% g, 7 42 〇1 ) added to the mixture in multiple portions. The mixture was warmed to room temperature and the separator was stirred at room temperature. The mixture was evaporated to dryness. The residue was redissolved in 5 mL of CH2Cl2, and 50 mL of 1% HCl was added to the mixture and stirred at room temperature for 3 Torr. The organic portion was separated, washed with brine, dried over Na 2 EtOAc and evaporated to dryness to afford 2.9 〇 5 g of 5-(3,3-didecyl-but-1-ynyl)_3_bromo-thiophene-2_ Methyl vinegar. Step II: To 5-(3,3-monomethyl-but-1-ynyl)-3-bromo- sin-2-carboxylate (48 mg, 0.16 mmol) and (R)-2- Addition of carbonic acid planing (23 mg, 0.048 mmol) and Pd(OAc)2 to a solution of aminyl-N,N-dimethyl-propanolamine (37 mg, 0.32 mmol) in anhydrous toluene (1 mL) (ll mg, 0.048 mm〇i). The oxygen from the mixture was removed by bubbling nitrogen through the solution for 10 minutes. 157033.doc -145- 201215604 Add BINAP (40 mg, 0.064 mmol) to the mixture and heat at 90 C for 16 hours under nitrogen. The mixture was diluted with ethyl acetate and passed through celite. washing. The filtrate was concentrated under reduced pressure, dried over Na.sub.2.sub.4.sub.sub.sub.sub.sub.sub.sub.sub.sub. -l-alkynyl)-3-((R)-l-didecylaminoindenyl-ethylamino)-thiophene-2-carboxylic acid methyl ester (25 mg, 47%). Step ΙΠ : 5-(3,3-Dimethyl-but-propynyl•dimethylaminecarbamimidylethylamino)-thiophene-2-furic acid methyl ester (315 mg, 0.937 mmol) as above Deuteration with the gas of trans-4-mercaptocyclohexylcarboxylic acid as described (Example 3 Step I) gave the desired product (41 8 mg, 97%). Step IV: 5-(3,3-Dimethyl-but-1-ynyl)_3-[((R)-i-diylylaminomethane-ethyl)-(trans-4-methyl- Cyclohexyl)-aminopurine benzoic acid. Step in product (3 7 mg '0.080 mmol) was hydrolyzed with lithium hydroxide as described below to give compound 2 (14 mg, 41%): NMR (400 MHz, DMSO): δ 7.05 (s, 1H), 5.22 ( q, 1H), 3.01 (s, 3H), 2.81 (s, 3H), 1.99 (t, 1H), 1.76-1.00 (m, 16H), 0.90 (d, 3H), 0.73 (d, 3H), 0.69 -0.35 (m, 2H); LCMS [M+H]+: 447.2. Preparation of compound 3

157033.doc -146- 201215604 5-(3,3_Dimethylbut_1-ynyl)-3-[((S)-l-dimethylaminecarbamyl-ethyl)- (anti-A Base-cyclohexylcarbonyl)-amino]-thiophene-2-carboxylic acid. Compound 3 was prepared using a procedure similar to that described above for the preparation of compound 2: LCMS [M+H] + : 447.4. Preparation of Compound 7

5-(3,3-Dimethyl_τ-1_alkynyl)_3_[(1-dimethylaminocarbamimidylethyl)·(trans-4-indolyl-cyclohexylcarbonyl)-amino Buthiophene-2-carboxylic acid. Compound 7 was prepared using a procedure similar to that described above for the preparation of compound 2: [CMS [Μ+Η] + : 446.99. Alternative Preparation of Compound 6 Step 1:

The acid hydride is prepared from a carboxylic acid by salting with ethylene dioxane (1" equivalent) in toluene (1 volume equivalent) in the presence of a catalytic amount (〇〇5 equivalents) of DMF at 〇 °C. And slowly warmed to room temperature (gas evolution). After 6 hours of mixing, the toluene was removed by rotary evaporation at 45 ° C until the mass of the mixture was about 157033.doc -147. 201215604 about twice the yield (50 weight % /.). The acid hydride can be stored at 〇〇Ct under nitrogen for use in subsequent steps. At 0 °C will be contained in 1 〇 % „ than bite

Commercially available 3-amino-5-expressol-2-carboxylate (5 g, 17.49 mmol) in /DCE/DCM (49.5 mL) with pyridine as solvent (2 91 g, 2 97 mL, 36.7 Mixing, followed by the addition of acid sulphate (6 7 〇g, 21.0 mmol, 50 〇/〇' in toluene). After 5 minutes, the bath was removed and stirred for 1.25 hours while the reaction reached room temperature. The treatment was carried out by adding brine. Then extracted with DCM (2×1 〇〇mL), combined and washed with 1 N HCl (50 mL), washed with 1:1 1 N NaOH (50 mL) / brine (50 mL) Back extraction 1 time, followed by drying over sodium sulfate, filtration and stripping to give a solid. It was wet-milled with hexanes and filtered and dried to give 4 g (yield: 68%). Analysis by LCMS (60-98 Me0H/H20, EtOAc, 5/7 min, C18); RT = 2.45 min, [M+H] = 407.14. Step 2:

The starting material decylamine (1 g, 2.3 mmol) and THF (9.5 mL) were added to dry simmer and placed under nitrogen. Cool with an ice bath. (Bis(trimethylsulfonyl)-amino) (2.9 mL, 1 M, 2.9 mmol) was added and the mixture was stirred at EtOAc for 25 min. To the cold mixture was added 2-bromoacetic acid tert-butyl ester (546 mg, 2·80 mmol). The reaction was then heated to 5 ° C and stirred for 72 hours. 157033.doc -148- 201215604 The brine and EtOAc were added and the product was extracted with EtOAc EtOAc EtOAcjEtOAc Purification was carried out by flash chromatography (Si 〇 2, ISCO instrument) using a gradient of EtOAc-hexanes (0-20% of 10 column volumes (CV) followed by 20 C of 2 CV). The pure fractions were taken and stripped to give the desired product as a solid (0.6 g, 48%). It was analyzed by LCMS (60-98 Me0H/H20, formic acid modifier, 5/7 min, C18); RT = 5.42 min, MH+ = 522.16. Step 3:

A solution of the starting material, butyl succinate (415 mg, 0.756 mmol) in DCM (2 mL) was cooled to 0 &lt;0&gt;C, followed by the addition of DCM (7 mL) (30%) (TFA/DCM solution)), allowed to reach room temperature overnight, using a rotary evaporator to remove solvent and TFA. After drying under high vacuum, the desired carboxylic acid (435 mg, quantitative yield) was obtained as a reddish brown glass. Analyzed by LCMS (60-98 MeOH/H20, EtOAc, 5/7 min, C18); RT = 3 - 50 min, MH+ = 466.1. Step 4 ··

157033.doc -149- 201215604 In a dry 100 mL flask, the starting material iodide (2.5 g, 4.3 mmol) was mixed in dioxane (54 mL) under a nitrogen atmosphere with an external ice bath. Cool and blow off the nitrogen on the reactants. Copper moth (41.2 mg, 0.216 mmol) was added followed by 3,3-dimercaptobut-1-yne (800 g, 6-70 mmol) and sparged with nitrogen for 5 min. Two gas-bis(triphenylphosphino)(165 mg, 0.234 mmol) was added, then the bath was removed and the reaction was stirred at room temperature overnight. The reaction is a homogeneous reaction. After about 16 hours, the reaction was checked and was completed by TLC (20% MeOH/DCM). Add EtOAC (50 mL) and pass through the gas. After fluorination, it was washed with EtOAc (3 x 25 mL) and combined. It was then dissolved in 20% MeOH / EtOAc until the product spot was very light. The fractions were combined and stripped and the product was a black glassy solid. Decolorized charcoal was added and stirred with about 10% MeOH / EtOAc. Filtration through diatomaceous earth and removal of solvent gave 2.9 g. Dissolved in DCM (250 mL), EtOAc (EtOAc)EtOAc. Analyzed by LCMS (60-98 MeOH/H.sub.2, EtOAc, EtOAc, EtOAc, EtOAc) Step 5:

The starting carboxylic acid (192 mg, 0.408 mmol) and HBTU (1.66 mL, 157033.doc -150 - 201215604 0.5 M, 0_830 mmol) (0.5 溶液 solution in DMF, prepared in advance and stored in the freezer ) placed together in a vial. DIEA (134 mg, 181 bL, 1.04 mmol) was added and subsequently added.嘻 η (61.4 mg, 72.1 μΐ^ ' 0.864 mmol), and the reaction was stirred at room temperature overnight. The reaction was monitored by HPLC and found to be proceeding. The mixture was extracted with EtOAc (2 mL). The product was purified by flash chromatography (EtOAc EtOAc (EtOAc) elute Analyzed by LCMS (60-98 MeOH/H.sub.2, EtOAc, EtOAc, EtOAc) Step 6:

Compound 6. The starting material oxime ester (130 mg, 0.275 mmol) in MeOH (5 mL) was combined with EtOAc (2 N, 5 mL, 10 mmol) and the mixture was stirred overnight at ambient temperature. The reaction was checked by HPLC and found to be free of residue. The MeOH was stripped and 15 mL of 1 N HCl (aq) and 15 mL brine were added. It was extracted with 2 x 30 mL of 1:1 diethyl ether-EtOAc (30 mL), dried over sodium sulfate, filtered and evaporated. Purification on semi-preparative 11?1^(:(40-95% CH3CN/H2〇; 0.1% TFA); homogeneously dissolving and mixing with corrected LCMS number 157033.doc -151 - 201215604 Compound 6 (54.5 mg, 42%) was obtained by LCMS (60-98 MeOH/H20, formic acid modifier, 5/7 min, C18); RT = l_62min, ΜΗ+=459·46. 1 :

(S)-2-Amino-1-morpholinylbutan-1-one hydrochloride. (S)-2-(((Benzyloxy)carbonyl)amino)butanoic acid (250 mg, 1.05 mmol) with HBTU (0.5 Μ in DMF, 2.13 mL, 1.16 mmol) and DIEA (550) Μΐ, 3.16 mmol) and morpholine (115 μΐ, 1.32 mmol) were mixed and stirred at room temperature for two hours, then HPLC showed the reaction was completed. Brine (10 mL) was added and EtOAc (EtOAc m. The organic extract was passed through a silica gel plunger (2 g, Bond-Elute) and washed with an excess of EtOAc until no other product was dissolved. The homogeneous fractions were combined and EtOAc was removed in vacuo. Dissolved in MeOH (3 mL) and stirred at 1 atmosphere of hydrogen (using a balloon) for 16 hours in the presence of 10% Pd/C. The reaction was filtered through a pad of celite and washed with additional MeOH (3.times.5 mL). Product formation was confirmed by TLC observation of the consumption of the starting material and stronger polar spots stained with indanone. It was used as such in the next step without further purification or characterization. Step 2: 157033.doc -152- 201215604

(S)-5-(3,3-Methylbutan-1-yl-1-yl)-3-((1- 吓 · 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基- Methyl formate. Prepared as the starting material as 3-bromo-5-(3,3-dimercaptobutanyl)°ephedo-2-carboxylate (1 〇〇 mg, 0.329 mmol), as in compound 14 Purification in the title compound (m. Analysis by LCMS (60-98 Me0H/H20&apos; decanoic acid modifier, 5/7 min, ci8); RT = 4.67 min, MH+ = 3 93.43. Used as is in the next step. Step 3:

Compound 12. Selling phenanthrene with (S)-5_(3,3-dimethylso-indole-alkynyl)_3_((1morpholinyl-1-oxobutan-2-yl)amine Methyl decanoate (84 mg, 0.21 mmol) was obtained as a starting material, which was obtained from compound 14 to afford compound 12 (14.7 mg &gt; 13%). Analysis by LCMS (60-98 Me0H/H20, succinic acid modifier </RTI> 5/7 min, C18); RT = 5.60 min, MH+ = 416.46.

Preparation of Compound U Step 1: 157033.doc -153- 201215604

Methyl 3-bromo-5-iodothiophene-2-carboxylate. BuLi (228 mL, 2.5 Μ, 570 mmol) was added dropwise to diisopropylamine and stirred for 30 minutes. The reaction mixture was cooled to -70 ° C, and then 2-MeTHF (500 mL) containing &lt;RTI ID=0.0&gt; The reaction mixture was stirred for 20 minutes. The reaction mixture was warmed to -60 Torr: iodine (132.6 g, added dropwise over 1 hour)

26.90 mL, 522.5 mmol) of 2-MeTHF (500 mL) was maintained at EtOAc &lt;RTI ID=0.0&gt;&gt; The reaction mixture was quenched with EtOAc EtOAc (EtOAc) (EtOAc) (EtOAc) Washed, dried over NazSO4, filtered and evaporated. The crude product was purified by a ruthenium gel using 5 〇〇 / EtOAc / hexanes as eluting solvent to afford methyl 3-bromo-5-iodo-thiophene-2-carboxylate 2 (75 g, 46% yield ). This material was recrystallized from methanol to give the desired product (53 g,

32〇/〇 yield). Analysis by LCMS (10_90% ch3CN/H20, formic acid modifier '5 min' C18); RT = 4.01 min, ΜΗ+=346.46, !H NMR (300 MHz, CDC13, ppm) 7.25 (S, 1H ), 3.88 (s, 3H). Step 2:

157033.doc • 154- 201215604 3-Methyl-5-(3,3-methylbutan-1-yl-1-yl)pyrazine-2-carboxylic acid methyl ketone beta in hydrazine. Under the 'under nitrogen atmosphere' in a dry flask, 3_bromo-5-mothene-2-yl decanoate (3.0 g, 8.6 mmol), 3,3-dimercapto--yne^^ Mg, 1.24 mL, 10·4 mmol) ' Copper iodide (200 mg, 1.05 mmol), N,N-diethylethylamine (2.62 g ' 3.62 mL, 25.9 mmol) and Tris (dba) Pd2 (86 mg , 0.094 mmol) was mixed in dimethyl decylamine (50 mL), then sandalwood for 12 hours while the reaction was allowed to reach room temperature. The reaction was monitored by HPLC and the disappearance of the starting material was monitored. The reaction was treated by the addition of water-brine (1:1 &apos; 100 mL) and extracted with isopropyl acetate (2 &lt;&lt; The combined extracts were washed with saturated brine (1×100 mL), dried over sodium sulfate, filtered and evaporated. Purification by flash chromatography gave 2.46 g (yield: Analysis by LCMS (10-90 CH3CN/H20, formic acid modifier, 5 min, C18), RT=5.60 min, MH+=301.09,4 NMR (300 MHz, CDC13, ppm) 7.05 (s,lH),3 · 89 (s, 3H), 1.32 (s, 9H). Step 3:

2-Amino-1-morpholinoethyl ketone hydrochloride. In the reaction flask, 2-(t-butoxycarbonylamino)acetic acid (175 mg, 1·〇mmol), morpholine (113 mg, 113 pL, 1.30 mmol), N-ethyl-N-iso Propyl-propan-2-amine (388 mg, 522 μί, 3.00 mmol), hexafluorophosphoric acid (stupidyl triazol-1-yloxy-dioxin 157033.doc -155- 201215604 aminol-methylene - dimethylammonium (2.5 mL, 0.5 Μ, 1.25 mmol) (solution in DMF) was mixed and stirred at room temperature for 48 hours, followed by verification of starting material depletion (as indicated by LCMS) The reaction is complete. Add water (2 mL) and 2 N NaOH (2 mL); extract with 1:1 EtOAc-iPr〇Ac (3×4 mL) and allow to pass nitrogen to the solution while heating to about 35-50 ° C over several hours To remove the solvent. LCMS demonstrated the formation of the desired product. MH+=245, MNa+=267. This material was treated with isopropanol containing 6 N HCl at room temperature until all starting material was consumed. The solvent was removed under vacuum and excess HC1&apos; was dried and the product was used in the next step without further purification. Step 4

5-(3,3-Dimethylbutylmethanesyl)_3_((2-morpholinyl-2-oxoethyl)-amino)thiophene-2-furic acid methyl ester Ethyl 3-bromo-5-(3,3-dimercapto-1-ynyl)thiophene-2-carboxylate (2.00 g, 6.64 mmol), carbonic acid (5.19 g, 15.9 mmol) at room temperature , [1-(2-diphenylphosphino-1-naphthyl)_2-naphthyl]·diphenylphosphine (414 mg, 0.664 mmol), acetic acid, bar (149 mg, 0.664 mmol) and a slight excess The amine hydrochloride was combined in toluene (60 mL). Degassing was carried out by bubbling nitrogen for 10 minutes, followed by standing at 80 ° C for 16 hours. The reaction was monitored by HPLC and found to be free of starting material residue. The reaction mixture was poured directly onto a silicone pre-wetted silicone plunger (about 25 g). Dissolve and wash with hexane 157033.doc - 156 - 201215604 (250 mL), followed by a step gradient elution: 50% EtOAc/hexanes (3 x 250 mL); 60% EtOAc/hexanes. The homogeneous fractions were combined to give 5-(3,3-dimethylbut-1-yn-1-yl)-3-((2-morpholinyl-2-yloxyethyl) as a glass. -Amino)thiophene-2-carboxylate (880 mg, 36%). Analysis was performed by LCMS (60-98% Me0H/H20, decanoic acid modifier, 7 min, C18); RT = 4.09 min, MH+ = 365.34. Step 5:

Compound 14. In a mixture of 3% 0 to bite (110 μί, 1.37 mmol) in dioxane (3 mL), 4-nonylcyclohexane helium (137 mg, 0.686 mmol), 5- (3) ,3-dimercapto-1-indol-1-yl)-3-((2-ythyl-2-ylideneethyl)-amino)thiophene-2-furic acid methyl ester (50 mg '0.14 mmol) and a catalytic amount of DMAP (1.6 mg, 0.014 mmol) were mixed. The mixture was placed in a microwave vial and heated at 150 ° C for 30 minutes. After the completion of the reaction was judged by HPLC, MeOH (2 mL) and 2 N NaOH (2 mL) were added, and the mixture was heated at 70 to 80 ° C for 2 hours, followed by aqueous treatment. Brine (10 mL) was added to the mixture, diluted with EtOAc (2 mL, 2 N, diluted to approximately 10 mL) and extracted with EtOAC (2×50 mL). Dry over sodium sulfate, filter and strip. Purified by reverse phase HPLC (30-100%; MeOH / water / 5 mM HCl). Compound 14 (13.1 mg, 19%) was obtained as a dry solid. Analysis was performed by 157033.doc -157-201215604 LCMS (60-98% Me0H/H20, formic acid modifier, 7 min, C18); RT = 5.21 min, ΜΗ+=475.45. 4 NMR (300 MHz, CDC13) δ 6.93 (s, 1Η), 5.01 (d, J=16.3 Hz, 1H), 4.03 (d, J=16.3 Hz, 1H), 3.80-3.60 (m, 5H), 3.51 (dd, J=13.5) , 9.1 Hz, 2H), 2.32 (t, J=11.5 Hz, 1H), 1.86 (d, J=13.2 Hz, 1H), 1.64 (dd, J=31.7, 15.2 Hz, 4H), 1.34 (s, 9H ), 0.78 (dd, J=28.1, 9.9 Hz, 5H).

Preparation of compound U

Compound 13. (S)-3-((l-(didecylamino)-indolyloxy-2-yl)amino)-5-(3,3-dimethylbutane-1·yne small Methylginate 2 methyl formate (136 mg, 0.848 mmol) was used as starting material, as described for the compound "Compound 13 (29.6 mg ' 30%). By LCMS (6〇98 Me〇H/H2〇) , citrate 157033.doc -158· 201215604 modifier, 5/7 minutes, C18) analysis; RT=5.28min, MH+=46i. Preparation of compound 15 Step 1: + h〇h2N&gt;〇

^ .HCI (S)-2-Amino-1-ylidenepropylamine hydrochloride. Using commercially available (8)_2_((t-butoxycarbonyl)-amino)propionic acid (400 mg ' 2.11 mmol), as in compound 14 φ, was obtained as a solid (s) 2 -amino-1- Sulinylpropan-1-one hydrochloride (446 mg, quantitative yield) was used without further purification. Step 2:

(S)-5_(3,3.methylbut-1-yn-1-yl)-3_((1-morphinyloxypropyl-2-yl)amino) succin-2-carboxylic acid vinegar. Prepared in the same manner using 3-methyl-5-(3,3-dimercaptobut-1-ynyl) porphin-2-decanoic acid vinegar (500 mg, 1.64 mmol), as in compound 14 Obtaining (s)_5_p,3-didecylbut-1-yn-1-yl)-3-((1-morpholinyl-1-oxopropan-2-yl)amino) thiophene as a solid Methyl 2-carboxylate (500 mg '80%). Analyzed by LCMS (60-98 〇/〇1^011/1120, citric acid modifier '5/7 min, 〇: 18); 1〇'=4.33 11^11, MH+=379.35 ° Step 3: 157033 .doc •159- 201215604

Chemical substance 15. (8)·5-(3,3·Didecylbut-1-yne·1·yl)-3-((1-morphinyl 1 oxypropan-2-yl)amino group). The thiophene-2-carboxylic acid methyl vinegar (461 mg '0.977 mmol) was prepared as the starting material, as described for the compound μ, to give the compound 15 (84. 〇 mg, 18%). It was analyzed by lcms (4 〇 8 〇 % cH3CN/H2 〇, formic acid modifier '7 min' Cl8); RT = 4 61 streams, mh + = 489". Preparation of Compound 16 Step 1:

3-Methoxy-2-((2-(methoxycarbonyl)_5_(3-methylbutynyl-1-β)thiophene-3-yl)amino)propanoic acid. 3-iodo-5-(3-methylbut-1-yn-1-yl)thiophene-2-furic acid formazan (5 1111]1〇1), 2-amino-3-methoxypropane A mixture of acid (7.5111111〇1), 2 (:03 (1〇mmol), Cul (0.5 mmol) and L-proline (1 mmol) in 3 mL DMSO was heated at 60 ° C for 14 hours. The mixture was partitioned between water and EtOAc. EtOAc (EtOAc m. Dissolve 1/10 to 1/8 ethyl acetate/petroleum ether 157033.doc •160-201215604 to give the desired product (26%). LCMS: 326.19 (MH+). Step 2:

3-((1-(Dimethylamino)-3-methoxycarbonyl-1-yloxypropan-2-yl)amino)-5-(3-methylbut-1-yn-1-yl) Methyl thiophene-2-carboxylate. Add N-mercaptoguanamine (75 mg, 80 μΐ^, 0.92 mmol), DIEA (238 mg, 321 μι ') to a solution of the starting acid (100 mg '0.31 mmol) in dry DMF (2.000 mL) 1.84 mmol) followed by HBTU (190 mg, 0.49 mmol). The reaction mixture was stirred with EtOAc EtOAc EtOAc. The crude material was purified by EtOAc (EtOAc) elute elute LCMS: 3 53.3 (MH+). Step 3:

3-((1-(Dimethylamino)-3-methoxy-1-oxopropan-2-yl)amino)_5_(3·decylbut-1-yn-1-yl) Methyl phenoxy-2-carboxylate (60 mg, 0.17 mmol), I57033.doc -161 - 201215604 (trans)-4-mercaptocyclohexane helium (82 mg, 0.51 mmol) and DCE (3 mL) The mixture was heated in a sealed tube at 90 ° C for 5 hours. The crude material was taken from EtOAc (EtOAc) elute elute elute elute Step 4: 〇 〇

Compound 16. Water (2 mL) and LiOH (34 mg, 0.82 mmol) were added to a solution of EtOAc (40 mg, 0.084 mmol) in THF (2 mL). The mixture was stirred at room temperature until no SM residue was detected by HPLC (about 6 hours). The solution was acidified by the addition of 2 N HCl until pH = 2. The THF was removed by evaporation and the residue was dissolved in 2N EtOAc and cooled in ice. The resulting precipitated compound 16 was collected by filtration and washed with water (95%). LCMS: 463.36 (MH+). Preparation of Compound 21 Step 1:

157033.doc -162- 201215604 2-((5-(3,3-Dimethylbut-1-yn-1-yl)-2-(methoxycarbonyl)thiophene-3-yl)amino)-3 - methoxypropionic acid. 5-(3,3-Dimethylbutan-1-yl)-3-bromo-β-ceto-2-carboxylate (1000 mg, 2.872 mmol), 2-amino-3-methoxy- Propionic acid (1.03 g, 8.62 mmol), K2C03 (794 mg, 5.74 mmol), Cul (54.7 mg, 0.287 mmol) and (2S)-. A mixture of each of the pyridine-2-carboxylic acid (66.1 mg' 0.574 mmol) in DMSO (5.0 mL) was heated at 60 ° C for 14 hours. The cooled mixture was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with EtOAc EtOAc EtOAc. The residual oil was loaded onto a silica gel column and eluted with 1/10 to 1/8 ethyl acetate/hexanes to give the desired product (46%). LCMS: 340.19 (MH+). Step 2:

3-((1-(Dimethylamino)-3-methoxy-1-oxoylpropan-2-yl)amino)_5·(3,3-dimethylbut-1-yne- Methyl 1-thio)-2-thioate. To 2-[[5-(3,3-dimethylbut-1-ynyl)-2-oxiranyloxy-3-thienyl]amino]-3-methoxy-propionic acid (200 mg, 0.589 mmol) Ν·曱 methylamine (144 mg, 154 pL, 1.77 mmol), DIEA (457 mg, 616 pL, 3.54 mmol), then added HBTU (358 mg) in anhydrous DMF (4.0 mL) '0.943 mmol). The mixture was stirred for 3 hours at room temperature, then diluted with EtOAc. The organics were washed with water and saturated NaHC03 solution, 157033.doc -163 - 201215604

The <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; LCMS: 367.32 (MH+); *H NMR (300 MHz, CDC13) δ 7.22 (d, J = 8.2 Hz, 1H), 6.54 (s, 1H), 4.39 (dd, J = 14.0, 6.9 Hz, 1H), 3.71 (s, 3H), 3.53 (ddd, J=15.1, 9.4, 6.4 Hz, 2H), 3.27 (s, 3H), 3.01 (s, 3H), 2.91 (s, 3H), 1.22 (s, 9H) . Step 3:

To 3·[[2-(dimethylamino)-1-(decyloxymethyl)-2-oxo-ethyl]amino]-5-(3,3-dimethylbutene- Add pyridine (25.9 mg, 26.5 μί, 0.328 mmol) to a solution of methyl 1-ethynyl)thiophene-2-f-acid (1 mg, 0.273 mmol) in DCE (2.000 mL). Base cyclohexane ruthenium chloride (65 _8 mg, 0.410 mmol); the mixture was at 13 Torr in the microwave. (The next heating was 1200 s. The crude product was purified eluting with EtOAc EtOAc EtOAc EtOAc (EtOAc) LCMS: 491.39 (MH+). Step 4: Ο 157033.doc

Ο

201215604 Racemate 21. Add lithium hydroxide (58 mg, 2.4 mmol) to the solution of the starting ester (12 mg, 〇24 mm 〇1) in water (23 mL) and THF (2.3 mL). The mixture was stirred for 12 hours, then was partitioned to pH = 2 with 6 N HCl. THF was removed by evaporation, and the precipitated racemates 21 were collected by filtration and purified by Gilson HPLC. LCMS: 477.39 (MH+). Step 5:

3-[[(lS)-2-(dimethylamino)-I(methoxymethyl)_2_ oxo-ethyl b (trans-4-methylcyclohexylcarbonyl))] _5_ (3 3•Dimethylbutan-4-ynyl)thiophene-2-carboxylic acid Separation of the two enantiomers using SFC gave 21: whelk-0 column (10×250); mobile phase: 15% EtOH, 85 % C02 ; flow rate: 10 mL / min; pressure: 1 bar. Preparation of compound 23

(S)-5-(3,3-dimethylbutynyl)_3·((3_methoxymorpholinyl 157033.doc -165- 201215604 oxopropan-2-yl)amino)thiophene Methyl 2-carboxylate (compound (k2)). The anhydrous 1,4-dioxane used in the reaction was deoxygenated by bubbling nitrogen for 30 minutes. 3-Bromo-5-(3,3-dimethylbut-1-ynyl)thiophene-2-furic acid decyl ester (compound (kl), 515.7 mg, 1.71 mmol), (S)-2-amine 3-methoxy-1-morpholinylpropan-1-one (500 mg, 2.23 mmol), dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphine ( A mixture of S-phos, 70.3 mg, 0.171 mmol) and cesium carbonate (1.67 g ' 5.14 mmol) was dissolved in 15 mL of 1,4-dialdehyde and the mixture was further degassed with argon for 10 minutes. The catalyst Pd2(dba)3 (78 mg, 0.086 mmol) was added to the mixture and the reaction was sealed and heated at 90 °C for 18 hours. The reaction was cooled to room temperature, diluted with EtOAc andEtOAc The organic layer was dried over anhydrous MgSO4, filtered and evaporated. The crude material was taken on EtOAc (EtOAc) elute elute elute elute LCMS: 409.48 (MH+). Compound (k3). (S)-5-(3,3-Dimethylbut-1-ynyl-1-yl)-3-((3-methoxy-1-infrared-1-yloxypropyl-) 2-yl)amino) porphin-2-carboxylic acid oxime ester (150 mg '0.37 mmol), 4-methylcyclohexane ruthenium chloride (177 mg, 1.1 〇 mmol) and ° ratio (58.1 mg ' A mixture of 59.4 μιη, 0.734 mmol) was dissolved in 1,2-dichloroethane (7.5 mL) and heated in a sealed tube at 901: for 14 hours. The sterol was added to the reaction, followed by evaporation of the solvent. The residue was purified with EtOAc EtOAc EtOAc (EtOAc) LCMS: 533.36 (MH+). Compound 23. To a solution of (k3) (160 mg, 0.30 mmol) in water (3 mL) and 157033.doc - 166 - 201215604 THF (3 mL), oxidative chain (72 mg, 3.0 mmol) was added. The mixture was stirred at room temperature for 12 hours. The reaction was acidified with 6N HCl and THF was removed by evaporation. The resulting precipitate was filtered, washed with water and dried to afford Compound 23 (95%). LCMS: 519.41 (MH+). 4 NMR (300 MHz, DMSO) δ 13.43 (s, 1H), 7.28 (s, 0.5H), 7.07 (s, 0.5H), 5.83 (t, J = 7.2 Hz, 0.5H), 5.41 (t, J =6.7 Hz, 0.5H), 3.79-2.89 (m, 14H), 2.11-1.00 (m, 17H), 0.87-0.39 (m, 4H).

Preparation of compounds Step 1:

Prepared according to the indoleamine formation procedure of compound 6 to give the desired product, which was isolated and used in the next step without further purification (119 mg, 99%). Analysis by LCMS (60-98 Me0H/H20, succinic acid modifier, 5/7 min, C18); RT = 4.25 min, ΜΗ+ = 503.04. Step 2:

157033.doc -167- 201215604 Compound 26. Prepared according to the hydrolysis procedure of compound 6 to give compound 26 (62 mg, 52%). Analysis by LCMS (40-80% CH3CN/H20, formic acid, 7 min, C18); RT=4.61 min, ΜΗ+=489·1. Preparation of compound 35 〇

Compound 35. The preparation method is the same as compound 23. LCMS: 503.3 5 (ΜΗ+). NMR (300 MHz, DMSO) δ 13.35 (brs, 1 Η), 7.34 (s, 0.4H), 7.02 (s, 0.6H), 5.66 (t, J = 7.0 Hz, 0.4H), 5.17 (t, J= 6.8 Hz, 0.6H), 3.77-2.81 (m, 10H), 2.13-0.98 (m, 21H), 0.96-0.43 (m, 4H). Preparation of Compound 56 ·

157033.doc •] 68 - 201215604 Compound 56. The preparation method is the same as compound 23. LCMS: 517.36 (MH+). 4 NMR (300 MHz, DMSO) δ 13.55 (br, 1H), 7.44-6.97 (m, 1H), 5.80-5.06 (m, 1H), 4.36-3.08 (m, 8H), 2.15-0.95 (m, 20H) ), 0.89-0.45 (m, 9H). Preparation of Compound 61

η

Compound 61. The method is as in compound 23 » LCMS: 5 33.36 (ΜΗ+). 4 NMR (300 MHz, CDC13) δ 7.50 (s, 0.4H), 6.76 (s, 0.6H), 5.52 (dd, J=9.4, 5.7 Hz, 0.4H), 5.27 (dd, J=10.7, 4.9 Hz , 0.6H), 4.09-3.54 (m, 11H), 3.42-3.18 (m, 3H), 2.14-1.22 (m, 20H), 0.91-0.59 (m, 4H) » Preparation of Compound 64 157033.doc .169- 201215604

Compound 64. The preparation method is the same as compound 23. LCMS: 517.43 (MH+). NMR (300 MHz, CDC13) δ 7.43 (s, 0.5Η), 6.68 (s, 0.5H), 5.37-5.00 (m, 1H), 3.96-3.33 (m, 9H), 2.05-1.07 (m, 20H) , 0.96-0.50 (m, 8H) 〇Preparation of compound 78

Compound 78 was prepared as described for compound 82: LC-MS: 515 M+l peak appeared at 1.45 min. LC-MS: 515.2 MH+ peak appeared at 3.2 min; NMR (300 MHz, CDC13) δ 7.67-7.49 (d, 1 Η), 6.79-6.67 (d, 1H); 5.23-4.98 (m, 1H), 4.85-4.61 (m, 2H), 4.42 (ddd, J=38.6, 20.9, 6.5 Hz, 1H), 4.11 (dd, J=36.5, 8.5 Hz, 1H), 3.88-3.74 (m, 2H); 3.49 (dd, J =59.9, 11 Hz, 2H); 2.14-1.82 (m, 3H); 1.77-1.39 (m, 7H), 1-39-1.27 (m, 9H); 1.04-0.54 (m, 9H). 157033.doc -170· 201215604 Preparation of Compound 79

Compound 79 was prepared as described for compound 82: LC-MS: 503 MH+ peak appeared at 1.68 min. Preparation of Compound 83

Compound 83. The method is similar to compound 82. LCMS: 445.0 (MH+). 4 NMR (300 MHz, CDC13) δ 6.94 (s, 0.5H), 6.91 (s, 0.5H), 5.15 (t, J = 9.5 Hz, 0.5H), 4.34 (t, J = 9.4 Hz, 0.5H) , 3.84-3.32 (m, 2H), 2.94 (s, 1.5H), 2.88 (s, 1.5H), 2.60-2.26 (m, 1H), 2.23-1.97 (m, 1H), 1.94-1.16 (m, 17H), 0.95-0.57 (m, 5H). Preparation of Compounds 91 and 92 157033.doc -171 - 201215604

The two enantiomers of Compound 83 were isolated using SFC under the following conditions: column: Whelk-O (l〇x250); mobile phase: 15% EtOH, 85% C02; flow rate: 10 mL/min; pressure: 100 bar. Preparation of Compound 94 Step 1:

(2S)-2-(Benzyloxycarbonylamino)butyric acid (1.2 g, 4.9 mmol), (IS,4S)-6-oxa-3-azabicyclo[2.2.1]g DIEA (1.9 g, 2·6 mL, 15 mmol) was added to a solution of EtOAc (EtOAc, EtOAc). The mixture was stirred for 4 hours then diluted with EtOAc and H20. The organic layer was washed with EtOAc (EtOAc m. The crude material was purified with 20-70% EtOAc / hexane. The desired product (1.2 g, 76%) was obtained as a colourless oil. LC-MS: 3 19 MH+ peak appeared at 2.34 min. To]\[-[(13)-1-[(18,48)-2-oxa-5-azabicyclo[2_2.1]heptane-5-carbonyl]propyl]carbamic acid benzoic acid Pd(OH)2 (120 mg, 0.85 mmol) was added to a solution of EtOAc (EtOAc,EtOAc. The mixture was stirred under a H2 balloon for 2 hours. The crude material was filtered through a layer of diatomaceous earth. Concentrated sputum. The residue was used in the next step. LC-MS: 1 84 MH+ peak appeared 157033.doc -172- 201215604 at 1.0 min 〇 Step 2:

3 -Bromo-5-(3,3 -dimethylbuty-1 -ynyl)porphin-2-carboxylic acid oxime ester (75 mg, 2.5 mmol), (2S)-2-amino-l- [(lS,4S)-2-oxa-5_azabicyclo[2.2.1]hept-5-yl]butan-i-ketone (6〇〇mg &gt; 3.26 mmol)

A mixture of Pd2(dba)3 (230 mg, 0.25 mmol), rac-BINAP (312 mg, 〇 5 mmol) and cesium carbonate (2.4 g' 7.5 mm 〇i) was degassed and filled with hydrazine. Dioxane (1 〇 mL) was added to the mixture and bubbled with N2 for 20 minutes. The mixture was stirred at 90 &lt;0&gt;C for 18 h and diluted with EtOAc. The crude reaction mixture was filtered through a pad of celite and concentrated. The crude material was purified with EtOAc EtOAc (EtOAc) LC-MS: 405 MH+ peak appeared at 3.28 min. Step 3:

5-(3,3-Dimercapto-i-alkynyl)oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl]propyl]amino]thiophene-2-furic acid Oxime ester 157033.doc

S • 173· 201215604 (5 00 mg, 1.24 mmol), 4-mercaptocyclohexane argon (993 mg, 6.18 mmol), Py (980 mg, 1.0 mL, 12 mmol) and DMAP (151 mg, 1.24) The mixture in mmol (20 mL) was refluxed for 24 h. The mixture was diluted with EtOAc (EtOAc)EtOAc. The crude material was purified with a column (0-60%EtOAc / EtOAc). Thus, the desired product (600 mg, yield: 92%) was obtained. LC-MS: 529.52 MH+ peak appeared at 4.5 min. Step 4:

Compound 94. To 5-(3,3-dimethylbut-1-ynyl)-3-[(trans-4-methylcyclohexylcarbonyl)-[(18)-1-[(18,48)-3- A solution of methyl oxa-6-azabicyclo[2.2.1]heptane-6-carbonyl]propyl]amino]thiophene-2-carboxylate (600 mg, 1.14 mmol) in MeOH (10 mL) Add NaOH (5.7 mL, 1 Μ, 5.67 mmol). The mixture was stirred overnight and then neutralized with HCl to ΡΗ=1. The mixture was concentrated in vacuo and extracted with DCM. The organic extract was dried over Na 2 SO 4 and concentrated in vacuo. The crude material was purified with EtOAc (EtOAc:EtOAc) 1&gt;(:-1^8:515.2]\411+ peak appeared at 3.2 min° NMR (300 MHz, CDCl3) 3 7.67-7.49 (d, lH), 6.79-6.67 (d, 1H); 5.23-4.98 ( m, 1H), 4.85-4.61(m, 2H), 4.42 157033.doc -174- 201215604 (ddd, J=38.6, 20.9, 6.5 Hz, 1H), 4.11 (dd, J=36.5,8·5 Hz, 1H), 3.88-3.74 (m, 2H); 3.49 (dd, J=59.9, H Hz, 2H); 2.14-1.82 (m, 3H); 1.77-1.39 (m, 7H), 1.39-1-27 ( m, 9H); 1.04-0.54 (m, 9H).

Step 1: (8)-5-(3,3-Dimethylbutan-1- fast-;|-yl)-3-((1-methyl-2-oxo-heptan-3-yl) Amino) sinter-2-carboxylic acid methyl vinegar. Methyl 3-ce-5-(3,3-dimethylbut-1-yn-1-yl)-cephen-2-indole (1.4 g, 4.66 mmol), carbonic acid (3.0 g, 9.33) Methyl) and (S)-3-amino-1-methylcycloheptan-2-one hydrochloride (1.0 g, 5.60 mmol) in toluene (14 mL) I bar of acetic acid (105 mg, 0.47 mmol) followed by (±)_BINAP (58 1 mg, 〇·93 mmol). The reaction mixture was heated to 90 &lt;0&gt;C and was taken until the starting material was consumed (as monitored by HPLC and LCMS). The reaction mixture was cooled to room temperature and filtered through celite and rinsed with dichloromethane. The solvent was removed under reduced pressure and the crude material was purified eluted eluted elut elut elut elut elut elut elut elut elut elut elut 1-Alkyn-1-yl)-3-((1-methyl-2-oxaazepane-3-yl)amino) thioglycol-2-decanoate (ug, 65%). Ms: m/z (observed) [M+H]+ 〇Ή NMR (300 MHz, MeOD) 6 6.60 (s, 1H), 4.45 (d, J = 10.8 Hz, 1H), 3.84-3.73 (m, 4H), 3.02 (s, 3H), 2.04- 157033.doc -175- 201215604 1.75 (m, 4H), 1.60-1.40 (m, 2H), 1.3 0 (s, 9H). For palmar SFC: 99:1 S/R ratio (Chiralpak IC 30% (40:60:0.2% MeOH/IPA/ ESA)/C02). Step 2: 5-(3,3-Dimethylbut-1-yn-1-yl)-3-(4-methyl-]\-((8)-1-methyl-2-oxoza Methyl cycloheptan-3-yl)cyclohexanecarbamamino)thiophene-2-carboxylate. (S)-5-(3,3-Dimercapto-1-yn-1-yl)-3-((1-indolyl-2-oxazepan-3-yl)amino group The thiophene-2-decanoate (1.1 g, 3.04 mmol) was dissolved in DCE (11 mL). Add σ specific bite (245 pL, 3.04 mmol), DMAP (37 mg, 0·30 mmol) and trans-4-methylcyclohexanecarbazide (1.22 g, 7.59 mmol) and heat the reaction mixture to 90 °C. Until the starting material was consumed (monitored by TLC and HPLC). The reaction mixture was cooled to room temperature and was washed with 2N HCM, sat. NaHC03 and brine. The organic layer was dried (Na2SO4) filtered and solvent was evaporated. The crude product was purified by column chromatography eluting with EtOAc-EtOAc (EtOAc) 4-Methyl-N-((S)-1-indolyl-2- oxazolidine-3-yl)% hexylaminocarbyl) porphin-2-carboxylic acid methyl ke (m.35) g, 91%) 〇MS: m/z (observed) 487.28 [M+H]+. </ RTI> <RTIgt; 1.9-1.4 (m, 10H),! 37] 19 (m, 12H), 1.06 (ddd, J = 15.6, 12.7, 3.4 Hz, 1H), 0.81 (d, J = 6.5 Hz, 3H), 0.76-0.55 (m, 2H). Step 3: 5-(3,3-Dimethylbut_1-yne-1-yl)-3-(4-methyl•methyl_2_oxyl 157033.doc -176· 201215604 Azepanene- 3-yl)cyclohexanecarbamamino)thiophene-2-carboxylic acid. 5-(3,3-Dimethylbutan-1-yl-1-yl)-3-(4-methyl-1&lt;|'-((8)-1-methyl-2-oxazepane Ethyl-3-yl)cyclohexanecarboxamido) thiophenecarboxylate (1.3 g, 2.67 mmol) was dissolved in THF (6.5 mL) and water (6.5 mL) and lithium hydroxide (192 mg ' 8.01 mmol) ). The reaction mixture was stirred at room temperature until the starting material was consumed (monitored by TLC). The reaction mixture was acidified with EtOAc (EtOAc)EtOAc. The organic layer was dried (Na2SO4) filtered elute MS: m/z (observed) 473.26 [M+H]+, 471.47 [M-H]' NMR (300 MHz,

MeOD) δ 7.45 (s, 1H), 5.28 (d, J = 10.8 Hz, 1H), 3.78 (dd, J = 15.4, 11.3 Hz, 1H), 3.01 (Sj 3H), 2.19-2.02 (m, 1H) , 1.97-1.38 (m, 10H), 1.33 (s, 9H), 1.27-1.19 (m, 1H), 1.17-0.98 (m, 1H), 0.81 (d, J=6.5 Hz, 3H), 0.67 (ddd , J=21.7, 14.4, 10.6 Hz, 2H). For palmar HPLC: 99:1 S/R (Chiralpak IC, 100% ACN/0.1% TFA). • Preparation of compound 143

Step 1: (8)-5-(3,3-Dimethylbutan-1-ynyl)_3_[(2,4-dioxabenzhydryl)-[1-(morphin-4-yl) )propyl]amino]-porphin-2-methyl formate. (s)-5-(3,3-dimethyl 157033.doc -177· 201215604 butyl-1-ynyl)-3-((1-morpholinyl-oxime-oxo-butan-2-yl) Amino)thiophene-2-carboxylic acid methyl ester (450 mg, 1.15 mmol), 2,4-dibenzoylhydrazine chloride (1.20 g '800 pL, 5.73 mmol) and pyridine (185 called 2 29 di-ethane) The solution in 9 mL) was heated in a 9 〇t oil bath for 14 hours, then diluted with MeOH and evaporated. The residue was eluted with a gradient of 1% to 7 % Et EtOAc / hexanes (35 min) Purification by chromatography, yield 62 〇 mg, 96%. MS: m/z (observed) 565.2 [m+h]+. Step 2: (S)-5-(3,3-dimethylbuty-1 _Alkynyl)_3_[(2 4_diphenylidene (morpholine-4-carbonyl)propyl]amino]-thiophene-2-formic acid β to (s)_5_(3 3_didecyl -1-ynyl)-3-[(2,4-dioxabenzoinyl)_!;!_(morpholine_4_carbonyl)propyl]amino]methyl thiophene-2-carboxylate ( 620 mg '1.1 mm 〇i) A solution of LiOH (263 mg '11 min〇I) in water (10 mL) was added to a solution in THF (10 mL). The mixture was stirred at ambient temperature for 15 hours. 6 N HCl is acidified to pH = 1 'and evaporating THF solvent to obtain acidic solution Cooled to 〇·丨〇 , , , , , , 胶 胶 ' ' ' ' ' ' ' ' ' ' 用水 用水 用水 用水 用水 用水 用水 用水 用水 用水 用水 用水 556 556 556 556 556 556 556 556 556 556 556 556 556 556 556 556 556 H NMR (400 MHz, CDC13) δ 7.68 (s, 0.5H), 7.29 (m, 2H), 7.22-7.04 (m, 1H), 6.96 (s, 0.5H), 5.49 (m, 1H), 4.26-3.42 (m, 8H), 1.96'1.45 (m, 2H), 1.31 (s, 9H), 0.96 (m, 3H).

• 178- 157033.doc 201215604 Step 1: (S)-5-(3,3-Dimethylbut-1-ynyl)-3-[(2,4-dioxabenzylidene)_~〇 Methyl-2-oxo-bito-3-yl)amino]-snext-2-carboxylic acid A. (§)_5_(3,3-Dimercapto-1-ynyl)-3-[N-(l-indolyl-2-oxindole _3_yl)amino] 0 thiophene- 2-nonanoate (470 mg, 1.349 mmol) '. ratio. Ding (196 pL, 2.43 mmol) 'DMAP (16.5 mg, 0.13 mmol) and 2,4-dichlorophenylhydrazine chloride (380 μι ' '2.7 mmol) dissolved in DCE (4.7 mL) and the mixture was heated to 90 ° C Overnight. The reaction was cooled and quenched by the addition of 2N HCl to pH 3. The mixture was extracted with CH.sub.2Cl (2.times.sup.5) and the combined organics were washed with saturated aqueous NaH.sub.3 (10 vol.) and brine and dried (M.s. The solution was evaporated and the residue was purified by EtOAc (4 g of ISC(s) column eluted with 5% to 40% EtOAc / hexanes (4 column volume); 40% retention (3 Column volume) and followed by a gradient of 4〇%-9〇% EtOAc (5 column volumes)). Yield: 614 mg, 87.29%. MS: m/z (observed) 521.1 [M+H]+. Step 2: (8)-5-(3,3-Methylbut-1-ynyl)-3-[(2,4-dioxabenzhydryl-2-yloxypiperidin-3- Aminothiophene-2-carboxylic acid. (s)-5-(3,3-Dimethylbut-1-ynyl)-3-[(2,4-dichlorobenzylidene)-indole-(1-methyl-2-oxo Methylpiperidin-3-yl)amino]-thiophene-2-carboxylic acid methyl ester (614 mg, 1.18 mmol) was dissolved in THF (3 mL) and water (3 mL) and LiOH (113 mg, 4.71)

Mmo1). The mixture was stirred overnight at ambient temperature. The pH was adjusted to 7 (1 N NaOH) and the solution was extracted with Et EtOAc (2×6 vol.). The combined extracts were washed with water, brine (8 volumes each) and evaporated to dryness. The residue was dissolved in MeCN 157033.doc • 179-201215604 and water and lyophilized to give 140. MS: m/z (observed) 507.0 [M+H]+ 〇*H NMR (300 MHz, d6-DMSO) δ 7.46 (d, J = 8.2 Hz, 1H), 7.39 (s, 1H), 7.27 ( d, 1H), 7.15 (s, 1H)S 4.65 (s, 1H), 3.28 (s, 2H), 2.90 (s, 3H), 2.35 (s, 1H), 2.20-2.03 (m, 1H), 1.88 (s, 2H), 1_30 (d, J = 3.5 Hz, 9H). Preparation of Compound 148

Step 1: (S)-(1-Ethyl-2-oxopiperidin-3-yl)carbamic acid tert-butyl ester. (S)-(2-Sideoxypiperidin-3-yl)amino decanoic acid tert-butyl ester (1 g, 4_67 mmol) was dissolved in THF (10 mL) and the solution was cooled to EtOAc. A 1 Torr solution of LiHMDS (5.4 mL) in THF was added and the mixture was stirred for 1 hour. Iodoethane (410 pL '5.1 mmol) was added and the reaction was removed from the cooling bath and warmed to room temperature and was taken overnight. The reaction was quenched with EtOAc (EtOAc) (EtOAc) The combined extracts were washed with brine &apos; dried, filtered and evaporated. The desired product was isolated by silica gel chromatography to give N-[(3S)-1-ethyl-2-oxooxy-3-bryridinyl]aminodecanoic acid tert-butyl ester. Yield: (190 mg, 16.8%). MS: m/z (observed) 507.0 [M+H]. 4 NMR (400 MHz, CDC13) δ 6.86 (d, 157033.doc -180- 201215604 J=7.8 Hz, 1H), 3.85 (s5 1H), 3.30-3.15 (m, 5H), 1.84 (ddd, J=26.1 , 16.9, 12.3 Hz, 5H), 1.38 (s, 10H), 1.01 (t, J = 7.1 Hz, 3H). Step 2: (S)-3-Amino-1-ethylpiperidin-2-one hydrochloride. Dissolving N-[(3S)-1-ethyl·2-oxo-3-piperidinyl]amino decanoic acid tert-butyl ester in diethyl ether (1.9 mL) and adding 4 N HCl to dioxime The solution in (0.4 mL) was burned and the mixture was stirred at room temperature overnight. A solution of 4 N HCl in dioxane was added and the mixture was stirred for 5 hours. The solvent was evaporated and the product was taken in <RTI ID=0.0></RTI> </RTI> &lt;RTI ID=0.0&gt; 1-Alkynyl-3-[indolyl-(1-ethyl-2-oxooxypiperidine-3-yl)amino]methylthiophene-2-carboxylate. (S)-3-Amino- 1-ethyl·piperidin-2-one hydrochloride (140 mg, 0.78 mmol) and carbonic acid (638 mg, 1.96 mmol) dissolved in 1,4-dioxane (4 mL). -5-(3,3-Dimercaptobut-1-ynyl) 0-cetin-2-carboxylic acid methyl vinegar (197 mg, 0.65 mmol) and the mixture was degassed by N2 purification for 2 hours. Add Pd (OAc) 2 (14.7 mg, 0.065 mmol) and rac-BINAP (81.3 mg, 0.13 mmol) and the mixture was further purified with N2 for 30 min then heated to EtOAc overnight. Diluted by volume, filtered through diatomaceous earth and evaporated to dryness. The product was purified by silica gel chromatography (120 g ISCO column eluting with 10% to 50% EtOAc/heptane (4 column volumes); at 50% Purified (3 column volumes) followed by a gradient of 50%-90% EtOAc (7 column volumes). The desired product was about 10 The volume of the column was dissolved. The yield was 1 〇〇mg, 42.3%. MS: m/z (observed value) 363.4 [M+H]+. I57033.doc 201215604 Step 4: (S)-5-(3,3-two Methylbut-1-ynyl)·3-((trans)-4-methyl_Ν-ίΐπ « v G yl-2_ oxoxypiperidin-3-yl)cyclohexanecarbamamino)thiophene _2-formic acid 曱_. (S)- 5-(3,3-Dimethylbut-1-ynyl)-3-[indole-(1-ethyl-2-oxooxypiperinyl) The oximation reaction of the amine]° thiophene-2-carboxylate ester yielded 58 mg '43% as described in the other examples. MS: m/z (observed) 487.2 [Μ+Η]+. Step 5: (S)-5-(3,3-dimethylbut-1-ynyl)_3·((trans)_4_methyl_ν·(ι_ethyl_2_ oxoxypiperidin-3-yl) ring Hexylcarbendyryl)thiophene-2-formic acid.(s)_5_(3,3-Dimercapto-1-ynyl)_3_((trans)_4•decylethyl_2_sideoxy silver The hydrolysis reaction of pyridine-3-yl)cyclohexaneguanidino)thiophene-2-decaptoate (58) was carried out as described in the other examples to give 148. Yield 54 mg, 930 / 〇. MS: m/z (observed) 473 2 [M+H]+.4 NMR (400 MHz, CDC13) δ 6.76 (s, 1H), 3.68-3.58 (m, 1H), 3.51 (m, 1H), 3.41 (m, 2H) ), 3.18 (m,1H), 2.37 (dd, J=23.5, 12.2 Hz, 1H), 2.08 (m, 2H), 1.95 (d, J=13.6 Hz, 1H), 1.73 (m, 2H), 1.62-1.41 ( m, 4H), 1.26 (s, 9H), 1.12 (m, 5H), 0.73 (d, J = 6.5 Hz, 3H), 0.69-0.57 (m, 2H). Preparation of Compound 149

157033.doc -182- 201215604 Step 1: (SH1-Isopropyl-2-oxopiperidinyl-3-yl)carbamic acid tert-butyl ester. (S)-(2-Sideoxypiperidinyl)aminocarbamic acid tert-butyl ester (121 g of 5 mmol) was dissolved in DMSO (12 mL), added to the milk, 7 39 mmol), then added 2_Iodopropane (74〇#, 74 mm〇i) and the mixture was stirred for 72 hours. The reaction was quenched with EtOAc (2×4 mL). The combined extracts were washed with brine, dried, filtered and evaporated. The desired product is isolated by silica gel chromatography to obtain N-K38)-1-isopropyl-2-oxoyl-3-piperidinyl]amino decanoic acid tert-butyl

Hey. Product. (430 mg, 29.5%). MS: m/z (observed) 279.1 [M+Na]+.咕 NMR (400 MHz, d6-DMSO) δ 6.83 (d, J=8.I

Hz, 1H)? 4.68-4.52 (m, 1H), 3.88 (d5 J=6.8 Hz 1H) 3 12 (dd, J-13.0, 7.2 Hz, 2H), 1.98-1.85 (m, 1H) 1 75 (dd J-12.3,6·8 Hz, 2H),1·56 (d, J=17.8 Hz, 1H), 1 38 (s 11H), 1.03 (dd, J=6.7, 2.0 Hz, 7H) 〇Step 2 · · ® (S)-3-Amino-1-isopropylpiperidin-2-indole hydrochloride. The protecting group of N-[(3S)-1-isopropyl-2-oxooxy-3-indolyl]carbamic acid tert-butyl ester was removed as described for compound i48 and used without purification. Step 3: (S)-5-(3,3-Dimethylbut-1-ynyl)-3-[indol (1-isopropyl-2-oxopiperidin-3-yl)amine ] Thiophene-2-carboxylic acid methyl vinegar. '(S)-3-Amino-1-isopropyl-α-bottom-2-one hydrochloride (Μ) mg, 1.68 mm〇l) with 3-bromo-5- as described for compound ι48 (3,3-dimethylbut-1-ynyl)thiophene-2_f acid f ester 157033.doc • 183· 201215604 (421 mg, ΐ·4〇mmol) in cesium carbonate (1.37 g, 4.2 mmol), Pd(OAc) 2 (31 mg, 0.14 mmol) and rac-BINAP (174 mg, 0.28 mmol) were reacted in i,4·dioxane (4 mL). Yield 314 mg, 59%. MS: m/z (observed) 399.2 [M+Na]+. Step 4: (S)-5-(3,3-Dimercapto-1-ynyl)-3-((trans)-4-methyl-N-(l-isopropyl-2-yloxy) (piperidin-3-yl)cyclohexanecarbamoylamino)thiophene-2-carboxylic acid methyl ester (S)-5-(3,3-dimercaptobut-1-ynyl)-3-[Ν The brewing reaction of -(1-isopropyl-2-oxaxopiperidin-3-yl)amino]methyl thiophene-2-decanoate (3 14 mg) was carried out as described in the other examples. The product was eluted by silica gel chromatography (80 g ISC(R) column with a gradient of 5% to 40% EtOAc/heptane (4 column volumes); maintained at 40 〇/〇 (3 column volumes) and This was followed by a gradient of 40% to 90% EtO Ac (5 column volumes)). MS: m/z (observed) 501 · 2 [M+H]+. Step 5: (S)-5-(3,3-Dimethylbut-1-ynyl)-3-((trans)-4-methyl-N-(l-isopropyl-2-sided oxygen Base brigade bite-3-yl) cyclohexanthicylamino)porphyrin_2_ formazan. (s)_5_(3,3-Dimethylbut-1-ynyl)-3-((trans)-4-methyl-N-(l-isopropyl-2-yloxy-slightly bite-3 The hydrolysis reaction of the thiophene ruthenium amide (4 〇〇 mg, 0.80 mmol) was carried out as described in the other examples. Product by self

MeCN/H20 was lyophilized and separated to give 149. Yield 279 mg, 69%. MS: m/z (observed) 487.2 [M+H]+. 4 NMR (400 MHz, CDC13) δ 6.63 (s, 1H), 4.78-4.64 (m, 1H), 3.66-3.47 (m, 1H), 3.21-3.05 (m, 2H), 2.16 (m, 1H), 2.02-1.80 (m, 4H), 1.61 (m, 1H), 1.36 (m, 3H), 1.16-1.08 (s, 9H), 1.09-0.99 157033.doc •184- 201215604 (m, 6H), 0.96- 0.90 (m5 3H), 0.62 (d, J = 6.5 Hz, 3H), 0.54 (m, 2H). Preparation of Compound 150

Step 1: (S)-(l-(2-Methoxyfluorenyl)-2-oxooxybenzylidene-3-yl)carbamic acid tert-butyl ester. (S)-(2-Sideoxypiperidine-3-yl)amino decanoic acid tert-butyl ester (1.16 g, 5.42 mmol) was dissolved in DMSO (12 mL). KOH (395 mg, 7.05 mmol) was added followed by kappabromo-2-methoxyethane (66 〇 0, 7.0 mmol) and the mixture was stirred overnight. The reaction was quenched by the addition of EtOAc (2 &lt;&lt;&gt;&gt; The combined extracts were washed with brine, dried, filtered and evaporated. The desired product is isolated by silica gel chromatography to give (SHl-(2-methoxyethyl) 2 </RTI> <RTIgt; Yield: (l. 〇 4g, 70.4%). Step 2: (S)-3-Amino-1-(2-methoxyethyl)-piperidine-2-one hydrochloride. ^^(2-methoxyethyl)-2-oxopiperidinyl)aminocarbamate in isopropyl and add 4% of the money (5th like butyl mixture) at ambient temperature After 16 hours, it was evaporated to dryness. The residue was re-dissolved 157033.doc • 185· 201215604 on MeCN/H20 and dried, and used without further purification or characterization. Yield 767 mg, 1 〇〇〇 /. Step 3: (S)-5-(3,3-Dimethylbutan-5-hydroxylethyl)-2.oxoxypiperidin-3-yl)amino]thiophene-2-carboxylic acid Methyl ester. '(S)-3-Amino-i-(2-methoxyethyl)-piperidine-2-one hydrochloride (796 mg, 3.81 mmol) and 3-bromo as described for compound 148 -5-(3,3-Dimethylbut-1-ynyl)thiophene-2-carboxylic acid methyl vinegar (957 mg ' 3.18 mmol) in cesium carbonate (3.11 g, 9.5 mmol), Pd(OAc) 2 (71 Mg, 0.32 mmol) and rac-BINAP (395 mg, 0.64 mmol) in the presence of 1,4_2. Reaction D yield 430 mg, 34.5% in methane (2〇mL); MS: m/z (observed) 393.2 [M+H]+ ; Step 4: (S)-5-(3,3-dimethyl Butyl-1-ynyl)-3-((trans)-4-methyl-N-(l-(2-methoxyethyl)-2-oxopiperidin-3-yl)cyclohexane Methyl decylamino)thiophene-2-carboxylate. (S)-5-(3,3-Dimercapto-1-inyl)-3-[indole-(1-(2.nonyloxyethyl)-2-oxoxypiperidin-3- The deuteration reaction of methylamino]thiophene-2-carboxylate (430 mg) was carried out as described in the other examples. MS: m/z (observed) 517.2 [M+H]+; Step 5: (S)-5-(3,3-dimethylbut-1-ynyl)-3-((trans)-4 -Methyl-N-(l-(2-methoxyethyl)-2-oxopiperidin-3-yl)cyclohexanecarboamido)thiophene-2-carboxylic acid. (S)-5-(3,3-Dimethylbut-1-ynyl)-3-((trans)-4-indolyl-N-(l-(2-methoxyethyl)-2 -Sideoxypiperidin-3-yl)cyclohexanecarbamimidino)thiophene-2-157033.doc • 186-201215604 Hydrolysis of decylcarboxylate (400 mg, 〇·80 mmol) as described in other examples get on. The desired 150 was separated by lyophilization from MeCN/H2. Yield 158 mg, 27.8%. MS: m/z (observed) 503.1 [M+H]+. NMH (400 MHz, CDC13) δ 6.58 (m, 1 Η), 3.53-3.39 (m, 2 Η), 3.35 (m, 2H), 3.26 (m, 3H), 3.12 (s, 3H), 2.23 (m, 1H) ), 1.91 (m, 2H), 1.76 (m, 1H), 1.55 (m5 1H), 1.46-1.24 (m, 4H), M〇(s, 6H), 0.98 (s, 5H), 0.57 (d, J=6.4 Hz, 3H), 0.51 (m, 3H) 〇' Preparation of compound 134

Step 1: \(S)-S-(3,3-Dimethylbutan-i-alkynyl)_3-[indole-(1-ethyl-2-oxaazeppan-3-yl)amine Base] thiophene-2-carboxylate. (8)_3_Amino-ethyl azepan-2-one hydrochloride (384 mg, 1.99 mmol) and cesium carbonate (1.62 g, 5 mmol) were dissolved in 1,4-dioxane (8 mL). Ethyl 3-bromo-5-(3,3-didecylbut-1-ynyl)thiophene-2- decanoate (500 mg, 1.66 mmol) was added and the mixture was degassed for 2 hours by A purification. Pd(〇Ac) 2 (37 mg, 0.17 mmol) and rac-BINAP (207 mg, 0.33 mmol) were added and the mixture was further purified with N.sub.2 for 30 min then heated to EtOAc overnight. After cooling to room temperature, the mixture was diluted with EtOAc (10 vol. The product was purified by silica gel chromatography (0% to 90% EtOAc /EtOAc). Yield 530 mg, 96%. MS: m/z (observed) 377.6 157033.doc -187- 201215604 [M+H]+. NMR (300 MHz, CDC13) δ 7.85 (d, 1H), 6.43 (s, 1H), 3.84 (s, 3H), 3.52 (dd, 4H), 1.86 (d, 6H), 1.33 (s, 8H), 1.16 (t, 3H). Step 2: (S)-5-(3,3-Dimethylbutyrynyl)_3_((transmethylethyl 2 -oxazepan-3-yl)cyclohexanecarboxamide Base) thiophene-2-carboxylic acid methyl vinegar. (S)-5-(3,3-Dimercapto-indenyl-alkynylethyl-2-oxaazepidine-3-yl)amino]porphyrin-2-decanoic acid vinegar (300) The oximation reaction of mg) was carried out as described in the other examples. Yield 250 mg. MS: m/z (observed) 5〇1 7 [M+H]+. Step 3 ···(S&gt;-5-(3,3-dimethylbut_1-ynyl)_3_((trans)_4_methyl-N-(l-ethyl_2.oxazepane -3-yl)cyclohexanecarbamamino)thiophene-2-carboxylic acid. (s) 5-(3,3-dimethylbut-1-ynyl)-3-((trans)-4 _Methyl-N-(l-ethyl 2 -oxazepan-3-yl)cyclohexanecarbamimidyl)thiophene-2-carboxylate (15 mg, 0·30 mmol Dissolved in a mixture of THF (15 mL) and H.sub.2 (3 mL), EtOAc (EtOAc, EtOAc) The aqueous phase was separated and acidified with 1N EtOAc (EtOAc) eluted with EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc 487.7 [M+H]+.4 NMR (300 MHz, CDC13) δ 6.74 (s, 1H), 5.07 (dd, 1H), 3.81 (dd, 1H), 3.71-3.20 (m,6H), 2.19- 1.37 (m,7H), 1.34 (d, J = 3 9 Hz 9H), 1.17 (q, J = 7.2 Hz, 4H), 0.85-0.62 (m, 5H). I57033.doc -188· 201215604 Preparation of Compound 135

step 1 :

(S)-5-(3,3-dimethylbut-1-ynyl)_3-[(2,4-dioxabenzhydrylethyl-2-oxazepane-3-yl) Amino]-thiophene-2-carboxylic acid oxime ester β(S)-5-(3,3-dimethylbut-1-ynyl)-3-[indole-(1-ethyl-2-oxo Azetidin-3-yl)amino]0-cephen-2-carboxylic acid methyl (200 mg, 0.50 mmol), oxime ratio 0 (196 pL ' 2.43 mmol), DMAP (6 mg, 0.05 mmol) And 2,4-dibenzoquinone chloride (1.0 mmol) was dissolved in DCE (14 mL) and the mixture was heated to 90 ° C overnight. The reaction was cooled and diluted with 2N EtOAc to EtOAc (EtOAc) EtOAc (EtOAc m. Observed value) 549 6 [M+H]+. Step 2: (S)-5-(3,3-Dimethylbut-1-ynyl)-3_[(2,4_dibenzophenanthryl) Ν (ι ethyl-2-oxazepan-3-yl)aminophenylthiophene-2-carboxamidine. (s)_5 (3,3-dimethylbutyrynyl)-3-[ (2,4-dioxabenzhydryl)·Ν♦ethyl 2-oxazacycloheptan-3-yl)amino]-porphinecarboxylic acid methyl (3〇mg, 〇.〇ί mmol) Hydrolysis was carried out as described for compound 134 to give the desired yield of 25 mg, 90%. MS: m/z (observed) 535 5 [m+h]+. ^ NMR (300 MHz, CDC13) δ 7.42 (d, J = 8.3 Ηζ, 1η) 7 25 7 η 157033.doc -189- 201215604 (m, 1H), 6.94 (s), 5.39 (d, J = 11.4 Hz , 1H), 3.93-3.73 (m, 1H), 3.64-3.45 (m, 2H), 3.38 (d, 1H), 2.22-1.38 (m, 6H), 1.30 (d, 6H), 1.23_l.ii ( m, 2H). Preparation of Compound 136

Step 1: (S)-2-(((Benzyloxy)carbonyl)amino)-3-(2-((t-butoxycarbonyl)-(methyl)amino)ethoxy)propanoic acid Methyl ester. At _3〇. Under the nitrogen, add the difluorinated diethyl 2 (1 26 g, 8.95 mmol) to the nitrogen-propionate-1,2-dicarboxylic acid (s)-i_ stupyl methyl ester 2 methyl ester under a nitrogen atmosphere. Rg. 5/owo/. C/z chaos 2005' 3357) (5.02 g, ι7·9 mmol) in chloroform (50 mL) and 2-hydroxyethyl-(decyl)amine decanoic acid Ester (15 6 g , 89 5

It is stirred in the solution. The solution was stirred overnight at room temperature, then diluted with dichlorohexane (2 squeaked and washed with water (3×l 〇 mL) in backwashing. The combined organic extracts were dried and evaporated in vacuo to give a crude product. ^ Petroleum ether as a dissolving agent, purified by diochromic chromatography to give (8)-2-(benzyloxyamino-amino(methylamino)ethoxy)propanoic acid- τ 9 as a colorless oil. House 1: 3.5 g, 47%. NMR (400 MHz, CDC13) δ 1 〇ττ ^^-36 (8,9^, 2.77 (s, 3Η), 3. 3.47 (m,4 Η), 3.60-3.68 4 w,, 4 Η), 3.81 (S, 1 Η), 4.17 (s 157033.doc • 19〇· 201215604 Η), 5·05 (s, 2 Η), 7·24-7·30 (m, 5 Η). Step 2 · · (S)-2-(((Benzyloxy)carbonyl)amino)_3_(2_(methylamino)ethoxy)-propionic acid methyl ester. (S)- 2-(Standylmethyloxycarbonylamino (t-butoxycarbonyl(methyl)amino)ethoxy)propionate (410 mg, 1 mmol) in CH2C12 (5 mL) and TFA (5 mL The mixture in the mixture was stirred at room temperature for 1 hour. After evaporating the solvent, the product was purified by reverse phase HPLC to give (S)-2-(benzoyloxycarbonylamino)-3-(2-(methyl) Amino) ethoxy) propionate. Yield 31 〇 mg mg '100%. Step 3: (S)-(4-Methyl-5-oxo-1,4-oxazepine Alkyl) benzyl carbamate. To (s)-2-(benzyloxycarbonylamino)-3-(2-(decylamino) group at -30 ° C under nitrogen atmosphere Addition of trimethylaluminum to a solution of methyl ethoxy)methyl propionate (3 1 mg, 1 mmol), ethyl acetate (88 mg '1 mmol, 1 eq.) in 5 mL of dry dichloromethane (i mL, 2 mm〇l, 2 Μ, in hexane, 2 equivalents of solution stirred at ambient temperature for 3 〇 minutes. The reaction was quenched with 5 mL of 1 Ν hydrochloric acid at -30 ° C. Dilute with 5 mL of water. Separate the phases and extract the aqueous phase with dichloromethane (3×3 〇 mL), dry over sodium sulfate and evaporated to give a brown solid. Purification by chromatography gave (S)-4-mercapto-5-oxo-1,4-oxathiazepine-6-ylamino phthalic acid benzyl ester as a white solid. 120 mg, 43%. NMR (400 MHz, CDC13) δ 3.07 (s, 3 Η), 3.11-3.38 (m5 1 Η), 3.33-3.36 (m, 1 Η), 3.44- 3.49 (m,1 Η), 3.88-4.04 (m,3 Η), 4.61 (s,1 Η), 4.17 (s' 1 157033.doc • 191· 201215604 H), 5.11 (s, 2 H), 6.10 ( s,1 Η), 7.26-7.37 (m,5 Η). Step 4: (S)-6-Amino-4-methyl-i,4-oxazepan-5-one. (8)_4_Mercapto-5-o-oxy-1,4-oxazepane-6-ylcarbamic acid benzyl ester (1000 mg, 3.59 mmol) was dissolved in MeOH (25 mL) In the process, degassing was carried out by ν2 for 10 minutes. 10% palladium on charcoal (380 mg) was added and the mixture was stirred under hydrogen for 12 hours. The reaction mixture was filtered through celite and concentrated to give a colourless oil. MS: m/z (observed) 144.9 [M+H]+. Step 5: (S)-5-(3,3-Methylbutyr-1-blockyl)-3-[1^-(4-methyl-5-sideoxy-1,4_oxaza aza Cycloheptane-6-yl)amino]thiophene-2-carboxylic acid methyl ester "(s)-6-amino-4-mercapto-1,4-oxazepan-5-one ( 〇.5 g, 3.5 mmol) and carbonic acid planer (3.39 g, 10.4 mmol) were dissolved in 1,4-dioxane (7.5 mL). 3-Bromo-5-(3,3-dimercaptobut-1-ynyl)thiophene-2-carboxylate methyl ester 〇 4 g, 3.48 mmol) was added and the mixture was degassed by N 2 purification for 2 hours. Add to

Pd(OAc)2 (76 mg '0.35 mmol) and rac-BINAP (431 mg, 0.69 mmol) and the mixture was further purified with N2 for 3 min, then heated to 1 〇〇〇c overnight. After cooling to room temperature, the mixture was diluted with EtOAc (i vol.) and then evaporated and evaporated. The product was purified by chromatography on EtOAc (EtOAc/EtOAc). MS: m/z (observed) 365 5 [M+H]+. 1h NMR (300 MHz, CDC13) δ 7.77 (d, 1H), 6.70 (s, 1H), 4.28 (s, 1H), 3.95-3.79 (m, 5H), 3.78-3.42 (m, 4H) 3.10 (s , 3H), 1.32 (s, 9H). 157033.doc -192- 201215604 Step 6: (S)-5-(3,3-Dimethylbut-1-blockyl)-3-[(trans)-4-yl-N-(4-A Methyl 5-tertiaryoxy-1,4-oxazepan-6-yl)cyclohexanecarbamimidyl] methyl thiophene-2-carboxylate. (S)-5-(3,3-dimethylbut-1-ynyl)-3-[N-(4-methyl-5. oxo-1,4-oxazepane) Methyl-6-yl)amino]thiophene-2-carboxylate (250 mg '0.65 mmol) was deuterated in the manner described for compound 134 using EtOAc (1.3 mmol). Yield 80 mg. MS: m/z (observed) 489.7 [M+H]+. 4 NMR (300 MHz, CDC13) δ 7.54 (s, 1H), 7.20 (s, 1H), 5.64 (dd, 1H) , 4.51 (dd, 1H), 4.36 (dd, 1H)S 4.00 (d, 3H), 3.87 (d, 3H), 3.71 (dd, 1H), 3.59 (s, !Η), 3.48-3.37 (m, 1H), 3.16 (d, 2H), 3.09 (d, 3H), 1.63 (dd&gt; 3H), 1.58 (s, 3H), 1.57-1.35 (m, 2H), 1.33 (d, 9H), 〇·82 (dd, 3H), 0.70 (s, 2H) Step 7: (8)·5-(3,3-Dimethylbuti-i-alkynyl)-3_[(trans)_4_methyl_Ν_(4·A (5)-oxyl-1,4-oxazepanyl-6-yl)cyclohexanecarboxamido]thiophene-2-carboxylic acid. (S)-5-(3,3-didecyl)丁小快基)_3_[(反)_4_Methyl_Ν·(4_methyl, 5-oxo-oxime, oxime-oxazepan-6-yl)cyclohexaneguanamine Base thiophene-2-carboxylate (8〇mg, 〇11 mm〇i) as for The hydrolysis was carried out as described in 134 to obtain the desired yield of 52 mg, 98%. MS: m/z (observed) 475.7 [Μ+Η]+» NMR (300 MHz, d6-DMSO) δ 7 41 ( • VS, (H, 1H) -0.97 (m, 2H), 〇.77 (d, 3H), 0.69-0.43 (m, 2H). 157033.doc •193· 201215604 Preparation of Compound 137

Step 1: (S)-5-(3,3-Dimethylbut-1-ynyl)_3-[(2,4-dioxabenzhydryl)-indole-(1_methyl-2-oxo Azacycloheptan-3-yl)amino]-thiophene-2-furic acid methyl ester. (S)-5-(3,3-Dimethylbutan-1-yl)-3-[Ν-(1-methyl-2-oxazacycloheptan-3-yl)amino]thiophene -2-decyl decanoate (160 mg, 0.42 mmol), 0 bite (340 μΐ^, 4.2 mmol), DMAP (5 mg, 0.04 mmol) and 2,4-dichlorobenzamide (176 mg, 0.84 mmol) was dissolved in DCE (5 mL) and the mixture was heated to 90 ° C overnight. The reaction was cooled and diluted to pH 3 with 2N EtOAc. The organic phase was washed with brine and dried (MgSO4). The solution was evaporated and the residue was purified EtOAc EtOAc EtOAc. Yield: 100 mg. MS: m/z (observed) 535.5 [M+H]+. 4 NMR (300 MHz, CDC13) δ 7.72 (s, 1H), 7.35-7.34 (m, 1H), 7.25 (t, 2H), 7.06 (dd, 1H), 5.62 (d, 1H), 3.95-3.78 ( m, 4H), 3.35-3.14 (m, 1H), 3.09 (d, 3H), 1.71 (d, 4H), 1.44 (dd, 1H), 1.31 (s, 9H). Step 2: (S)-5-(3,3-Dimethylbutan-4-ynyl)_3_[(2,4_dioxabenzhydryl)·Ν_(1_methyl-2-oxonitrogen heterocycle Heptane-3-yl)amino]-thiophene-2-carboxylic acid. (s) 5_(3,3-Dimercapto-i-alkynyl)_3_[(2,4_diphenanthrylmethyl)_157033.doc -194· 201215604 2-oxazepane Methyl 3-amino)amino]-thiophene-2-carboxylate (100 mg, 0.19 mmol) was obtained as described for compound 134 to afford desired 137. Yield 20 mg, 19%. MS: m/z (observed) 521.5 [M+H]+. 4 NMR (300 MHz, CDC13) δ 7·43 (d, 1H), 7.35 (d, 1Η), 7.28-7.25 (m, 1Η), 7.22 (s, 1Η), 7.13 (d, 1Η), 6.97 (s, 1H), 5.37 (d, 1H), 3.98-3.68 (m, 2H), 3.33 (t, 1H), 3.13 (d, 3H), 1.86 (s, 6H), 1.33 (m, 9H) . Preparation of compound 13%

Step 1: (S)-5-(3,3-Dimethylbut-1-ynyl)_3_[N_(i-(2-decyloxyethyl)_2-oxazepan-3- Methyl) thiophene-2-carboxylate. (S)-3-Amino-1-(2-methoxyethyl)-azetidine-2-rehydrochloride (1.0 g, 4.5 mmol) and cesium carbonate (3.66 g' 11.2 mmol) ) dissolved in 1,4-dioxane (15 mL). Add 3 -&gt;Smell-5-(3,3-methylbutan-1-ylidene) to acetonitrile-acetic acid methyl acetate (1.13 g, 3.74 mmol) and purify the mixture by N2 Degas for 2 hours. Pd(OAc)2 (84 mg '0.37 mmol) and rac-BINAP (465 mg, 0.75 mmol) were added and the mixture was further purified with N2 for 30 min then heated to i s overnight. After cooling to room temperature, the mixture was diluted with EtOAc (10 vols), filtered over Celite and evaporated. The product was purified by EtOAc (EtOAc/EtOAc) Yield 6 〇〇 mg, 40%. MS: m/z (observed) 407.6 [M+H]+. NMR (300 MHz, CDC13) δ 157033.doc •195· 201215604 6.42 (s, 1H), 4.16 (dd, 1H), 3.82 (s, 3H), 3.57 (ddd, 6H), 3.33 (s, 3H), 1.62 (s, 6H), 1.32-1.28 (m, 9H). Step 2: (S)-5-(3,3-Dimethylbut-1-ynyl(trans)_4_methyl·Ν·(1_(2_methoxyethyl)-2-oxazepine Alkyl-3-(yl)cyclohexanecarbamamino)thiophene-2-carboxylic acid methyl ester. (S)-5-(3,3-Dimercaptobutynyl)methoxyethyl)-2-oxaazepidine-3-yl)amino]π-cetin-2-formic acid decyl ester The deuteration reaction of (3 〇〇 mg) was carried out as described in the other examples. The yield is 8 〇 mg. MS: m/z (observed) 531.7 [M+H]+. NMR (300 MHz, CDC13) δ 7·61 (s, 1H), 5.40 (d, 1H), 3.89-3.63 (m, 5H), 3.59-3.23 (m, 8H), 2.17-1.37 (m, 14H) , 1.33 (s, 9H), 0.76 (dd, 4H). Step 3: (S)-5-(3,3-Methylbut-1-ynyl)_3_((trans)_heart methyl_ν_(ι·(2·曱oxyethyl)-2- Oxacycloheptan-3-yl)cyclohexanecarbamamino)thiophene-2-carboxylic acid. (S)-5-(3,3-dimercapto-1-ynyl)·3·((trans)_4_methyl·n_(k(2_ methoxyethyl)-2-oxazepine Methyl alk-3-yl)cyclohexanecarbamimidino)thiophene-2-furoate (80 mg, 0.15 mmol) was obtained as described for compound 134 to afford desired 138. Yield 40 mg, 42%. MS: m/z (observed) 517.7 [M+H]+. NMR (300 MHz, CDC13) δ 6.74 f V s, 1H), 5.09 (dd, 1H), 3.93-3.41 (m, 6 Η), 3.35 (d, 3H), 2·22 1.41 (m, 14H), 1.35 (d, 9H), 0.82 (dd, 3H), 0.74 (s, 1H). Preparation of Compound 145 157033.doc •196· 201215604

step 1

Step 2

Steps 1 and 2: (S)-3-Amino-1-(2-(dimethylamino)ethyl)azepane-2-one. N-[(3S)-2-oxazepan-3-yl]amino decanoic acid terpene vinegar (1. g, 4.38 mmol) was dissolved in DMF (25 mL) and NaH (210 mg, 5.26 mmol) was added under C. The mixture was stirred for 1 hour, followed by the addition of Mo-Ziyi dimethyl-ethylamine (1.0 g, 6.57 mmol). It was stirred for 24 hours, then quenched with aqueous EtOAc (EtOAc)EtOAc. The organic layer was washed with brine and dried over Na.sub.4 and used for the next step. The crude material was dissolved in 4 n EtOAc (10 mL) in dioxane and stirred for 3 hr. The clear reaction mixture became cloudy and a white precipitate formed. The reaction mixture was concentrated, then redissolved in MeCN and HzO and lyophilized. The product was used as such in the next step. MS: m/z (observed) 200.2 [M+H]+. Step 3: (S)-5-(3,3-Dimethylbut-1-ynyl)_3·[Ν-(1-(2-dimethylaminoethyl)· 2-oxo-nitrogen heterocycle Heptan-3-yl)amino]methyl thiophene-2-furoate β(3)_3_amino-1-(2-didecylaminoethyl)-azepane-2_ Keto dihydrochloride (5 mg, 2.1 mmol) and carbonic acid planer (1.73 g, 5 3 mm 〇i) were dissolved in 14 dioxane (10 mL). Add 3_bromo·5_(3,3-didecyl-alkynyl)thiophene-2- 157033.doc •197- 201215604 methyl decanoate (532 mg, 1.77 mmol) and degas for 2 hours by N2 purification . Pd(OAc)2 (40 mg, 0.18 mmol) and rac-BINAP (220 mg, 0.35 mmol) were added and the mixture was further purified with N2 for 30 min and then was then warmed overnight. After cooling to room temperature, the mixture was diluted with EtOAc EtOAc EtOAc. The product was purified by silica gel chromatography (EtOAc EtOAc EtOAc EtOAc EtOAc The product is dissolved in the final dissolving agent. Yield 400 mg, 35%. MS: m/z (observed) 420.4 [M+H]+. 4 NMR (300 MHz, CDC13) δ 7.83 (d, 1H), 6.43 φ (s, 1Η), 4.14 (d, 1H), 3.83 (s, 3H), 3.74-3.25 (m, 4H), 2.46 (d , 2H), 2.29 (d, 6H), 2.05 (d, 2H), 1.76 (d, 4H), 1.40-1.08 (m, 9H). Step 4: (S)-5-(3,3-Dimethylbut-1-ynyl)-3-((trans)-4-methyl-N-(l-(2-dimethylamino) Ethyl)-2-oxaazepperin-3-yl)cyclohexanecarbamoylamino)thiophene-2-furic acid methyl ester. (S)-5-(3,3-Dimethylbut-1-ynyl)-3-[indole-(1-(2-dimethylaminoethyl)-2-oxazepine Alkyl-3-yl)amino]thiophene-2-carboxylic acid methyl vinegar (200 mg, 0.3 mmol) was dissolved in 1,2-dichloroethane (10 mL). Add 0 to bite (40 pL, 0.49 mmol), DMAP (4 mg, 0.03 mmol) and trans-4-mercaptocyclohexanone (100 mg, 0.62 mmol). The mixture was heated to 90 ° C for 48 hours, then diluted with 1 N HCM, EtOAC and water. The organic layer was washed with brine and dried (Na 2 SO 4 ). The solvent was evaporated and the residue was purified eluting with EtOAc EtOAc EtOAc EtOAc Doc -198- 201215604 m/z (observed) 544.7 [M+H]+. 4 NMR (300 MHz, CDC13) δ 7.58 (s, 1H), 5.33 (d, 1H), 3.82 (s, 3H), 3.68 (dt, 1H), 3.60-3.33 (m, 2H), 3.25 (dd, 1H), 2.62 (s, 1H), 2.42 (d, 3H), 2.25 (d, 7H), 2.00 (s, 12H), 1.68 (ddd, 15H), 1.32-1.27 (m, 12H), 1.15-0.85 (m, 4H), 0.78 (d, J = 6.5 Hz, 3H), 0.71 - 0.56 (m, 2H). Step 5: (S)-5-(3,3-Dimethylbut-1-ynyl)-3-((trans)-4-methyl-N_(l-(2-dimethylamino) (2-)-(3,3-dimethylbut-1-yne) )3-((trans)-4methyl-N-(1-(2-dimethylaminoethyl)-2-oxaazepidine_3_yl)cyclohexylcarbamate Methyl thiophene-2-carboxylate (90 mg) was dissolved in THF (6 mL) and H20 (2 mL). The mixture was stirred overnight at ambient temperature and then concentrated. The residue was diluted with EtOAc (EtOAc)EtOAc. The organic layer was triturated with EtOAc and MeCN to afford 145 as a white solid. MS: m/z (observed) 530.4 [M+H]+. ^ NMR (300 MHz, CD3OD) δ 7.38 (s, 1H), 5.21 (d, 1H), 4.41-4.15 (m, 1H), 3.86-3.63 (m, 1H), 3.59-3.35 (m, 3H), 3.00 (d, 6H), 2.22-2.20 (m, 1H), 1.74 (dt, 6H), 1.33 (s} 9H), 1.17 (s, 2H), 0.82 (d, 3H), 0.77-0.48 (m, 2H). Preparation of Compound 146 157033.doc -199- 201215604

Step 1: (S)-5-(3,3-Dimethylbut-1-ynyl)-3-[N-(l-isopropyl-2-oxazepan-3-yl) Amino] thiophene-2-carboxylate. (S)-3-Amino-1-isopropyl-azepane-2-one hydrochloride (700 mg, 2.8 mmol) with 3-bromo-5-(3,3-dimethyl Methyl butyl-(alkynyl)thiophene-2-carboxylate (850 mg, 3.4 mmol) was reacted as described for compound 149. MS: m/z (observed) 391.4 [M+H]+ 〇!H NMR (300 MHz, CDC13) δ 7.89 (d, 1H), 6.41 (s, 1H), 4.96 (s, 1H), 4.20- 4.00 (m, 2H), 3.83 (s, 3H), 3-45-3.04 (m, 2H), 2.06-1.48 (m, 5H), 1.31 (s, 9H), 1.14 (d, 3H), 1.08 ( d, 3H). Step 2: (S)-5-(3,3-Dimethylbutan-1-yl)-3-((trans)-4-methyl-N-(l-isopropyl-2-oxonitrogen Heterocyclic heptane_3_yl)cyclohexanecarbamamino)thiophene-2-carboxylic acid methyl vinegar. (S)-5-(3,3-Dimethylbut_1_ynyl)_3 as described for compound 149 with trans-4-methylcyclohexane helium (14 mg, 0.87 mmol) -[Ν-(1-Isopropyl-2-oxazepan-3-yl)amino]β-cetin-2-carboxylic acid (17 mg, 0.45 mmol) was deuterated. The product was purified by EtOAc (EtOAc EtOAc) elute Ms: m/z (observed value) 515.4 [M+H]+. 4 NMR (300 MHz, CDC13) δ 7.61 (s, 1Η), 5.34 (d, 1Η), 4.88 (s, 1Η), 3.82 (s, 3Η), 3.45-3.20 (m, 2H), 2.30-2.12 ( m, 1H), 2.01-1.32 (m, 17H), 1 30 (d, 9H), 157033.doc •200· 201215604 1·〇9 (d,6H), 0.94 (d,2H),0.88 (t, 3H), 0.79 (s, 1H), 〇72, 〇·55 (m, 1H). Step 3: (S&gt;-5-(3,3·dimethylbutan-2-alkynyl)_3_((trans)_4_methyl_Ν·(1-isopropyl, 2-oxazepane_ 3_yl)cyclohexanecarbamamino)thiophene-2-formic acid. (s^ 5-(3,3-dimethylbutan-alkynyl)·3_((trans)4methylΝ·(1 Methyl isopropylidene-2, oxazacycloheptan-3-yl)cyclohexanecarboxamido)thiophene-2-carboxylate was hydrolyzed as described for the compound 149 to give the desired 146^ MS: m /z (reserved value) 501.4 [M+H].4 NMR (300 MHz, CDC13) δ 6.65 (s 1H), 5.00-4.92 (m, 1H), 4.84 (s, 2H), 3.51-3.27 ( m,2H), 2.28-2.11 (m,ih),2.07-1.87 (m,3H),1.86-1.69 (m,4H), 1.67-1.44 (m, 4H), 1.49-1.31 (m, 3H), 1.26 (d, 9H), i.〇6 (dt, 6H), 0.81 (s, 1H), 0.75-0.69 (m, 3H), 0.66 (s, 2H).

Step 1: (S)-5-(3,3·Dimethylbut-1-ynyl)-3-[(2,4-dioxaphenyl)-Ν-(4-methyl-5 Methyl-oxo-1,4-oxazepan-6-yl)amino]thiophene-2-carboxylate. (S)-5-(3,3-Dimercapto-1-ynyl)-3-[indole-(1-ethyl-2-oxazacycloheptan-3-yl)amino] Methyl thiophene-2-carboxylate (1〇〇mg '0.26 mmol), 〇bite (34 μί, 〇_42 mmol), DMAP (3 mg '0.03. 157033.doc •201 · 201215604 mmol) and 2,4 - One gas (0.5 mmol) was dissolved in DCE (10 mL) and the mixture was heated to 90 ° C overnight. The reactants were treated as described for compound 137. Yield 100 mg. MS: m/z (observed) 537.1 [M+H]+. Step 2: (8) _5_(3,3-Dimethylbutan-1-yl)_3](2,4_diphenanthryl)-N_(4_ decyl-5-sideoxy-1 , 4-oxazepane-6-yl)amino] thiophene-2-carboxylic acid. (S)-5-(3,3-dimercapto-l-alkynyl;)-3_[(2,4-dioxaphenyl)-indole-(4-mercapto-5-side oxygen The thiol-2-carboxylic acid oxime ester (0.19 mmol) was hydrolyzed as described for compound 137 to give desired 147. Yield 97 mg. MS: m/z (observed) 523.2 [M+H]+. H NMR (300 MHz, CDC13) δ 7.64-7.54 (m, 1H), 7.58 (d, 1H), 7.33 (s, 1H), 7.27-7.20 (m, 1H), 7.17 (dd, 5H), 7.04 (s, .5H), 4.63 (d, 1H), 4.38 (s, 2H), 4.06 (s, 1H), 3.90 (dd, 1H), 3.69 (s, 1H), 3.31 (m, 1H), 3.18 -3.08 (m, 3H), 1.34-1.24 (m, 9H). Preparation of Compound 117

Step 1: (S)-5-(3,3-monomethylbutan-1-ylidene-1-yl)-3-((1-indolyl-2-l-oxyl octazone-3-yl)amine Methyl thiophene-2-carboxylate. To 3-bromo-5-(3,3-dimethylbut-1-an-1-yl). Methyl ceto-2-carboxylate (1.18 g, 3.90 mmol), cesium carbonate (1.27 g, 3.90 mmol) and (S)-3-amino-1-methyl0-bottom-2-one (0.60 g, 157033.doc •202- 201215604 4.7 mmol) Add acetic acid to a degassed suspension in toluene (12 mL) at (85 mg, 0.39 mmol). Then add (±)-BINAP (243 mg, 0.39 mmol) . The reaction mixture was heated to 90 ° C and stirred until the starting material was consumed (by HPLC and LCMS). The reaction mixture was cooled to room temperature, filtered through celite, and rinsed with di-methane. The solvent was removed under reduced pressure and the crude material was purified eluted eluted eluted elut elut elut elut elut elut elut elut elut (1.03 g). Crystallization from hydrazine to give the desired (S)-5-(3,3-dimethylbut-1-yn-1-yl)-3-((1-methyl-2-oxopiperidin-3) -Based on the amino group), methyl phenoxylate (453 mg, 45%) was sold. MS: m/z (observed) 349.13 [M+H]+. iH NMR (300 MHz, MeOD) δ 6·80 (s, 1H), 4.10 (dd, J = 10.3, 5.6 Hz, 1H), 3.76 (s, 3H), 3.47-3.35 (m, 2H), 2.94 ( s, 3H), 2.28 (dt, J=9.5, 5.1 Hz, 1H), 2.05-1.90 (m, 2H), 1.86-1.68 (m, 1H), 1.30 (s, 9H). Palmer HPLC: &gt;99:1 S/R ratio (Chiralpak AD-H, 40% EtOH/Hex). Step 2: 5-(3,3-Dimethylbut-l_yne_i_yl)_3_(trans_4_methyl_N_((S)q methyl·2_ oxopiperidin-3-yl Cyclohexylcarbamino)thiophene-2-carboxylic acid methyl ester. (S)-5-(3,3-Dimethylbutylmyl)indenyl-2-oxopiperidin-3-yl)amino)porphyrin-2-carboxylic acid decyl ester (670 ΐ·ΐ·92 mmol) was dissolved in DCE (7 mL). Add pyridine (156,} 92 mm 〇1), DMAp (23 mg, 0.19 mmol) and trans-4-methylcyclohexane hydrazine chloride (772 g, 48 〇 mmol) and heat the reaction mixture to 9 〇t until The starting material was consumed (monitored by TLC and HPLC). The reaction mixture was cooled to room temperature and washed with 2 n HCl, 157033. doc - 203 - 201215604 saturated NaHC 3 and brine. The organic layer was dried (Na 2 SO 4 ), filtered and solvent was evaporated under reduced pressure. The crude product was purified by column chromatography eluting with EtOAc EtOAc EtOAc (EtOAc) --N-((S)-1-methyl-2-oxopiperidin-3-yl)cyclohexanecarboxamido)thiophene-2-indenoate (85 mg, 93%) . MS: m/z (observed) 473.47 [M+H]+. 4 NMR (300 MHz, MeOD) δ 7.16 (d, J = 82.0 Hz, 1H), 5.41 (dd, J = 12.3, 5.6 Hz, 1H), 3.82 (d, J = 1.6 Hz, 3H), 3.79-3.72 (m, 1H), 3.50 (td, J=12.0, 3.6

Hz, 1H), 3.26 (dd, J=8.6, 4.3 Hz, 1H), 2.94 (d, J=6.2 Hz, 3H), 2.46 (ddd, J=16.6, 14.1, 3.7 Hz, 1H), 2.18-1.36 (m, 8H), 1.33 (s, 9H), 0.81 (d, J = 6.5 Hz, 3H), 0.68 (dd, J = 20.7, 11.0 Hz, 2H). Step 3 ··· 5-(3,3-Dimethylbutan-1^4•yl)_3_(trans-4_methylmethyl-2_ oxoxypiperidin-3-yl)cyclohexanecarboxamide Thiophene-2-carboxylic acid. 5_(3 3_Dimethylbut-1-yn-1-yl)-3-(trans-4-indenyl-N-((S)-1-indolyl-2-yloxypyrylene-3 -yl)cyclohexanecarbamimidyl)thiophene-2-carboxylic acid oxime ester (85 mg, 1.80 mmol) dissolved in THF (4.3 mL) and water (4.3 mL) with lithium hydroxide (129 mg, 5.39) Mm). The reaction mixture was stirred at room temperature until the starting material was consumed (monitored by TLC). The reaction mixture was acidified with 3 n EtOAc and washed with ethyl acetate and brine. The organic layer was dried (NhSOd, filtered and evaporated in vacuo to afford

Crystallization from MTBE/heptane gave Compound 117 (695 mg, 84%). MS: m/z (observed) 459.24 [M+H] +, 457.19 [M-Η]. Towel NMR 157033.doc -204· 201215604 (300 MHz, MeOD) δ 7.15 (d, J=78.0 Hz, 1H), 5.28 (dd, J=12.1, 5.6 Hz, 1H), 3.76 (dd, J=ll. l, 6.7 Hz, 1H), 3.49 (td, J = 12.1, 3.9 Hz, 1H), 2.95 (d, J = 2.7 Hz, 3H), 2.46 (ddd, J = 16.7, 14.1, 3.6 Hz, 1H), 2.23-2.01 (m, 2H), 1.99-1.84 (m, 1H), 1.83-1.38 (m, 6H), 1.33 (s, 9H), 0.81 (d, J=6.5 Hz, 3H), 0.77-0.58 ( m, 2H). For palmar HPLC: 99:1 S/R (Chiralpak IC, 100% ACN/0.1% TFA) 制备 Preparation of compound 122 Step 1 ··

5-(3,3-Dimethylbut-1-ynyl)-3-[[(1 and)-1-(morpholine-4-ylcarbonyl)propyl]amino]thiophene-2-furic acid ester. 3-bromo-5-(3,3-dimethylbut-1-ynyl)thiophene-2-carboxylate (2 g ' 6.64 mmol), (R) 2 -amino-1 morpholinyl A suspension of 1-ketone (2.06 g ' 9.96 mmol), Cs2C03 (6.5 g, 20 mmol) in toluene (40 mL) was deoxygenated by argon gas purge for 60 minutes and added

Pd(OAc) 2 (150 mg, 0.664 mmol) and (±) BINAP (413 mg, 0.664 mmol). Purification was continued for another 30 minutes and the mixture was at 100. (The mixture was stirred for 16 hours. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was cooled to room temperature] diluted with EtOAc (100 mL) and passed through EtOAc (EtOAc). (30 mL) washed, dried over Na2SO4 and concentrated. The crude product was obtained by column chromatography (10 〇 2 〇〇 石 石 ,, 157033.doc -205 - 201215604 20 〇 〇 EtOAc / petroleum ether Purification of '5-(3,3-dimethylbut-1-ynyl)-3_[[(lR)-l-(morpholin-4-carbonyl)propyl]amino);]thiophene_2_ Methyl formate (1.6 g, 61% 'yellow solid). TLC: 40% EtOAc / pet ether, Rf: 0.41. Analysis by LCMS: ΜΗ+=393·2; ipi NMR (400 MHz, CDC13): 7.33 d, J = 8 Hz; interchangeable with D20; 1H), 6·53 (s, 1H), 4.21-4.20 (m, 1H), 3.81 (s, 3H), 3.67-3.54 (m, 8H), 1.89-1.86 (m, 1H), 1.76-1.71 (m, 1H), 1.30 (s, 9H), 0.99 (t, J=7.6 Hz; 3H). Step 2:

5-(3,3-dimercapto-i-alkynyl)·3_[(trans-4_methylcyclohexylcarbonyl(morpholine-4-carbonyl)propyl]amino]thiophene-2-carboxylic acid Ester. 5-(33-Dimethylbut-1-ynyl)-3-[[(lR)-l-(morpholine-4-carbonyl)propyl]amino]thiophene-2-carboxylate (1 g , 2.6 mmol) of the solution in dichloroethane (5 mL) was stirred under a ratio of bite (15 mL, 15 volumes) and DMAP (156 mg, 1.275 mmol). Add dropwise to this solution. Di-ethane (2 〇 mL) containing anti--4 methylcyclohexaneformamidine chloride (6.14 g, 38·3 mmol). After the addition was completed, the reaction mixture was stirred at 10 ° C for 16 hours. The progress of the reaction was monitored by TLC. When the reaction was completed, the reaction mixture was diluted with dichloromethane (1 mL), using 2 N HCl aqueous solution (2×3 〇mL), water (3 〇mL), 1 〇% 157033. doc • 206· 201215604

Wash NaHC03 solution (2x30 mL), brine (3 mL), dry over Na2SO4, and then the residue was purified by column chromatography (i 〇〇 〇〇 〇〇 〇〇 丨〇 丨〇 丨〇 〇 〇 / / Purification of '5-(33-dimethylbutan-alkynyl)- 3 [(trans-4-methylcyclohexylcarbonyl)[(ir)-^(morpholine-4-ylcarbonyl)propyl]amino Thiophene-2_ formic acid vinegar (1 g '76%, yellow solid). TLC: 40% EtOAc / petroleum ether ' Rf : 0.45. Analysis by LCMS (column: BEH C-18 (2.1x50 mm) ' Phase: A: 0.01 M NH4HCO03 aqueous solution, B: MeCN, time (min)/% B gradient: 〇min/40%, 2/95, 4/95, 4.1/20, flow rate: 0.4 mL/min, sample diluent :MeCN) : mh+=517 2, tR=2.68 min » A NMR (400 MHz, CDC13): 7.42 (s,1H), 5.25-5.19 (m, 1H), 3.83-3.58 (m, 12H), 2.0 ( Bs, 1H), 1.66- 1.59 (m, 6H), 1.42-1.31 (m, 9H), 0.91-0.78 (m, 8H), 0.69-0.66 (m, 3H). Step 3:

5-(3,3-Dimethylbut-1-ynyl)_3_[(trans_4_methylcyclohexylcarbonyl)-[(1R) ^ (Merlin-4-reradyl)propyl]amino group叹 吩 _2 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 5 5 - 5 5 5 5 5 5 Methyl]amino]thiophene-2-furic acid methyl ester (70 mg, 0.14 mmol) was added to a stirred solution of THF and water (l:i) (4 mL). 157033.doc • 207· 201215604

LiOH.H20 (28.3 mg '0.675 mmol) was stirred for 3 hours. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the mixture was crystallised eluted with EtOAc (EtOAc) The combined EtOAc layers were washed with EtOAc EtOAc. The residue was purified by preparative EtOAc (EtOAc EtOAc EtOAc) )-[(lR)_i_(morpholine-4-carbonyl)propyl]amino]thiophene-2-carboxylic acid (25 mg, 37%, white solid). TLC: 10% MeOH/CHCl3, Rf: 0.38. Analysis by LCMS (column: Zorbax SB-CN (250 x 4.6 mm, 5 μιη), mobile phase: A: 0.01 M HCOONH4 aqueous solution, B: MeCN, time (min) / ° / 〇Β gradient: 0 min / 30%, 8/90, 15/90, 15.1/30, flow rate: 1.04 mL/min, sample diluent: MeCN): MH+ = 503.2, tR = 5.36 min. 4 NMR (400 MHz, DMSO-d6): 13.65 (bs, interchangeable with D20; 1H), 7.06 (bs, 1H), 5.15 (bs, 1H), 3.69-3.44 (m,8H), 2.08-2.04 (m , 1H), 1.68-1.38 (m, 6H), 1.35-0.87 (m, 12H), 0.85-0.53 (m, 8H). Preparation of Compound 123 Step 1:

3-[(4-chlorobenzylidene)-(2-morpholinyl-2-oxo-ethyl)amino]-5-(3,3- 157033.doc -208- 201215604

Dimethylbut-1-ynyl)thiophene-2-carboxylic acid. Here. 5(33-Dimethylbut-1-ynyl)-3-(2-morpholinyl-2-oxoethoxyethylamino)thiophene-2-furic acid methyl ester (200 mg, 〇·5) 5 mmol) pyridine (2 mL '10 volumes) and DMAP (33.6 mg, 0.275 mm 〇1) were added to the stirred solution in dichloroethane (1 mL). Add 4- to this solution dropwise Gas Benzolium (0.7 mL, 5.5 mmo1). After the addition, the reaction mixture was stirred at 100 ° C for 16 hours. The response process is monitored by TLC. Upon completion, the reaction mixture was diluted with EtOAc EtOAc EtOAc EtOAc (EtOAc) . The residue was purified by column chromatography (1 〇〇 2 〇〇 石 石 ,, 50 〇 / 〇 EtOAc / petroleum ether) to give 3·[(4-benzophenanthryl)-(2- Morpholinyl-2-oxo-ethyl)amino]-5-(3,3-dimercapto-1-ynyl)thiophene-2-furic acid methyl ester (190 mg, 67%, white solid). TLC: 50% EtOAc/ petroleum ether, Rf: 0.31. By LCMS analysis (column: 161^]^3-&lt;:-18 (4.6x50 mm, 3 μηι), mobile phase: A: 0.1% HCOOH aqueous solution, B: MeCN, time (min)/% B Gradient: 0 min/10%, 4/90, 8/90, 8.01/10, flow rate: 1.0, mL/min, sample diluent: MeCN): MH+ = 503.2, tR = 4.65 min. NMR (400 MHz, DMSO-d6): 7.38-7.26 (m, 4H), 7.11 (s, 1H), 5.11 (d, J = 16.8 Hz; 1H), 4.23 (d, J = 16.8 Hz; 1H) 3.70 (s, 3H), 3.60-3.46 (m, 8H), 1.27 (s, 9H). Step 2: 157033.doc •209· 201215604

3_[(4_Chlorobenzoyl)_(2_morpholinyl_2_sideoxy-ethyl)amino]_5_(3,3-dimethylbut-1-ynyl)thiophene-2- Formic acid. To 3-[(4-chlorobenzylidene)-(2-morpholinyl-2-oxo-ethyl)amino]-5-(3,3-dimercapto-) at room temperature To a stirred solution of a mixture of THF and water (1..1) (4 mL) was added EtOAc (47.5 mg, EtOAc, EtOAc. 1.13 mmol) and the mixture was stirred for 16 hours. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the~~~~~~~~~~~~~~ The organic layer was washed with water (3×20 mL), brine The residue was purified by wet trituration with EtOAc (2×50 mL) to afford 123: 3-[(4-chlorobenzylidenyl)-(2-morpholin-2-yloxy-ethyl)amino] -5-(3,3-Dimethylbut-1-ynyl) porphin-2-decanoic acid (139.3 mg, 75%, green solid). TLC: 10% MeOH/CHCl3, Rf: 0.38. Analysis by LCMS (column: Xterra MS-C-18 (4.6 x 50 mm, 3 μηι), mobile phase: A: 0.1% aqueous solution of HCOOH, B: MeCN, time (min)/% B gradient: 0 min/10 %, 4/90 ' 8/90 ' 8.01/10 ' Flow rate: 1.0 mL/min, sample diluent: MeCN) : MH+=489.0, tR=4.21 min 〇NMR (400 MHz, DMSO-d6): 13.47 (br s, interchangeable with D20; iH), 7.37 (d, J=8.4

Hz; 2H), 7.26 (d, J=8.4 Hz; 2H), 7.12 (s, 1H), 5.12-5.08 (m, 1H), 4.24-4.20 (m, 1H), 3.59-3.46 (m, 8H) , 1.27 (s, 9H). 157033.doc •210· 201215604 Preparation of Compound 124 Step 1:

Methyl 5-(3,3-methylbutan-1-yl)-3-[(2-morphin-2-yloxy-ethyl)amino 1thiophene-2-carboxylate. To a 1 〇〇 mL 2-neck round bottom flask was fed 2-amino-1-morphinyl-ethanone hydrochloride (62 〇 mg, 3.43 mmol), 3-MI-5-(3,3-di) Methyl decyl-1-ynyl)thiophene-2-carboxylate (1 〇3 g, 3.43 mmol) and Cs2C 〇3 (3.35 g ' ΐ〇·3 mmol). Dioxane (30 mL) was added and nitrogen was bubbled through the suspension for 30 minutes. Then Pd2(dba)3 (56.5 mg, 0.0617 mmol) was added followed by dicyclohexyl-[2_(2 6-dioxyloxy)phenyl]phosphine ("sPHOS" 102 mg, 0.248 mmol). The reaction was heated to 105 ° C overnight; according to partial conversion (by LCMS), 2 〇〇 mg sPHOS, 112 mg Pd 2 (dba) 3 and 1 oxane were added and the reaction was carried out for another 3 days at 10 ° C. Then LCMS analysis showed complete conversion. The mixture was cooled, filtered through celite, and concentrated. Chromatography on ruthenium dioxide followed by concentrating in vacuo gave the desired product as a white solid that precipitated during concentration. Analysis by LCMS (column: C4, mobile phase: a: 〇1% HCOOH aqueous solution, b: MeCN, time (min)/% b gradient: paradox/6〇〇/〇, 7/98, flow rate: L0 mL/min): MH+=365 2 〇, tR=i 32 Μ. .咕诵1 _ MHz, CDCl3): 7.38 (br s,1H),6 58 (s,h),* 〇3 (d, 2H), 3.85 (s53H), 3.70 (brs,6H), 3.45 (brs, 2H) ! 3〇(S5 9H) 〇157033.doc -211- 201215604 Step 2:

3-[(2,4-dioxabenzhydryl)-(2-morphinyl-2·sideoxy-ethyl)aminodibu 5-(3,3-dimethylbut-1-yne Methyl thiophene-2-formic acid. 5-(3,3-Dimethylbutan-l-alkynyl)-3·(2-morphinyl-2-oxoethoxyethylamino)β-cetin-2-carboxylic acid formazan (200 mg, 0.55 mmol) of the stirred solution in di-hexane (1 mL) was stirred at 〇 ° C with pyridine (2 mL, 10 vol) and DMAP (33.6 mg, 0.275 mmol). To this solution was added dropwise 2,4-dibenzoquinone chloride (0.77 mL, 5·5 mmol). After addition, the reaction mixture was stirred under hydrazine (9) for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with EtOAc (EtOAc) (EtOAc (EtOAc) (EtOAc) concentrate. The residue was purified by column chromatography (100-200 EtOAc (EtOAc:EtOAc) -2-Sideoxy-ethyl)amino]-5-(3,3-dimercaptobut-1-ynyl)°Cetyl-2-decanoate (180 mg, 60 〇/〇, White solid). TLC: 50% EtOAc / petroleum ether. Analysis by LCMS (column: Xterra MS-C-18 (4.6 &lt; 50 mm, 3 μιη), mobile phase: A: 0.1% aqueous solution of HCOOH, Β: MeCN, time (min)/% Β gradient: 0 min/10%, 4/90, 8/90, 8.01/10%, flow rate: ι·〇mL/min, sample diluent: MeCN): MH+=537.2, tR=4.78 -212- 157033.doc 201215604 ηιίη ^ΗΝΜΙΙΗΟΟΜΗζ,ΟΜ^Ο-άβ):?^〕^,.;!^),?.〗? -7.35 (m,1Η), 7.22-7.20 (m, 1Η), 5.15 (d, J=i6.4 Hz; 1Η), 4.21 (d, J=16.8 Hz; 1H), 3.83 (s, 3H), 3.58-3.44 (m, 8H), 1.24 (s, 9H). Step 3:

3-[(2,4-dichlorobenzyl)-(2-l-butyl-2-oxo-ethyl)amino]_5_ (3,3-dimethylbutan-l-alkynyl) ) thiophene-2-formic acid. To 3-[(2,4-dichlorobenzylidene)-(2-morpholinyl-2-oxo-ethyl)amino]-5-(3,3-dimethyl at room temperature Methylbutan-1-ynyl)thiophene-2-carboxylate (180 mg, 0.335 mmol) was added to a stirred solution of a mixture of THF and water (i: 1) (4 mL)

Li0H_H20 (52.3 mg, 1.24 mmol) ' and the mixture was stirred for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was acidified (pH 1) with EtOAc (60 mL). The organic layer was washed with water (3×20 mL), brine (20 mL) and dried and evaporated. The crude residue was purified by EtOAc (2×5 mL) to afford 124·············· Base]_5_(3,3-dimethylbut-1-ynyl)thiophene-2-nonanoic acid (139 mg, 79%, white solid). TLC: 10% MeOH / CHCl3, Rf: 0.39. Analysis by LCMS (column · Zodiac Sil 120-3-C-18-aq. (4.6 &gt;&lt; 50 mm), mobile phase: 157033.doc -213 - 201215604 A : 0.01 M HCOONH4 aqueous solution, B: MeOH , time (min) / ° / 〇 B gradient: 0 min / 60 ° / 〇, 3 / 90, 8 / 90, 8.01 / 60, flow rate: 1.0 mL / min, sample diluent: MeOH / MeCN): MH + = 523.0, tR = 2.73 min. 4 NMR (400 MHz, DMSO-d6): 13.7 (br s, interchangeable with D20; 1H), 7.62-7.61 (m, 1H), 7.40-7.38 (m, 1H), 7.23-7.20 (m, 1H), 7.12 (s, 1H), 5.15-5.11 (m, 1H), 4.23-4.19 (m, 1H), 3.58-3.44 (m, 8H), 1.24 (s, 9H). Preparation of Compound 125 Step 1:

5-(3,3-Dimethylbut-1-ynyl)-3-[(4-methylbenzylidene)-(2-morpholinyl-2-oxo-ethyl)amino ] Thiophene·2·methyl formate. 5-(3,3-Dimercapto-1-indolyl)-3-(2-morphinyl-2-oxoethoxyethyl) decanophene-2-propenoate (200 mg' 0.55) The stirred solution of mmol in di-hexane (1 mL) was stirred with pyridine (2 mL, 10 vols) and DMAP (33.6 mg, 0.275 mmol) at 0 °C. To this solution, 4_mercaptobenzyl hydrazine gas (0.73 mL, 5.5 mmol) was added dropwise and the reaction mixture was taken at 1 Torr. Stir under the arm for 16 hours. The progress of the reaction was monitored by TLC. When the reaction is completed, the reaction mixture is used.

Diluted with EtOAc (80 mL), washed with 2N aqueous HCI (2×30 mL), water (30 mL), 10% NaHC03 (2×30 mL), brine (30 mL)

Na2S〇4 was dried and concentrated. The residue was purified by column chromatography (1 〇〇 〇〇 矽 157033.doc • 214 - 201215604 </ RTI> 50% EtOAc/ petroleum ether) to give 5-(3,3-dimercapto- 1-Alkynyl-3-((4-methylbenzimidyl)-(2-morpholinyl-2-oxo-ethyl)amino] thiophene-2-decanoate (200 mg , 75%, white solid). TLC: 50% EtOAc / petroleum ether. By LCMS analysis (column: Xterra MS-C-18 (4.6 &gt;&lt; 50 mm, 3 μηι), mobile phase: A: 0.1% aqueous solution of HCOOH, B: MeCN, time (min) / % B gradient: 0 min/10%, 4/90, 8/90, 8.01/10, flow rate: 1.0 mL/min, sample diluent: MeCN): MH+=483.2, tR=4.49 min. 4 NMR (400 MHz,

DMSO-d6): δ 7.16-7.06 (m, 5H), 5.10 (d, J = 16.8 Hz; 1H), 4.18 (d, J = 16.4 Hz; 1H), 3.71 (s, 3H), 3.58-3.57 ( m, 4H), 3.45 (br s, 4H), 1.26 (s, 9H). Step 2:

5-(3,3-Dimethylbut-1-ynyl)-3-[(4-methylbenzimidyl)-(2·morpholinyl-2-oxo-ethyl)amino 】 thiophene-2-carboxylic acid. To 5-(3,3-dimercapto-1-indolyl)-3-[(4-mercaptophenylhydrazone)-(2-norlinyl-2-ylideneoxy)-at room temperature Ethyl)amino]thiophene-2-carboxylic acid methyl ester (200 mg, 0.415 mmol) in THF

To a stirred solution of a mixture of water (1:1) (4 mL) was added &lt;RTI ID=0.0&gt;&gt; The progress of the reaction was monitored by TLC. Upon completion of the reaction, the mixture was crystallised with EtOAc EtOAc EtOAc EtOAc The organic layer was washed with water (3×20 mL), brine (20 mL) and dried and evaporated. The residue was purified by wet-milling with Et20 (2×5 mL) to give &lt;RTI ID=0.0&gt; 2-morpholinyl-2-oxo-ethyl)amino]thiophene-2-carboxylic acid (140 mg, 72%, white solid). TLC: 10% MeOH / CHCl3, Rf: 0.44. By LCMS analysis (column: Xterra MS-C-18 (4.6 &gt;&lt; 50 mm, 3 μιη), mobile phase: A: 0.1% aqueous solution of HCOOH, B: MeCN, time (min) / % B gradient: 0 min/10%, 4/90, 8/90, 8.01/10, flow rate: 1.0 mL/min, sample diluent: MeCN): ΜΗ_=467·0, tR=4.08 min. NMR (400 MHz, DMSO-d6): 13.4 (br s, interchangeable with D20; 1H), 7.16-7.06 (m, 5H), 5.11-5.06 (m, 1H), 4.21-4.17 (m, 1H), 3.59 -3.46 (m, 8H), 2.25 (s, 3H), 1.26 (s, 9H). Preparation of Compound 126 Step 1:

N-[(lS)-l-(morpholin-4-carbonyl)propyl]carbamic acid tert-butyl ester. To (S)-2-(t-butoxycarbonylamino)butyric acid (18.5 g, 91.1 mmol), HBTU (43.4 g, 109 mmol), DIPEA (47.6 mL, 273 mmol) at 0 °C Morpholine (9.5 mL, 110 mmol) was added to a solution in CH2C12 (400 mL). The reaction was monitored by TLC 157033.doc -216· 201215604 process. The mixture was diluted with EtOAc (3 mL) (EtOAc) The residue was purified by column chromatography (100-200 EtOAc (EtOAc:EtOAc) T-butyl formate (22 g, 89%, colorless gum). TLC system: 50% EtOAc: petroleum ether, Rf: 0.53. ΜΗ+=273·0. 4 NMR (CDC13, 400MHz): 5.38 (d, J=7.6 Hz; 1H), 4.55-4.50 (m, 1H), 3.71 (m, 8H), 1.77-1.71 (m, 1H) ), 1.56-1.51 (m, 1H), 1.43 (m, 9H). Step 2:

^ 〇rC/HCI ’' o (2S)-2-amino-1-laninyl-but _i_feed hydrochloride e in 〇. Add 2 M HC1 to a solution of n_[(is)_ Μ morpholine 4-carbonyl)propyl]amino decanoic acid tert-butyl ester (23 g, 84 mmol) in CH2C12 (100 mL) The solution in Et2(R) (10 mL) was stirred at room temperature for 16 hours. The reaction process was monitored by TLC. Upon completion of the reaction, the reaction mixture was concentrated, and the residue was washed with Et.sub.2 (2.times.20 mL) and then dried to afford (2S)-2-aminos. TLC: 50% EtOAc: petroleum ether, Rf: 〇 。 5. MH+=173.2.1h NMR (DMSO-d6,400MHz): 8.37 (bs, interchangeable with D20 '2H), 4.33 (d, J=5.2 Hz; 1H), 3.63-3.40 (m,8H), 1.82-1.65 ( m, 2H), 1·91 (t, J = 7.47 Hz; 3H) 〇 Step 3: 157033.doc -217- 201215604

HO, /OH

Br

Methyl 3-bromo-5-phenyl-thiophene-2-carboxylate. Add 3 ΜΚπ〇 to a solution of 3,5-dibromothiophenecarboxylic acid, ester (2_〇g, 6.7 mmol) and phenyl-acid (812 mg, 6 66 mm 〇1) in toluene (60 mL) 3 aqueous solution (6 63 rainbow) and the reaction mixture was deoxygenated by bubbling argon for 1 hour. Pd(pph3)4 was added, and further bubbling with argon for 30 minutes' and the mixture was stirred at 90 °C for 3 hours. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The residue was purified by column chromatography (100-200 mesh EtOAc, EtOAc / EtOAc / EtOAc) to afford EtOAc EtOAc , white solid). TLc: 5% EtOAc / petroleum &lt; Rf: 0.42. Analysis by LCMS (column: Xterra MS-C-18 (4.6 x 50 mm, 3 μηι), mobile phase: a: 〇1〇/〇HCOOH aqueous solution, B: MeCN, time (min)/%B gradient: 0 Min/10%, 4/90, 8/90, 8.01/10, flow rate: 1.0 mL/min, sample diluent: MeCN): ΜΗ+=297·0, tR=4.86 min. NMR (400 MHz, CDC13): 7.61-7.59 (m, 2H), 7.45-7.39 (m, 3H), 7.29 (s, 1H), 3.91 (s, 3H). Step 4:

157033.doc -218- 201215604 3-[[(lS)-l-(morpholine-4)carbonyl)propyl]amino]_5_phenyl-thiophene-2-carboxylic acid methyl vinegar ° 3_bromo-5- Methyl phenyl-thiophene-2-furoate (500 mg, 1.7 mmol), (S)-2-amino group·ι·τ]•ketone HC1 (530 mg, 2 54 mm〇1), Cs2C03 (1.65 g, 5.08 mmol) suspension in toluene (30 mL) was purged with argon for 60 minutes to remove oxygen, and Pd(〇Ac)2 (38 mg, 0.17 mmol), (±)BINAP (106 mg) was added. , 0.17 mmol). The purification was continued for another 3 minutes and the mixture was stirred under a lott for 16 hours. The reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was cooled to EtOAc EtOAc (EtOAc) The filtrate was washed with water (2~35 mL), brine (30 mL) and dried over Naj. The residue was purified by column chromatography (EtOAc EtOAc EtOAc (EtOAc) • 5-Phenyl-thiophene-2-indenoate (400 mg, 40 〇/〇' white solid). TLC: 50 〇/〇 EtOAc/石油叫' Rf: 0.36. Analysis by LCMS (column: again) ^]^8-(:-18(4.6x50 mm ' 3 μιη) ' Mobile phase: a : 0.1% HCOOH water soluble solution, B : MeCN, time (min) / 〇/oB gradient: 〇min/1〇0/〇, 4/90, 8/90, 8.01 八, flow rate: 1·〇mL/min, sample diluent: MeCN): ΜΗ+=389·2, tR NMR (400 MHz, DMSO-d6): 7.73-7.71 (m, 2H), 7.49-7.40 (m, 4H), 4 88_4 86 (m, m), 3.75 (s, 3H), 3.63- 3.55 (m, 6H), 3.46-3.42 (m, 2H), 1.77- 1.75 (m, 1H), 1.60-1.57 (m, 1H), 0.84 (t, j = 7 6 HZ; 3H). Step 5: 157033.doc •219- 201215604

3-[(Reverse-4-methylcyclohexyl)-[(lS)-l-(morpholine-4-isopropenyl)propyl]aminopurin-5-phenyl-thiophene-2-carboxylic acid methyl ester . To a solution containing ^[[())-((•#-4-yl)propyl]amino]-5-phenyl-cephen-2-pyrumate (3〇〇) at 〇°C A solution of mg, 0.773 mmol) of DCE (20 mL) was added. Specific bite (3 raL, 10 volumes) and DMAP (47 mg, 0.39 mmol) followed by dropwise addition of trans-4-mercaptocyclohexylfluorene (1.24 g, 7.73 mmol) in DCE (5 mL) Solution. After the addition, the reaction mixture was mixed for 1 hour under 1 Torr. The progress of the reaction was monitored by TLC. When the reaction is completed, the reaction mixture is used.

Diluted with EtOAc (80 mL), washed with 2N aqueous HCI (2×30 mL), water (30 mL), 10% NaHC03 (2×30 mL), brine (3 〇 mL)

NadO4 was dried and concentrated. The residue was purified by column chromatography ( EtOAc EtOAc (EtOAc) (lS)-l-(Mallin-4-yl)propyl]amino]_5-phenyl-«&gt; deceno-2-decanoate (220 mg, 56%, white solid). TLC: 40% EtOAc / petroleum ether. Rf: 0.38. Analysis by LCMS (column: heart again)\48-〇18 (4.6x50 mm, 3 μιη), mobile phase: A: 0.1% HCOOH aqueous solution, B: MeCN 'time (min)/%B gradient: 0 Min/io%, 4/90, 8/90, 8.01/10, flow rate: 1.0 mL/min, sample diluent: MeCN): MH+ = 513.1, tR = 4.89 min. NMR (400 MHz, DMSO-d6): 7.82-7.74 (m, 2H), 7.56-7.44 (m, 4H), 5.59 (br 157033.doc -220 - 201215604 s, 1H), 5.30-5.26 (m, 1H ), 3.80-3.44 (m, 11H), 2.04-1.91 (m, 2H), 1.70-1.16 (m, 8H), 0.95-0.52 (m, 8H). Step 6:

3·[(trans-4-indolylcyclohexylcarbonyl)-[(1S)_i·(morpholine_4_carbonyl)propyl]amino]_

5-phenyl-thiophene-2-carboxylic acid. To 3_[(trans_4_fluorenylcyclohexylcarbonyl)-[(lS)-l-(morpholin-4-carbonyl)propyl]amino]_5-phenyl-thiophenecarboxylic acid methyl ester (at room temperature) 220 mg '0.429 mmol) was added to a stirred solution of THF and water (1 mL), EtOAc. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction was acidified with EtOAc (EtOAc) (EtOAc) The organic layer was washed with water (3x20 mL) The residue was purified by trituration with EtOAc (EtOAc (EtOAc): -Phenyl-thiophene-2-carboxylic acid (120 mg, 56%, white solid). TLC: 1% MeOH/CHCl3. Rf : 0_33. Analysis by LCMS (column: Xterra MS-C-18 (4.6 x 50 mm, 3 μιη) 'mobile phase: a : 0.1% aqueous solution of HCOOH, B: MeCN, time (min) / % B gradient: 0 min/10 %,4/90,8/90,8.01/10, flow rate: 1·0 mL/min, sample diluent:]^6〇^): 1^11+=499.0, “mine=497.0, tR=4.29 min 4 NMR (400 MHz, DMSO-d6): 13.4 (br s, interchangeable with D20; 2H), 7.80-7.71 (m, 2H), 7.50-7.43 (m, 157033.doc -221- 201215604 4H), 5.61 (br s, 1H), 5.29-5.25 (m, 1H), 3.72-3.40 (m, 8H), 2.11-2.05 (m, 1H), 1.85-1.82 (m, 1H), 1.71-1.40 (m, 6H ), 1.32-1.15 (m, 2H), 0.91-0.81 (m, 3H), 0.77-0.5 (m). Preparation of Compound 127 Step 1:

N-(2-Sideoxy-2-thiomorpholyl-ethyl)aminocarboxylic acid tert-butyl ester. Add sulfur to a solution of N-Boc glycine (2 g, 12 mmol), HBTU (9.1 g, 23 mmol) and DIPEA (6 mL, 34 mmol) in CH2C12 (50 mL) at 0 〇C Daimler (1 · 64 mL, 17.2 mmol) and the mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was diluted with CH2C12 (100 mL), washed with water (3×50 mL), brine (30 mL), dried over NadCU, and concentrated. The crude product was purified by column chromatography (100-200 mesh Purified by 50% / EtOAc / pet ether (EtOAc) (EtOAc:EtOAc: . TLC: 97% EtOAc: petroleum ether. Rf: 0.48. Analysis by LCMS (column: BEH C-18 (2.1x50 mm, 1.7 μηη), mobile phase: A: 0.025% TFA in water, Β: 0.025% TFA/MeCN, time (min)/%B gradient: 0 min /15%, 3/95, 4/95, 4.1/15, flow rate: 0.4 mL/min, sample diluent: MeCN): MH+ = 261.2, tR = 1.62 min. NMR (400 MHz, CDC13): 5.51 (br s,1H), 3.95-3.88 (m, 4H), 2.80 (s, 2H), 2.64-2.61 (m, 4H), 1.45 (s, 157033.doc •222 · 201215604 9H) 〇Step 2:

2-Amino-1-thiomorpholinyl-ethanone. A solution of tert-butyl 2-(2-oxo-2-thiomorpholinyl-ethyl)amine decanoate (2.9 g, 11 mmol) in CH2C12 (50 mL) Et 2 O (50 mL) containing 2 M HCl was added and the mixture was stirred at room temperature for 16 hr. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was concentrated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ). MH+ = 161.1. NMR (400 MHz, DMSO_d6): 8.33 (br s, interchangeable with D20; 211), 3.86-3.85 (m, 2H), 3.76-3.74 (m, 2H), 3.63-3.60 (m, 2H), 2.67-2.64 (m, 2H), 2.58-2.55 (m, 2H). Step 3:

5-(3,3-dimethylbut-1-ynyl)-3-[(2-o-oxy-2-thionaphthyl-ethyl)amino] porphin-2-carboxylic acid methyl vinegar . Purification by gas stream for 6 minutes to 3_ _ 5-(3,3-dimercaptobut-1-ynyl) porphin-2- decanoate (5 〇〇 mg, 166 mmol), 2 -Amino-1-thio- phenothione ethyl ketone hydrochloride (487 mg, 249 157033.doc .223 - 201215604 mmol) and Cs2C〇3 (1.62 g, 4.98 mmol) in toluene (30 mL) The suspension was deoxygenated, followed by the addition of Pd(OAc)2 (37.3 mg, 0.160 mmol) and BINAP (103 mg, 0.160 mmol). The purification was continued for another 30 minutes, and the mixture was stirred at 10 ° C for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to rt EtOAc (EtOAc)EtOAc. The filtrate was washed with water (2×35 mL), brine (30 mL). The residue was purified by column chromatography (100-200 EtOAc, 30%EtOAc / petroleum ether) to afford 5-(3,3-dimethylbut-1-ynyl)-3-[(2- Methyloxy-2-thio- phenanyl-2-ethyl)amino]n-cephen-2-indolecarboxylate (180 mg, 28%, white solid). TLC: 50% EtOAc/ petroleum ether, Rf: 0.53. Analysis by LCMS (column: another 16 coffees)^-(:-18 (4.6x50 mm, 3 μηι), mobile phase: a: 0.1% HCOOH aqueous solution 'B: MeCN' time (min)/%B gradient: 〇min/io%,4/90, 8/90,8.01/10 ' Flow rate: lo mL/min, sample diluent:

MeCN) : MH+ = 381.0, tR = 4.7 l min. NMR (400 MHz, DMSO_d6): 7.26 (br s, interchangeable with 〇2〇; iH),6·99 (s,1H), 4.14 (d, J=4.8Hz; 2H), 3.75-3.69 (m, 7H ), 2.65-2.57 (m, 4H), 1.28 (s, 9H). Step 4:

157033.doc -224- 201215604 5_(3,3-Dimethylbut-1-ynyl)-3-[(trans-4-methylcyclohexylcarbonyl)-(2-sided oxythiomorpholinyl) Methyl) thiophene-2-carboxylate. 5-(3,3-Dimethylbut-1-ynyl)-3-[(2-o-oxy-2-thiomorpholinyl-ethyl)amino]. A solution of thiophene methyl 2-formate (180 mg, 0.473 mmol) in DCE (10 mL) was stirred with pyridine (2 mL, 10 vols) and DMAP (29 mg, 0.24 mmol). A solution of trans-4-mercaptocyclohexylfluorene chloride (760 mg ' 4.74 mmol) in DCE (5 mL) was then added dropwise at 0 °C. After the addition, the reaction mixture was stirred for 16 h at EtOAc (EtOAc) EtOAc (EtOAc) (EtOAc) , 10% NaHCO3 solution (2×30 mL), brine (3 mL), washed with Na2SO4 and concentrated. The residue was purified by column chromatography (100-200 mesh gelatin, 40% EtOAc/ petroleum ether) 5-(3,3-Dimethylbut-1-ynyl)-3-[(trans-4-methylcyclohexylcarbonyl)-(2-o-oxy-2-thiopheninyl-B Ethyl) decanophene-2-carboxylic acid decyl ester (200 mg '84%, white solid). TLC: 40% EtOAc / petroleum ether, Rf: 0.53. Analysis by LCMS (column: Xterra MS-C -18 (4.6x50 mm, 3 μηι) 'Mobile phase: a : 0.1% HCOOH in water, B: MeCN, time (min)/%B Gradient: 〇min/10%, 4/90, 8/90, 8.01/ 10 ' Flow rate: 1.0 mL/min, sample diluent: MeCN): ΜΗ+=505·1, tR=5.38 min. 4 NMR (400 MHz, DMSO-d6): 7.24 (s, 1H), 4.90 (d, J=16.8Hz; 1H), 3.84 (d, J=16.4 Hz; 1H), 3.77 (s, 3H), 3.74-3.62 (m, 4H), 2.60-2.50 (m, 4H), 2.11-2.05 (m, 1H), 1.71-1.47 (m, 5H), 1.40-1.23 (m, 11H), 0.77 (d, J = 6 Hz; 3H), 0.67-0.64 (m, 2H). I57033.doc -225- 201215604 Step 5:

5·(3,3-Dimethylbutyla-alkynyl)_3_[(trans-4-methylcyclohexylcarbonyl)·(2_sideoxy-2-thioporin-ethyl)amine Base] porphin_2_formic acid. To 5-(3,3-dimethylbut-1-ynyl)-3-[(trans-4-indolylcyclohexylcarbonyl)-(2-o-oxy-2-thiomorpholinyl-B Add Li〇H.H2〇 (45 mg, methyl) thiophene-2-decanoate (180 mg, 0.357 mmol) in 1:1 THF/water (4 mL) 1.1 mmol) and the mixture was stirred for 16 hours. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the~~~~~~~~~~~~~~~~~~~ The organic layer was washed with water (3×20 mL), brine (20 mL), dried over Na? The residue was purified by preparative EtOAc (EtOAc EtOAc EtOAc) )-(2-Sideoxy-2-thiomorpholino-ethyl)amino] porphin-2-decanoic acid (135 mg, 77%, white solid). TLC: 10% MeOH / CHCl3, Rf: 0.35. Analysis by LCMS (column: Xterra MS-C-18 (4.6 x 50 mm, 3 μιη), mobile phase: A: 0.1% aqueous solution of HCOOH 'B: MeCN, time (min)/% B gradient: 0 min/10 %, 4/90, 8/90, 8.01/10, flow rate: lo mL/min, sample diluent: MeCN): MH+ = 491.2, tR = 4.85 min. 'H NMR (400 MHz, DMSO-d6): 13.45 (br s, interchangeable with D20; 1Η), 7.21 (s, 1H), 4.90 (d, J = 16.8 Hz; 1H), 3.84 (d, J=l4 .4 Hz; 1H), 3.72- 157033.doc •226- 201215604 3.63 (m, 4H), 2.64-2.59 (m, 4H), 2.12-2.06 (m, 2H), 1.69 1.53 (m, 4H), 1.40 -1.33 (m, 11H), 0.77 (d, J = 6.4 Hz; 3H) 0.70-0.61 (m, 2H). Preparation of Compound 128 Step 1:

+ H-&amp;&lt;] • % bromine _5_(2_cyclopropylethynyl)thiophenecarboxylate. A suspension of Cul (380 mg, 1·99 mmoDMi〆-dioxane (30 mL) was deoxygenated by argon gas at room temperature for 30 minutes, followed by addition of 42 〇 mmol). Purification was continued for 15 minutes followed by the addition of diisopropylamine (ι 9 η mmol). Methyl 3,5-dibromothiophene-2-carboxylate (2〇67 mmol) was then added. The reaction mixture was stirred at room temperature for 15 minutes, then cooled in ice water and a mixture containing cyclopropyl acetylene (〇 56 mL, 6 7 mmol) was added at 5-10 °C. Oxane (1 〇 mL). After the addition, the reaction mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the mixture was diluted with EtOAc (EtOAc) The combined filtrates were concentrated and the crude obtained was purified by column chromatography (100-200 EtOAc EtOAc EtOAc EtOAc EtOAc Methyl thiophene-2-carboxylate (1.45 g, 76%, yellow liquid). TLC: 2% Et〇Ac/5 oil shout, Rf: 0.5. Analysis by LCMS (column: BEH C-18 (2.1x50 mm, 1_7 μιη), mobile phase: a : 5 mM CH3C02NH4 aqueous solution, B · 157033.doc -227- 201215604

MeCN, time (min) / % B gradient: 〇 min / 3%, 0.1 / 3, 1.5 / 90, 2.1 / 90, 2.3 / 100, 2, 8 / 50, flow rate: 0.4 mL / min, sample diluent: MeOH): MH+ = 285.1, tR = 2.05 min. 4 NMR (400 MHz, CDC13): 7.02 (s, 1H), 3.86 (s, 3H), 1.49-1.46 (m, 1H), 0.96-0.83 (m, 4H) ° Step 2:

5-(2-Cyclopropylethynyl)-3-[(2-morpholinyl-2-oxo-ethyl)amino]methyl thiophene-2-carboxylate. 3-bromo-5-(2-cyclopropylethynyl)thiophene-2-carboxylate (35 mg, 1.23 mmol), 2-amino-1-morpholinylacetone hydrochloride (332 mg, 1.84 mmol) and a suspension of Cs2C03 (1.2 g, 3.7 mmol) in toluene (10 mL) was degassed by bubbling argon for 50 minutes, followed by addition

Pd(OAc) 2 (28 mg, 0.12 mmol) and (earth) BINAP (76 mg, 0.12 mmol). The purification was continued for another 10 minutes and the mixture was taken up at 1 () for 1 hour. The reaction was monitored by TLC. Upon completion of the reaction, the mixture was cooled to room temperature, diluted with EtOAc (50 mL) and filtered over Celite. The filtrate was washed with water (2×20 mL), brine (30 mL), dried over Na2SO4 and concentrated. The obtained residue was purified by column chromatography (10 〇 2 〇〇 矽 , , 40 40 40 Purification to give methyl 5-(2-cyclopropylethynyl)-3·[(2·loryl-2-oxo-ethyl)aminophene-2-carboxylate (5 〇 mg, 120/〇) 'Yellow solid.) TLC: 60% EtOAc/ petroleum ether, Rf: 0.35. 157033.doc 228-201215604 MH+=349.2. 4 NMR (400 MHz 'DMSO-d6): 7.32 (br s, interchangeable with D20; 1H ), 6.53 (s, 1H), 3.99 (d, J = 4.8 Hz; 2H), 3.81 (s, 3H), 3.70-3.67 (m, 6H), 3.44-3.42 (m, 2H), 1.49-1.41 ( m, 1H), 0.92-0.88 (m, 2H), 0.84-0.81 (m, 2H). Step 3:

5-(2-cyclopropylethynyl)-3-[(trans-4-methylcyclohexylcarbonyl)-(2-morpholinyl-2-

Methyl oxy-ethyl)amino]thiophene-2-carboxylate. To 5-(2-cyclopropylethynyl)-3-[(2-morpholino-2-oxo-ethyl)amino]thiophene-2-carboxylic acid oxime ester (50 mg ' 0.14 mmol) and A solution of trans-4-mercaptocyclohexylcarbazide (230 mg, 1.43 mmol) in CH2C12 (5.0 mL) was added dropwise to a solution of Et3N (0.2 mL) in CH2C12 (5.0 mL). The reaction was spoiled at 9 ° C for 16 hours. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was diluted with EtOAc (50 mL). EtOAc EtOAc EtOAc (EtOAc) Dry and thick Ifg. The residue obtained was purified by column chromatography (100-200 EtOAc, 50% EtOAc/ petroleum ether as solvent) to afford 5-(2-cyclopropylethynyl)-3-[(trans-4-) Cyclohexylcarbonyl)-(2 morpholino-2-yloxy-ethyl)amino] thiophene-2-decanoate (22 mg, 3 〇 0 / 〇, yellow solid). TLC: 60. /. EtOAc/petroleum ether, Rf: 〇 35. By L(:ms analysis (column: BEH C-18 (2.1X50 mm, 1 7 pottery), mobile phase: 157033.doc -229- 201215604 A : 5 mM CH3C02NH4 aqueous solution, B: MeCN, time (min) /%B Gradient: 0 min/3%, 0.1/3, 1.5/90, 2.1/90, 3/100, 4/100, flow rate: 0.4 mL/min, sample diluent: MeOH): ΜΗ+=473· 4. tR = 2.02 min. NMR (400 ΜΗζ, DMSO-d6): 7.21 (s, 1 Η), 4.91 (d, J = 16.8 Hz; 1H), 3.84 (d, J = 16.8 Hz; 1H), 3.77 ( s, 3H), 3.54 (br s, 4H), 3.43-3.31 (m, 4H), 2.09-2.03 (m, 1H), 1.66-1.46 (m, 5H), 1.40-1.23 (m, 4H), 0.97 -0.92 (m, 2H), 0.87-0.80 (m, 2H), 0.77 (d, J = 6.4 Hz; 3H), 0.6. Step 4:

5-(2-Cyclopropylethynyl)_3·[(trans-4.methylcyclohexylcarbonyl)-(2-morpholinyl_2_sideoxy-ethyl)amino]thiophene-2-carboxylic acid. To 5-(2-cyclopropylethynyl)-3-[(trans-4-methylcyclohexylcarbonyl)-(2-morpholinyl-2-oxo-ethyl)amino group at room temperature Add 〇h.h20 (5.3 mg, 0.62 mmol) to a stirred solution of thiophene-2-carboxylate (2 mg, 0.042 mmol) in 1:1 THF / water (6 mL) Stir for 16 hours. The progress of the reaction was monitored by TLc. Upon completion of the reaction, the mixture was acidified (pH EtOAc) (EtOAc) The organic layer was washed with water (2×1 mL), brine (1 mL), dried over NaCI 4 and concentrated to give &lt;RTI ID=0.0&gt; Hexylcarbonyl)-(2-morpholinyl-2-oxo-ethyl)amino]thiophen-2-pyruic acid (8 mg, 39%, white solid). TLC : 10% 157033.doc 201215604

MeOH/CHCl3' Rf: 0.3. Analysis by LCMS (column: 8 £110 18 (2.1 x 50 mm, 1.7 μηη), mobile phase: A: 5 mM CH3C02NH4 in water, B: MeCN, time (min)/%B gradient: 〇min/3%, 0.1/3, 1.5/90, 2.1/90, 2.8/50, flow rate: 0.4 mL/min, sample diluent: MeOH): MH+ = 457.5. tR = 1.34 min. 4 NMR (400 MHz, DMSO-d6): 13.45 (br s, interchangeable with D20; 1H), 4.91 (d, J = 16.4 Hz; 1H), 3.84 (d, J = 16.4 Hz; 1H), 3.54-3.53 (m, 4H), 3.39-3.31 (m, 4H), 2.10-2.05 (m, 1H), 1.68-1.48 (m,

5H), 1.40-1.23 (m, 4H), 0.97-0.92 (m, 2H), 0.88-0.79 (m, 2H), 0_77 (d, J = 6.4). Preparation of Compound 129 Step 1:

5-(3-methoxy-3-methyl-but-1-ynyl)-3-[(2-morpholin-2-yloxy-ethyl)amino]thiophene-2-carboxylic acid Ester "3-bromo-5-(3-decyloxy-3-indolyl-1-propanyl) °ephedo-2-carboxylate (prepared as previously described, 1.6 g, 5.0 mmol), 2 - A suspension of the amino-1-ylidene-ethanone hydrochloride (1.48 g' 7.57 mmol) and Cs2C03 (4.93 g, 15.1 mmol) in toluene (10 mL) was removed by bubbling with argon for 50 minutes. Oxygen was added followed by Pd(OAc)2 (113 mg, 0.504 mmol) and (±) BINAP (3 14 mg, 〇·5〇4 mmol). The purification was continued for another 10 minutes and the mixture was stirred at 10 °C for 16 hours. The reaction was monitored by TLC. The reversed-231 - 157033.doc 201215604 should be processed. Upon completion of the reaction, the reaction mixture was cooled to room temperature and diluted with EtOAc (100 mL) Filtration via celite. The filtrate was washed with water (2 χ 5 〇 mL), brine (30 mL), dried over NajO4 and concentrated. The residue was purified by column column chromatography (100-200 mesh gelatin, 60% EtOAc/ petroleum ether Purification as a dissolving agent to give 5-(3-methoxy-3-methyl-but-1-ynyl)·3_[(2-morpholinyl-2-oxo-ethyl)amino] Thiophene-2-decanoate (700 mg, 37%, yellow solid). TLC: 50% EtOAc / petroleum ether, Rf: 0.35. Analysis by LCMS (column: Xterra RP-18 (4.6xl00 mm, 5 Μιη) 'Mobile phase: A : 0.1% CH3C02NH4 aqueous solution, B: MeCN, time (min)/%B Gradient: 〇min/10%, 4/70, 6/95, 14/95, 15/10, flow rate: 0.8 mL/min, sample diluent: MeCN): ΜΗ+=379·2 » !Η NMR (400 MHz, DMSO-d6): 7.27-7.25 (m, interchangeable with D20; 1H), 7.09 (s, 1H) , 4.16 (d, J = 4.8 Hz; 2H), 3.73 (s, 3H), 3.62-3.56 (m, 4H), 3.4 9-3.44 (m, 4H), 3.28 (s, 3H), 1.46 (s, 6H). Step 2:

5-(3-methoxy-3-methyl-but-1-ynyl)-3-[(trans-4-methylcyclohexylcarbonyl)·(2-morpholinyl-2·sideoxy- Ethyl)amino]thiophene-2-f acid methyl ester. To 5-(3-methoxy-3-methyl-but-1-ynyl)-3-[(2-morpholinyl-2-oxo-ethyl)amino group at 〇 °C Methyl thiophene-2-carboxylate (300 mg, 〇·79 mmol) '157033.doc -232- 201215604 0 A solution of bite (4.0 mL) and DMAP (49 mg, 0.40 mmol) in DCE (5 mL) A solution of trans-4-methylcyclohexylmethyl chloride (1.3 g, 7.3 mmol) in DCE (5 mL) was added dropwise. The solution was then mixed at 90 ° C for 16 hours. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) (EtOAc) (EtOAcjjjjjjjjjjjj concentrate. The residue was purified by column chromatography (100-200 EtOAc, 50%EtOAc/ petroleum ether as solvent) to afford 5-(3-methoxy-3-methyl-but-1-ynyl) -3-[(trans-4-methylcyclohexylcarbonyl)-(2-morpholinyl-2-oxo-ethyl)amino]thiophene-2-decanoate (301 mg, 75%, White solid). TLC: 50% EtOAc/ petroleum ether, Rf: 0.3. Analysis by LCMS (column: BEH C-18 (2.1x50 mm, 1.7 μηη), mobile phase: A: 5 mM aqueous solution of CH3C02NH4, B: MeCN, time (min)/% Β gradient: 0 min/3%, 0.1/3, 1.5/90, 2.1/90, 2.3/100, 2.8/50, flow rate: 0.4 mL/min, sample diluent: MeOH): MH+ = 505.5. tR = 1.92 min. NMR (400 MHz, DMSO-d6): 7.36 (s, 1H), 4.92 (d, J = 16.8 Hz; 1H), 3.87 (d, J = 16.8 Hz; 1H), 3.78 (s, 3H), 3.54 ( m, 4H), 3.41-3.39 (m, 4H), 3.29 (s, 3H), 2.11 (m, 1H), 1.67-1.55 (m, 3H), 1.48 (m, 6H), 1.42-1.23 (m, 4H), 0.77 (d, J = 6.4 Hz; 3H), 0.71 - 0.62 (m, 2H). Step 3: 157033.doc 233 · 201215604

5-(3-methoxy-3-methyl-butyl_ι-alkynyl)_3-[(trans-4-methylcyclohexyl)(2-morphin-2-oneoxy-B Amino] porphin-2_carboxylic acid. To 5-(3-decyloxy-3-methyl-butan-alkynyl)_3_[(trans-4-indolylcyclohexyl)&gt; (2·morpholinyl-2-sideoxy) at room temperature Addition of LiOH.H20 (45 mg, 1.1 mm) to a stirred solution of methyl-ethyl)amino]thiophenecarboxylate (18 mg, 0.357 mmol) in 1:1 THF/water (4 mL) The mixture was stirred for 16 hours. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the mixture was acidified (pH 1) and extracted with EtOAc (80 mL). Washed with brine (10 mL), dried over Na 2 SO 4 and concentrated to give 129: 5-(3- methoxy-3-indolyl-but-1-ynyl)_3·[(anti_4_ fluorenyl) Benzyl)-(2-morphinyl-2-yloxy-ethyl)amino]. phene-2-carboxylic acid (125 mg, 72%, white solid). TLC: 10% MeOH/CHCl3, Rf: 0.4. Analyzed by LCMS (column: BEH C-18 (2.1x50 mm, 1.7 μπι), mobile phase: A: 5 mM aqueous solution of CH3C02NH4, B: MeCN, time (min)/%B gradient: 〇min /3°/,,,,,,,,,,,,,,,,,,,,,, 4 NMR (400 MHz, DMSO-d6): 13.62 (br s, interchangeable with D20; 1H), 7.33 (s, 1H), 4.92 (d, J = 16.4 Hz; 1H), 3.87 (d, J = 16.8 Hz) ; 1H), 3.54- 3.40 (m, 8H), 3.29 (s, 3H), 2.09 (m, 1H), 1.65-1.52 (m, 157033.doc 234- 201215604 4H), 1.48 (s, 6H), 1.39 -1.23 (m, 4H), 0·77 (d, J = 6.4 Hz; 3H), 0.68-0.65. Preparation of Compound 130 Step 1:

Methyl phen-2-carboxylate. Crude 3-bromo-5-(4-mercapto-pentynyl) n-phene-2-yl decanoate (prepared as described above, 1.55 g, 5.16 mmol), 2-amino-___ _ ketone hydrochloride (1.39 g, 7.75 mmol) and Cs2C 〇 3 (5. 〇 5 g, 15)

5-(4-decylpent-1-ynyl)-3-[(2-morpholinyl-2-oxaoxy-ethyl)amino]thiamidine) in indole (35 mL) The suspension was deoxygenated by purging with an argon stream for 3 Torr, followed by the addition of Pd(OAc)2 (116 mg, 0.510 mmol) and (±) BINAP (322 mg, 0.520 mmol). The purification was continued for another 3 minutes and the mixture was stirred at 100 ° C for 16 hours. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was cooled to room temperature, diluted with Et EtOAc (1 mL) and filtered over Celite. The filtrate was washed with water (2×2 〇 mL), brine (3 mL), dried over NaCI and concentrated. The residue was purified by column chromatography (100-200 EtOAc, 30% EtOAc/ petroleum ether as solvent) to afford 5-(4-mercapto-1 ethynyl) _3_[(2 morpholine) Base 2 • pendant oxy-ethyl)amino] porphin-2-carboxylic acid decyl ester (12 〇 mg 'white solid). TLC: 40% EtOAc / petroleum enrichment, Rf: 0.5. MH+ = 365.2. NMR (400 MHz, DMSO-d6): 7.2 (br s, interchangeable with D20; 1H), 6.99 (s, 1H), 4·15 157033.doc -235 - 201215604 (d, J=4.4 Hz; 2H), 3.72 (s, 3H), 3.60-3.56 (m, 4H), 3.49-3.45 (m, 4H), 2.38 (d, J=6.4 Hz; 2H), 1.88-1.81 (m, 1H), 0.98 (d, J=6.8Hz; 6H) ° Step 2:

3-[(trans-4-methylcyclohexylidene)-(2-morphinyl-2-l-oxy-ethyl)aminodi 5-(4-decylpent-1-ynyl)thiophene Methyl-2-carboxylate. To a 5-(4-methylpent-1-ynyl)-3-[(2-morpholinyl-2-yloxy-ethyl)amino]thiophene-2-carboxylic acid oxime at 0 °C Add anti-4-methylcyclohexyl hydrazine chloride (530 mg, 3-27 mmol) to CH2C12 (5.0 mL) in a solution of EtOAc (EtOAc (EtOAc) (EtOAc) The solution was then stirred at 9 (TC for 16 h. The reaction was monitored by TLC. The mixture was diluted with EtOAc (50 mL) with 2 N EtOAc (2×10 mL), water (10) (mL), 10% NaHCO3 solution (1 mL), brine (10 mL), washed with Na2SO 4 and concentrated. The residue was purified by column chromatography (100-200 mesh, 40% EtOAc/ petroleum ether Purification as a dissolving agent to give 3-[(trans-4-indolylcyclohexylcarbonyl)-(2-morpholinyl-2-oxoethyl)amino]-5-(4-mercaptopentane- 1-Quick-based) Benzene-2-carboxylic acid (6 mg, 37%, yellow solid). TLC: 40% EtOAc/ petroleum ether, Rf: 〇35. Analysis by LCMS (column.HALOC-18 (2.1x50 mm, 2 7 μιη), mobile phase: A: 5 mM CH3C02NH4 in water, Β: MeCN, time 157033.doc •236- 201215604 ( Min)/%B Gradient: 0 min/3%, 0.5/3, 2/90, 2.5/90, 3.0/100, 3.5/50, flow rate: 0·5 mL/min, sample diluent: MeOH): MH+ =489.5.tR=2.84 min. 4 NMR (400 MHz, DMSO-d6): 7.24 (s, 1H), 4.92 (d, J = 16.8 Hz; 1H), 3.86 (d, J = 16.8 Hz; 1H), 3.77 (s, 3H), 3.54 (br s, 4H), 3.44-3.38 (m, 4H), 2.41 (d, J=6.4Hz; 2H), 2.12-2.02 (m, 1H), 1.89-1.85 (m , 1H), 1.67-1.55 (m, 4H), 1.29-1.23 (m, 4H), 0.98 (d, J=6.8Hz; 6H). Step 3:

3-[(trans-4-methylcyclohexylcarbonyl)-(2-morpholinyl-2-l-oxy-ethyl)amino] 5-(4-methylpent-1-ynyl)indole Phen-2-carboxylic acid. To 3-[(trans-4-methylcyclohexylcarbonyl)-(2-heptyl-2-oxo-ethyl)amino]_5-(4-methylpentan-1-) at room temperature Add a solution of methyl alkynyl thiophene-2-decanoate (60 mg, 0.12 mmol) in 1:1 THF/water (4 mL). Stir for 16 hours. The progress of the reaction was monitored by TLC. When the reaction is complete, the reactants are acidified with a 1 M HCl aqueous solution (pH about 1).

Extracted with EtOAc (75 mL). The organic layer was washed with water (2.sub.2 mL), brine (10 mL), dried over NazSO4 and concentrated to give &lt;RTI ID=0.0&gt; Oxy-ethyl)amino]-5-(4-decylpent-1-yne 157033.doc -237-201215604 base)thiophene-2-carboxylic acid (35 mg, 60 ° / hydrazine, yellow solid). TLC : 10%

MeOH/CHCl3, Rf: 0.33. Analysis by LCMS (column: X-Bridge Shield RP C-18 (4.6 x 75 mm, 3.5 μπι), mobile phase: A: 0.01% HCOOH in water, B: MeCN, time (min)/%B gradient: 〇min /5%, 3/95, 6.5/95, 7/100, 8/5, flow rate: 0.8 mL/min ' Sample diluent: MeCN): MH+ = 475.2, tR = 5.44 min. 4 NMR (400 MHz, DMSO-d6): 13.5 (br s, interchangeable with D20; 1H), 7.22 (s, 1H), 4.91 (d, J = 16.8 Hz;, 1H), 3.86 (d, J = 16.8 Hz;, 1H), 3.34-3.40 (m, 8H), 2.41 (d, J=6.4Hz; 2H), 2.11-2.06 (m, 1H), 1.90-1.83 (m, 1H), 1.65-1.52 (m , 3H), 1.38-1.23 (m, 3H), 0·99 (s, 3H) » Preparation of Compound 131 Step 1:

(3S)-3-Aminopyrrolidin-2-one. A suspension of (S)-2,4-diaminobutyric acid dihydrochloride (5.0 g, 27 mmol) and HMDS (65 mL) in MeCN (100 mL). The progress of the reaction was monitored by TLC. After the reaction was completed, the~~~~~~~~~~~~~~~~~~~~~~~~~~ The combined CHC13 layers were concentrated to give (3S)-3-aminopyrrolidin-2-one (2.2 g, 82%, brown solid). TLC: 30% MeOH-CHCl3, Rf = 0.5. ΜΗ+=100·9. NMR (DMSO-d6, 400MHz): 7.62 (bs, interchangeable with D20; 1H), 157033.doc -238· 201215604 3.15-3.04 13-J.04 (m, 2H), 2.26-2.07 (m, ; old) , 1.70-1.57 (m, 1H). 3.21 (t, J=8.3Hz; 1H), 3 1H), 1.92 (bs, interchangeable with D2〇 Step 2:

Tert-butyl benzoate. Add b〇c anhydride (4 36 g, 20.0 mmol) to a solution of (3S)-mmol) and Et3N (3.0 mL, 22 • mm 〇1) in CH2C12 (25 mL) and stir the reaction at room temperature丨 6 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the mixture was diluted with CH.sub.2Cl.sub.2 (50 mL). The residue was triturated with EtOAc (EtOAc (EtOAcMeOHMeOHMeOHMeOHMeOHMeOH Third butyl ester (2.8 g, 70%, brown solid). TLC: 10% MeOH-CHCl3, Rf = 0.35. 4 NMR (CDC13, 3-amine, s. s. s. s. s. s. s. s. s. s. ), 4.15 (ms 1H), 3.40-3.30 (m, 2H), 2.69-2.68 (m, 1H), 2.00-1.94 (m, 1H), 1.45 (s, 9H). Step 3: 157033.doc

N-[(3S)-1-ethyl-2-oxo-pyrrolidin-3-yl]carbamic acid tert-butyl •239· 201215604 S曰. Add n-[(3S)-2-Sideoxypyrrolidine to a stirred suspension of sodium nitride (300 mg, 7.5 mmol) in THF (20 mL) over 10 min. a bath of 3-butyryl carboxylic acid tert-butyl ester (1.0 g, 5.0 mm 〇l) in DMF (6 mL) was then added THF (10 mL) containing ethyl EtOAc (0.406 mL, 5.0 mmol) . The reaction was then stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the mixture was diluted with EtOAc (EtOAc) (EtOAc) The residue was purified by column chromatography (100-200 EtOAc, EtOAc/EtOAc) Aminobutyric acid terpene vinegar (550 mg, 48%, light brown liquid) TLC: 10% MeOH / CHCl3, Rf: 0.57. Analysis by LCMS (column: Sunfire C-18 (4.6 x 250 mm, 5 μιη), mobile phase: A: 0.01 M CH3C02NH4 in water, Β: MeCN, time (min) / % B gradient: 0 min / 30% ' 8/80, 15/80, 15.1/30, flow rate: 1.0 mL/min ' Sample diluent: MeCN): MH+ = 229.8. tR = 5.78 min. 4 NMR (400 MHz, CDC13): 5.13 (br s,1H), 4.14 (br s, 1H), 3.43-3.28 (m, 4H), 2.64-2.63 (m, 1H), 1.86-1.76 (m, 3H ), 1.45 (s, 9H), 1.13 (t, J = 7.2 Hz; 3H). Step 4:

(3S)-3-Amino-1-ethyl-pyrrolidin-2-one. To the tert-butyl N-[(3S)-1-ethyl-2-oxo-pyrrolidin-3-yl]carbamate at 0 ° C (550 mg, 157033.doc -240· 201215604

To a solution of hexane (5 mL) was added EtOAc (EtOAc)EtOAc. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the solution was concentrated to give (3S)-3-amino-1-ethyl-pyrrolidin-2-one (400 mg, 71%, brown oil). The analysis by LCMS (column. Sunfire C-18 (4.6 &gt;&lt; 250 mm, 5 μηι) 'mobile phase: A: 0·05% TFA aqueous solution, Β : MeCN, time (min) / 0 / 〇 B Gradient: 0 min / 20%, 10 / 80, 15 / 80, 15.1/20, flow rate: 1.0 mL / min, sample diluent: 1:1 A and B): MH + = 129.2. tR = 2.56 min. [a] D: -27.8 deg. (c = 1.15% in MeOH). NMR (400 MHz, DMSO-d6): 8.64 (br s, interchangeable with D2〇; 1«〇, 3.95-3.89 (m, 1H), 3.41-3.20 (m, 4H), 2.41-2.34 (m, 1H) , 2.01-1.93 (m, 1H), 1.05 (t, J = 7.2 Hz; 3H). Step 5:

5-(3,3-Dimethylbut-1-ynyl)_3_[[(3S)-1-ethyl-2-oxo-pyrrolidin-3-yl 1amino]thiophene-2-indole Methyl ester 3-bromo-5-(3,3-dimercaptobutyl) porphin-2-decanoic acid methyl vinegar (500 mg, 1.66 mmol), (3S)-3-amino group 1- A suspension of ethyl-n compared to bite 2-ketone (500 mg, 1_66 mmol) and Cs2C03 (1.62 g, 4,98 mmol) in toluene (10 mL) was deoxygenated by purging with argon for 60 minutes. Then, Pd(〇Ac) 2 (37 mg, 0.17 mm 〇i) and (±) BINAP (10 〇 3 mg, 0·166 mmol) were added and purification was continued for another 30 minutes. Anti-157033.doc -241 - 201215604 The contents were then stirred at 100 ° C for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, diluted with EtOAc (l. The filtrate was washed with water (2 mL 20 mL The residue obtained is purified by column chromatography (100-200 EtOAc (EtOAc:EtOAc) 3S)-l-Ethyl-2-oxo-pyrrolidin-3-yl]amino]thiophene-2-decanoate (300 mg, 51%, light brown solid). TLC: 50% EtOAc / Petroleum ether, Rf: 0.44. Analysis by LCMS (column: Xterra RP-18 (4.6 &gt;&lt; 100 mm, 5 μιη), mobile phase: A: 0·01 M CH3C02NH4 aqueous solution, Β : MeCN, time (min) / % B gradient: 0 min/10%, 4/70, 6/95, 14/95, 15/10, flow rate: 0.8 mL/min, sample diluent: MeCN): ΜΗ+=349·1. tR = 7.19 min. [a]D: 14.9 deg. (c=1.01% in MeOH), palm purity 93.0% (288 nm, Chiralpak AD-H column (4.6x250 mm, 5 μηι), mobile phase: 30% EtOH (0.1% TFA) / 70% hexane (0.1% TFA), 1.0 mL / min, RT) » NMR (400 MHz, DMSO-d6): 6.95 (s, 1H), 6.93 (d, J = 6.8 Hz; Interchangeable with D20; 1H), 4.33-4.27 (m, 1H), 3.72 (s, 3H), 3.36-3.19 (m, 4H), 2.60-2.50 (m, 1H), 1.83- 1.73 (m, 1H), 1.43 (s, 9H), 1.05 (t, J = 7.2 Hz; 3H). Step 6:

157033.doc -242- 201215604 5-(3,3-Dimethylbut-1-ynyl)-3-[[(3S)-l-ethyl-2-oxo-indolyl-3- Methyl]-(trans-4-methylcyclohexylcarbonyl)amino]porphin-2-carboxylate. To _5_(3,3·didecylbut-1-ynyl)-3-[[(3S)-l-ethyl-2-oxo-pyrrolidin-3-yl] at 〇 °C Methylamino]thiophene-2-carboxylate (220 mg, 0.632 mmol), ° bite (2.0 mL, 10 vol) and DMAP (38 mg, 0.32 mmol) in dioxane (5 mL) A stock solution of σ 4-decylcyclohexane hydrazine chloride (0.898 g, 6.32 mmol) in dichloroethane (5 mL) was added dropwise to the mixture. After the addition, the reaction mixture was stirred at 10 ° C for 16 hours. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the mixture was diluted with EtOAc EtOAc EtOAc (EtOAc) . The residue obtained was purified by column chromatography (100-200 EtOAc, 40%EtOAc / pets ether) to afford 5-(3,3-didecylbut-1-ynyl)-3-[[ 3S)-l-ethyl-2-yloxypyrrolidin-3-yl]-(trans-4-methylcyclohexylcarbonyl)amino]thiophene-2-carboxylic acid methyl ester (200 mg, 67%, Off-white solid) TLC: 40% EtOAc / petroleum ether, R. Analysis by LCMS (column: HALO C-18 (2.1 x 100 mm, 1.7 μηη), mobile phase: A: 5 mM aqueous solution of CH3C02NH4, B: MeCN, time (min)/% B gradient: 0 min/3%, 0.5/3, 2/90, 2.5/90, 3.0/100, 3.5/50, flow rate: 0.5 mL/min, sample diluent: MeOH): ΜΗ+=473·5. tR = 2.89 min. [a]D··-15 ·4 deg. (c=l.0% in MeOH), for palm purity 97.6% (300 nm, Chiralpak AD-H column (4.6x250 mm, 5 μπι), Mobile phase · 15% EtOH / 85% hexane, 0.8 mL / min, RT). NMR (400 MHz, DMSO-d6): 7.18 (s, 0.39H), 7.01 (s, 0.55H), 157033.doc -243 - 201215604 5.47 (t,J=9.2Hz; 0.6H), 4.17-4.13 ( m, 0.44H), 3.76 (s, 3H) 3.25-3.05 (m, 3H), 3.03-2.67 (m, 1H), 2.32-2.19 (m, 1H) 2.11-1.95 (m, 2H), 1.59 (m ,6H), 1.28-1.27 (m,10H),1·23 0.99 (m,2H), 0.97-0.92 (m) 〇Step 7:

5-(3,3-dimethylbut-1-ynyl)-3-[[(3S)-l-ethyl-2-yloxy-indolyl-3-yl]-(trans-4 -Methylcyclohexylcarbonyl)amino]thiophene-2-carboxylic acid. At room temperature, 5-(3,3-dimethylbut-1-ynyl)-3-[[(3S)-l.ethyl 2_sideoxy~° ratio B bit-3 -(-)-(trans-4-indolylcyclohexyl)amino] porphin-2-decanoic acid methyl vinegar (200 mg, 0.423 mmol) in 1:1 THF/water (6 mL) To the solution was added Li0H.H20 (53.3 mg, 1.59 mmol), and the mixture was stirred for 3 hours. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the pH was adjusted to about 1 with aq. 1 EtOAc (EtOAc) (EtOAc) 131 : 5-(3,3-Dimethylbutan-1-yl-2-ethyl-2-oxo-pyrrolidin-3-yl]-(trans-4-methylcyclohexylcarbonyl)amino ] 嗟--2- citric acid (100 mg, 51%, off-white solid). TLC: 10% MeOH / CHCl3, Rf: 0.4. Analysis by LCMS (column: 8 £11 〇 18 (2.1 x 50 mm ' 1.7 Μηι), mobile phase: A : 5 mM CH3C02NH4 aqueous solution 'B : MeCN ' time (min) /% B gradient: 〇min/30/〇, 157033.doc -244- 201215604 0.1/3 ' 1.5/90 ' 2.1/ 90 , 3.0/50 , 3.0/100 , 3.5/100 , 4.0/100 ' Flow rate: 0.5 mL/niin, sample diluent: MeOH): MH -457.5. tR = i.4l min. [a]D:_9 2 Deg· (c=1.0%, in

MeOH), palm purity 87 7〇/〇 (3〇〇nm, Chiralpak 1C column (4.6x250 mm), mobile phase: 2〇0/. Et〇H (0.1% DEA)/80% hexane (0.1% DEA), 0.8 mL/min, 40 °C) 'H NMR (400 MHz, DMSO-d6): 13.60 (br s, interchangeable with d2〇; ih), 7.12 (s, 0.33H), 6.97 ( s, 0.65H), 5.50 (t, J=9.6Hz; 0.64H), 4.10-4.02 (m, 0.47H), 3.32-3.11 (m, 3H), 3.04-3.00 (s, 1H), 2.41-1.90 (m, 3H), 1.60-1.45 (m, 5H), 1·35_101 (m, 11H), 1〇1-〇86 3H). Preparation of Compound 132 Step 1:

5-but-1-ynyl-3-[(2-morpholino-2-oxo-ethyl)amino]thiophene-2-carboxylic acid methyl ester. 3-bromo-5-(butyl-i-alkynyl)thiophene-2-carboxylate (prepared as previously described, 2.0 g, 7.3 mmol), 2-amino-1 morpholinyl ethyl ketone hydrochloride (1.98 g '11.0 mmol) and Cs2C〇3 (7.16 g, 22.0 mmol) in a suspension of toluene (30 mL) were degassed by bubbling argon for 5 minutes, then added

Pd(OAc) 2 (164 mg, 0.732 mmol) and (soil)-BINAP (455 mg, 0.732 mmol). The purification was continued for another 10 minutes and the mixture was stirred at rt for 16 hours. The reaction was monitored by TLC. Upon completion of the reaction, the reaction 157033.doc • 245 - 201215604 was cooled to room temperature and diluted with EtOAc (100 mL) And the filtrate was filtered through EtOAc (EtOAc) (EtOAc)EtOAc. To give methyl 5-but-1-ynyl-3-[(2-morpholin-2-yloxy-ethyl)amino]thiophene-2-carboxylate (1. g, 40%, yellow TLC: 60% EtOAc/ petroleum ether, Rf: 0.35. MH+=337.1. 4 NMR (400 MHz, DMSO-d6): 7.24 (s, interchangeable with D20; 1H), 6.99 (s, 1H), 4.14 (d, J = 4.8 Hz; 2H), 3.72 (s, 3H), 3.60-3.56 (m, 4H), 3.48-3.44 (m, 4H), 2.50-2.44 (m, 2H), 1.15 (t, J =7.6Hz; 3H) 〇Step 2

5-but-1-ynyl-3-[(trans-4-methylcyclohexylcarbonyl)-(2-morpholino-2-isoxyl-ethyl)amino]thiophene-2-carboxamide ester. To 5-but-1-ynyl-3-[(2-morpholinyl-2-oxo-ethyl)amino]thiophene-2-carboxylic acid oxime ester (3 〇〇 mg, 0.892 mmol), pyridine (3.0 mL) and DMAP (55 mg, 0.44 mmol) were added dropwise to EtOAc (1. <RTI ID=0.0></RTI> </RTI> <RTIgt; The solution in 10 mL) was then stirred at 90 ° C for 16 hours. The progress of the reaction was monitored by TLC. When the reaction is complete, the mixture is diluted with EtOAc (80 mL) using 2N aqueous HCI (30 mL), 10% NaHC03 (2×20 mL), water (10 mL), brine (20 157033.doc •246· 201215604

Washed in mL), dried over NaJCU and concentrated. The residue was purified by silica gel column chromatography (100-200 mesh, 50 ° / EtOAc / petroleum ether as solvent) to give 5-but-1-ynyl-3-[(trans-4-) Cyclohexylcarbonyl)-(2-morpholinyl-2-oxo-ethyl)amino]°Cet-2-pyrubic acid vinegar (3 50 mg, 85%, yellow solid). TLC. 603⁄4 EtOAc/ petroleum ether </RTI> Rf: 0.3. By [CMS analysis (column: BEH C-18 (2.1x50 mm, 1·7 μηι), mobile phase: a : 5 mM aqueous solution of CH3C02NH4 ' B : MeCN, time (min) / % B gradient: 0 min / 3%, 0.1/3, 1.5/90, 2.1/90, 2.3/100, 2.8/50, 3/3, flow rate: 0.4 mL/min, sample diluent: MeOH): MH+ = 461.2. tR = 1.91 min. 4 NMR (400 MHz, DMSO-d6): 7.27 (s 1H) 4.92 (d, J = 16.4 Hz; 1H), 3.85 (d, J = 16.8 Hz; 1H), 3.77 (s 3H), 3.54-3.58 ( m, 4H), 3.44-3.38 (m, 4H), 2.53-2.47 (m, 2H), 2.10-2.04 (m, 1H), 1.67-1.55 (m, 3H), 1.50-1.47 (m, 1H), 1.41-1.21 (m, 3H), 1.16 (t, J=7.6Hz; 3H), 0.95 〇

Step 3 5-but-1-ynyl-3-3_[(trans-4-methylcyclohexylcarbonyl)-(2-norpoline_2-sideoxy-ethyl)amino]porphyrin-2-carboxylic acid . To 5-but-1-ynyl-3-[(trans-4-methylcyclohexylcarbonyl)-(2-morpholinyl-2-oxo-ethyl)amino]thiophene at room temperature 2_ Methyl formate (350 mg, 0.76 mmol) in 1:1 THF / water (6 mL) EtOAc EtOAc EtOAc. Mix for 16 hours. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the mixture was acid~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Yield 132 : 5-but-1-ynyl-3-[(trans-4-indolylhexyl)-(2-pipelinyl-2-yloxy-ethyl)amino]» Phen-2-carboxylic acid (145 mg, 42%, yellow solid). TLC: 10% MeOH/CHCl3, Rf: 0.5. Analysis by LCMS (column: BEH C-18 (2.1x50 mm, 1.7 μm), mobile phase: A: 5 mM CH3C02NH4 in water, B: MeCN, time (min)/%B gradient: 0 min/3 %, 0.1/3, 1.5/90, 2.1/90, 2.3/100, 2.8/50, 3/3, flow rate: 0.4 mL/min, sample diluent: MeOH): MH+ = 445.1. tR = 1.24 min. 4 NMR (400 MHz, DMSO-d6): 13.5 (s, interchangeable with D20; 1H), 7·24 (s, 1 Η), 4.92 (d, J = 16.4 Hz; 1H), 3.85 (d, J = 16.4 Hz; 1H), 3.54-3.53 (m, 4H), 3.39-3.31 (m, 4H), 2.52-2.46 (m, 2H), 2.08-2.05 (m, 1H), 1.65-1.51 (m, 4H), 1.38-1.23 (m, 3H), 1.16 (t, J = 3.6 Hz; 3H), 0.7. Preparation of Compound 133 #杂七-2.·如化合物131 » Step 3 ··

Λ

N-[(3S)-l-(2-methoxyethyl&gt;-2-trioxypyrrolidin-3-yl]carbamic acid tert-butyl ester. At 0 ° C, after 1 〇 Adding [[38]2_Sideoxypyrrolidin-3-yl]carbamic acid to a suspension of sodium hydride (600 mg, 15 157033.doc • 248·201215604 mmol) in THF (30 mL) a solution of the third butyl ester (2.0 g, 10 mm 〇 1) in KDMF (4 〇 mL) followed by (2-bromoindolyl) decyl ether (〇94 mL, 1 〇mmol) in THF (10 mL) The solution was stirred and the reaction was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC.

Diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The residue was purified by hydrazine column chromatography (100-200 mesh, MeOH / CHCl3 as eluting solvent) to afford N-[(3S)-1 1-(2-methoxyethyl)-2- oxo-pyrrole Pyridin-3-ylaminobenzoic acid tert-butyl ester (800 mg, 31 ° /., yellow gum). TLC: 10% MeOH/CHCl3, Rf: 0.42. MH+=259.2. 4 NMR (400 MHz, DMSO-d6): 7.07 (d, J = 8.8 Hz; 1H), 4.10-4.03 (m, 1H), 3.41 (s, 3H), 3.29-3.19 (m, 6H ), 2.24-2.17 (m, 1H), 1.80-1.72 (m, 1H), 1.38 (s, 9H). Step 4:

(3S)-3-Amino-1-(2-methoxyhexyl)pyrrole bite 2-ketone. To N-[(3S)-l-(2-methoxyethyl)-2-oxo-n-r-pyridin-3-yl]amino decanoic acid tert-butyl ester (〇°c) To a solution of dioxane (1 mL) was added EtOAc (2 mL). The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was concentrated to give (3S)-3-amino-1-(2-decyloxyethyl)pyrrolidin-2-one 157033.doc -249 - 201215604 (600 mg, 99%, brown Gum). MH+ = 159.2. NMR (400 MHz, DMSO-d6): 8.49 (br s, 2H), 3.96-3.95 (m, 1H), 3.45 (s, 3H), 3.44-3.31 (m, 2H), 3.30 (br s, 3H) , 2.40-2.33 (m, 1H), 1.94-1.89 (m, 1H). Step 5 ··

5-(3,3-Dimethylbut-1-ynyl)-3-[[(3S)-l-(2-methoxyethyl)-2-yloxy-pyrrolidin-3-yl Amino] methyl thiophene-2-carboxylate. Ethyl 3-bromo-5-(3,3-dimethylbut-1-ynyl)thiophene-2-indole (773 mg, 2.57 mmol), (3 S)-3-amino-1-( A suspension of 2-nonyloxyethyl)pyrrolidin-2-one (750 mg, 3.86 mmol) and Cs2C03 (2.51 g, 7.71 mmol) in toluene (15 mL) was deoxygenated by argon gas purge for 60 minutes. And then add

Pd(OAc) 2 (57.7 mg, 0.257 mmol) and (±)-BINAP (160 mg, 0.257 mmol). The purification was continued for another 30 minutes, and then the reaction was stirred at 10 ° C for 16 hours. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction was cooled to EtOAc. The filtrate was washed with water (2×50 mL) brine (20 mL) The residue was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) -l-(2-methoxyethyl)-2-oxo-oxyl-methyl thiophene-2-carboxylate (650 mg, 67%, orange gum) . TLC: 157033.doc •250· 201215604

50% EtOAc/petroleum ether, Rf: 0.25. Analysis by LCMS (column: BEH C-18 (2.1x50 mm, 1.7 μηη), mobile phase: A: 5 mM CH3C02NH4 in water, B: MeCN, time (min)/%B gradient: 0 min/3%, 0.1/3, 1.5/90, 2.1/90, 2.3/100, 2.8/50, flow rate: 0.4 mL/min, sample diluent: MeOH): MH+ = 379.2. tR = 1.89 min. For palm purity: 99.5% (maximum curve) (Chiralpak AD-H column (4.6 &gt;&lt;25〇111111, 5 0111), mobile phase: 2〇%£1〇11/8〇〇/〇 Hexane, 0.8 mL/min, RT). 4 NMR (400 MHz, DMSO-d6): 6.96-6.93 (m, 1H and D20 interchange; 2H), 4.35-4.28 (m, 1H), 3.72 (s, 3H), 3.47-3.44 (m, 2H), 3.41-3.31 (m, 4H), 3.26 (s, 3H), 2.58-2.56 (m, 1H), 1.81-1.76 (m, 1H), 1.27 (s, 9H). Step 6:

5-(3,3-Dimethylbut-1-ynyl)-3-[[(38)-1-(2-methoxyethyl)-2-oxo-pyrrolidin-3-yl 】-(trans-4-indolylcyclohexylcarbonyl)amino]methyl thiophene-2-carboxylate. To 5-(3,3-dimethylbut-1-ynyl)-3-[[(3S)-l-(2-decyloxyethyl)-2-yloxy-n-pyrrolidine_3 Methyl]thiophene-2-yl decanoate 3 (65 mg, 1.72 mmol), pyridine (6.5 mL, 10 vol) and DMAP (105 mg, 0.858 mmol) in dichloroethane (30 mL) A solution of 4-mercaptocyclohexaneformamidine chloride (2.75 g, 17.2 mmol) in di-hexane (10 mL) was added dropwise to a stirred 0 ° C solution. Stir under the arm for 16 hours. 157033.doc -251 - 201215604 The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was diluted with EtOAc (150 mL), EtOAc EtOAc EtOAc EtOAc . The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) )-1-(2-methoxyethyl)-2-yloxypyrrolidin-3-yl]-(trans-4-indolylcyclohexylcarbonyl)amino]thiophene-2-furic acid methyl ester (350 mg, 67% 'pink solid). TLC: 60% EtOAc/ petroleum ether &apos; Rf: 0.28. Analysis by LCMS (column: BEH C-18 (2.1x50 mm ' 1.7 μιη)' mobile phase: A: 5 mM CH3C02NH4 in water, B: MeCN, time (min)/%B gradient: 0 min/3%, 0.1/3, 1.5/90, 2.1/90, 2.3/100, 2.8/50, flow rate: 0.4 mL/min, sample diluent: MeOH): MH+ = 503.5. tR = 2.18 min. Palm purity: 99.7% (300 nm, Chiralpak AD-H column (4.6x250 mm, 5 μπι), mobile phase: 20% EtOH (0.1% DEA) / 80% hexane (0.1% DEA), 0.8 mL /min, 40.〇.4 NMR (400 MHz, DMSO-d6): 7.18 (s, 0·3Η), 7.02 (s, 0.7H), 5.54-5.49 (m, 0.7H), 4.23-4.19 (m , 0.3H), 3.76 (s, 3H), 3.39-3.32 (m, 3H), 3.28-3.16 (m, 6H), 2.26-1.96 (m, 3H), 1.60-1.33 (m, 7H), 1.29 ( s, 9H), 0.76 (d, J=6.4Hz; 3H), 0.69-0.59 (m, 2H) ° Step 7:

157033.doc •252· 201215604 5-(3,3-Dimethylbut-1-ynylmethoxyethyl)_2_sideoxy·&quot;Bilo bite-3-kib (anti-methyl ring Hexacarbonyl)amino]thiophene-2-carboxylic acid. To 5-(3,3-dimercaptobut-1-ynyl)-3-[[(3S)-l-(2-methoxyethyl)-2-oxo-pyrrole at room temperature Stirring of pyridine-3-3-yl X-trans-4-yl-cyclohexylcarbonyl)-amino]thiophene-2-carboxylate (3 〇〇 mg, 0.597 mmol) in 1:1 THF/water (10 mL) U〇h.H20 (53.3 mg, 0.895 mmol) was added to the solution and the mixture was stirred for 3 hr. Monitor the reaction by tlC

Cheng. Upon completion of the reaction, the mixture was acidified to EtOAc (EtOAc) (EtOAc) (EtOAcjjjjjjjjj -(3,3-dimethylbut-1-ynyl)-3-[[(3S)-l-(2-methoxyethyl)-2- oxo-D is more than -3- Base]-(trans-4-methylcyclohexylcarbonyl)amino]thiophene-2-carboxylic acid (120 mg, 41%, off white solid). TLC: 10% MeOH/CHCl3, Rf: 0.3. Analysis by LCMS (column: HALO C-18 (2.1 x 100 mm, 2.7 μηη), mobile phase: A: 5 mM CH3C02NH4 in water, B: MeCN, time (min)/%B gradient: 0 min/3%, 0.5/3, 2/90, 2.5/90, 3.0/100, 3.5/50, flow rate: 0.5 mL/min, sample diluent: MeOH): MH+ = 489.4. tR = 1.85 min. Palm purity: 99.7% (292 nm, Chiralpak AD-H column (4.6x250 mm, 5 μπι), mobile phase: 20% EtOH (0.1% DEA) / 80% hexane (0.1% DEA), 0.8 mL /min,40. NMR (400 MHz, DMSO-d6): 13·5 (br s, interchangeable with D20; 1H), 7.12 (s, 0.3H), 6.97 (s, 0.7H), 5.56-5.51 (m, 0.7H), 4.14-4.09 (m, 0.3H), 3.45-3.36 (m, 3H), 3.28-3.27 (m, 2H), 3.25-3.23 (m, 1H), 3.20-3.16 (m, 2H), 3.13- 157033.doc -253· 201215604 3.09 (m,1H), 2.32-2.18 (m,1H),2.10-1.96. Preparation of Compound 139 Step 7-7. As with compound; 133. Step 8:

5-(3,3-Dimethylbut-1-ynyl)_3-[[(3S)-l-(2-hydroxyethyl)-2-yloxy-indolyl-3-yl]- (trans-4-methylcyclohexylcarbonyl)amino]thiophene-2-carboxylic acid. To 5-(3,3-dimercaptobut-1-ynyl)-3-[[(3S)-l-(2-decyloxyethyl)-2-oxooxy group at 〇 °C - pyrrolidine-3.yl]-(trans-4-methylcyclohexylcarbonyl)amino]. BBr3 (0.050 mg, 0.49 mmol) was added to a solution of EtOAc (EtOAc) (EtOAc (EtOAc) The progress of the reaction was monitored by TLC. The reaction was quenched with EtOAc (EtOAc (EtOAc) The resulting organic layer was washed with EtOAcq. The residue was purified by preparative RP-HPLC (aq. EtOAc EtOAc (EtOAc) elute -(2-hydroxyethyl)-2-oxo-pyrrolidin-3-yl]-(trans-4.methylcyclohexylcarbonyl)amino]thiophene-2-carboxylic acid (20 mg, 25%, shallow Green solid). TLC: 10% MeOH/CHCl3, Rf: 0.2. Analysis by LCMS (column: BEH C-18 (2.1 &gt;&lt; 50 mm, 1.7 μιη), mobile phase: a: 0.1% aqueous solution of HCOOH, B: MeCN 'time (min) / % B gradient: 157033. Doc •254- 201215604 0 min/3%, 0.1/3, 1.5/90, 1.8/90, 2.2/95, 3.2/95, 3.8/3, flow rate: 0.4 mL/min, sample diluent: MeOH): ΜΗ +=475·6. tR = 1.7 min. Palm purity: 99.5% (292 nm, Chiralpak AD-H column (4.6x250 mm, 5 μιη), mobile phase: 20% EtOH (0.1% DEA) / 800 / hexane 0.1% DEA), 0.8 mL /min, RT). 4 NMR (400 MHz, DMSO-d6): 13.6 (br s, interchangeable with D20, 1H), 7·10 (s, 0.31H), 6.97 (s, 0.64H), 5.55 (t, J = 10 Hz; 0.65 H), 4.68-4.61 (m, interchangeable with D20, 1H), 4.05 (t, J = 9.6 Hz; 0.30H), 3.45-3.35 (m, 4H), 3.13-3.03 (m, 4H), 2.19-1.95 (m, 3H), 1.57_1.33 (m, 6H). Preparation of compound 141: as compound 131. Step 3:

N-[(3S)-1-isopropyl-2-oxo-pyrrolidin-3-yl]carbamic acid tert-butyl vinegar. Add N-[(3S)-2-Sideoxypyrrolidin-3-yl]amine to a suspension of sodium hydride (300 mg '7.5 mmol) in THF (20 mL) over 10 min. A solution of tert-butyl phthalate (1·〇g, 5.0 mmol) in DMF (6 mL), followed by isopropyl iodide (0.75 mL, 7.5 mmol) in THF (10 mL) The mixture was stirred at room temperature for 6 hours. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the mixture was diluted w~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The residue was purified by hydrazine column chromatography (1 EtOAc, 2% MeOH/CHCH) to afford N-[(3S) ss. T-butyl citrate (2 〇〇 mg, 10%, yellow liquid). TLC. 10% MeOH/CHCl3, Rf: 0.74. iH-NMR (400 MHz, DMSO-d6): 7.04 (d, J = 8.8 Hz; interchangeable with D20; 1 imprint, 4.11 - 1.05 (m, 2H), 3.25-3.20 (m, 1H), 3.20-3.11 ( m, 1H), 2.23- 2.18 (m, 1H), 1.38 (s, 9H), 1.07-1.03 (m, 6H). Step 4:

(3S)-3-Amino-1-isopropyl-pyrrolidin-2-one. To a solution of N-[(3S)-1-isopropyl-2-oxoylpyrrol-3-yl]carbamic acid tert-butyl ester (490 mg, 2.15 mmol) at 〇 ° C Et20 (6 mL) containing 2 M HCl (1 mL) was added to a solution of EtOAc (10 mL), and the mixture was stirred at room temperature for 16 hr. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the solution was concentrated to give (3S)-3-amino-1-isopropyl-pyrrolidin-2-one (350 mg, 96%, pale yellow). 1H NMR (400 MHz, DMSOd6): 8.56 (brs, lH), 4.16-4.10 (m, 1H), 3.95-3.89 (m, 1H), 3.40-3.36 (m, 1H), 3.27-3.23 (m, 1H), 2.39-2.34 (m, 1H), 1.92-1.88 (m, 1H), 1.12-1.07 (m, 6H). Step 5: 157033.doc -256- 201215604

5-(3,3-Dimethylbutan-1-yl)-3-[(1-isopropyl-2-oxo-carboindole-3-yl)amino]thiophene-2-carboxylic acid ester. 3-bromo-5-(3,3-dimethylbutan-indolyl) thiophene-2-decanoate (500 mg, 1.66 mmol), (3S)-3-amino-i-isopropyl A suspension of pyridine-pyrrolidin-2-one (353 mg, 2.49 mmol) and Cs2C03 (1.62 g, 4.98 mmol) in toluene (10 mL) was deoxygenated by argon flow for 6 min. Next, Pd(OAc)2 (37 mg, 0·17 mmol) and (±) BINAP (103 mg, 0.166 mmol) were added, and purification was continued for another 3 minutes, and the reaction was stirred at 100 ° C for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with EtOAc (l. The mash was washed with water (2×20 mL), brine (20 mL), dried over Na.sub.sub.sub.sub.sub.ssssssssssssssssssssssssssssssssssssssssss Purification to give 5-(3,3-dimercaptobut-1-ynyl)-3-[(1-isopropyl-2-yloxy_°bi-L--3-yl)amino] sigh Phen-2-carboxylic acid (260 mg, 410/〇, white solid). TLC: 50% EtOAc / petroleum ether. Analysis by LCMS (column: BEH C-18 (2.1 &gt;&lt; 50 mm, 1·7 μπι), mobile phase: A: 5 mM CH3C〇2NH4 aqueous solution, Β: MeCN, time (min)/0/ 〇B Gradient: 0 min/3%, 0.1/3, 1.5/90, 2.1/90, 2.3/100, 2.8/50, flow rate: 0.4 mL/min, sample diluent·· MeOH) ·· MH+=363.4 » tR = 2.01 min. For palmar HPLC (Chiralpak AD-H column (4.6x250 157033.doc •257-

S 201215604 mm, 5 μηι), mobile phase: 20% EtOH/80% hexane, 0.8 mL/min, RT): 39.6% and 60.4% (maximum curve). NMR (400 MHz, DMSO-d6): 6.93 (s, 1H), 6.92 (s, interchangeable with D20; 1 deduction, 4.32-4.26 (m, 1H), 4.17-4.10 (m, 1H), 3.72 (s, 3H), 3.36-3.29 (m, 1H), 3.21-3.14 (m, 1H), 2.60-2.54 (m, 1H), 1.79-1.71 (m, 1H), 1.28 (s, 9H), 1.12-1.07 ( m, 6H). Step 6 ··

5-(3,3-dimethylbut-1-ynyl)-3-[(l-isopropyl-2-yloxypyrrolidin-3-yl)-(trans-4-methylcyclo) Methyl carbonyl)amino]thiophene-2-carboxylate. Here. Under the armpit, 5-(3,3-dimethylbut-1-ynyl-2-yloxy-pyrrolidine-3-yl)amino][]-phen-2-pyrimidine A solution (260 mg, 0.720 mmol), a ratio of D to 0 (4.0 mL, 20 volumes) and DMAP (43 mg, 0.36 mmol) in a stirred solution of di-ethane (10 mL) A solution of 4-methylcyclohexane helium (1.155 g, 7.202 mmol) in dichloroethane (5 mL) was added and the mixture was stirred at 100 ° C for 16 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was diluted with EtOAc (50 mL), washed with 2 N EtOAc (10 mL), 10% NaHCO3 (3×20 mL), water (10 mL), brine (20 mL) dried and concentrated with NazSO4 . The residue was purified by hydrazine column chromatography (100-200 mesh, 60% EtOAc / pet. EtOAc as solvent) to afford 5-(3,3-dimethylbut-1-ynyl)-3-[( 1-isopropyl-2-sidedoxy_ 157033.doc -258· 201215604

<RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; TLC: 50% EtOAc/petroleum ether, Rf: 0·3: mp.: LCMS (column: BEH 018 (2.1x50 mm ' 1.7 μιη) 'mobile phase: a : 5 mM aqueous solution of CH3C02NH4, B ·· MeCN ' time (min)/%B gradient·· 0 min/3%, 0.1/3, 1.5/90, 2.1/90, 2.3/100, 2.8/50, flow rate: 0.4 mL/min, sample diluent: MeOH): ΜΗ +=487·5. tR = 2.28 min. For palmar HPLC (Chiralpak AD-H column (4.6 x 250 mm, 5 μιη), mobile phase: 5% EtOH (0.1% DEA) / 95% hexane (0.1% DEA), 0.8 mL/min, RT): 41.2% and 58.8% (at 300 nm). NMR (400 MHz, DMSO-d): 7.18 (s, 0.4H), 7.00 (s, 0.6H), 5.46 (t, J = 9.2 Hz; 0.6H), 4.16-4.13 (m, 0.4H), 4.09 -4.04 (m, 1H), 3.77 (s, 3H), 3.16-3.10 (m, 1H), 2.98-2.96 (m, 1H), 2.25-2.21 (m, 1H), 2.11-1.97 (m, 2H) , 1.59-1.52 (m, 4H), 1.46-1.41 (m, 2H), 1.28 (s, 9H). Step 7:

5-(3,3-Dimethylbut-1-ynyl)-3-[[(3R)-l-isopropyl-2-yloxy-indolyl-3-yl]-(anti- 4-methylcyclohexylcarbonyl)amino]thiophene-2-carboxylic acid. To 5-(3,3-didecylbutan-1-yl)-3-[(1-isopropyl-2-yloxy-&quot;bi-haridin-3-yl)- at room temperature (trans-4-methylcyclohexylcarbonyl)amino]thiophene-2-carboxylate (240 157033.doc -259- 201215604

Mg, 0.493 mmol) LiOH.H 2 〇 (62.2 mg, 1.48 mmol) was added to a solution of 1:1 in THF/water (6 mL) and the mixture was stirred for 3 hours. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction was acidified to EtOAc (EtOAc) (EtOAc)EtOAc. The crude product was purified by preparative HPLC (purified with ethanol / hexanes) to afford 141: 5-(3,3-didecylbut-1-ynyl)-3-[[(3R) -l-isopropyl-2-oxo-pyrrolidin-3-yl]-(trans-4-methylcyclohexylcarbonyl)amino]thiophene-2-furic acid (65 mg, 70%) TLC: 10% MeOH/CHCl3, Rf: 0.4. Analysis by LCMS (column: BEH C-18 (2.1x50 mm, 1.7 μηη), mobile phase: A: 5 mM CH3C〇2NH4 aqueous solution, B: MeCN, time (min)/%B gradient: 0 min/3 %, 0.1/3, 1.5/90, 2.1/90, 2.3/100, 2.8/50, 3/3, flow rate: 0.4 mL/min, sample diluent: MeOH): MH+ = 473.2. tR = 1.39 min. For palmar HPLC (Chiralpak IA column (4.6x250 mm, 5 μιη), mobile phase: 5% EtOH (0·1ο/〇TFA)/50/〇i-PrOH (0.1% TFA)/90°/〇 Alkane (0.1% TFA), OJmL/mir^RThQS^^o/oGlLMSQPnmpiHNMRWOOMHz, DMSO-d6): 13.6 (br s, interchangeable with D20; 1H), 7.13 (s, 0.48H, 6.96 (s, 1H), 5.48 (t, J=9Hz; 1H), 4.11-4.07 (m, 3H), 3.34-3.31 (m, 0.57H), 3.16-3.10 (m, 1.62H), 2.98-2.93 (m, 1H), 2.32- 1.96 (m, 4H), 1.60-1.43 (m, 8H), 1.29 (s, 9H), 1.05-1.01 (m, 6 H). Preparation of compound 142 ##厂(5 .* as above for the preparation of compound 141 157033.doc -260- 201215604 Step 7:

5-(3,3-dimethylbut-1-ynyl)_3-[[(3S)-1-isopropyl-2-oxooxypyrrole-3-yl]-(trans-4-曱基环己叛基)Amino] 叹 _2_2_carboxylic acid. The product mixture of step 7 (Compound 1 41 above) was subjected to a palm preparative HPLC to give 142:5·(3,3-dimethylbut-1-ynylisopropyl-2-ylooxy-» Biha-3-yl]-(trans-4-methylcyclohexylcarbonyl)amino][alpha]cephene-2-carboxylic acid (100 mg, 70%), TLC: 10% MeOH/CHCl3, Rf: 〇· 4. Analysis by LCMS (column: BEH C-18 (2.1x50 mm, 1.7 μηι), mobile phase: A: 5 mM CH3C〇2NH4 aqueous solution, Β: MeCN, time (min)/%B gradient: 0 min /3%, 0.1/3, 1.5/90, 2.1/90, 2.3/100, 2.8/50, 3/3 ' Flow rate: 0.4 mL/min, sample diluent: MeOH): MH+=473.2, tR =1.39 min For palm purity (Chiralpak column (4.6x250 mm, 5 μηι), mobile phase: 5% EtOH (0.1% TFA) / 5% i-PrOH (0.1% TFA) / 90% hexane (〇.1 〇/0 TFA), 0.7 mL/min, RT): 99.9% (at 299 nm). NMR (400 MHz, DMSO-d6): 13.6 (br s, interchangeable with D2〇; 1H), 7.13 (s, 0.48) H), 6.96 (s, 1H), 5.48 (t, J = 9 Hz; 1H), 4.11-4.07 (m, 3.67 H), 3.36-3.32 (m, 0.83H), 3.16-3.10 (m, 1.8H) , 2.97-2.93 (m, 1H), 2.32-1.96 (m, 4H), 1.60-1.43 ( m, 8H), 1.29 (s, 9H), 1.05-1.01 (m) 157033.doc • 261 · 201215604 Preparation of Compound 144 Step 1:

Br

Ο +

Methyl 3-bromo-5-[2-(1-methylcyclopropyl)ethynyl]thiophene-2-carboxylate. Cul (7l mg, (2) is suspended in a suspension called 丨 工 工 恶 四 四 四 四 四 四 四 除 除 除 除 除 除 除 除 除 除 263 263 263 263 263 263 263 263 263 263 263 263 263 263 263 263 263 263 263 263 263 263 263 263 263 263 263 263 , 〇.375 _〇1) and continue to purify for 15 minutes. Add monoisopropylamine (3.56 mL, 25.0 mmol) and 3,5-dibromothiophene-2-methylhydrazine from day (3.75 g' 12.5 mm〇i And the reaction was stirred at room temperature for a few minutes. The mixture was cooled in ice water and L ethynyl-didecylcyclopropane (ethyl acetate solution 'mg, 12.5 mmol) was added and the reaction was dropped at room temperature. The progress of the reaction was monitored by TLC. The mixture was then diluted with a mixture of 〇心(2〇社), filtered through Shishizao soil, and the cake was washed with Et〇Ac (2xl 〇虹). The combined filtrate was concentrated. Purification by preparative grade Ηριχ (using hydrazine and HCOOH aqueous solution as the eliminator) gave methyl 3-bromo-5-[2-(1-methylcyclopropyl)ethynyl]thiophene-2-indoleate (35 〇) Mg, light yellow solid) TLC. 2/〇 EtOAc/oil shout, Rf · 〇 5. Analyzed by LCMS (column. BEH C-18 (2.1x5〇mm, ! 7 μιη), mobile phase: A: 0 ·1/〇HCOOH Water>Valley Liquid ' b : MeCN, time gradient:

Paradox /3% ' Please, plan, 1.8 touch, 2.2/95, 3 escape, 3·8/3, flow rate: 0.4 mL/min ' Sample thinner: Me〇H) : μη+=3〇ι 2 , tR 157033.doc -262. 201215604 =2.11 min. *11 NMR (400 MHz, CDC13): 7.01 (s, 1H), 3.87 (s, 3H), 1.34 (s, 3H), 1.04-1.02 (m, 2H), 0.75-0.72 (m, 2H). Step 2:

Φ 5-[2-(l-Methylcyclopropyl)ethynyl]-3-[(2-morpholinyl-2-p-oxy-ethyl)amino]thiophene-2-carboxylic acid methyl ester. 3-bromo-5-[2-(l-fluorenylcyclopropyl)ethynyl]thiophene-2-decanoate (350 mg, 1.17 mmol), 2-amino-1-morpholinyl-ethanone A suspension of the hydrochloride salt (316 mg ' 1.84 mmol) and Cs2C03 (1.14 g, 3.68 mmol) in toluene (10 mL) was degassed by bubbling argon for 50 minutes, followed by the addition of Pd(OAc)2 ( 26 mg, 0.12 mmol) and (±) BINAP (72 mg, 0.12 mmol). The purification was continued for another 10 minutes and the mixture was stirred for 16 hours. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the mixture was cooled to room temperature, diluted with EtOAc (50 mL) and filtered over EtOAc. The filtrate was washed with water (2×20 mL), brine (3 mL), dried The residue was purified by hydrazine column chromatography (1 EtOAc, EtOAc / petroleum ether elut -[(2-Morpholinyl-2-l-oxy-ethyl)amino]thiophene-2-indole TLC : 60% EtOAc / EtOAc / EtOAc (EtOAc) , 4.12 (d,

Oxalate (220 mg '52%, yellow solid). Olefin 'Rf: 0.4. . 4 N1V d6): 7.23 (s, interchangeable with D20; iH) 6 157033.doc 201215604 J=4.4Hz; 2H), 3.71 (s, 3H), 3.60-3.56 (m, 4H), 3.48-3.45 (m, 4H), 1.30 (s, 3H), 0.98-0.95 (m, 2H), 0.80-0.79 (m, 2H). Step 3:

3-[(trans-4-methylcyclohexylcarbonyl)-(2-morpholinyloxy-ethyl)amino]-5-[2-(1-methylcyclopropyl)ethynyl]thiophene Methyl formate. Here. Underarm, 5-[2-(1-methylcyclopropyl)ethynyl]-3-[(2-morphinyl-2-yloxy-ethyl)amino] succin-2-carboxylic acid To a solution of methyl vinegar (220 mg, 0.607 mmol), Et3N (1.27 mL, 9.10 mmol) in CH2C12 (5.0 mL), EtOAc (EtOAc, EtOAc, The solution in CH2C12 (10.0 mL) was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the mixture was diluted with Et 〇Ac (50 mL). Washed with 2N HCl aqueous solution (2×10 mL), 10% NaHCO3 (20 mL), water (10 mL), brine (20 mL), Na2S04 Dry and concentrate. The residue was purified by silica gel column chromatography (1 〇〇 2 〇〇m, 50% EtOAc / petroleum as solvent) to afford 3-[(-----------cyclohexyl)- (2-Molinyl-2-p-oxy-ethyl)amino]-5-[2-(1·methylcyclopropyl)ethyl hexyl]. Methyl ceto-2-carboxylate (260 mg, 88%, off-white solid).

TLC . 60% EtOAc / petroleum puzzle 'Rf: 0.3. Analysis by LCMS (column: BEH C-18 (2.1x50 mm, 1_7 μιη), mobile phase: a: 5 mM 157033.doc -264- 201215604 CH3C02NH4, B: MeCN, time (rnin)/%B gradient: 〇min/3%, 1.5/45, 2.5/45, 3.2/95, 4.7/95, 5/3, flow rate: 〇·4 mL/min, sample diluent: MeOH): MH+=487.1 'tR 3.72 min. NMR (400 MHz, DMSO-d6): 7.23 (s, 1H), 4.91 (d, J = 16.8 Hz; 1H), 3.83 (d, J = 16.4 Hz; 1H), 3.77 (s, 3H), 3.54-3.53 (m, 4H), 3.42-3.39 (m, 4H), 2.09-2.04 (m, 1H), 1.70-1.34 (m, 5H), 1.31 (s, 3H), 1.30-1.23 (m, 2H) ), 1.03-1.01 (m, 2H), 0.82-0.78 (m, 2H), 0.77 (d, J = 6.4 Hz; 3H). Step 4:

3-[(trans-4-methylcyclohexylcarbonyl)-(2-morpholinyl-2-oxo-ethyl)amino]-5-[2-(1-methylcyclopropyl)acetylene Base] thiophene-2. formazan. To 3-[(trans-4-methylcyclohexylcarbonyl)-(2-morpholinyl-2-oxo-ethyl)aminopyr-5-[2-(1-methyl) at room temperature Cyclopropyl)ethyl hexafluoroacetate (2 60 mg, 0.534 mmol) was added to a stirred solution of 1:1 THF/water (6 mL). Mg, 1_60 mmol) and the reaction was stirred for a few hours. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the mixture was acidified (pH 1) with EtOAc (50 mL). The organic layer was washed with water (2×10 mL), brine (10 mL), dried over Na2SO4 and concentrated to give 144: 3-[(4- 4- ylcyclohexylcarbonyl)- _-ethyl)amino]-5-[2-(1-methylcyclopropyl)ethylidene] sinotic _2_decanoic acid (55 157033.doc -265· 201215604 mg ' 21%, off-white solid ). TLC: 10% MeOH/CHCl3, Rf: 0.4. Analysis by LCMS (column: BEH C-18 (2.1x50 mm, l, 7 μιη), mobile phase: A: 5 mM CH3C02NH4, B: MeCN, time (min)/%B gradient: 〇min/3% , 1.5/45, 2.5/45, 3.2/95, 4.7/95, 5/3, flow rate: 〇·4 mL/min, sample diluent: MeOH): ΜΗ+=471·5, tR 2.06 min. NMR (400 MHz, DMSO-d6): 13.45 (s, interchangeable with D20; 1H), 7.21 (s, 1H), 4.91 (d, J = 16.4 Hz; 1H), 3.84 (d, J = 16.4 Hz; ), 3.54-3.53 (m, 4H), 3.39-3.32 (m, 4H), 2.11-1.98 (m, 1H), 1.60-1.51 (m, 4H), 1.37-1.34 (m, 2H), 1.31 (s , 3H), 1.19-1.17 (m, 2H), l.〇2-1.00 (m,2H) 〇Preparation of compound 151 Step 1:

3-Mo-5-(4-phenyloxyphenyl) porphin-2-carboxylic acid methyl vinegar. To a solution of 3,5-dimethylene benzoate (2.0 g, 6.7 mmol) and 4-phenoxyphenyl glycine (1.43 g, 6.66 mmol) in toluene (60 mL) Add 3 M K2C03 in water (7 mL). The mixture was degassed by bubbling with argon for 1 hour, followed by addition of Pd(PPh3)4 (0.74 g' 〇·66 mmol) and purification continued for another 30 minutes. The reaction was then stirred at 90 ° C for 3 hours. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the mixture was diluted w~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc (1.2 g, 46%, white solid). TLC: 5% EtOAc/ petroleum ether, Rf: 0.4. Analysis by LCMS (column · BEH C-18 (2.1x50 mm, 1.7 μηη), mobile phase: A: 0.1% HCOOH aqueous solution, Β: MeCN, time (min)/% B gradient: 0 min/3% , 0.1/3, 1.5/90, 1.8/90, 2.2/95, 3.2/95, 3.8/3, flow rate: 0.4 mL/min, sample diluent: MeOH): MH+ = 389.2, tR = 2.27 min. NMR (400 MHz, CDC13): 7.55-7.53 (m, 2H), 7.40-7.36 (m, 2H), 7.21 (s, 1H), 7.18-7.16 (m,1H), 7.07-7.01 (m,4H) , 3·91 (s, 3H). Step 2:

3-([(2-Nipyl-2-yloxy-indolyl)amino]-5-(4-phenoxyphenyl) porphin-

Methyl 2-formate 3-bromo-5-(4-phenoxyphenyl)thiophene-2-furoate (1.2 g, 3.0 mm〇i), 2-amino-1-morpholinyl ethyl ketone A suspension of the hydrochloride salt (720 mg, 4.0 mmol) and Cs2CO3 (3.01 g, 9.24 mmol) in toluene (20 mL) was deoxygenated by bubbling argon for 60 minutes, followed by the addition of Pd(OAc)2 ( 70 mg, 0.31 mm 〇l) and (±) BINAP (389 mg, 0.660 mmol). Purification was continued for 30 minutes and then the reaction was stirred at i〇〇aC for 16 hours. The progress of the reaction was monitored by TLC 157033.doc •267- 201215604. After the reaction was completed, the mixture was cooled to room temperature, diluted with EtOAc (100 mL) and filtered over Celite. The filtrate was washed with water (2×4 〇 mL), brine (30 mL). The residue was purified by chromatography on silica gel column (100-200 mesh &quot; 65% EtOAc / petroleum ether as solvent) to give 3-[(2-morpholin-2-yloxy-ethyl)amine ]_5_(4_Phenoxyphenyl) porphin-2-indole methyl ester (1.2 g, 86 ό/〇, brown solid). TLC: 60% EtOAc/ petroleum ether, R. Analysis by LCMS (column: BEH C-18 (2.1 &gt;&lt; 50 mm, 1.7 μιη), mobile phase: a : 0.1 〇 /. HCOOH 7jc solution, B : MeCN, time (min) / % B gradient :〇min/3%, 0.1/3, 1.5/90, 1.8/90, 2.2/95, 3.2/95, 3.8/3, flow rate: 0.4 mL/min, sample diluent: MeOH): MH+=453.4, tR =1.95 min. 4 NMR (400 MHz, CDC13): 7.58-7.55 (m, 2H), 7.43 (br s, interchangeable with D20; 1H), 7.38-7.35 (m, 2H), 7·17_ 7.13 (m, 1H), 7.05 -6.99 (m, 4H), 6.72 (s, 1H), 4.11 (d, J = 5.2 Hz; 2H), 3.85 (s, 3H), 3.72-3.69 (m5 6H), 3.49-3.48 (m, 2H) 〇Step 3:

3-[(trans-4-methylcyclohexylcarbonyl)-(2-morpholinyl-2-l-oxy-ethyl)amino] 5-(4-phenoxyphenyl) porphin-2 - formic acid methyl vinegar at 3-[(2-?157033.doc -268· 201215604 phenyl-2-yloxy-ethyl)amino]-5-(4-phenoxy) Addition of phenyl)thiophene-2-decanoate (300 mg, 0.66 mmol) and Et3N (1.4 mL, 9.9 mmol) in CH2C12 (5 mL) Chloro(1.06 g, 6.60 mmol) in CH2C12 (5 mL) elute The progress of the reaction was monitored by TLC. Upon completion of the reaction, the mixture was diluted with EtOAc (EtOAc) (EtOAc (EtOAc) (EtOAc) . The residue was purified by hydrazine column chromatography (100-200 EtOAc, 50% EtOAc/ petroleum ether as solvent) to afford 3-[(trans-4-methylcyclohexylcarbonyl)-(2-morpholine) Methyl 2-ethyloxy-ethyl)amino]-5-(4-phenoxyphenyl)thiophene-2-furoate (3 〇〇 mg, 790 〇, white solid). TLC: 50% EtOAc / petroleum ether. Analysis by LCMS (column: pur0Spher RP-18 (2.〇xl〇〇mm, 2.1 μπι), mobile phase: A: 5 mM CH3C02NH4, B: MeCN, time (min)/%B gradient: 〇min/ 3./, 1.5/45, 2.5/45, 3.2/95, 4.7/95 '5/3 ' Flow rate: 0.6 mL/min, sample diluent: MeOH): ΜΗ = 577.1, tR = 4.12 min. Ifi NMR (400 MHz, CDC13): 7.61-7.59 (m, 2H), 7.49 (s5 1H), 7.40-7.36 (m, 2H), 7.18- 7.15 (m, 1H), 7.06-7.02 (m, 4H) 5,5,5,5,5,5 3H), 1.33-1.26 (m, 2H), 0.79 (d, J = 6.4 Hz). Step 4: 157033.doc -269- 201215604

3-[(trans-4-indolylcyclohexyl)·(2_morpholinyl 2 oxo-ethyl)amino] 5-(4-phenoxyphenyl)thiophene_2_ Formic acid. To 3 [(trans-4-methylsulfonylcyclohexylcarbonyl)-(2-morpholinyl 2-sideoxy-ethyl)amino]_5_(4-phenoxyphenyl)thiophene at room temperature Add methyl hydrazine (3 〇〇 mg, 〇 52 mmol) to a stirred solution of 1:1 THF / water (20 mL). Stir for 6 hours. The progress of the reaction was monitored by tlc. Upon completion of the reaction, the mixture was acidified with a 1 M HCl aqueous solution (pH 1) and used.

EtOAc (60 mL) was taken. The organic layer was washed with water (3×20 mL), brine (20 mL) and dried over Naj.sub.4 and concentrated to give 151: 3-[(trans-4-indolylcyclohexylcarbonyl)-(2-morpholinyl-2-oxooxy) Base-ethyl)amino]-5-(4-phenoxyphenyl) porphin-2-furic acid (110 mg, 38%, white solid). TLC: 10 〇/〇 MeOH/CHCl3, Rf: 0.32. Analysis by LCMS (column: 8 ugly 11 (: -18 (2.1 x 50 mm ' 1.7 μιη), mobile phase: A: 5 mM CH3C02NH4, B: MeCN, time (min) / 0 / 〇 B gradient: 〇 min /3%, 1.5/45 '2.5/45, 3.2/95, 4.7/95 '5/3, flow rate: 0.6 mL/min, sample diluent: MeOH): MH+=563.0, tR=2.43 min. NMR (400 MHz, DMSO-d6): 13.3 (br s, interchangeable with D20; out), 7.75· 7.73 (m, 2H), 7.50 (s, 1H), 7.45-7.41 (m, 2H), 7.22-7.18 (m, 1H), 7.09-7.07 (4H), 4.95 (d, 1=16.4 Hz; 1H), 3.92 (d, J=15.6Hz; 1H), 3.55-3.36 (m, 8H), 2.22-2.16 (m, 1H) ), 1.75-157033.doc -270- 201215604 1.72 (m,1Η),1·60. Preparation of Compound 152 Step 1-2: as described above for the preparation of compound 151. Step 3:

3_[(2,4-one gas benzoyl)-(2-morphinyl-2-yloxy-ethyl)amino]_5_(4-phenoxyphenyl)thiophene-2-carboxylic acid methyl ester . At 〇° (:, to 3_[(2_?-linyl-2-yloxy-ethyl)amino]-5-(4-phenoxyphenyl)thiophene-2-carboxylic acid decyl ester (300 2,4-Dichlorobenzene (6 % mL, 6.6 mmol) in CH2C12 (v. %), and a solution of Et3N (1.4 mL, 9.9 mmol) in CH2C12 (5 mL). The solution was stirred at room temperature for 16 hours. The reaction was monitored by TLC. The mixture was diluted with EtOAc (100 mL) &lt;2&gt; 2 N HCl (2 x 20 mL), water (20) (mL), 10% NaHCO3 solution (2×20 mL), brine (20 mL), washed with NadO4 and concentrated. The residue was purified by gel column chromatography (100-200 mesh silica gel, 55% EtOAc/ petroleum ether as solvent) (purification) to give 3-[(2,4-dichlorobenzhydryl)-(2.morpholinyl-2-oxo-ethyl)amino]-5-(4-phenoxybenzene Methyl) phenanthrene-2-carboxylate (330 mg, 80%, white solid). TLC: 50% EtOAc/oil shout, Rf: 〇·35. Analysis by LCMS (column: pur0Spher RP-18 (2.0 Xl00 mm, 2.1 μηι) 'Mobile phase: a : 5 mM CH3C02NH4, B : MeCN, time 157033.doc •271 - 201215604 (m In)/%B gradient: 0 min/3%, 1.5/45, 2.5/45, 3.2/95, 4.7/95, 5/3, flow rate: 0.6 mL/min, sample diluent: Me〇H): MH+ =626.8, tR=3.97 min ° *H NMR (400 MHz, CDC13): 7.41-7.35 (m, 5H), 7.27-7.26 (m, 1H), 7.22-7.14 (m, 2H), 7.10-7.08 (m , 2H), 6.98-6.95 (m, 2H), 5.39 (br, 1H), 4.09 (br, 1H), 3.90 (s, 3H), 3.70-3.58 (m, 8H). Step 4:

3-[(2,4-Dichlorobenzhydryl)-(2-morpholinyl-2-oxo-ethyl)amino]-5-(4-phenoxyphenyl)thiophene-2 - Formic acid. To 3-[(2,4-dioxaphenyl)-(2-morpholin-2-yloxy-ethyl)amino]-5-(4-phenoxy) at room temperature Phenyl) porphin-2-carboxylic acid vinegar (320 mg, 0.52 mmol) in 1:1 THF / water (20 mL) EtOAc (EtOAc) Stir for 16 hours "The progress of the reaction was monitored by TLC. Upon completion of the reaction, the mixture was acidified with EtOAc (EtOAc) (EtOAc) The organic layer was washed with water (3×20 mL) The crude residue 甩Et20 (2×5 mL) was triturated to give 152: 3-[(2,4-dichlorobenzhydryl)-(2-morpholin-2-yloxy-ethyl)amino] 5-(4-Phenoxyphenyl)thiophene-2-carboxylic acid (120 mg, 38%, white solid). TLC: 10% MeOH/CHCl3, Rf: 0.3. Borrowing 157033.doc • 272- 201215604 by LCMS (column: BEH C-18 (2.1xl〇〇mm, i.7 μιη), mobile phase: A: 5 mM CH3C02NH4 in water, Β : MeCN, time (min) /%B gradient: 〇min/3%, 1.5/45, 2.5/45, 3.2/95, 4.7/95 ' 5/3 ' Flow rate: 0.6 mL/min, sample diluent: MeOH): ΜΗ+=610· 8. tR = 2.37 min. 4 NMR (400 MHz, DMSO-d6): 13.5 (br s, interchangeable with D2 ;; iH), 7.57-7.53 (m, 3H), 7.44-7.36 (m, 4H), 7.31-7.29 (m, 1H) , 7.21-7.17 (m, 1H), 7.08-7.03

(m, 4H), 5.19-5.15 (m, 1H), 4.31-4.27 (m, 1H), 3.60-3.45 (m, 8H). Preparation of Compounds 93 and 94

Step 1: 5-(3,3-Dimethylbut-1-ynyl)_3_[(trans-4-methylcyclohexylcarbonyl b..." small [(3-oxa-6-azabicyclo[ 2.2.1]Heptane-6-carbonyl]propyl]amino acetal _2_ methyl formate. To (2S)-2-[[5-(3,3·didecylbut-1-ynyl) _2·曱Omino-3-ylphenyl]-(trans-4-indolylcyclohexylcarbonyl)amino]butyric acid (prepared as described for compound 82) (200 mg, 0.45 mmol) in DMF ( Diisopropylethylamine (311 μιη, 1.79 mm〇1), HBTU (339 mg, 0.89 mmol) and 6-oxa-3-gasheterobicyclo[2·2 i] were added to the solution in 5 mL) The mixture was stirred for 2 hours, then diluted with EtOAc. The solution was washed with H.sub.2 and brine. Evaporation solvent and product 157033.doc -273 - 201215604 with 0-50% EtOAc /hexanes were dissolved and purified by Shixi rubber column chromatography to obtain the desired product 5-(3,3-dimethylbutanyl)_3 [(anti-4 methylcyclohexyl H(lS)- L-[(3-oxaaza:cyclo^2g-glycosyl)propyl]amino]thiophene-2-carboxylic acid methyl ester. Step 2: The above obtained vinegar was dissolved in MeOH (3 mL) Add 1 n NaOH (1.34 mL) solution. Overnight 'then neutralized with 1 n HCl to pH = 3. The product was extracted (EtOAc) and concentrated. The two isomers were eluted with MeOH EtOAc EtOAc EtOAc EtOAc The material was purified by supercritical fluid chromatography (whelk-O, eluted with 8% MeOH/TFA, CO 2 ) to afford two isomers: Compounds 93 and 94. 94 to give the indicated structure. Compound 93: MS: m/z ( observed) 515.0 [M+H]+. Compound 94: MS: m/z (observed) 515.0 [PCT+11] + ;1111^]^ 11(300]^1^,€〇(:13)5 7.67-7.49 (d, 1H), 6.79-6.67 (d, 1H); 5.23-4.98 (m, 1H), 4.85-4.61 (m, 2H) , 4.42 (ddd, 1H), 4·11 (dd, 1H), 3.88-3.74 (m, 2H); 3.49 (dd, 2H); 2.14-1.82 (m, 3H); 1.77-1.39 (m, 7H) , 1.39-1.27 (m, 9H); 1.04-0.54 (m, 8H). Preparation of Compound 121

Step 1: 3-((2-Morphoyloxyethyl)amino)-5-phenylthiophene-2-carboxylic acid A 157033.doc -274- 201215604. 3-Bromo-5-phenyl-pyrene-2-carboxylic acid methyl vinegar (375 mg, 1.27 mmol), 2-amino-1-cylinyl ethyl ketone hydrochloride (344 mg, 1.91 mmol), Cs2C03 (l · 24 g, 3.81 mmol) suspension in toluene (10 mL) was degassed by bubbling 1 L of gas for 1 hour, and Pd(OAc) 2 (29 mg, 0.13 mmol), (±) was added. -BINAP (79 mg, 0·13 mmol). The purification was continued for another 30 minutes and the mixture was stirred at 100 ° C for 16 hours. The reaction process was monitored by TLC. Upon completion of the reaction, the~~~~~~~~~~~~~~ The filtrate was washed with water (2×35 mL) brine (30 mL). Purification of the residue by column chromatography ( 〇〇 〇〇 〇〇 石 ) )) using 30% EtOAc/Petroleum_ as the eluent to give 3-((2-morpholinyl-2- side oxygen) Methyl ethyl)amino)_5_phenylthiophene-2-carboxylic acid methyl ester (200 mg, 43.6%, white solid). TLC system: 50 〇/〇 EtOAc/petroleum ether, Rf: 〇·38. MS: m/z (observed) 361.0 [M+H]+. 4 NMR (400 MHz, CDC13) δ 7.73-7.71 (m, 2H), 7.49-7.40 (m, 3H), 7.35-7.33 (m, 2H), 4.25 (d, 2H), 3.75 (s, 3H), 3.65-3.58 (m, 4H), 3.50-3.49 (m, 4H). Step 2: 3-[(trans-4-methylcyclohexylcarbonylmorpholinyloxyethyl)aminopyridyl 5-phenylthiophene-2-carboxylic acid methyl ester. Here. 〇3~((2_morpholinyl-2-oxoethyl)amino)-5-phenylthiophene-2-carboxylic acid decyl ester (2〇〇mg, 0.55 mmol), Et3N (0.76 mL· , 5.55 mmol), in a solution of (:1120:12 (5 mL·), add trans-4-methylcyclohexylformamidine chloride (883 mg, 5.5 mm 〇1) in CH2C12 (5 mL) The solution was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. When the reaction was completed, the mixture was diluted with Et.sub.2Ac (80 I57033.doc - 275 - 201215604 mL), using 2 N HCl aqueous solution (2 x 30 mL), Wash with water (30 mL), 10% NaHCO3 (2.times.30 mL), brine (30 mL), dry over Na.sub.ss.ss.ssssssssssssssssssssssssssss -200 mesh oxime) purification of the residue to give 3-[(trans-4-indolylcyclohexylcarbonyl)-N-(2-morpholinyl-2-oxoethyl)amino]-5-phenyl Methyl thiophene-2-carboxylate (100 mg purified, 37.4%, white solid): EtOAc: EtOAc (EtOAc) 4 NMR (400 MHz, CDC13) δ 7.76-7.74 (m, 2H), 7.61 (s, 1 Η), 7.51-7.45 (m, 3 Η), 4.97 (d, 1 Η), 3.91 (d, 1Η), 3.81 (s, 3H), 3.55-3.39 (m, 8H), 2.18 (br s, 1H), 1.78-1.75 (m, 1H), 1.58-1.50 (m, 3H) ), 1.40-1.31 (m, 3H), 0.75 (d, 3H). Step 3: 3-[(trans-4-methylcyclohexylcarbonyl)·Ν-(2-morpholinyl-2-oxooxy) Ethyl)amino-5-phenylthiophene-2-carboxylic acid. 3-[(trans-4-methylcyclohexylcarbonyl)-N-(2-morpholino-2-yloxy) at room temperature Ethyl)amino]-5-phenylthiophene-2-carboxylic acid decyl ester (100 mg, 0.206 mmol) was added to a 1:1 mixture of THF and water (4 mL). The mixture was stirred for 16 hours. The reaction was monitored by EtOAc (EtOAc) (EtOAc) (EtOAc) Washed with brine (20 mL), dried over Na.sub.2SO.sub.sub.sub. ]-5-Phenylthiophene-2-carboxylic acid (70 mg, 72%, white solid). TLC system: 10% MeOH/CHCl3. Rf: 0.31. MS: m/z (observed) 469.0 [M+H]+. 4 NMR (400 MHz, CDC13) δ 157033.doc -276- 201215604 13.42 (br s, interchangeable with D2〇; 1 field, 7.73-7.72 («1,211), 7.57-7.41 (m,4H), 4.96 ( d, 1H), 3.93 (d, 1H), 3.55-3.40 (m, 8H), 1.23 (m, 4H), 0.75 (d, J = 6 Hz).

Compound 153 was prepared in a similar manner as described for compound 95. MS: m/z (observed) 473.3 [M+H]+. NMR (300 MHz, CDC13) δ 7.61 (s, 0.6H), 6.75 (s, 0.4H), 5.30 (br s, 0.6H), 5.08 (d, 0.4H), 4.00-3.61 (m, 1H) ), 3.39-3.13 (m, 1H), 3.09 (s, 1.2H), 3.05 (s, 1.8H), 2.23-1.39 (m, 14H), 1.34 (two single peaks, 9H), 0.75 (m, 5H). Preparation of compound 154

Compound 154 was isolated from a sample of compound 117 by palm chromatography on a Chiralpak-IC column using 0 1% TFA/MeCN. Ms: m/z (observed) 459.4 [M+H]+.咕NMR (3〇〇MHz, cDci3) § 6-84 (s, 1H), 3.80-3.48 (m, 2H), 3.36-3.15 (m5 1H), 3.05 (s, 3H), 2.65-2.35 (m, 1H), 2, 35-1.93 (m, 4H), 1.93-1.75 (m, 157033.doc -277- 201215604 2H), 1.74-1.45 (m, 4H), 1.35 (s, 9H), 0.84 (d, 3H), 0.77-0.63 (m, 1H). Preparation of Compound 10

Prepared according to the procedure of compound 14. Analysis by LCMS (LCMS method mll7: 60-98% MeOH; 5/7 min (gradient/operation) using phthalic acid modifier, 7 min, (C18)); RT = 5.56 min, MH+ = 487.48 ( Strong). Preparation of compound 11

Prepared according to the procedure of compound 14. Analysis by LCMS (LCMS method ml 17 : 60-98% MeOH; 5/7 min (gradient/operation) using citric acid modifier, 7 min, (C18)); RT = 5.5 min, ΜΗ+= 487. 5 (strong). Preparation of compounds Step 1: 157033.doc -278- 201215604

CAS -1027708-01-5

3-((lR,4R)-N-(2-(Tertidinoxy)-2-oxoethyl)-4-methylcyclohexylmethylamino)-5-iodothiophene-2 - Methyl formate. In a dry flask, guanamine (CAS-1027708-01-5) (1 g, 2.333 mmol) and THF (9.500 mL) were added and placed under nitrogen. Cool with an ice bath. (Bis(trimethylsulfonyl)amino)lithium (4.0 mL, 1 Torr, 2.916 mmol) was added and stirred at EtOAc for 25 min. T-butyl 2-bromoacetate (850 mg, 4.1 mmol) was added, and the reaction was warmed to ambient temperature and stirred at 5 ° C for 24 hours. Aqueous treatment was carried out and partitioned between brine and ethyl acetate to give EtOAc. Purified by silica gel flash chromatography. Ethyl acetate was used to dissolve the mixture with 〇 2 〇% (10 column volumes), followed by dissolution in 2% by weight of ethyl acetate (2 column volumes). The pure soluble fraction was obtained, and the solvent was removed to give 〇6 g solid 17-1: 3-((lR,4R)-N-(2·(Tertidinoxy)·2_sideoxyethyl) _4_methylcyclohexanecarbamamine) 5-iodothiophene-2-carboxylate (49% of theory). Analysis by LCMS (LCMS method mU7: 6 〇 98% MeOH; 5/7 min (gradient/operation), using formic acid modifier, 7 min, (C18)); RT = 5.42 min, MH+ = 522.16 (strong ). Step 2: 157033.doc -279- 201215604

TFA ^0····(&gt;〇Η 17-1

DCM xl l^s^C02Me 17-2 2-((lR,4R)-N-(5-Moth-2-(methoxyhistyl) phenan-3-yl)-4-methylcyclohexene Amine amino) acetic acid. Compound 17-1 (3.7 g ' 6.741 mmol) was dissolved in DCM (3 5 mL) and cooled to dryness using an external ice bath. TFA (15 mL, 194.7 mmol; 30% (TFA/DCM solution)) was added to this solution, allowing to slowly reach room temperature overnight as the ice bath melted. After stirring overnight, the reaction was tested by HPLC: the starting material was consumed. The solvent was removed under vacuum to give 2 g of reddish brown glass 17-2: 2-((lR,4R)-N-(5-iodo-2·(methoxycarbonyl)thiophen-3-yl)-4 -nonylcyclohexanecarbamamino)acetic acid (51% of theory). Analysis by LCMS (LCMS method mll7: 60-98% MeOH; 5/7 min (gradient/operation), using formic acid modifier, 7 min, (C18)); RT = 3.43 min, MH+ = 466.11 (strong ). Step 3:

Cul PdCI2(PPh3)2 dioxane

^Ο·&quot;〇0Η

2-((lR,4R)-N-(5-(3,3-dimethylbut-1-yn-1-yl)-2-(methoxycarbonyl) sold phen-3-yl)-4- Methylcyclohexanecarbamamino)acetic acid. 17-2 (2.5 g, 4.315 mmol) was mixed in a dry 100 mL flask under a nitrogen atmosphere at 157033.doc -280.201215604 alkane (54 mL) and cooled with an external ice bath and The nitrogen on the reactants was blown off. Copper oxide (41.18 mg, 0.2162 mmol) was added followed by 3,3-dimercaptobut-1-yne (800 μΐ^, 6.700 mmol) and was bubbled with air for 5 min. Dichloro-bis(triphenylphosphino)palladium (164.9 mg, 0.2343 mmol) was added, then the bath was removed and the reaction was stirred at room temperature overnight. The reaction was the opposite; and TLC (20% MeOH / DCM). Show that the reaction is complete. Purified by the addition of EtOAc (50 mL), EtOAc (EtOAc (EtOAc) The fractions were combined and the solvent was removed to give a white solid. The solid was dissolved in ethyl acetate and washed with aq. 1N EtOAc (EtOAc) EtOAc. EtOAc. ((lR,4R)-N-(5-(3,3-Dimercapto-1-yn-1-yl)-2-(methoxycarbonyl)thiophen-3-yl)-4-indolyl ring Hexanecarbamido)acetic acid. Analysis by LCMS (LCMS method mll7: 60-98% MeOH; 5/7 min (gradient/operation), using phthalic acid modifier, 7 min, (C18)); RT = 4.63 min, ΜΗ+=420 · 36 (strong). Step 4:

3-((lR,4R)-N-(2·(diethylamino)-2·sideoxyethyl)-4-methylcyclohexanecarbamamino)-5-(3,3- Methyl dimercapto-1-yn-1-yl)thiophene-2-furoate. 157033.doc -281- 201215604 Compound 17-3 (290 mg, 0.6912 mmol) and HBTU ( 1.659 mL, 0.5 Μ, 0.8294 mmol) (0.5 M solution in DMF, prepared in advance and stored in a freezer) Put them together in a vial. DIEA (134.0 mg, 180.6 pL, 1.037 mmol) was added followed by diethylamine (61.45 mg, 72.12 m, 0.8 640 mmol) and the mixture was stirred at room temperature overnight. The completion of the reaction was checked by HPLC and LCMS. Aqueous treatment with brine (60 mL), EtOAc (EtOAc) (EtOAc) It was purified by flash chromatography on a silica gel column 12 eluting with 0-50% ethyl acetate-hexane. The solid product 17-4: 3-((1 ft, 411)-:^-(2-(diethylamino)-2-oxoethyl)-4-mercaptocyclohexane was obtained. Methylamino)-5-(3,3-dimercapto-1-yn-enyl)thiophene-2-furic acid methyl ester. Analysis by LCMS (LCMS method m21 7 : 60-98% acetonitrile; 5/7 min (gradient/operation) using formic acid modifier, (C4)); RT = 2.33 min, MH+ = 473.47 (strong). Step 5:

Compound 17. Starting material 17-4 (90 mg, 0.189 mmol) was combined with 2N sodium hydroxide (5 mL, 10 mmol) and stirred overnight. The completion of the reaction was judged by HPLC using the disappearance of the starting material. The methanol was removed under vacuum. Add 15 mL of 1 N HCl (aq) and 15 mL of brine. Extracted with 2x3 0 mL 1:1 EtOAc (EtOAc) (EtOAc) (EtOAc) Purification using HPLC (C18, 40-95% CH3CN/H20; 0.1% TFA), mp. Analysis by LCMS (LCMS method m21 7 : 60-98% acetonitrile; 5/7 min (gradient/operation), using formic acid modifier, (C4)); RT = 1.87 min, MH+ = 461.44 (strong). Preparation of compound 25

Prepared according to the procedure of compound 17. Analysis by LCMS (LCMS method m208: 40-80% MeOH; 5/7 min (gradient/operation), using formic acid modifier, 7 min, (C18)); RT = 3.53 min, MH+ = 489.1 (strong ). Preparation of Compound 27

Prepared according to the procedure of compound 17. Analysis by LCMS (LCMS method m208: 40-80% MeOH; 5/7 min (gradient/operation) using phthalic acid modifier, 7 min, (C18)); RT = 4.76 min, ΜΗ+=503 · 10 (strong). Preparation of Compound 28 157033.doc -283 - 201215604

Prepared according to the procedure of compound 17. Analysis by LCMS (LCMS method m208: 40-80% MeOH; 5/7 min (gradient/operation) using phthalic acid modifier, 7 min, (C18)); RT=3.21 min, MH+=461.06 ( Strong). Preparation of Compound 41

Prepared according to the procedure of compound 17. Analysis by LCMS (LCMS method m208: 40-80% MeOH; 5/7 min (gradient/operation), using phthalic acid modifier, 7 min, (C18)); RT=4.12 min, ΜΗ+=503 · 10 (strong). Preparation of Compound 42 42

Prepared according to the procedure of compound 17. Analysis by LCMS (LCMS method m21 7 : 60-98% acetonitrile; 5/7 min (gradient/operation) using formic acid modifier, (C4)); RT = 2.30 min, ΜΗ+=474·94 ( Strong). 157033.doc - 284- 43 201215604 Preparation of compound 43

0 Prepared according to the procedure of Compound 17. Analysis by LCMS (LCMS method m2 17 : 60-98% acetonitrile; 5/7 min (gradient/operation) using citric acid modifier, (C4)); RT = 3.34 min, MH+ = 502.99 (strong) . Preparation of Compound 44

Prepared according to the procedure of compound 17. Analysis by LCMS (LCMS method m21 7 : 60-98% acetonitrile; 5/7 min (gradient/operation) using citric acid modifier, (C4)); RT = 3.5 min, MH+ = 502.99 (strong) . Preparation of Compound 45

Prepared according to the procedure of compound 17. Analysis by LCMS (LCMS method m21 7 : 60-98% acetonitrile; 5/7 min (gradient/operation), using citric acid to change 157033.doc -285 - 201215604, (C4)); RT = 3.8 min , ΜΗ+=474·96 (strong). Preparation of compound 46 Ό.

Prepared according to the procedure of compound 17. Analysis by LCMS (LCMS method m217: 60-98% acetonitrile; 5/7 min (gradient/operation) using formic acid modifier, (C4)); RT = 3.8 min, MH+ = 472.62 (strong). Attack compound 97

This compound was prepared according to the procedure of Compound 14. Analysis by LCMS (LCMS method mll7: 60-98% MeOH; 5/7 min (gradient/operation), using formic acid modifier, 7 min, (Cl8)); RT = 5.30 min, MH+ = 489.47 (strong ) ° Preparation of compound 98

157033.doc -286 201215604 This compound was prepared according to the procedure of compound 14. Analysis by LCMS (LCMS method mll7: 60-98% MeOH; 5/7 min (gradient/operation), using formic acid modifier '7 min, (C18)); RT = 5.22 min, MH+ = 447.43 (strong ). Preparation of Compound 96

Step 1: (8) _3-((4-(Tertidinoxy)-4-oxobutan-2-yl)amino)-5-(3,3-dimethylbut-1-yne Methyl 1-thio)-2-carboxylate. Methyl 3-bromo-5-(3,3-dimercapto-1-yn-1-yl)thiophene-2-carboxylate (4.73 g, 15-70 mmol), (3S)-3-aminobutyric acid A suspension of tributylidene (2.5 g, 15.70 mmol) and acid-depleted (15.35 g '47.10 mmol) in 1,4-dioxane (79 mL) was degassed with a nitrogen stream for 30 min. Pd2(dba)3 (719 mg, 0.79 mmol) and S-phos (645 mg' 1.57 mmol) were added and the mixture was placed in a sealed tube at 9 Torr. Underarm heating up overnight. The reaction mixture was diluted with DCM and filtered over EtOAc. The filtrate was concentrated and purified by flash chromatography (EtOAc / hexane) to afford (S)-3-((4-(t-butoxy)-4-oxobutan-2-yl)amino)- 5-(3,3·Dimethylbut-1-yne-157033.doc •287- 201215604 1-base) sinter-2-carboxylic acid methyl vinegar (5·5 g, 92%). Ms: ▲ (〇bs): 38〇 3 [M+H]+. Step 2: 3-((trans)^M(S)-4-(t-butoxy)_4_sideoxybut-2-yl)4methylcyclohexanecarbamamino)-5-(3 , 3_dimethylbutanyloxy)thiophene-2-carboxylic acid formazan. To (S)-3-((4-(Tertidinoxy)_4 oxobutan-2-yl)amino)-5-(3,3--indenyl-i-alkyne Add pyridine (5) to thiophene-2-methyl formate (5 5 g, 14.49 mmol) and trans-4-methylcyclohexane chlorobenzene (3 49 g, 21 74 mmol) in DCE (145 mL) % agency, 72 45 mmol). The reaction was stirred overnight at 9 (rc) in a sealed tube. 2 g of trans- 4-methylcyclohexanecarbazide was then added, followed by 2 mg of DMAp. The reaction mixture was stirred again at 90 ° C overnight. Diluted with DCM, followed by EtOAc (EtOAc m.). Butyl-2-yl&gt; 4-methylcyclohexane decylamino)-5-(3,3-dimethylated-1-n-1-yl)thiophene-2-carboxylic acid methyl ester (4.5 g, 61.7 %).MS: m/z (obs): 504.3 [M+H], Step 3: (S)-3-((trans)-N-(5-(3,3-di-T-butan-1- Alkyn-1-yl)-2-(methoxybenzyl)porphin-3-yl)-4-methylcyclohexanecarbamamino)butyric acid. To contain 3_((anti)_N_((S) -4-(Tertibutoxy)_4_Sideoxybutan-2-yl)-4-methylcyclohexanecarbamamino)-5·(3,3-dimercapto-indenyl) To a solution of methyl thiophene-2- decanoate (4.5 g, 8.93 mmol) in EtOAc (EtOAc)EtOAc. Co-evaporation with DCM (3x20 157033.doc -288- 201215604 mL) and dry under vacuum Overnight, (s)_3_((trans)_n_(5-(3,3-dimethylbut-1-yne·1·yl)-2-(methoxycarbonyl)thiophene-3-yl) 4 methyl ring was obtained. Hexanemethionine)butyric acid (4.7 g, quantitative).ms: m/z (obs): 448.0 [M+H]+. Step 4: 3- ((trans)-N-((S)- 4-(Dimethylamino)·4_sideoxybut-2-yl)-4-methylcyclohexylmethylamino)-5-(3,3-diylbuty-1-block_ 1_base) porphin-2·methyl formate. Contains (S)-3-((trans)-N-(5-(3,3-didecylbutyn-1-yl)_2_ _ (methoxy a few groups of thiophene)-4-methylcyclohexylamino-butyric acid (400 mg, 0-89 mmol), EDC (257 mg, 1.34 mmol), H0Bt (181 mg &gt; 1.34 mmol) and Add dimethylamine (4.47 mL, 8.94 mmol, 2 M in THF) to EtOAc (EtOAc). Washed with HCl and sodium bicarbonate. The organic layer was dried, evaporated and purified <jjjjjjjjjjjjjjjjj - 4-oxobutan-2-yl)-4-methylcyclohexanecarbamamine)_5_(3,3-dimethylchundin-1-fast-1- ) 0-thiophene carboxylic acid Yue _2_ ester (175 mg, 41.3. /〇). MS: m/z (obs): 475.3 [M+H]+. Step 5: 3-((Re)-N-((S)-4-(dimethylamino)_4-oxobutan-2-yl)-4-methylcyclohexanecarbamyl) -5-(3,3-Dimethylbutane-acetylene)-thiophene-2-carboxylic acid. To contain 3-((trans)-N-((S)-4-(didecylamino)_4_sideoxybutane 2_*)_4·nonylcyclohexanecarbamamine)_5-( 3,3-Dimercapto-1-yn-1-yl-1-yl)thiophene-2-yl decanoate (170 mg '〇·36 mm〇i) in THF (3 mL) and water (1 mL) 157033. Doc -289- 201215604 Adds monohydrated nitrogen oxides (75 mg' 179 _〇1). The reaction mixture was stirred overnight, acidified with 1 M HCl, and the organic solvent was removed. The precipitate obtained in the furnace was washed with water and dried under vacuum to give %: 3 ((trans)-N-((S)-4-(didecylamino)-4 4 oxetyl-2-yl ) _4 methylcyclohexanylamino)·5-(3,3-dimercaptobutyl)·block phene-2-carboxylic acid (1) 〇mg, 66, 7%). Purple compound 101, 102, 103

Step 1: After 3-((t-butoxy)amino)butyl. Add Boc_ anhydride to 3-aminobutyric acid (14.4 g, 139.0 mmol) in a solution of Q 5 M aqueous sodium hydroxide and 1,4-dioxane (1:1 mixture, 46 mL) 3〇47 〇丄 "5 y · b mmol". The reaction was stirred at room temperature overnight, concentrated to remove organic solvent and extracted with EtOAc (2.times.25 mL). The combined organics were dried and concentrated to give 3-((t-butoxycarbonyl)amino)butyric acid (25 3 g, Step 2: (4- s-oxy-4-(pyrrolidin-1-yl) _2-yl) tert-butyl carbazate. To 3-((t-butoxycarbonyl)amino)butyric acid (165 g, 8l 2 ° v & 丄z rnmol), 157033.doc -290· 201215604 EDC (1.71 g, 8.93 mmol) & H〇Bt (12i g, 8 93 _〇1) was added triethylamine (3 4 〇mL, 24.36 mmol) to a mixture in DMF (40 mL), then added Pyrrolidine (746 g L, 8.93 mmol). The reaction mixture was stirred at room temperature for several days, diluted with water (4 mL) and extracted with EtOAc (3 &lt;&lt; Subsequent washing with saturated sodium bicarbonate solution, followed by drying and concentration to give (4-dioxy-4-(pyrrolidin-1-yl)butan-2-yl)carbamic acid tert-butyl ester (76 mg, 36.5%) Step 3: 3-Amino-1-("pyrrolidine-1-yl)butan-1-indole hydrochloride. (Pentyloxy_4_(D-r-pyridin-1-yl) Butyl-2-ylaminocarbamic acid tert-butyl ester (76 mg, 2.96 mmol) dissolved in 1,4-dioxalate (5 mL '4.0 Μ) of HC1 Treated and stirred overnight at room temperature. The reaction mixture was concentrated to dryness to give 3-amino-l-(1 -1 -1 -1 -1 -yl)butan-1-one (570 mg, Quantitative) Step 4: 5-(3,3-Dimethylbut-1-yn-1-yl)-3-((4-trioxy-4-(pyrrolidinyl)-yl) Methyl-amino)thiophene-2-carboxylate. 3-Bromo-5-(3,3·dimethylbutyridin-1-yl)°Cet-2-carboxylic acid 曱g (782 mg , 2.60 mmol), 3-amino-1 -(p-pyrrolidine-1-yl)butan-1-one hydrochloride (500 mg, 2.60 mmol) and carbonic acid (2.54 g, 7.79 mmol) The suspension in 1,4-di 11 methane (13 mL) was degassed with a stream of nitrogen for 30 minutes. Pd2(dba)3 (119 mg, 0.13 mmol) and S-Phos (107 mg, 0-26 mmol) were added and The reaction mixture was heated in a sealed tube at 90 ° C for 48 hours. The crude reaction mixture was transferred to celite, succinated to dryness and purified by flash chromatography (EtOAc / EtOAc) to yield 5- (3, 3-二157033.doc -291 · 201215604 methylbut-1-yn-1-yl)-3-((4-o-oxy-4-(pyrrolidin-4-yl)butan-2-yl)amino ) 叹 -2- -2- methyl formate (42 〇 mg, 43 〇 0 / 〇). MS: m/z (〇bs): 377.3 [M+H], Step 5: 5 (3,3--methylbut-1-yne_i_yl) ((trans)_4-methyl_N_( 4_Sideoxy·4·(pyrrolidin-1-yl)butan-2-yl)cyclohexanecarbamoylamino)thiophene-2-carboxylic acid methyl ester. To the methyl 5-(3,3-dimercapto-1 -yne d-yloxy-4-4(pyrrolidinyl)butan-2-yl)amine) 42〇mg, j 12 _〇1) Add anti-___methylcyclohexane formazan (Iv79 mg, 1.12 mmol) to a solution in dCE (7 mL). Add pyridine (9 〇, 1 The reaction mixture was stirred at 90 ° C EtOAc (EtOAc m. _ dimethylbutyrynyl)3_((trans)-4-methyl-N-(4-olyl-4-yl(pyrrolidinyl)-butanyl)cyclohexanecarboxamide Methyl thiophene-2-carboxylate (21 〇mg, 37 6%) MS: m/z (obs): 501.4 [M+H]+. Step 6: Compounds 101, 102, 103. ,3_Dimethylbutyne small group) 3_((trans)-4.indolyl-N-(4-sideoxy_4_(pyrrolidinyl)-butan-2-yl)cyclohexane Addition of lithium hydroxide monohydrate (i76 mg, 4-19 mmol) to a solution of guanidino)thiophene-2-carboxylate (21 mg, 〇42 mm 〇1) in THF (3 mL) and water (1 mL) The reaction mixture was stirred overnight at room temperature and allowed to 6 M HCI acidification. The organic solvent was removed and the resulting precipitate was filtered, washed well with water and dried to give racemic 5-(3,3-dimercapto-indole-alkynyl)^ 157033.doc - 292. 201215604 ((Reverse)-4-methyl-N-(4-olyl-4-(°pirindol-1-yl)but-2-yl)cyclohexanyl)thiophene -2-decanoic acid 101 (121 mg, 59.3%). A portion of the racemic material (90 mg) was then separated into two enantiomers 102 and 103 by supercritical fluid chromatography (SFC). Compound 105

5-(3,3-Dimethylbut-1-ynyl)-3-[(trans-4-methylcyclohexylcarbonyl)-[(lS)-l-methyl-3-merinyl-3 -Sideoxy-propyl]amino]porphyrin-2-carboxylic acid. Prepared according to the procedure of Compound 101. Preparation of Compound 106

H,C 5-(3,3-Dimethylbut-1-ynyl)-3-[(trans-4-methylcyclohexylcarbonyl)-[(lR)-l-fluorenyl-3-morpholine 3-Benzyloxy-propyl]amino]thiophene-2-carboxylic acid. Prepared according to the procedure of Compound 101.

Preparation of Compound UQ 157033.doc •293 - 201215604

5-(3,3-Dimethylbut-1-ynyl)-3-[(trans-4-methylcyclohexylcarbonyl)-[(lS)-l-methyl-3-(4-methyl)派&quot;桊-l-yl)-3-sideoxy-propyl]amino] 叹 -2-2 -carboxylic acid. Prepared according to the procedure of compound 96. Preparation of compound 111

CH, 5-(3,3-Dimethylbutan-1-yl)-3-[[(lS)-3-(ethylamino)-1_methyl-3-oxo-propyl] -(trans-4-methylcyclohexylcarbonyl)amino]thiophene-2-furoic acid. Prepared according to the procedure of compound 96. Preparation of Compound 113

5-(3,3-Dimethylbut-1-ynyl)-3-[(trans-4-methylcyclohexylcarbonyl)-[(lS)-l-methyl-3-[methyl-( 1-Methyl-4-piperidinyl)amino]-3-oxo-propyl]amine 157033.doc -294- 201215604 base] porphin-2-carboxylic acid. Prepared according to the procedure of compound 96. Preparation of Compound 114

5-(3,3-Dimethylbut-1.ynyl)-3_[[(ls)_3_[2.methoxyethyl(methyl)amino M-methyl-3-oxo- Propyl (anti-4_methylcyclohexyl)amine group]

Sighing -2-carboxylic acid. Prepared according to the procedure of compound 96.

Preparation of compound 11S

5-(3,3-dimethylbutan-1-alkynyl)_3_[[(1s)_3_(4-methoxypiperidinyl)-1-methyl-3-oxopropyl]]( Anti-4-methylcyclohexylcarbonyl)amino]thiophenecarboxylic acid. Prepared according to the procedure of compound 96. Preparation of compound U6 h3c,

157033.doc 201215604 5-(3,3-Dimercapto-1-ynyl)_3_[[(1s)-3_(3methoxyazetidin-1-yl)-1-methyl- 3-Sideoxy-propyl] (trans-4 methylcyclohexylcarbonyl)amino] thiophene-2-carboxylic acid. Prepared according to the procedure of compound 96. Preparation of Compounds 21 and 22

3-[[(lS)-2-(dimethylaminomethoxymethyl)_2_ oxo-ethyl b (trans-4-methylcyclohexylcarbonyl)amine b) 5_(3 3_ Dimethylbutynyl)thiophene-2-carboxylic acid and 3-[[(lR)-2-(dimethylamino)(methoxymethyl)_2-sideoxy-ethyl]-(anti- 4-Methylcyclohexylcarbonyl)amino]·5-(3,3-:methylbutynyl)thiophene-2-carboxylic acid. Separation of the two enantiomers using SFC under the following conditions: column: Whelk-〇 (l〇x250); mobile phase: 15% EtOH, 850/〇C02; flow rate: 10 mL/min; pressure: 100 bar . Preparation of Compound 24

3-[Cyclohexylcarbonyl-[(1S)-1_(decyloxymethyl)_2_morpholinyl-2·sideoxy-ethyl]amino]-5-(3,3-dimethylbutyl) _1_Alkynyl) porphin_2_carboxylic acid. According to

Prepared by the procedure described for compound 23. lCMS: 353.3 (MH+). 4 Nly[R (300 MHz, DMSO) δ 13.43 (s, 1H), 7·28 (s, 0.5H), 7.07 (s, 157033.doc •296· 201215604 0.5H), 5.83 (t, J=7.2 Hz, 0.5H), 5.41 (t, J = 6.7 Hz, 0.5H), 3.79-2.89 (m, 14H), 2.11-1.00 (m, 17H), 0.87-0.39 (m, 4H). Preparation of Compound 36

3-[Cyclohexylcarbonyl-[(lS)-l-(methoxymethyl)-2-yloxy-2^pyrrolidin-1-yl-ethyl]amino]-5-(3, 3-Dimethylbut-1-ynyl)thiophene-2-carboxylic acid. Prepared according to the procedure described for compound 23. LCMS: 489.34 (MH+). 4 NMR (300 MHz, DMSO) δ 13.35 (brs, 1H), 7.34 (s, 0.4H), 7.02 (s, 0.6H), 5.60 (t, 0.4H), 5.18 (t, 0.6H), 3.77- 2.81 (m, 10H), 2.13-0.80 (m, 23H) ° Preparation of compound 63

5-(3,3-Dimethylbut-1-ynyl)-3-[(4-ethylcyclohexylcarbonyl)-[(lS)-l-(methoxyindolyl)-2 - side oxygen Base-2 - ^Bilo bite-1 -yl-ethyl]amino]porphin-2-indole. Prepared according to the procedure described for compound 23. LCMS: 517.36 (MH+). H NMR (300 MHz, CDC13) δ 7.64 (s, 0.4H), 6.85 157033.doc 297· 201215604 (s, 0.6H), 5.36 (dd, 0.4H), 5.02 (t, 0.6H), 4.00- 3.15 (m, 10H), 2.13-0.98 (m, 24H), 0.96-0.43 (m, 4H) ° Preparation of compound 68

5-(3,3-Dimethylbut-1-ynyl)-3-[[(lS)-l-(didecylaminomethane)butyl]-(trans-4-methylcyclohexane Carbonyl)amino]thiophene-2-carboxylic acid. Prepared according to the procedure described for compound 23. LCMS: 475.33 (MH+); 4 NMR (300 MHz, CDC13) δ 7.60 (s, 0.4H), 6.74 (s, 0.6H), 5.32 (dd, 0.4H), 5.07 (dd, 0.6H), 3.39 ( s, 3H), 3.10-2.94 (m, 4H), 2·14-1·22 (m, 29H) ° Preparation of Compound 99

3-[[3·(Dimethylamino)-1-methyl-3-oxo-propyl]-(trans-4-methylcyclo157033.doc - 298 - 201215604 hexylcarbonyl)amino] -5-(3,3-Dimethylbut-1-ynyl)thiophene-2-carboxylic acid. Prepared according to the procedure described for compound 23. LCMS: 459.59 (MH+). *H NMR (300 MHz, DMSO) δ 13.5 (br, 1 Η), 7.60 (s, 0.6H), 7.35 (s, 0.4H), 5.01-4.95 (m, 0.6H), 4.65-4.49 (m, 0.4 H), 3.65 (br, 0.4H), 3.25 (br, 0.6H), 3.00 (s, 1.8H), 3.85 (s, 1.2H), 2.80 (s, 1.2H), 2.75 (s, 1.8H) , 2.60-1.75 (m, 2H), 1.60-1.12 (m, 8H), 1.30 (s, 9H), 0.85 (d, 3H), 0.75 (d, 3H), 0.65-0.50 (m, 1H). #制备化合物104

5-(3,3-Dimercapto-1-ynyl)-3-[(trans-4-methylcyclohexylcarbonyl)-(2-methyl-3-morpholino-3-yloxy) -propyl)amino]thiophene-2-carboxylic acid. Prepared according to the procedure described for compound 23. LCMS: 503.35 (MH+). 4 NMR (300 MHz, CDC13) δ 6.94 (s, 0.5H), 6.80 (s, 0.5H), 4.07-3.95 (m, 1H), 3.75-3.33 (m, 10H), 2.15-2.01 (m, 1H) ), 1.73-1.40 (m, 7H), 1.32 (s, 9H), 1.13-1.02 (m, 3H), 0.80 (d, 3H), 0.80-0.60 (m, 2H) ° 157033.doc -299- 201215604 Preparation of Compounds 108 and 109

5-(3,3·Dimethylbut-1-ynyl)_3_[(trans-4.methylcyclohexylcarbonyl)-[(2s)_2_methyl-3-morpholinyl-3-sideoxy _propyl]amino]thiophene-2-carboxylic acid and s_(3,3-dimethylbutyr-1-ynyl)-3-[(trans-4-methylcyclohexylcarbonyl)-[(2R)_2_ Methyl 3- 3-morpholinyl-3-oxo-propyl]amino] thiophene-2-carboxylic acid. Separation using SFC under the following conditions: column: whelk-O (10x250); mobile phase: i5〇/0 EtOH, 85% C〇2; flow rate: 1 〇 mL/min; pressure: 1 〇〇 bar. Preparation of Compound 107

5-(3,3-dimethyl butyl small alkynyl) 3 [(anti- 4 methylcyclohexylcarbonyl b)

0.5H), 4.35-4.23 k ) Amino] porphin-2·carboxylic acid. According to the combination. LCMS: 445.25. 4 NMR (3〇〇 MHz, [), 5.57-5.34 (m, 0.5H), 3.85-3.61 (m, 1H), 3.33-3.00

Preparation of the compound, ..., 2.15 - 1.85 (m, 1H), 1.70 - 1.45), 0.80 - 0.60 (m, 5H) ° 157033.doc 201215604

3-[[2-丨2-Dimethylaminoethyl(methyl)aminophenyl 2_sideoxy-ethyl](trans-4-methylcyclohexylcarbonyl)amino]-5-( 3,3-Dimercapto-i-alkynyl)thiophene-2-carboxylic acid. Prepared according to the procedure described for compound 6 [CMS: 490.23 (MH+). * NMR (300 MHz, CDC13) δ 6.98 (s, 1 Η), 4.92_ 4.15 (m, 5H), 3.65-2.73 (br, 10H), 2.35-2.21 (m, 1H), 1.73- 1.50 (m, 5H), 1.32 (s, 9H), 1.33-1.22 (m, 2H), 0.85 (d, 3H), 0.80-0.60 (m, 2H) ° Preparation of Compound 119

5-(3,3-dimethylbut-1-ynyl)_3_[(trans_4_methylcyclohexylcarbonyl)-[2_(4-methylpiperazin-1-yl)-2-oxanoxy Base-ethyl]amino] thiophene-2-carboxylic acid. Prepared according to the procedure described for compound 6. [CMS: 488.25. NMR (300 MHz, DMSO) δ 7.20 (s, 1H), 3.55-2.71 (m, 8 Η), 3.45 (s, 3 Η), 2.75 (s, 2H), 2.15-2.05 (m, 1H), 1.63-1.50 (m, 5H), 1.32 (s, 9H), 1.33-1.22 (m, 2H), 0.75 (d, 3H), 0.70-0.60 (m, 2H). 157033.doc 201215604 Preparation of compound 120

5-(3,3-dimethylbut-1-ynyl)-3-[(trans-4-methylcyclohexylcarbonyl)_[(3s)-2-sideoxy&quot;Λ洛 bit-3 -yl]amino]porphin-2-carboxylic acid. Prepared according to the procedure described for compound 23. LCMS: 431.24 (ΜΗ+). ^ NMR (300 MHz, CDC13) δ 7.04 (s, 1H), 6.59 (d, J=5.5 Hz, 1H), 4.67 (dd, J=14.7, 9.8 Hz, 1H), 3.97-3.78 (m, 1H) , 3.68 (t, J=8.7 Hz, 1H), 2.90-2.71 (m, 1H), 2.23-1.67 (m, 7H), 1.61-1.38 (m, 2H), 1.32 (s, 9H), 1.03-0.82 (m, 5H). Preparation of Compound 100

OH 3_[[(1R)_3-(dimethylamino)-1-methyl-3-oxo-propyl]-(trans-4-methylcyclohexylcarbonyl)amino]-5-( 3,3-Dimethylbut-1-ynyl)thiophene-2-carboxylic acid. Separation using SFC under the following conditions: column: Whelk-0 (10x250); mobile phase: 15% EtOH, 85% C02; flow rate: 10 mL/min; pressure: 100 bar. Preparation of Compound 55 157033.doc •302· 201215604

Step 1: l_((lR,4R)-3-Phenyl-4-indolylcyclohexyl)ethanone. Odor was bubbled through the underarms (2R,5R)_5·isopropenyl-2-methyl-cyclohexanol (5 g, 32.4 mmol commercially available 25.75/〇 epimerization mixture to (1R) )·Alcohol based) A solution of DCM (140 mL) and Me〇H (3 mL) until the solution turned blue (30 min, via a sintered diffuser). Excess ozone was flushed with oxygen (5 min). Dimethyl thioether mL, i37 was added at the same temperature and the reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was concentrated and the obtained oil was purified eluting eluting eluting eluting eluting eluting eluting ^ • Benzyl-4-methyl-cyclohexyl]ethanone (4.23 g, 84%, colorless oil). The product was used in the next step without further analysis. Step 2: (lR,4R)-3-hydroxy-4-methylcyclohexanecarboxylic acid. Bromine (14.3 g' 89.4 mmol) was added to an ice-cooled solution of NaH (14.1 g, 352 mmol) in water (120 mL) and 1,4-dioxane (90 mL). To the obtained yellow solution, l_((lR,4R)-3-carbyl-4-mercaptohexyl)ethyl ig (4.23 g, 27.1 mmol) was added dropwise to dioxo (200 mL) and water (54 mL) The solution in ). The resulting solution was stirred at 1 〇 157 033.doc - 303 - 201215604 15 ° C for 3 hours. Excess NaOBr was decomposed by the addition of sodium sulfite solution (3.3 g in 30 mL of water), acidified with 10% HCl and extracted with DCM. The combined organic extracts were washed with brine, dried and concentrated to give (l,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 3-Ethyloxy_4_methylcyclohexanecarboxylic acid. Add (1,4R)-3-hydroxy-4-methylcyclohexane decanoic acid (4 17 g, 26 4 mmol) to the solution in DCM (120 mL). g, 158 mmo 1), acetic anhydride (10·8 g '1〇5 mm〇i). The reaction mixture was stirred at room temperature for 15 hours. The solvent was removed in vacuo and aq. 3N EtOAc (25 mL). The reaction mixture was stirred for 30 minutes, then a saturated aqueous solution of NaHCO (500 mL) was slowly added until the mixture reached pH 9-10. This solution was then extracted with EtOAc (2×l 50 mL). The aqueous phase was acidified with aq. EtOAc (EtOAc) The combined organic layers were dried with EtOAc EtOAc EtOAc EtOAc Step 4: Acetic acid (2R,5R)-5-(gas carbonyl)-2-methylcyclohexyl ester. Add DMF (2 drops) to a solution of (ir,4R)-3-(ethyloxy)-4-methylcyclohexanonecarboxylic acid (666 mg, 3.33 mmol) in DCM (13 mL) Ethyl dichloride (464 mg, 3.66 mmol) was carefully added under ice-cooling. Remove the ice bath after 5 minutes. After a further 4 hours, the reaction mixture was concentrated and the residue was used directly in the next step. Step 5: 5-(3,3-Dimethylbutan-1-yl)-3-((1 R,4R)-3-(ethyloxy)-4-methyl-N-(2-淋 基 -2- 侧 侧 侧 侧 侧 侧 157 157 157 157 157 157 157033.doc • 304· 201215604 methyl ester. The round bottom flask was fed with 5-(3,3-dimercaptobut-1-ynyl)-3-[(2-morpholinyl-2-oxo-ethyl)amino]thiophene- 2-Carboxymate (606 mg, 1.66 mmol) in DCE (24 mL), (2R,5R)-5-(chlorocarbonyl)-2-methylcyclohexyl ester (727 mg, 3.33 mmol), then fed Pyridine (1.97 g, 24.9 mmol) and DMAP (10 mg, 0.083 mmol) were added. The solution was refluxed overnight. Water and brine were added and the mixture was extracted twice with EtOAc. The combined organic layers were washed twice with 1N aqueous HCl solution and 1N aqueous NaOH solution, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (100-200 mesh eluting eluting with 50% EtOAc/hexanes as solvent) to give 5-(3,3-dimethylbut-1-ynyl)-3- ((lR,4R)-3-(ethyloxy)-4-methyl-N-(2-morpholinyl-2-oxoethyl)cyclohexaneguanidino)thiophene-2- Formate (347 mg, 38%). TLC system: 50% EtOAc / hexanes, Rf: 0.27. MS: m/z (observed) 547.31 [M+H]+. Step 6: Compound 55. 5-(3,3-Dimercapto-1-ynyl)-3-((lR,4R)-3-(ethyloxy)-4-methyl-N-(2-morpholinyl) -2-Ethyloxyethyl)cyclohexanecarbamimidyl) thiophene-2-carboxylic acid methyl ester (347 mg '0.635 mmol) dissolved in MeOH (3 mL) & 2 N aqueous EtOAc (3 mL, EtOAc The mixture was stirred overnight at room temperature. Add brine (6 mL), 1 N aqueous HCl (7 mL) and water (10 mL). The mixture was extracted with EtOAc, dried over Naz. The residue was purified by Gilson preparative HPLC [gradient: 40°/. Solvent b to 70. /. Solvent B, B = MeCN (containing 0.1% TFA); A = water (containing 〇.1 〇 / 〇 TFA + 1% MeCN) was purified to give 55 (198 mg, 63%, white solid). Preparation of Compound 71 157033.doc -305- 201215604

Step 1: 5-(3-Methylbut-1-ynyl)-3-((lR,4R)-4-methylcyclohexanecarbamoylamino)thiophene-2-carboxylic acid methyl ester. A 10-μmL 2-neck round bottom flask was fed with methyl 5-iodo-3-[(trans-4-indolylcyclohexylcarbonyl)amino]thiophene-2-indole (2.85 g '7.01 mmol) under nitrogen. ), DMF (28 mL) and triethylamine (2.13 g, 2.93 mL, 21.0 mmol). 3_Mercapto-i-yne (4 mL), copper (1) (200 mg, 1.05 mmol) and PdCl2 (PPh3) 2 (98 mg, 0.14 mmol) were added rapidly. After one day, EtOAc and water were added to the reaction mixture. The mixture was filtered through diatomaceous earth' and the layers were separated. The aqueous layer was re-extracted with EtOAc (EtOAc)EtOAc. Use 5. / 〇 EtOAc / hexane as a dissolving agent, purified by column chromatography (ioo soo) to give 5-(3-mercaptobut-1-ynyl)-3-((lR,4R)- Methyl 4-cyclohexanecarbamamino)thiophene-2-carboxylate (1.78 g, 73%, off-white solid). MS: m/z (observed) 348 [M+H]+. Step 2: 3-((lR,4R)-N-(2-Tertioxy-2-oxoethyl)-4-methylcyclohexylmethylamino)-5-(3- Methylbut-1-ynyl) phenoxy-2-carboxylic acid methyl vinegar. 5-(3-methylbut-1-ynyl)-3-((lR,4R)-4-methylcyclohexanecarbamoyl)thiophene-2· 157033.doc -306- 201215604 decyl carbamate A solution of (1.35 g ' 3.89 mmol) and THF (15 mL) was cooled in an ice bath. LiHMDS (5.05 mL, 1 Torr in THF, 5.05 mmol) was then &lt;&apos;&apos;&apos; After 2 minutes, 2 - dimethylacetic acid tert-butyl ester (909 mg, 4.66 mmol) was added and the mixture was heated at 60 ° C overnight. Water and EtOAc were added. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were washed sequentially with brine, water, dried over Na 2 EtOAc and concentrated. Purification by column chromatography (100-200 mesh silica gel) using 5% to 20% EA/petroleum ether afforded 3-((1 R,4R)-N-(2-t-butoxy-2 -ethyloxyethyl)-4-mercaptocyclohexaneguanidino)-5-(3-indolyl-1-ynyl)thiophene-2-carboxylic acid methyl ester (1.13 g, 63%, colorless Oily). MS: m/z (observed) 462 [M+H]+. Step 3: 2-((lR,4R)-N-(2·(曱-oxycarbonyl)-5-(3-methylbut-1-ynyl)thiophen-3-yl)-4-methylcyclohexane Alkanoylamino)acetic acid. To 3-((lR,4R)-N-(2-tert-butoxy-2-oxoethyl)-4-methylcyclohexanecarbamamino)-5-(3) at room temperature Methyl hydrazin-1-yl-alkynyl thiophene-2-yl decanoate (1.13 g, 2.45 mmol) EtOAc (3 mL, EtOAc. After 3 hours, the reaction mixture was concentrated in vacuo <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; -5-(3-Methylbutyr-i-alkynyl)thiophene-3-yl)-4-indolylcyclohexanecarbamoylaminoacetic acid (812 mg, 82%, white solid). MS: m/z (observed) 406 [M+H]+ 〇 Step 4: 3_((lR,4R)-4-Methyl-N-(2- </ RTI> </ RTI> -Azaspiro[3.3] 157033.doc -307- 201215604 Hept-6-yl)ethyl)cyclohexanecarbamoyl)_s_(3_f-butyl-j-alkynyl)thiophene-2-carboxylate. To 2_((1R4R)_N_(2_(methoxycarbonyl)-5-(3-methylbutynyl)thiophene-3-yl)-4-indolylcyclohexanecarboxamidine under nitrogen at room temperature Addition of 3-(ethyliminomethyleneamino)-N to a solution of DIPEA (156 mg, 1.21 mmol) in DCM (6 mL) N-dimethylpropanolamine (68 mg, 0.439 mmol), 6-oxa-2-azaspiro[3·3]heptane (2〇4 mg, 0.731 mmol). After stirring at room temperature overnight, the reaction was concentrated in vacuo. EtOAc and water were added and the aqueous layer was separated and evaporated with Et Et. The combined organics were dried over NasSCU and concentrated. Crude 3_((1R,4R)_4methyl_N_(2_sideoxy-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethyl)cyclohexanecarboxamidine The amino)-5-(3-mercaptobut-1-ynyl)thiophene-2-carboxylic acid decyl ester was used in the next step without further purification. MS: m/z (observed) 487 [M+H]+. Step 5:

Compound 71 » to 3_((1R 4r)_4_methyl_N_(2 oxo-2-(2-oxa-6-azaspiro[3.3]hept-6-yl)ethyl) at room temperature Cyclohexanecarbamamino)_5_(3-methylbut-1-ynyl)thiophene-2-indolinate (86 mg, 〇177 mm〇1) M

A solution of 2 n NaOH (3.5 mL, 7.00 mmol) was added EtOAc (3 mL) and EtOAc (3 mL). twice. The combined organics were dried over NkSCU and concentrated. The residue was purified with EtOAc EtOAc EtOAc (EtOAc) Preparation of Compound 62 157033.doc -308· 201215604

Step 1: 3-((lR,4R)-4-methyl-N-(2-morpholinyl-2-oxoethyl)cyclohexanecarbamamino)-5-(3-methyl Ding_1· fast base) 嗟--2 - formic acid A series. The starting moth (856 mg '丨·60 mmol), DMF (8.6 1111〇, triethylamine (486 111§'67〇4['4.81111111〇1) and 3) were fed into a 1 mL mL 3-neck flask. -methylbuty-1_yne (142 mg, 2.08 mmol). The mixture was cooled in an ice bath and rapidly added to the moth copper (45.8 mg, 0.240 mmol) and PdCl2 (PPh3) 2 (22.5). Mg, 0.032 mmol), and the cold bath was removed. After 5 hours, 2.5 mL of 3-mercapto-l-alkyne was added. Stirring was continued for 1 day, then EtOAc and water were added to the mixture. The aqueous layer was then re-extracted with EtOAc and EtOAc (EtOAc)EtOAcEtOAc. ((lR,4R)-4-mercapto-N-(2-morpholino-2-yloxyethyl)cyclohexaneguanidinyl)-5-(3-methylbutyl_ι_ fast Methyl) thiophene-2-carboxylate (448 mg, 59%, white solid). MS: m/z ( observed) 475.45 [M+H]+. Step 2: Compound 62. 3-((l , 4R)-4-methyl-N-(2-morpholino-2-yloxyethyl)cyclohexanecarbamamino)-5- (3-methylbut-1-ynyl)thiophene-2-furic acid methyl vinegar (248 mg '0.523 mmol) dissolved in MeOH (3 mL) and 2 N NaOH water soluble 157033.doc 201215604 solution (3 mL, 6.00 mmol The mixture was stirred vigorously. After 90 minutes, brine (6 mL), 1N EtOAc (EtOAc) (EtOAc) And concentrated. The residue was purified by Gilson preparative HPLC (gradient: 40% solvent B to 70% solvent B, B=MeCN (with 0.1% TFA); A = water (containing 0.1% TFA + 1% MeCN)) Yield 62 (78.7 mg, 32%, white solid).

Step 1: Compound 67 methyl ester. Add 3-(ethylimino) to a solution of the starting material (148 mg, 0.366 mmol) in DCM (61.4 mg, 0.4 Methyleneamino)-N,N-dimercapto-propan-1-amine (EDC, 68.1 mg, 0.439 mmol) and added dimethylamine aqueous solution after 10 minutes (123 mg, 138 pL 40°/〇w/ w solution, 1.1 0 mmol). After 1 hour, water and brine were added and the layers were separated. The aqueous layer was re-extracted with DCM and the combined organics dried over Na 2 EtOAc, filtered and concentrated. The residue was used directly in the next step without further purification. MS: m/z (observed) 433.42 [M+H] + &lt; To a solution of the starting compound (158 157033.doc -310 - 201215604 mg, 0.366 mmol) in MeOH (3.5 mL), EtOAc (EtOAc) ). After 1 hour, brine (6 mL), 2N EtOAc (EtOAc) The combined organics were dried with Na2SO4, filtered and concentrated. The residue was purified by Gilson preparative HPLC (gradient: 10% solvent B to 90% solvent B, B=MeCN (with 0.1% TFA); A = water (with 0.1% TFA + 1% MeCN)) 9.4 mg, 6%, white solid). Preparation of compound 69

Step 1: Compound 69 methyl ester. Add 3-(ethylimino) to a solution of the starting material (148 mg, 0.366 mmol) in DCM (61.4 mg, 0.4 (N-N-N-dimethyl-propan-1 -amine. (EDC, 68-1 mg, 0.439 mmol). After 5 min, pyridine (63 mg, 0.73 1 mmol) was added. After 6 hours, the mixture was concentrated in vacuo. Add EtOAc and brine. The aqueous layer was separated and extracted with EtOAc. The combined organics were dried with Na2SO4, filtered and concentrated. The residue was used directly in the next step without further purification. MS: m/z (observed) 474.03 [M+H] +. Step 2: Compound 69. To 3-((lR,4R)-4-methyl 157033.doc -311 - 201215604 base-N-(2- oxo-2-(piperazin-1-yl) at room temperature with vigorous stirring Ethyl)cyclohexaneguanidino)-5-(3-methylbut-1-ynyl) °e-phene-2-indole vinegar (173 mg, 0.366 mmol) in MeOH (3 mL) A 2 N aqueous NaOH solution (3 mL, 6.00 mmol) was added to the solution. After 30 minutes, the mixture was concentrated under vacuum at &lt;33 °C. The residue was purified by Gilson preparative HPLC (gradient: 10% solvent B to 90% solvent B, B=MeCN (with 0.1% TFA); A = water (containing 0.1% TFA + 1% MeCN)) 16.3 mg, 10%, white solid). Preparation of Compound 70

Step 1: Compound 70 methyl ester. Add DMAP (2.7) to a solution of the starting material (182 mg, 0.449 mmol) in DCM (8 mL) Mg, 22.4 μιηοΐ), 3-(ethylimidodecylamino)-N,N-dimethyl-propan-1-amine (EDC, 139 mg, 0.898 mmol), followed by addition of 2 N A Amine in THF (898 pL, 1.80 mmol). After stirring overnight, water and brine were added and the mixture was extracted with DCM. The organics were dried (Na 2 SO 4 ), filtered and concentrated. The residue was filtered through EtOAc (EtOAc)EtOAc. MS: m/z (observed) 419.39 [M+H]+. Step 2: Compound 70. To 3-((lR,4R)-4-methyl-N-(2-(decylamino)-2-sideoxy 157033.doc -312- 201215604 ylethyl)cyclohexanecarboxamido) -5-(3-Methylbut-1-ynyl)thiophene-2-carboxylic acid formazan (84 mg, 0.201 mmol) in EtOAc (4 mL) 7.00 mmol) and the mixture was stirred vigorously. After 30 minutes, brine (6 mL) and aq. The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified by Gilson preparative HPLC (gradient: 15 / / solvent B to 90% solvent B, B = MeCN (with 0.1% TFA); A = water (containing 0.1% TFA + 1% MeCN)) 70 (58.5 mg, 71%, white solid). Preparation of Compound 82

Step 1: (S)-3-((l-(Tert-butoxy)-1-oxobutan-2-yl)amino)-5-(3,3-dimethylbut-1- Alkyn-1-yl)thiophene-2-carboxylic acid decyl ester. 3-Bromo-5-(3,3-dimethylbut-1-ynyl) ° cephen-2-pyruic acid methyl vinegar (1, 3.3 111111 〇 1), 犷 &amp; 〇 - BINAP (413 Mg, 0.66 mmol), (2S)-2-aminobutyric acid tert-butyl ester hydrochloride (780 mg, 3.98 mmol), Pd2 (dba) 3 (304 mg, 0.33 mmol) and cesium carbonate (3.25 g, 10 mmol) of the mixture was degassed and filled with N2, and 157033.doc -313- 201215604

Add 1,4-dioxin (15 mL). The mixture was bubbled with N2 for 30 minutes and at 90 °C for 16 hours. The progress of the reaction was monitored by LC-MS. Upon completion of the reaction, the reaction mixture was cooled to room temperature, diluted with EtOAc (2 EtOAc) and filtered over EtOAc. The filtrate was concentrated in vacuo. The residue was purified by 矽_丨〇% Et0AC/hexane eluting with hexane column chromatography to give ((t-butoxy)-1-oxobutan-2-yl)amino)_5_(3 , 3_dimethylbutanyl- hydrazin-2-yl decanoate (1.1 g '83%, colorless oil). MS: m/z (observed) 378 [M+l]+. Step 2: 3_[[(1S)-1-tert-butoxycarbonylpropyl]-(trans-4-methylcyclohexylcarbonyl)amino]-5·(3,3-dimethylbuty_ι Methyl alkynyl thiophene-2-formic acid. To 3 [[(1S)_ 1-t-butoxycarbonylpropyl]amino]-5-(3,3-dimethylbutynyl)thiophene-2-decanoate (1.05 g, 2.77 mmol) Add nyridylpyridine (2.2 g '2.2 mL, 27.7 mmol), DMAP (68 mg, 〇·55 mmol) and trans-4-mercaptocyclohexanemethyl hydrazine to a solution in DCE (10 mL) ( 2.22 g, 13.8 mmol). The mixture was mixed for 16 hours at 9 °C. Upon completion of the reaction, the reaction mixture was cooled to EtOAc EtOAc m. The residue was purified by EtOAc (EtOAc) elute elute Methyl carbonyl)amino] 5-(3,3-dimethylbut-1-ynyl)thiophene-2-carboxylate (1. g, 71.7%, white solid). MS: m/z (observed) 526 [M+l]+. Step 3: (S)-2-((lr,4S)-N-(5-(3,3-dimethylbut-1_yne-1-yl)_2·(methoxyphore 157033.doc 314- 201215604 Thiophen-3-yl)-4-methylcyclohexanecarbamamino)butyric acid 3-[[(lS)-l-t-butoxycarbonylpropyl]-(anti-4-indenyl) Cyclohexylcarbonyl)amino]-5-(3,3-dimethylbutan-1-yl)°ephthyl-2-carboxylate (900 mg, 1-8 mmol) in TFA (5 mL ' 64.9 mmol) The solution in the mixture was stirred for 1.5 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc (30 mL)EtOAc.EtOAc. 3,3-Dimercapto-1-yne-1·yl)-2-(methoxycarbonyl)thiophen-3-yl)-4-hydrazinylcyclohexanecarbamoyl)butyric acid (800 mg, 99%, white solid). MS: m/z (observed) 448 [M+l]+. Step 4: Compound 82 methyl ester. To (2S)-2-[[5-(3,3-dimethylbut-1-ynyl)-2-methoxycarbonyl-3-thienyl]-(trans-4-indolylcyclohexylcarbonyl) Add DIEA (0.14 mL, 0.8 mmol), HBTU (114 mg '0.3 mmol) and 1-methyl sulphonazine to a solution of amido]butyric acid (9 mM mg, 0-2 mmol) in DMF (1 mL) 6〇mg '0.6 mmol). The reaction mixture was stirred with EtOAc EtOAc EtOAc m. The residue was purified by EtOAc/EtOAc (EtOAc) elute MS: m/z (observed) 530 [M+l]+. Step 5: mg, compound 82. To a solution of the oxime ester in MeOH (1.5 mL) was added NaOH (0.75 mL, 1 EtOAc, 0.75 mmol). The solution was stirred overnight and then neutralized with HC1 to pH = 3.0. The mixture was concentrated in vacuo. The residue was dissolved in 〇 〇 〇 MeOH / DCM and purified by column chromatography to afford 82 (48 157033.doc •315 - 201215604

Yield 720/〇, white solid)*&gt; MS: m/z ( observed) 516 [M+1]; H NMR (300 MHz, CDC13) δ 6.82 (s, 1H), 5.32 (s, 1H) , 2.89 (d, J = 5.4 Hz, 4H), 2.54-2.32 (m, 16H), 1·3 〇 (d, J = 30.3 Hz, 11H), 1.03-0.56 (m, 9H). Preparation of Compound 65

Step 1: (2S,3S)-2-Amino-3-methoxybutyric acid tert-butyl ester. To a solution of (2S,3S)-2-amino-3-indolyl-butyric acid (500 mg ' 3.7 mmol) in tert-BuOAc (100 mL) was added EtOAc (3 77 mg, 0.23 mL , 3.75 mmol) and stirred at room temperature for 3 days. The reaction mixture was poured into aq. EtOAc (EtOAc) (EtOAc (EtOAc) (EtOAcjjjjjjjj (530 mg, 72%, white solid) "4 NMR (300 MHz, CDC13) δ 3.68 (dd, J = 13.8, 5.5 Hz, 1H), 3.64-3.47 (m, 1H), 3.27 (d, J=ll .l Hz, 3H), 1.96 (d, J=7.0 Hz, 2H), 1.41 (s, 9H), 1.08 (t, J=7.6 Hz, 3H). Step 2: 3-(((2S,3S)-l-(T-butoxy)-3-methoxy-1-oxobutan-2-yl)amine 157033.doc -316- 201215604 base) Methyl 5-(3,3-dimethylbut-1-ynyl-1-yl)thiophene-2-carboxylate. Methyl 3-bromo-5-(3,3-dimercapto-1-ynyl)thiophene-2-carboxylate (649 mg '2.2 mmol) in dioxane (10 mL) (2S,3S)-2-Amino-3-oxooxybutyric acid tert-butyl g (530 mg, 2.8 mmol), rac-BINAP (268 mg &gt; 0.43 mmol) 'Pd2(dba) 3 (197 mg » 0.21 mmol) and carbonic acid I (2.1 g, 6.5 mmol). The reaction mixture was bubbled with N2 for 30 minutes and heated to 90 °C for 18 hours. The reaction was cooled to room temperature, diluted with EtOAc (20 mL) The filtrate was concentrated. The residue was taken up in EtOAc / EtOAc (EtOAc) elute Methyloxybutan-2-yl)amino)-5-(3,3-dimethylbut-1-yn-1-yl)thiophene-2-furic acid methyl ester (590 mg, 1.4 mmol, 67%) , yellow oil). MS: m/z (observed) 409.88 [M+l]+. Step 3: 3-(((2S,3S)_l-(Tertibutoxy)-3-indolyl--oxo-butan-2-yl)amino)-5-(3,3-di A solution of decyl-1-yn-1-yl-1-yl)thiophene-2- decanoate (520 mg, 1.270 mmol) in TFA (2.0 mL, 25-96 mmol) was stirred at room temperature for 2 hr. The mixture was concentrated, diluted with EtOAc EtOAc (EtOAc)EtOAc. The residue was used in the next step. MS: m/z (observed) 353.89 [M+l]+. Step 4: 5-(3,3-Dimethylbut-1-yn-1-yl)-3-(U2S,3S)-3-methoxy-1-morpholinyl-1-oxetoxy Methyl-2-yl)amino)thiophene-2-carboxylate. To (2S,3S)-2- 157033.doc -317· 201215604 ((5-(3,3 -dimercapto-1-yn-1-yl)-2-(methoxy) ketone _3_yl)amino)-3-methoxybutyric acid (90 mg, 0.25 mmol) in DMF (1 mL) was added with EtOAc ( 145 mg, 0.38 mmol), DIEA (99 mg, 0.14 mL , 0.76 mmol) and praline (166 mg, 0.16 mL, 0.76 mmol). The reaction mixture was stirred at rt EtOAc (EtOAc)EtOAc. The residue was taken up in EtOAc / EtOAc (EtOAc) elute , 3S)-3-methoxy-1-morphinyl-1-oxobutan-2-yl)aminocethiophene-2-carboxylic acid oxime S (88 mg, 82%). MS: m/ z (observed) 422.9 [M+l] +. Step 5: Compound 65 methyl ester to 5-(3,3-dimethylbut-1-yn-1-yl)-3-(((2S, 3S)-3-Methoxy-1-?-yl-1-yloxybutan-2-yl)amino)porphin-2-carboxylic acid methyl ester (88 mg '0.2 1 mmol) in DCE (2 mL) Pyridine (165 mg '0.17 mL '2.1 mmol) and DMAP (3 mg, 0.02 mmol) and 4-methylcyclohexanecarbazide (167 mg, 1.0 mmol) were added to the solution. Stirred for 15 hours at 90 ° C. The progress of the reaction was monitored by LC-MS. The reaction mixture was cooled to room temperature and diluted with EtOAc (20 mL). Washed, dried over EtOAc (EtOAc m. Observed value) 546.9 [M+l]+. Step 6: Compound 65. The starting vinegar (5 〇 mg, 0.09 mmol) was dissolved in MeOH (3 157033.doc -318.201215604)

Add NaOH (0.46 mL, 1.0 Μ, 0.46 mmol) to mL). The reaction mixture was stirred overnight at room temperature, then neutralized with 1 N HCl to pH = 3 and concentrated. The residue was purified by EtOAc (EtOAc) eluting MS: m/z (observed) 532.9 [M+l] + ; NMR (300 MHz, CDC13) δ 7.95-6.80 (d, J=3.1 Hz, 1H), 5.57-5.23 (m, 1H), 4.01- 3.55 (m, 9H), 3.54-3.23 (m, 3H), 3.14 (m, 4H), 2.04 (m, 1H), 1.67-1.58 (m, 4H)S 1.45-1.19 (m,12H),1.11- 0.96 (m, 1H), 0.91-0.47 (m, 4H). Preparation of Compound 66

5-(3,3-dimercapto-1-alkynyl)-3-[indole (lS,2S)-l-(dimethylaminecarbamyl)_ 2methoxy-propyl]-(reverse 4-methylcyclohexylcarbonyl)amino]thiophene-2-furoic acid. Compound 66 was prepared by the same method as Compound 65. MS: m/z (observed 490.9 [Μ+1Γ; NMR NMR (300 MHz, CDC13) δ 6.96-6.70 (» H), 5.43-5.18 (m, 1H), 3.45-2.88 (m, 9H), 1.85- 0.53 (m, 27H). Preparation of compound % $ I57033.doc • 319· 201215604

5-(3,3-Dimethylbut-1-ynyl)-3-[(trans-4-methylcyclohexylcarbonyl)-[(lS)-2-methyl-1-(morpholine-4) -carbonyl)propyl]amino]thiophene-2-carboxylic acid. Compound 85 was prepared as described for 65.

Preparation of compounds

5-(3,3-Dimethylbut-1-ynyl)-3-[[(lS)-l-(dimethylaminecarbamyl)-2-methyl-propyl]-(anti- 4-methylcyclohexylcarbonyl)amino]thiophene-2-furoic acid. Compound 86 was prepared in the manner described for 65. Preparation of Compound 75

157033.doc 320-201215604 Step 1: ((2R,3R)-l-(Dimethylamino)-3-yl-1-yloxybut-2-yl)carbamic acid benzyl ester. Add TBTU (647 mg, to a solution of (2R,3R)-2-(((phenylhydroxy)carbonyl)amino)-3-hydroxybutyric acid (340 mg, 1.3 mmol) in DMF (2 mL) 2.0 mmol), DIEA (694 mg, 0.94 mL, 5.4 mmol), N-methylmethylamine hydrochloride (329 mg, 4.0 mmol). The solution was diluted with EtOAc (20 mL). The residue was purified by EtOAc (EtOAc) elut elut elut elut elut elut elut Benzene-2-ylaminobenzyl phthalate (300 mg, 82% 'white solid). MS: m/z (observed) 280.96 [M+l] + ; !H NMR (300 MHz, CDC13) δ 7.45-7.30 (m 5H), 5.92 (d, J = 8.3 Hz, 1H), 5.20-5.02 (m, 2H), 4.61 (ddd, J=21.5, 8.3, 4.2 Hz, 1H), 4.02-3.84 (m, 1H), 3.17 (s, 3H) 2.97 (s,3H),1.20 (d,J= 6.0 Hz, 3H). Step 2: ((2R,3R)-l-(Dimethylamino)-3-methoxy-l-oxobutan-2-yl)carbamate. To ((2R,3R)-l-(dimethylamino)_3_yl-1-yloxybut-2-yl)carbamic acid in the dark at 0 ° C (3) 〇〇mg, 1 1 mmol) Add a solution of Ag2〇 (i.2 g, 5.4 mmol) and Mel (1.5 g, 0.7 mL, 11 mmol) in DCM (10 mL) and drop at room temperature 3 day. The reaction mixture was filtered through a pad of celite and concentrated. The residue was taken up in EtOAc (EtOAc) elute Thus, ((2R,3R)-1-(-methylamino)-3-methoxyoxybutan-2-yl)amino 157033.doc -321 - 201215604 formate (120 mg, 38%). MS: m/z (observed) 295.1 [M+l]+. To the obtained ((2R,3R)-l-(didecylamino)-3-methoxy-1-oxobutan-2-yl)carbamate (120 mg, 0.41 mmol) in MeOH Pd(OH)2 (28 mg, 0.2 mmol) was added to the solution in (10 mL) and spoiled under H2 balloon for 1 hour. The mixture was filtered through a layer of diatomaceous earth. The filtrate was concentrated and used in the next step. MS: m/z (observed) 161 [M+l]+. Step 3: 3-(((2R,3R)-l-(Dimethylamino)-3-methoxy-1-oxobutan-2-yl)amino)-5-(3,3 -Dimethylbut-1-yn-1-yl)thiophene-2. formamidine methyl ester. (2R,3R)-2-amino-3-methoxy-indole, hydrazine-dimethyl-butanamine (70 mg, 0.44 mmol), carbonic acid (388 mg, 1.2 mmol), rac-BlNAP ( 50 mg, 0.08 111111〇1),? (!2(仙&amp;)3(36 1^,0.04 111111〇1) and 3-bromo-5-(3,3-methylbutan-1-yl)°Cet-2-carboxylic acid A A mixture of (120 mg, 0.4 mmol) in dioxane (2 mL) was then evaporated from N? The mixture was diluted with EtOAc (20 mL). EtOAc EtOAc EtOAc. Purification by Shih Tzu Chromatography to give 3-(((2R,3R)-l-(dimethylamino)-3-methoxy-1-oxobutan-2-yl)amine -5-(3,3-Dimercapto-1-yn-1-yl)thiophene-2-carboxylic acid decyl ester (100 mg, 66%). MS: m/z ( observed) 380.9 [M+ l]+ Step 4: Compound 75 methyl ester. To 5-(3,3-dimethylbut-1-ynyl)-3-[[(lR,2R)-l-(didecylamine oxime) ))-2-methoxy-propyl]amino]thiophene-2-decanoate 157033.doc -322- 201215604 (100 mg, 0.26 mmol) in a solution of DCE (3.0 mL) Bite (208 mg, 0_2 mL, 2.6 mmol), DMAP (3 mg, 0.03 mmol) and trans-4-methyl The reaction mixture was cooled to room temperature with EtOAc (20 mL). Diluted, washed with EtOAc EtOAc (EtOAc)EtOAc. MS: m/z (observed) 505.2 [M+l]+. Step 5:

Compound 75. NaOH (0.9 mL, 1 Μ, 0.9 mmol) was added to a solution of EtOAc (EtOAc) (EtOAc) The mixture was acidified to pH = 3 with HCl and concentrated. The residue was purified by EtOAc (EtOAc) elute MS: m/z (observed) 490.97 [M+l] + ; NMR (300 MHz, CDC13) δ 6.80 (s, 1H), 5.27 (dd, J = 17.1, 7.9 Hz, 2H), 3.86-2.84 ( m, 10H), 1.86-0.54 (m, 25H). Preparation of Compound 74

5-(3,3-dimethylbut-1-ynyl)-3-[[(lR,2R)-2-methoxy-1-(morpholin-4.carbonyl)propyl) (anti- 4-methylcyclohexylcarbonyl)aminothiophene-2-carboxylic acid. Compound 74 was prepared as described for compound 75. MS: m/z (observed 157033.doc -323 - 201215604 value) 532.99 [M+l] + ; NMR (300 MHz, CDC13) δ 6.80 (s, 1H), 5.44-5.23 (m, 1H), 4.00- 3.29 (m, 10H), 3.19-2.97 (m, 3H), 1.89-0.42 (m, 25H). Preparation of Compound 72

5-(3,3-dimethylbut-1-ynyl)-3-[[(lR,2S)-2-methoxy-1-(morpholin-4-carbonyl)propyl]-(inverse 4-methylcyclohexylcarbonyl)amino]thiophene-2-carboxylic acid. Compound 72 was prepared in the manner described for compound 75. MS: m/z (observed) 532.99 [M+l] + ; 4 NMR (300 MHz, CDC13) δ 7.01-6.71 (m, 1 Η), 5.51-5.20 (m, 2H), 3.97-3.30 (m, 9 H), 3.27-2.84 (m, 3H), 1.83-0.56 (m, 27H) « Preparation of Compound 57

Step 1: 157033.doc •324· 201215604 ((2 S,3R)-1-(methylsyl)-3-methoxy-1·oxaoxybutan-2-yl)aminocarboxamidine Tributyl ester. Add DIEA (665 mg) to a solution of (2S,3R)-2-(t-butoxycarbonylamino)-3-methoxy-butyric acid (400 mg, 1.7 mmol) in DMF (3 mL) , 0.9 mL, 5.1 mmol), HBTU (976 mg, 2·6 mmol) and N-mercaptomethylamine (580 mg, 0.62 mL, 40% w/w, 5.1 mmol) and stirred overnight at room temperature. The mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The residue was taken up in 0-60% EtOAc / EtOAc elute elute elute Butyl-2-yl)aminobutyl citrate (350 mg, 1.3 mmol, 78%). To the obtained ((2S,3R)-l-(didecylamino)-3-methoxycarbonyl-1-oxobutan-2-yl) carbamic acid tributyl vinegar (350 mg, 1.3 mmol) Dioxane containing HCl (5 mL, 4_0 Μ, 20 mmol) was added and stirred at room temperature for 2 hr. Concentrate and use it directly in the next step. Step 2: 3-(((2S,3R)-l-(dimethylamino)_3·methoxy-^-oxybutan-2-yl)amino)-5-(3,3-di Methyl methyl-1-_1-acetyl-1-yl)thiophene-2-carboxylic acid methyl ester. Add to a solution of 3-bromo-5-(3,3-dimethylbutyrynyl)thiophene-2-indoleate (3〇1 ,, 1 mmo1) in dioxane (5 mL) (2S,3R)-2-amino-3-methoxy-N,N-dimercapto-butylamine (HCl(1)) (256 mg, 1-3 mmol), rac-BINAP (125 mg , 0.2 mmol), Pd2 (dba) 3 (92 mg, 0.1 mmol) and carbonic acid planer (978 mg, 3 〇mm〇1). The solution was bubbled with &amp; 3 Torr and heated to 90. (: maintained for 18 hours. The progress of the reaction was monitored by LC-MS. When the reaction was completed, the reaction mixture was cooled to room temperature and diluted with Et 〇Ac (3 〇 mL) 157033.doc • 325 - 201215604, via Shiyoshi. The layers were filtered and concentrated. The residue was purified eluting with EtOAc EtOAc EtOAc (EtOAc) -nonyloxy-1-oxobutan-2-yl)amino)_5_(3,3-dimethylbut-1-yn-1-yl)methyl phen-2-carboxylate (280 mg, 73.6%) MS: m/z (observed) 380.96 [M+l] +. Step 3: Compound 57 methyl ester to 5-(3,3-dimethylbutylmethane). [(成幻-卜(二曱基胺甲基)-2-methoxy-propyl]amino]D-cephene-2-indolinate

(280 mg '0.73 59 mmol) Add 0-pyridine (582.1 mg, 595.2 pL, 7.359 mmol), DMAP (17.98 mg, 0.1472 mmol) and trans-4-mercaptocyclohexane to a solution of DCE (4.119 mL). Alkalyl chloride (59 i.2 mg, 3.680 mmol). The mixture was stirred at 10 ° C for 24 hours. The progress of the reaction was monitored by LC-MS. Upon completion of the reaction, the reaction mixture was cooled to EtOAc EtOAc m. The residue was purified by EtOAc (EtOAc) elute MS: m/z (observed) 504.96 [M+l]+. Step 4: Compound 57: To a solution of the title compound (EtOAc, EtOAc (EtOAc) The solution was mixed overnight. The reaction was monitored by LC-MS. Upon completion of the reaction, the reaction mixture was acidified with 1 M aqueous EtOAc and concentrated. The residue was purified by EtOAc (EtOAc) elute MS: m/z (observed) 490.97. 157033.doc -326- 201215604 NMR (300 MHz, CDC13) δ 6.90 (s,1H),5_25 (dd,J=20.9, 9.5 Hz, 2H), 3.55-3.22 (m, 4H), 3.02 (dd, J = 14.8, 10.4 Hz, 6H), 2.12-1.00 (m, 20H), 0.90-0.52 (m, 5H). Preparation of Compound 58

5-(3,3-Dimercapto-1 -ynyl)-3-[[(18,2)-2-methoxy-1-(morpholin-4-carbonyl)propyl]-( Trans-4-methylcyclohexylcarbonyl)amino]thiophene-2-carboxylic acid. Compound 58 was prepared as described for compound 57. Preparation of Compound 87

5-(3,3-Dimethylbut-1-ynyl)-3-[[(lS)-l-(ethoxymethyl)-2-morpholinyl-2-yloxy-ethyl 】-(trans-4-methylcyclohexyl)amino]porphin-2-carboxylic acid. Compound 87 was prepared as described for compound 57. Preparation of Compound 88 157033.doc •327- 201215604

3-[[(lS)-2-(dimethylamino)-1·(ethoxymethyl)&gt;^(trans-4-methylcyclohexylcarbonyl)amino]-5-(3,3 -dimethyl

Side oxy-ethyl I 2-carboxylic acid. Compound 88 was prepared in a manner to prepare compound 59 for compound 57-but-1-ynyl)thiophene-

Step 1: Compound 59 methyl ester. To a solution of the starting material methyl ether (66 mg, EtOAc) in DCM (2 mL). The reaction mixture was stirred for 1 h (from EtOAc EtOAc (EtOAc) (EtOAc) The desired alcohol (44 mg, 68.7%) was obtained. MS: m/z (observed) 490.97 [M+l] +. Step 2 ·· Compound 59. To 3-((lr,4S)-N-(( 2S,3R)-l-(Dimethylamino)-3-hydroxy-1-oxobutan-2-yl)-4-methylcyclohexanecarbamamino)-5-(3,3 Methyl dimethylbutan-1-ynyl-1-yl)thiophene-2-carboxylate (54 mg, 0.11 mmol) at 157033.doc -328-201215604

A 1.0 M aqueous NaOH solution (0.33 mL, 0.33 mmol) was added to a solution in MeOH (3 mL). The solution was stirred overnight, acidified with aq. The residue was purified by EtOAc (EtOAc) elute MS: m/z (observed) 476.97 [M+l] + ; NMR (300 MHz, CDC13) δ 7·02-6·87 (m, 1H), 5.61 (dd, J=43.5, 7.6 Hz, 2H ), 4.19-3.90 (m, 2H), 3.24 (s, 4H), 3.16 (s, 3H), 2.97 (d, J=18.4 Hz, 3H), 2.83 (s, 2H), 2.06 (d, J= 9.8 Hz, 2H), 1.89-1.06 (m, 11H), 0.95-0.57 (m, .6H) o Preparation of Compound 60

5-(3,3-dimercapto-l-alkynyl)-3-[[(lS,2R)-2-hydroxyl-(morpholin-4-carbonyl)propyl]-(trans-4 -Methylcyclohexylcarbonyl)amino]thiophene-2-carboxylic acid. Compound 60 was prepared as described for compound 59. Preparation of Compound Μ 157033.doc -329- 201215604

Step 1: (S)-3-((l,3-di-t-butoxyl_a-oxypropan-2-yl)amino)-5-(3,3-dimethylbutene- Methyl 1-yn-1-yl)thiophene-2-carboxylate. Ethyl 3-bromo-5-(3,3-dimethylbut-1-ynyl)thiophene-2-carboxylate (1 g, 3.3 mmol), rac-BINAPOU mg '0.66 mmol), (2S)- 2-Amino-3-t-butoxy-propionic acid vine hydrochloride (1.0 g' 4·〇mrn〇l), pd2(dba)3 (304 mg, 〇·33 mmol) and carbonic acid (3.25) The mixture of g, i 〇 mmol) was degassed and filled with N2. To the reaction mixture was added 1,4-dioxane (i5 mL), which was bubbled with N2 for 30 min and stirred at 90 ° C for 24 hours. The progress of the reaction was monitored by LC-MS. Upon completion of the reaction, the~~~~~~~~~~ The residue was purified by EtOAc (EtOAc) elute Ethyl 5-(3,3-dimercapto-1-yn-1-yl)thiophene-2-decanoate (1.0 g '68.8%, white solid). MS: m/z (observed) 438.0 [M+l]+. Step 2: To 3-[[(lS)-2-tert-butoxy-1-(t-butoxymethyl)_2_sideoxy-ethyl]amino]-5-(3,3 -dimercapto-i-alkynyl)thiophene-2-furic acid methyl ester (1. 〇157033.doc -330-201215604 g, 2.3 mM) added to the solution in DCE (2 mL) t&gt; ratio. Dilute (1.08 g, 1.1 mL, 13.71 mmol), DMAP (28 mg, 0.23 mmol), and &lt;RTI ID=0.0&gt;&gt; The progress of the reaction was monitored by LC-MS. Upon completion of the reaction, the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The residue was purified by EtOAc (EtOAc) elute MS: m/z (observed) 562 [M+l]+. To a solution of the starting material alkoxy ester (1.0 g, 1.78 mmol) in EtOAc (30 mL). The reaction was monitored by LC-MS. When the reaction is completed, the reaction mixture is concentrated. The residue was purified with EtOAc EtOAc (EtOAc) MS: m/z (observed) 450 [M+l]+. Step 4: Compound 33 methyl ester. Add HBTU (104 mg, 0.28 mmol), DIEA (72 mg, 96 μιη, 0.54 mmol) and a solution of hydroxy acid (81 mg, 0.18 mmol) in DMF (2.0 mL). (48 mg, 0.54 mmol) and stirred at room temperature for 2 h. The progress of the reaction was monitored by LC-MS. Upon completion of the reaction, the~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The residue was purified by EtOAc (EtOAc) elute MS: m/z (observed) 519-0 [M+l] + » 157033.doc -331 - 201215604 Step 5: Compound 33. To a solution of compound 33 in EtOAc (50 mg, EtOAc) (EtOAc) (EtOAc) Upon completion of the reaction, the reaction mixture was acidified to pH = 3 and concentrated with 6 M EtOAc. The residue was purified by EtOAc (EtOAc) elute MS: m/z (observed) 505.0 [M+l]+. Preparation of compound 3 4

3-[[(lS)-2-(dimethylamino)-1-(methyl)) 2 oxo-ethyl b (anti-methylcyclohexyl)amino]-5 -(3,3-Dimethylbutynyl)thiophene-2-carboxylic acid. Compound 34 was prepared as described for compound 33. Preparation of compound 112

step 1 :

Methyl)amino)thiophene-2-carboxylate. 3-bromo-5-(3,3-dimethylbutan-yl-alkynyl) porphin-2-pyrucylate (200 mg, 〇.66 mmol), decyl fluorenyl 157033.doc -332- 201215604 Indole-2-one (102 mg, 0.8 mmol), carbonated (649 mg, 1.99 mmol) ' rac-BINAP (83 mg, 0·13 mmol) and Pd2 (dba) 3 (61 mg, 0.07 The solution of mmol) in dioxane (3.5 mL) was bubbled with N2 for 30 min and stirred at 95t for 18 h. The reaction was monitored by LC-MS. The reaction mixture was diluted with EtOAc (30 mL)EtOAc. The residue was taken up in 0-80%EtOAc / EtOAc elute Methyl 2-ethyloxypiperidin-4-yl)amino)thiophene-2-carboxylate (140 mg, 60.5%). MS: m/z (observed) 349.0 [M+l] &lt;+&gt; Step 2: Compound 112 methyl ester. 5-(3,3-Dimercapto-1-yn-1-yl)-3-((1-methyl-2-oxopiperidin-4-yl)amino)thiophene-2-indole Hydrazide ester (140 mg, 0.40 mmol), ° ratio 0 (318 mg, 325 μιη, 4.0 mmol), DMAP (5 mg, 0.04 mmol) and trans-4-methylcyclohexane ruthenium chloride (323 mg) , 2.0 mmol) of the mixture in DCE (2 mL) was refluxed overnight. The reaction was monitored by LC-MS. Upon completion of the reaction, the~~~~~~~~~~~~~~~~~~~~~~ The residue was purified by EtOAc (EtOAc) elute MS: m/z (observed) 444.9 [M+l]+. Step 3: Compound 112. To a solution of MeOH (3 mL) EtOAc (EtOAc (EtOAc) The progress of the reaction was monitored by LC-MS. Upon completion of the reaction, 157033.doc -333 - 201215604 The mixture was acidified to pH = 3 with 1 M aqueous HCl solution and concentrated. The residue was purified by EtOAc (EtOAc) elute MS: m/z (observed) 458 9 [M+l] + ; 'H NMR (300 MHz, CDC13) δ 6.8 〇 (Λ τ_10 , vu, J = 18.4 Hz, 1H), 5.10 (s, 1H) , 3.61-3.10 (m, 3H), 2.93-2.79 (m 4H) 2.09-1.90 (m, 5H), 1.87-1.46 (m, 6H), l.35_1〇4 (m, 9h), 0.86-0.76 ( m, 5H). ' Preparation of compound 8

3-[[(lS)-2-(diethylamino)-1-methyl-2_sideoxy-hexyl](antimethylcyclohexyl)amino]]5-(3,3-di Methyl butadiene + alkynyl) Compound 8 was prepared in the manner described for 82.

Dimethyl butyl + fast radical anti- 4 · methylcyclohexyl) qing ^ - 2 · side oxy-2- nitrate small base _ ethyl amide amino group 叹 吩 benzoic acid. Preparation of Compound 9 Compound 9 was prepared as described for 82. 157033.doc -334. 201215604 Preparation of compound 18

3-[[(lS)-2-(cyclopentylamino)-1-methyl-2-oxo-ethyl]-(trans-4-methylcyclohexylcarbonyl)amino]-5- (3,3-Dimercapto-1-ynyl)thiophene-2-carboxylic acid. Compound 18 was prepared in the manner described for 82. Preparation of compound 19

5-(3,3-Dimethylbutan-1-yl)-3-[(trans-4-methylcyclohexylcarbonyl M(1S)-1-methyl-2-oxooxy-2] (four Gas-methane-4-ylamino)ethyl]amino]porphin-2-carboxylic acid. Compound 19 was prepared as described for 82.

Preparation of Compound 2Q 157033.doc •335 - 201215604

OH

5-(3,3-Dimethylbut-1-ynyl)-3-[[(18)-2_(4-hydroxy-1-piperidyl)-1-methyl-2-oxo- Ethyl]-(trans-4-methylcyclohexylcarbonyl)amino]thiophene-2-carboxylic acid. Compound 20 was prepared as described for 82. Preparation of compound 29

5-(3,3-Dimethylbut-1-ynyl)-3-[[(lS)-2-[(3S)-3-hydroxylahydroidin-1-yl]-1-methyl- 2-sided oxy-ethyl]-(trans-4-methylcyclohexylcarbonyl)amino]thiophene-2-carboxylic acid. Compound 29 was prepared as described for 82. Preparation of Compound 30

157033.doc -336- 201215604 5-(3,3-Dimethylbut-1-ynyl)-3-[(trans-4-methylcyclohexylcarbonyl)-[(18)-1-methyl- 2-Phenoxy-2-(tetrahydrofuran-3-ylamino)ethyl]amino]thiophene-2-carboxylic acid. Compound 30 was prepared in the manner described for 82.

Preparation of compound U

5-(3,3-Dimethylbut-1-ynyl)-3-[[(lS)-2-[(4-hydroxycyclohexyl)amino]-1 gastric methyl-2-oxooxy -Ethyl]-(trans-4-methylcyclohexylcarbonyl)amino]thiophene-2-carboxylic acid·&gt; Compound 31 was prepared in the manner described for 82. Preparation of compound 32

CH» 5-(3,3·Dimercapto-1-ynyl)-3-[[(lS)-2-[(3R)-3-hydroxy'•Byrrolidin-1-yl]-1 -Methyl-2-oxo-hexyl]-(trans-4-methylcyclohexylcarbonyl)amino]thiophene-2-carboxylic acid. Compound 32 was prepared in the manner described for 82. Preparation of Compound 37 157033.doc -337- 201215604

5-(3,3-Dimethylbut-1-ynyl)-3-[[(lS)-2-[2-hydroxyethyl(methyl)amino]-1·•methyl-2- Sideoxy-ethyl]-(trans-4-indolylcyclohexylcarbonyl)amino]thiophene-2-carboxylic acid. Compound 37 was prepared as described for 82. Preparation of compounds

5-(3,3-Dimethylbut-1-ynyl)-3-[[(lS)-2-[2-methoxyethyl(methyl)amino]-1-methyl-2 -Phenoxy-hexyl]-(trans-4-methylcyclohexylcarbonyl)amino]thiophene-2-carboxylic acid Compound 38 was prepared as described for 82. Preparation of Compound 39

5-(3,3-Dimethylbut-1-ynyl)-3-[[(lS)-2-[(3S)-3-(hydroxymethyl)"pyrrolidin-1-yl]- 1-Methyl-2-oxo-ethyl]-(trans-4-methylcyclohexylcarbonyl)amine 157033.doc -338- 201215604 base]thiophene-2-carboxylic acid. Compound 39 was prepared in the manner described for 82. Preparation of Compound 40

HaC

CH»

5-(3,3-dimethylbut-1-ynyl)-3-[[(18)-2-(3-methoxy-1-piperidyl)-1-indenyl-2- side Oxyethyl-ethyl]-(trans-4-methylcyclohexylcarbonyl)amino]thiophene-2-carboxylic acid. Compound 40 was prepared in the manner described for 82. Preparation of Compound 47

5-(3,3-Dimethylbut-1-ynyl)-3·[(trans-4-methylcyclohexylcarbonyl)-[(lS)-l-methyl-2-(3-methyl)琳琳·4-yl)-2-sideoxy·ethyl]amino] 叹 -2--2-carboxylic acid. Compound 47 was prepared in the manner described for 82. Preparation of Compound 48

157033.doc •339· 201215604 5_(3,3-Dimethylbut-1-ynyl)-3-[[(lS)-2-[(2R,6S)-2,6-dimethyl-methyl 4-yl]-1·methyl-2_sideoxy-ethyl b (trans-4-methylcyclohexyl)amine]porphin-2·formic acid. Compound 48 was prepared as described for 82 to prepare compound 49

S-(6)-Dimethylbutanyl)_3_[(trans_4_methylcyclohexylcarbonyl h(is) small methyl winter (2-methylnorphin-4-yl)·2_sideoxy Ethyl]amino] anisole-2 formic acid. Compound 49 was prepared as described for 82. Preparation of Compound 50

5-(3,3-Dimethylbutynyl)-3-[[(ls) U,2-dimethylmorpholine_4_yl)_1_methyl-2-oxo-ethyl]( __4-甲其^ ^ w ^ Cyclohexylcarbonyl) Amino] thiophene

Phen-2-carboxylic acid. Compound 5 is prepared in the manner described for 82. Preparation of Compounds 157033.doc -340- 201215604 h3c

CHj 5-(3,3-dimethylbut-1-ynyl)-3-[(trans-4-methylcyclohexylcarbonyl)-[(18)-1-methyl-2-[methyl ( Tetrahydropyran-4-yl)amino]-2-oxo-ethyl]amino] Thiophene-2-carboxylic acid. Compound 51 was prepared as described for 82. Preparation of compound 52

5-(3,3-Dimethylbut-1-ynyl)-3-[[(lS)-2-(3-methoxyazetidin-1-yl)-1-methyl- 2-sided oxy-ethyl]•(trans-4·methylcyclohexyl)amino]porphin-2-carboxylic acid. Compound 52 was prepared as described for 82. Preparation of compound 53

5-(3,3-Dimethylbut-1-ynyl)-3-[[(lS)-2-(4-methoxy-1-piperidinyl)-157033.doc •341 · 201215604 1 -Methyl-2-oxo-ethyl]-(trans-4-methylcyclohexylcarbonyl)amino]thiophene-2-carboxylic acid. Compound 53 was prepared in the manner described for 82. Preparation of compound 54

5-(3,3-Dimethylbut-1-ynyl)-3-[[(lS)-2-(3-hydroxy-1-piperidyl)-1-methyl-2-oxooxy -ethyl]-(trans-4-methylcyclohexylcarbonyl)amino]thiophene-2-carboxylic acid. Compound 54 was prepared as described for 82. Preparation of Compound 66

5-(3,3-Dimethylbut-1-ynyl)-3-[[(lS,2S)-l-(dimethylamine)-2-methoxy-propyl]- (trans-4-methylcyclohexylcarbonyl)amino]thiophene-2-carboxylic acid. Compound 66 was prepared as described for 65. Preparation of Compound 76]57033.doc -342- 201215604

5-(3,3-Dimethylbut-1-ynyl)-3-[(trans-4-methylcyclohexylcarbonyl)-[(lS)-l-[methyl-(1-methyl-) 4-piperidinyl)amine-methylmethyl]propyl]amino]thiophene-2-carboxylic acid. Compound 76 was prepared in the manner described for 82. Preparation of Compound 77

5-(3,3-Dimethylbut-1-ynyl)-3-[[(lS)-l-[2-hydroxyethyl(methyl)aminemethanyl]propyl]_(anti- 4-Methylcyclohexylcarbonyl)amino]thiophene-2-furoic acid. Compound 77 was prepared in the manner described for 82. Preparation of Compound 80

5-(3,3-dimethylbut-1-ynyl)-3-[(trans-4-methylcyclohexylcarbonyl)-[(lS)-l-157033.doc -343 - 201215604 [methyl (Tetrahydrofuran-3-ylmethyl)amine methyl]propyl]amino]thiophene-2-carboxylic acid. Compound 80 was prepared in the manner described for 82. Preparation of Compound 81

5-(3,3-dimethylbut-1-ynyl)-3-[(trans-4-methylcyclohexylcarbonyl)-[(lS)-l-[methyl(tetrahydropyran-4) -yl)amine-mercapto]propyl]amino]thiophene-2-furoic acid. Compound 81 was prepared as described for 82. Preparation of Compound 84

5-(3,3-dimethylbut-1-ynyl)-3-[(trans-4-methylcyclohexylcarbonyl)-[(lS)-l-(1,4-oxazepine Alkyl-4-carbonyl)propyl]amino]thiophene-2-carboxylic acid. Compound 84 was prepared in the manner described for 82. Preparation of Compound 89

3-[[(lS)-l-(dimethylaminocarbamimidyl)propyl]-(trans-4-methylcyclohexylcarbonyl)amine 157033.doc • 344· 201215604 base]-5-(3- Methyl tau 89 is for J-1-ynyl)thiophene-2-carboxylic acid. Prepared in the manner described for compound 82. Preparation of compound 9 〇

4 groups of propyl) propyl] porphin-2-carboxylic acid. Compound 90 was prepared as described for 82.

• - _Alkynyl-3 - [(trans-4-methylcyclohexylcarbonyl Hdshi (?

Preparation of compound 7S

5-(3,3_monodecyl-1-ynyl)_3-1丨2-(isopropylamino)-2-o-oxy-ethyl 1 T-cyclohexylcarbonyl)amino]thiophene-2- Formic acid. Compound 73 was prepared according to the formula for compound S, υΊ+. MS: m/z (observed) 447.4 IJVL ten HJ. Preparation of Compound 1S6: Step 1:

+ °^νη2 157033.doc •345- 201215604 N-[(lS)-3-hydroxy-1-[[(3R)-tetrahydrofuran-3-yl]amine-based]propyl]aminocarboxamidine III Butyl ester. To a stirred solution of (S)-tetrahydrofuran-2-amine (2.53 g, 28.8 mmol) in anhydrous DCM (90 mL) EtOAc (5······ , 5 7.5 mmol) and stirred for 15 minutes while adding DCM containing lactone and the reaction was stirred at room temperature for 18 hours. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was poured into 10% EtOAc. EtOAc (EtOAc m. m. Filter and then concentrate. The crude compound was purified by EtOAc EtOAc (EtOAc:EtOAc: ! 1^(10%1^〇11-CHC13) Rf=0.37. LC-MS conditions: column HALO C18 (2.1x100 mm '2.7 μΜ), mobile phase A: 5 mM NH4OAc, B: acetonitrile; t/0/〇B: 0 min/3°/〇, 1.5/45, 2.5 /45, 3.2/95, 4.7/9, 5/03; flow rate: 0.6 mL/min, sample diluent: MeOH. MS: m/z (observed): 289.5 [M+H]+. Residence time: 1.3 min. 4 NMR (400 MHz, DMSO-d6): δ 7·94 (d, J = 6.8 Hz, 1H, interchangeable with D20) ' 6.77 (d, *7=8 Hz, 1H, interchangeable with D20), 4.22 (d , /=3.2 Hz) 3.98-3.94 (d, 7=12 Hz, 1H), 3.80-3.65 (m, 2H), 3.63-3.32 (m, 2H), 2.11-2.02 (m, 1H), 1.73-1.61 (m, 3H), 1.37 (s, 9H). Step 2: 157033.doc -346- 201215604

Hey. ~[(38)-2-Sideoxy-1-[(38)-tetrahydrobite--3-yl]"Bilo bite_3_yl]-tert-butyl carbamate. Add tri-n-butyl scale (2.47 mL, 10.4) to the stirred solution of di-t-butyl azodicarboxylate (959 mg ' 4.12 mmol) in anhydrous THF (9 mL) at room temperature. Methyl acetate was added for 15 minutes, followed by the addition of guanamine (600 mg, 2.08 mmol) at 〇 °C. The reaction was stirred for 1 § hours and the progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was poured into a saturated aqueous solution of NaH.sub.3, and extracted with DCM (2×l 50 mL) , then filtered and concentrated. The crude compound was purified by column chromatography eluting with EtOAc (EtOAc:EtOAc: TLC (10% MeOH-CHCl3) Rf = 0.53. LC-ELSD conditions: column HALO C18 (2.1 x 100 mm, 2.6 μΜ), mobile phase A: 5 mM NH4OAc, B: acetonitrile; t/〇/〇B: 0 min/3%, 0.5/3, 2/90 , 2.5/90, 3.0/100 '3.5/3, 4/3 ; Flow rate: 0.6 mL/min, sample diluent: MeOH, MS: m/z (observed): 271.1 [M+H]+. Residence time: 1·6 min. 4 NMR (400 MHz, DMSO-d6): δ 7.06 (d, J = 9.2 Hz, 1H, interchangeable with D20), 4.59-4.57 (m, 1H), 4.08-4.04 (m, 1H), 3.87-3.81 ( m, 1H), 3.64-3.60 (m, 2H), 3.29-3.19 (m, 1H), 2.23-2.16 (m, 1H), 2.09-2.00 (m, 1H), 1.90-1.82 (m, 1H), 1.78-1.69 (m, 1H), 1.61-1.54 (m, 3H), 1.44. 157033.doc • 347· 201215604 Step 3: (3S)-3-Amino-1-[(3S)-tetrahydrofuran_3_yl]pyrrolidine-2-one. Here. (:, N-[(3S)-2-Sideoxytetrahydrofuran-3-yl]pyrrolidinyl-3-yl]carbamate (495 mg ' 1.83 mmol) in anhydrous DCM (10 mL) To the stirred solution was added EtOAc (EtOAc EtOAc (EtOAc) (EtOAc) 400 MHz, E) MSO-d6): δ 8.45 (s, interchangeable with D2〇, 2 prints, 4.65-4.61 (111, out), 3.94- 3.84 (m, lH), 3.69-3.61 (m, 1H), 3.43-3.32 (m,lH), 2.39- 2.32(m,lH)5 2.13-2.06(m,lH),1.93-1.87(m,lH), 1.72-1.60(m,2H), 1.54-1.29(m , 2H), 1.25-1.18 (m, lH). Step 4:

5-(3,3-di-n-butyl-1-ynyl)-3-[[(38)-2-indolyl-1-[(38)-tetrahydrofuran-3-yl]pyrrolidin-3- Methylamino]thiophene-2-carboxylic acid methyl ester. 3-bromo-5-(3,3-dimethylbut-1-ynyl)°cephen-2-carboxylic acid vinegar (594 mg, 3.488 mmol), (3S)-3-amino-1-[ (3S) - 四风°夫鸣-3-yl]°Bilo-2-net (700 mg, 2.32 mmol), Cs2C03 (2.27 g, 6.98 mmol) on toluene 157033.doc -348- 201215604 (15 The suspension in mL) was deoxygenated by purging with argon for 6 minutes to remove oxygen, followed by addition of Pd(OAc)2 (52.2 mg, 0.232 mmol) and (±) BINAP (144 mg, 0.232 mmol) and further purification for 30 minutes. The mixture was stirred for 16 hours. The reaction was monitored by EtOAc (EtOAc) (EtOAc) Washed with brine (20 mL), dried over Na2 EtOAc (EtOAc)EtOAc. 〇mg '29%, yellow solid). TLC (50% EtOAc/ petroleum ether), Rf = 0.54. LC-MS conditions: column: HALO C18 (2.1x100 mm, 2.7 μΜ) 'mobile phase a : 5 mM NH4OAc, B: acetonitrile; t/% B : 〇min/30/〇, 1.5 /45,2.5/45,3.2/95,4.7/95,5/3 ;flow rate:0.6 mL/min, sample·· MeOH, MS: m/z (observed value): 391.0 [M+H]+. Time: 3·44 min. 4 NMR (400 MHz, DMSO-d6): δ 6.95 (s, 1H), 6.94 (d, J = 6.8 Hz, interchangeable with D20, 1H), 4.64-4.62 (m, lH) , 4.35-4.28 3.72 (s,3H), 3.69- 3.61 (m,3H), 3.37-3.25 (m,2H), 2.58-2.42 2.13-2.07 (m,lH), 1.99-1.77 (m,2H), 1.29 (s, 9H) 1.23-1.15 (m, lH) Step 5:

157033.doc 201215604 5-(3,3-Dimethylbut-1-ynyl)-3-[(trans-4-methylcyclohexylcarbonyl)_[(3S)_2-sideoxy-1-[ (3S) - tetrahydrocarbamate-3-yl] &quot; than bite _3_yl] aminyl] spurt_2_ methyl formate. To 5-(3,3-dimethylbut-1-blockyl)_3_[[(3S)_ 2-oxooxy-1 -[(3S)-tetrahydrofuran] at 0 °C 3-base]. Ratio _3 · yl] amino] thiophene -2- 2-carboxylic acid decyl ester (165 mg, 0-423 mmol), η ratio bite (6 mL), DMAP (25.8 mg '0.212 mmol) in di- ethane (2 〇 A stock solution of trans-4-mercaptocyclohexanone (679 g, 4.23 mmol) in dichloroethane (5 mL) was added dropwise to the solution of the mixture. After the addition, the reaction mixture was stirred at 100 ° C for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with EtOAc (150 mL), washed with 2 N EtOAc (40 mL), 10% NaHC03 (3×50 mL), water (30 mL), brine (20 mL) And concentrated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Petroleum ether), Rf = 〇.51. LC-MS conditions: column: HALO C18 (2.1 x 100 mm, 2.7 μΜ), mobile phase A: 5 mM NH4OAc, B: acetonitrile; t/% B: 0 min/3%, 1.5/45, 2.5/45, 3.2/95, 4.7/95, 5/3; flow rate: 0.6 mL/min, sample: MeOH. MS: m/z (observed): 515.3 [M+H]+. Residence time: 3.77 min 〇 Step 6: 157033.doc •350· 201215604

5-(3,3-Dimethylbut-1-ynyl)-3-[(trans-4-methylcyclohexylcarbonyl)-[(3S)-2- oxo-1-[(3S) -tetrahydrofuran-3-yl]pyrrolidin-3-yl]amino]thiophene-2-carboxylic acid. 'to 5-(3,3-dimercapto-1-ynyl)_3_[(trans-4_indolylcyclohexylcarbonyl)-[(3S)-2-sideoxy-1- at room temperature [(3S)-Tetrahydrofuran-3-yl]pyrrolidin-3-yl]amino]thiophene-2-decanoate (50 mg, 0.097 mmol) in 1:1 mixture of THF and water (2 mL) Added to the stirred solution

Li0H*H20 (12.3 mg'0_291 mmol) and stirred for 3 hours. The progress of the reaction was monitored by TLC. The pH of the reaction mixture was adjusted to ca. 1 using 1 M aqueous EtOAc. EtOAc (20 mL). Mg, 66%, off-white solid). TLC (10% MeOH / CHCl3) Rf = 0.4. LC-MS conditions: column: HALO C18 (2.1 x 100 mm, 2.7 μΜ), mobile phase A: 5 mM NH4OAc, B: acetonitrile; t/% B: 0 min/30/〇, 1.5/45, 2.5/45 , 3.2/95, 4.7/95, 5/3; flow rate: 0.6 mL/min, sample: MeOH. MS: m/z (observed): 501.259 [M+H]+. Residence time: 1.87 min. 4 NMR (400 MHz, DMSO-d6): δ 6.85 (s, 0.27H), 6.69 (s, 0.77H), 5.37-5.33 (m, 0.3H), 4.58-4.53 (m, 0.7H), 3.81- 3.71 (m, 2H), 3.65-3.54 (m, 2H), 3.32-3.13 (m, 1H), 2.83-2.82 (m, lH)s 2.14-1.98 (m, 3H), 1.95-1.77 (m, 3H) ), 1.57-1.50 (m, 3H), 1.50-1.40 (m, lH), 1.27 (s, 9H), 1.23-1.10. 157033.doc •351 · 201215604 Preparation of Compound 157

DMF 80 eC 69%

o Compound 157. The microwave vial was fed with starting acid (33 mg, 0.698 mmol), 4-(2-chloroethyl)morphine (hydrochloride) (195 mg, 1.05 mmol), potassium carbonate (290 mg, 2.10). Methyl) and DMF (6 mL). The reaction was heated in a microwave reactor at 80 C for 30 min then the reaction mixture was partitioned between EtOAc (100 mL) and water (1 mL). The organic layer was separated, washed with brine (EtOAc EtOAc) The residue obtained was purified by MPLC' using Isco Combiflash (40 g column) (0-8% [MeOH containing 2 hydrazine] / DCM, linear gradient, 24 column volume, 40 mL/min). The product obtained by evaporation of the fractions was an oil. The oil was dissolved in MeCN (10 mL) and treated with water (1 mL) and then evaporated and evaporated. 157 (282 mg, 0.482 mmol '69%) was obtained as a white solid. Analysis by LCMS (10-90% MeCN aqueous solution 'formic acid modifier, 5 min, C18). ESI-MS m/z calc. 585.32367 </ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; *H NMR (300.0 MHz, DMSO) δ 7.52 (s, 1 Η), 5.23 (d, J = 11.5 Hz, 1H), 4.39-4.33 (m, 1H), 4.29-4.23 (m, 2H), 3.61 (d , J=3.9 Hz, 1H), 3.54 (t, J=4.5 Hz, 4H), 3.25 (dd, J=4.3j 15.0 Hz, 2H), 2.90 (s, 3H), 2.57 (t, J=5.2 Hz , 2H), 2.44- 157033.doc -352 - 201215604 2.38 (m, 4H), 2.02-1.90 (m, 1H), 1.85-1.66 (m, H), 1.64-1.46 (m, 5H), 1.43-1.36 (m, 2H), l-3〇(s, 9H), 1.23-0.83 (m, 4H), 0.76 (d, J=6.5 Hz, 3H) and 〇.7〇_〇.48 (m, 2H) PPm. Preparation of Compound 158

Compound 158. To a 20 mL microwave vial was fed the starting acid (3 69 mg, 0.7807 mmol), 2,2-dimercaptopropionic acid methyl ester (141.1 mg, 135.0 μί, 0.9368 mmol), potassium carbonate (140.3 mg, 1.015 mmol), sodium hydride (95.66 mg '0.6382 mmol) and DMF (5 mL). The reaction was heated in a microwave reactor at 80 °C for 30 minutes, then the reaction mixture was partitioned between EtOAc and water (80 mL). The organic layer was separated, washed with brine (5 mL EtOAc) The residue obtained was purified by MPLC using Isco Combiflash (40 g column) (0-50% EtOAc/Heptane. The product obtained by evaporation of the solvent was an oil. The oil was dissolved in MeCN (1 mL). 158 (250 mg, 0 '421 mm 〇 1, 54%) was obtained as a white solid. Analysis by LCMS (60-98% MeCN aqueous solution, citric acid modifier, 7 «1111, €4) £31-]^111/2 calculated value 586.3077, experimental value 587.62 (M+1)+; residence time : 3.45 minutes. ΐΗ Ν · (3(κκ() m called DMSO) δ 7.55 (s, 1H), 5.91 (d, J=5.9 Hz, 1H), 5.79 (d, 157033.doc •353 - 201215604 J=5.9 Hz, 1H ), 5.21 (d, J=11.5 Hz, 1H), 3.59 (dd, J=11.2, 15.1 Hz, 1H), 3.24 (dd, 4.0, 15.0 Hz, 1H), 2.90 (s, 3H), 2.01-1.90 (m, 1H), 1.81-1.65 (m, 2H), 1.63-1.48 (m, 5H), 1.45-1.31 (m, 1H), 1.30 (s, 9H), 1.25-1.15 (m, 2H), 1.14 (s, 9H), 1.08-0.84 (m, 3H), 0.75 (d, J = 6.4 Hz, 3H) and 0.70-0.45 (m, 2H) ppm o Preparation of Compound 159

Compound 159. The microwave vial was fed with starting acid (3〇3 mg, 0.641 mmol), gas isopropyl isopropyl carbonate (117.4 mg, 0.7693 mmol), carbon brewing (115.2 mg '0.8334 mmol), sodium change (46 mg, 0·31 mmol·) and DMF (6 mL). In the microwave at 80. (The next heating was carried out for 30 minutes, then the reaction mixture was partitioned between EtOAc and EtOAc (EtOAc)EtOAc. Purified by MPLC using Isco Combiflash (40 g column) (〇 _ 100 ° / EtOAc / heptane linear gradient, 24 column volume, 40 mL / min). The product obtained by evaporation of the fraction was oil. The oil was dissolved in EtOAc (10 mL) EtOAc (EtOAc)EtOAc. Analysis by LCMS (6〇_98% MeCN aqueous solution 'tannic acid modifier' 7 min ' C4). ESI-MS m/z calculated 157033.doc •354- 201215604 588.2869, experimental value 589_60 (M+l ) + retention time: 3 〇 6 minutes. 4 NMR (400.0 MHz, DMSO) δ 7.55 (s, 1H), 5 91 (d J = 6 2 Hz, 1H), 5.78 (d, J = 6.2 Hz, 1H ), 5.23 (d, 8 Hz 1H) 4.81 (qn, J = 6.2 Hz, 1H), 3.61 (dd, J = u 4, 15 i Hz 1H) 3.29-3.22 (m, 1H), 2.90 (s, 3H) ), 1.94 (t, j=U 6 Hz, 1H) 1.79-1.33 (m, 1 OH), 1.30 (s, 9H), 1.24 (dd, j=i 5 6 2 Hz 6H), 1.20-0.90 (m, 3H), 0.76 (d, J = 6.4 Hz, 3H) and 0 73-0 48 (m, 2H) ppm o Preparation of Compound 160

Compound 160. Feed the starter acid (375 mg ' 0.793 mmol), 2-methylpropionic acid decyl ester (250 mg, 1.83 mmol), potassium carbonate (142.5 mg, 1.031 mmol), sodium iodide into a 20 mL microwave vial (97.2 mg, 26.5 μΐ^, 0.649 mmol) and DMF (6 mL). At 80. The mixture was partitioned between EtOAc and EtOAc (EtOAc (EtOAc)EtOAc. Purified by MPLC using Isco Combiflash (40 g column) (0-100 ° / EtOAc / heptane linear gradient, 24 column volume, 40 mL / min). The product obtained by evaporation of the fraction was oil. The oil was dissolved in MeCN (5 mL) <RTI ID=0.0>(</RTI> EtOAc (5 mL). 201215604 0.288 mmo 32%). Analyzed by LCMS (60-98% MeCN aqueous solution, citric acid modifier, 7 min, C4) ESI-MS m/z calc. 572.292, calc. 57.61 (^1+1 +) retention time: 3.18 minutes. *H NMR (300.0 MHz, DMSO) δ 7.55 (s, 1 Η), 5.91 (d, J = 6.0 Hz, 1H), 5.78 (d, J = 6.0 Hz, 1H), 5.21 (d, J=11.5 Hz, 2H), 3.57 (d, J=ll.l Hz, 1H), 3.27 (d, J=2.9 Hz, 1H), 2.90 (s, 3H), 2.60-2.50 (m , 1H), 2.01-1.87 (m, 1H), 1.82-1.33 (m, 9H), 1.30 (s, 9H), 1.29-1.11 (m, 2H), 1.09 (dd, J=1.2, 7.0 Hz, 6H), 1.03-0.86 (m, 1H), 0.76 (d, J = 6.4 Hz, 3 prints and 0.71 - 0.47 (m, 2H) ppm ° 161

Compound 161. The starting acid (320 mg, 0.677 mmol) and 4-(bromoindolyl)-5-mercapto-1,3-dioxol-2-one (156.8 mg, were locked in a 20 mL microwave vial. 0.8124 mmol), carbonic acid clock (121.6 mg, 0.8801 mmol), sodium moth (48.6 mg, 13·2 μΐ^ '0.324 mmol) and DMF (6 mL). It was heated in a microwave at 80 °C for 25 minutes, then the reaction mixture was partitioned between EtOAc and water (80 mL). The organic layer was separated, washed with brine (50 mL) &lt The residue obtained was purified by MPLC using Isco Combiflash (40 g column) (〇_i〇〇〇/〇Et〇Ac/157033.doc •356-201215604 hexane linear gradient, 24 column volumes, 40 mL/ Min) purification. The product obtained by evaporating the dissolved fraction was dissolved in MeCN (10 mL), treated with water (10 mL), and then the resulting solution was frozen, followed by lyophilization. 161 (210 mg '0.347 mmol, 51%) was obtained as a white solid. Analyzed by LCMS (60-983⁄4 MeCN aqueous solution, succinic acid modifier, 7 min, C4) ESI-MS m/z calc. 584.2556, calc. 585.57 (M+l)+; retention time: 2.61 min. 1HNMR(300.0)V[Hz,DMSO)δ7.52O, 1H), 5.28-5.08 (m, 3H), 3.61 (dd, J=11.3, 15.1, 1H), 3.29-3.22 (m, 1H), 2.90 ( s, 3H), 2.17 (s, 3H), 2.00-1.31 (m, 9H), 1.30 (s, 9H), 1.28-0.85 (m, 5H), 0_75 (d, J = 6.5 Hz, 3H) and 0.70 -0.46 (m, 2H) ppm. Preparation of Compound 162

Compound 162. To a 20 mL microwave vial was fed starting acid (300 mg, 0.6321 mmol), carbonic acid clock (113_6 mg, 0.8217 mmol), sodium moth (66.33 mg, 18.09 pL, 0.4425 mmol), DMF (10 mL) and 2,2-Dimercaptopropionic acid methyl ester (114.2 mg, 109.3 gL, 0.7585 mmol). It was heated in a microwave at 80 °C for 20 minutes, then the reaction mixture was partitioned between EtOAc and water (80 mL). The organic layer was separated, washed sequentially with water and brine brine The residue obtained was purified by MPLC using EtOAc (40 g column) (0-60% EtOAc / 157033.doc: 357 - 201215604 hexanes, gradient, 24 column volume, 40 mL/min). The product isolated from the column was dissolved in MeCN (10 mL) and treated with water (8 mL). 162 (3 16 mg, 0.534 mmol, 84%) was obtained as a white solid. Analysis by LCMS (60-98%)

MeCN aqueous solution, citric acid modifier, 7 min, C4). ESI-MS m/z calculated 588.2869, experimental value 589.6 (M+l)+; retention time: 3.04 minutes. 1H NMR (300.0 MHz, DMSO) δ 7.27 (s, 1H), 5.89 (d, J = 5.9 Hz, 1H), 5.82 (d, J = 5.9 Hz, 1H), 4.92 (d, J = 16.7 Hz, 1H ), 3.85 (d, J=16.6 Hz, 1H), 3.55 (br s, 4H), 3.41-3.35 (m, · 4H), 2.11-1.98 (m, 1H), 1.70-1.34 (m, 6H), 1.30 (s, 9H), 1.28-1.20 (m, 1H), 1.14 (s, 9H), 0.77 (d, J = 6.5 Hz, 3H) and 0.74-0.57 (m, 2H) ppm. Preparation of Compound 163

Compound 163. Feeding starter acid (300 mg, 0.597 mmol), carbonic acid unloading (107 mg, 0.776 mmol), moth (62.6 mg, 17.1 pL, 0.418 mmol), DMF (10 mL) and a 20 mL microwave vial Methyl 2,2-dimethylpropanoate (108 mg, 103 gL, 0.716 mmol). It was heated in a microwave at 80 ° C for 20 minutes, and then the reaction mixture was partitioned between Et 〇Ac and water (80 mL each). The organic layer was separated, washed sequentially with water, brine (di.g.), dried (MgSO4), filtered and concentrated. The residue obtained is obtained by 157033.doc -358- 201215604

MPLC was purified using an Isco Combiflash (40 g column) (0-60% EtOAc/hexanes gradient, 24 column volumes, 4 〇 mL/min). The product isolated from the column was dissolved in MeCN (10 mL) and treated with water (8 mL), and then the mixture was frozen and lyophilized. 163 (301 mg, 0.470 mmo, 79%) was obtained as a white solid. Analysis by LCMS (60-98% MeCN aqueous solution, formic acid modifier, 7 min, C4). ESI-MS m/z calculated 616.31824, found 617.56 (M+l)+; retention time: 3.49 minutes. NMR shows rotamer) H NMR (300.0 MHz, DMSO) δ 7.34 (s, 0.6H), 7.27 (s, 0.4H), 5.91-5.75 (m, 2H), 5.56 (t, J = 7.5 Hz , (H, MH) -1.35 (m, 6H), 1.34-1.16 (m, 12H), 1.13 (s, 9H) and 0.80-0.68 (m, 8H) ppm 〇 Preparation of compound 164

ο

Cl

Nal, K2C03 OMF 80 X 82% Compound 164 » Feeding starter acid (300 mg, 0.651 mmol), carbonic acid unloading (117 mg, 0.847 mmol), sodium (68.3 mg, 18.6 μM) into a 20 mL microwave vial ^,0.456 mmol), DMF (10 mL) and 2,2-dimethylpropanoic acid chloroacetate (118 mg, 113 pL, 0.782 mmol). It was heated in a microwave at 80 °C for 20 minutes, then the reaction mixture was partitioned between EtOAc and water (80 mL). The organic layer was separated, washed sequentially with water and brine brine The residue obtained was purified by 157033.doc -359 - 201215604 MPLC using Isco Combiflash (40 g column) (0-60% EtOAc/hexanes gradient, 24 column volume, 4 〇 mL/min). The product isolated from the column was dissolved in MeCN (10 mL) and treated with water (8 mL), and then the mixture was frozen and lyophilized. 165 (3 〇 8 mg, 0.532 mmol '82%) was obtained as a white solid. Analysis by LCMS (60-98% MeCN aqueous solution 'formic acid modifier, 7 min, C4). ESI-MS m/z calc. 574.3077, calc. 575. (4 NMR showed rotamer). NMR (300.0 MHz, DMSO) δ 7.31 (s, 0.6H), 7.24 (s, 0.4H), 5.90 (d, J = 6.0 Hz, 0.6H), # 5.81 (d, J = 5.0 Hz, 1.4H) , 5.58 (t, J=7.5 Hz, 0.4H), 5.16 (dd, J=6.2, 8.8 Hz, 0.6H), 3.10 (s, 1.8H), 3.05 (s, 1.2H), 2.85 (s, 1.8 H), 2.65 (s, 1.2H), 1.99-1.84 (m, 1H), 1.66-1.33 (m, 6H), 1.33-1.15 (m, 12H), 1.14 (s, 9H) and 0.79-0.49 (m , 8H) ppm. Preparation of Compound 165

Compound 165. Feed the starter acid (300 mg, 0.632 mmol), potassium carbonate (114 mg, 0.822 mmol), sodium sulphate (66.3 mg ' 18.1 μ!^, 0.442 mmol), DMF (10 mL) into a 20 mL microwave vial And chloromethyl isopropyl carbonate (116 mg, 0.758 mmol). It was heated in a microwave at 80 °C for 20 minutes, then the reaction mixture was partitioned between EtOAc and water (80 mL). The organic layer was separated, washed sequentially with water, brine (lilu. The resulting residue was obtained by MPLC using Isco 157033.doc •360· 201215604

Purified by Combiflash (40 g column) (0-80% EtOAc / hexanes gradient, 24 column volume, 40 mL / min). The product isolated from the column was dissolved in MeCN (10 mL) and treated with water (8 mL). 166 (291 mg, 0.479 mmol '76%) was obtained as a white solid. Analysis by LCMS (60-98% MeCN aqueous solution, formic acid modifier, 7 min, C4). ESI-MS m/z calculated 590.2662, found 591.59 (M+l)+; retention time: 2.59 min. !H NMR (300.0 MHz, DMSO) δ 7.27 (s, 1 Η), 5.84 (dd, J=6.2, 9.7 Hz, 2H), 4.91 (d, J = 16.7 Hz, 1H), 4.80 (seven peak, J= 6.2 Hz, 1H), 3.89 (d, J=16.7 Hz, 1H), 3.55 (br s, 4H), 3.45-3.35 (m, 4H), 2.13-1.98 (m, 1H), 1.79-1.33 (m, 7H), 1.30 (s5 9H), 1.24 (d, J = 6.2 Hz, 6H), 0.77 (d, J = 6.4 Hz, 3H) and 0.75-0.57 (m, 2H) ppm. Preparation of Compound 166

Compound 166. To a 20 mL microwave vial was fed the starting acid (7 1.49 mg '0.5173 mmol), moth (41.75 mg, 11.39 μιη, 0.2785 mmol), DMF (7 mL) and chloromethyl isopropyl carbonate ( 72.86 mg, 0-4775 mmol). It was heated in a microwave at 80 °C for 20 minutes, then the reaction mixture was partitioned between EtOAc and water (80 mL each). The organic layer was separated, washed sequentially with water and brine (yield: 80 mL), dried (MgSO4), filtered and concentrated. The residue obtained was purified by MPLC using Isco Combiflash (40 g tube 157033.doc - 361 - 201215604 column) (0-80% EtOAc/hexanes gradient, 24 column volume, 40 mL/min). The product isolated from the column was dissolved in MeCN (10 mL) and treated with water (8 mL). 166 (213 mg, 0.331 mmol, 83%) was obtained as a white solid. Analysis by LCMS (60-98% aqueous solution of MeCN, formic acid modifier, 7 min &apos; C4) ESI-MS m/z </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; (1H NMR shows rotamer NMR (300.0 MHz, DMSO) δ 7.36 (s, 0.6H), 7.27 (s, 0.4 Η), 5.89 (d, J = 6.3 Hz, 0.6H), 5.81-5.74 (m, 1.4H), 5.56 (t, J=7.4 Hz, 0.4H), 5.19 (dd, J=6.5, 8.5 Hz, 0.6H), 4.88-4.73 (m, 2H), 3.73-3.35 (m, 7.6H) , 3.23-3.12 (m, 0.4H), 1.97-1.84 (m, 1H), 1.66-1.34 (m, 6H), 1.32-1.07 (m, 17H) and 0.81 - 0.47 (m, 8H) ppm. 167

Compound 167. Feed the starter acid (300 mg, 0.651 mmol), potassium carbonate (117 mg, 0.847 mmol), sodium iodide (68.3 mg ' 18.6 μΐ^ ' 0.456 mmol), DMF (10 mL) into a 20 mL microwave vial Methyl isopropyl carbonate (119 mg, 0.782 mmol). It was heated in a microwave at 8 Torr: 20 min, then the reaction mixture was partitioned between EtOAc and water (80 mL). The organic layer was separated, washed sequentially with water, brine (lilu. The resulting residue was obtained by MPLC using Isco 157033.doc •362· 201215604

Purified by Combiflash (40 g column) (0-80% EtOAc / hexanes gradient, 24 column volume, 40 mL / min). The product isolated from the column was dissolved in MeCN (10 mL) and treated with water (8 mL). The mixture was then chilled and lyophilized. 167 (306 mg, 0.519 mmol, 80%) was obtained as a white solid. Analysis by LCMS (60-98% MeCN aqueous solution, formic acid modifier, 7 min, C4). ESI-MS m/z calc. 576.2869, found 577.57 (M+l)+; retention time: 3.05 min. (1^ NMR shows rotamer)! NMR (300.0 MHz, DMSO) δ

7.33 (s, 0.55H), 7.24 (s, 0.45H), 5.89 (d, J=6.3 Hz, 0.55H), 5.81 (dd, J=6.3, 8.0 Hz, 1H), 5.73 (d, J=6.3 Hz, 0.45H), 5.58 (t, J=7.5 Hz, 0.45H), 5.16 (d, J=2.4 Hz, 0.55H), 4.87-4.85 (m, 1H), 3.11 (s, 1.65H), 3.02 (s, 1.35H), 2.85 (s, 1.65H), 2.63 (s, 1.35H), 1.99-1.86 (m, 1H), 1.67-1.35 (m, 6H), 1.34-1.08 (m, 18H) and 0.82-0.51 (m, 8H) ppm. Preparation of Compound 168

Compound 168. Feeding starter acid (300 mg, 0.632 mmol), carbonic acid unloading (114 mg, 0.822 mmol), sodium hydride (66.3 mg, 18.1 pL, 0.442 mmol), DMF (l〇mL) into a 20 mL microwave vial And 4-(bromomethyl)-5-mercapto-1,3-dioxol-2-one (146 mg, 0.758 mmol). It was heated in a microwave at 80 °C for 20 minutes, then the reaction mixture was partitioned between EtOAc 157033.doc 363·201215604 and water (80 mL each). The organic layer was separated, washed sequentially with water and brine (8 mL), dried (MgSO4), filtered and concentrated. The residue obtained was purified by MPLC using EtOAc EtOAc EtOAc (EtOAc) The product isolated from the column was dissolved in MeCN (10 mL) and treated with water (8 mL), and then the mixture was frozen and lyophilized. 168 (29 mg, 0.476 mmol, 75%) was obtained as a white solid. Analysis by LCMS (6 〇 98% MeCN aqueous solution 'formic acid modifier, 7 min, C4). ESI-MS m/z calculated value 586.23486, experimental value 587.55 (M+l)+; retention time: 2.25 minutes. NMR (300.0 MHz, DMSO) δ 7.24 (s, 1H), 5.18 (d, J = 14.1 Hz, 1H), 5.12 (d, J = 14.1 Hz, 1H), 4.89 (d, J = 16.7 Hz, 1H) , 3.92 (d, J=16.7 Hz, 1H), 3.61-3.48 (m, 4H), 3.47-3.33 (m, 4H), 2.17 (s, 3H), 2.13-2.00 (m, 1H), 1.73-1.33 (m, 5H), 1.30 (s} 9H), 1.30-1.15 (ms 2H), 0.77 (d, J = 6.5 Hz, 3H) and 0.73-0.55 (m, 2H) ppm o Preparation of Compound 169

Compound 169. Feeding starter acid (300 mg, 0.597 mmol), carbonic acid unloading (107 mg, 0.776 mmol), sodium moth (62.6 mg, 17.1 μΐ^, 0.418 mmol), DMF (10 mL) into a 20 mL microwave vial And 4-(bromomethyl)-5- I57033.doc -364- 201215604 fluorenyl-1,3 - oxacyclo-2 -indole (138 mg, 0.716 mmol). It was heated in a microwave at 80 ° C for 20 minutes, then the reaction mixture was partitioned between EtOAc and water (80 mL). The organic layer was separated, washed sequentially with water and brine (8 mL), dried (MgSO4), filtered and concentrated. The residue obtained was purified by MPLC using EtOAc (40 g column) (0-100% EtOAc / hexanes &lt The product isolated from the column was dissolved in MeCN (10 mL) and treated with water (8 mL). 169 (280 mg, 0.441 mmol, 74%) was obtained as a white solid. Analysis by LCMS (60^98% MeCN in water, citric acid modifier, 7 min, C4). ESI-MS m/z calculated value 614.2662 ‘Experimental value 615.58 (M+l)+; retention time: 2.61 minutes. 1H NMR showed rotamer. 1H NMR (300.0 MHz, DMSO) δ 7.31 (s, 0.6 Η), 7.24 (s, 0.4H), 5.55 (t, J = 7.5 Hz, 0.4H), 5.25-5.05 (m, 2.6H), 3.78- 3.40 (m, 7.6H), 3.09-2.99 (m, 0.4H), 2.17 (Sj 3H), 1.98-1.85 (m, 1H), 1.65-1.33 (m, 6H), 1.32-1.05 (m, 12H) And 0.81-0.47 (m, 8H) ppm. Preparation of compound 170

Compound 170. Feed the starter acid (300 mg, 0.651 mmol), cesium carbonate (117 mg, 0.847 mmol), and enamel (68.3 157033.doc -365-201215604 mg ' 18·6 pL, 0.456) into a 20 mL microwave vial Methyl), DMF (10 mL) and 4-(bromomethyl)-5-methyl-1,3-dioxolone (151 mg, 0.782 mmol). It was heated in a microwave at 80 ° C for 20 minutes, and then the reaction mixture was partitioned between Et 〇Ac and water (80 mL each). The organic layer was separated, washed sequentially with water and brine (8 mL), dried (MgSO4), filtered and concentrated. The residue obtained was purified by MPLC using Isco Combiflash (40 g column) (0-100% EtOAc / hexanes gradient) 24 column volume, 40 mL / min. The product separated from the column was dissolved in MeCN (10 mL) and treated with water (8 mL), and then the mixture was frozen and lyophilized. 170 (290 mg, 0.506 mmol, 78%) was obtained as a white solid. Analysis by LCMS (60-98% aqueous solution of MeCN, formic acid modifier, 7 min, C4). ESI-MS m/z calculated value 572.2556, experimental value 573.61 (M+l)+; retention time: 2.66 minutes. 1H NMR showed rotamer. NMR (300.0 MHz, DMSO) δ 7.28 (s, 0.6H), 7.21. (s, 0.4H), 5.55 (t,J = 7.5 Hz, 0.4H), 5.24-5.12 (m, 2.2H), 5.02 (d) , J=14.2 Hz, 0.4H), 3.10 (s, 1.8H), 3.05 (s, 1.2H), 2.85 (s, 1.8H), 2.64 (s, 1.2H), 2.17 (s, 3H), 1.96 -1.85 (m, 1H), 1.66-1.33 (m, 6H), 1.32-1.05 (m, 12H) and 0.79-0.47 (m, 8H) ppm. Preparation of Compound 171

Compound 171. Feed the starter acid (300 mg ' 157033.doc -366- 201215604 0.632 mmol), carbonic acid clock (114 mg ' 0.822 mmol), Einna (66.3 mg ' 181 pL, 0.442 mmol) into a 20 mL microwave vial DMF (10 mL) and chloromethyl 2-methylpropionate (104 mg, 0.758 mmol). Heating at 80 ° C for 20 minutes in the microwave

The reaction mixture was partitioned between EtOAc and water (EtOAc). The organic layer was separated, washed sequentially with water and brine (yield: 80 mL), dried (MgSO4), filtered and concentrated. The resulting residue was purified by MPLC using EtOAc EtOAc (EtOAc) The product isolated from the column was dissolved in MeCN (10 mL) and treated with water (8 mL). 171 (214 mg, 0.368 mmol, 58%) was obtained as a white solid. Analysis by LCMS (60-98% MeCN aqueous solution, citric acid modifier, 7 min, C4). ESI-MS m/z calc. 5 74.2713, calc. 575.59 (M+l)+; retention time: 2.9 min. lH NMR (300.0 MHz, DMSO) δ 7.26 (s, 1 Η), 5.85 (dd, J=5.9, 16.9 Hz, 2H), 4.91 (d, J = 16.7 Hz, 1H), 3.86 (d, J = 16.7 Hz , 1H), 3.62-3.48 (m, 4H), 3.44-3.33 (m, 4H), 2.65-2.55 (m, 1H), 2.13-1.98 (m, 1H), 1.78-1.35 (m, 5H), 1.30 (s, 9H), 1.29-1.18 (m, 2H), l-〇8 (d, J=7.0 Hz, 6H), 0.77 (d, J=6.5 Hz, 3H) and 0.74-0.58 (m, 2H) Ppm. Preparation of Compound 172

Nal, K2C03 DMF 80 °C 77% 157033.doc -367- 201215604 Compound 172. Feed the starter acid (300 mg, 0.597 mmol), potassium bromate (107 mg '0.776 mmol), sodium iodide (62.6 mg, 17.1 μί, 0.418 mmol), DMF (10 mL) into a 20 mL microwave vial And 2-mercaptopropionic acid gas ester (97 _ 8 mg, 0.716 mmol). It was heated in a microwave at 80 °C for 20 min, then the reaction mixture was partitioned between EtOAc and water (80 mL). The organic layer was separated, washed with water and brine (yield: 80 mL), dried (MgSO4), filtered and concentrated. The residue obtained was purified by MPLC using EtOAc Combiflash (40 g column) (0-80% EtOAc/hexanes gradient, 24 column volume &apos; 40 mL/min). The product isolated from the column was dissolved in MeCN (10 mL) and treated with water (8 mL), and then the mixture was lyophilized and lyophilized. 172 (28 mg, 〇.46 () mmol ' 77%) was obtained as a white solid. Analysis by LCMS (60-98% MeCN aqueous solution, formic acid modifier '7 11^11' €4) ugly 81^8 111/2 calculated value 602.30255, experimental value 603.68 (PCT +1) +; residence time: 3.36 minutes. 111^111 shows rotamer 4 NMR (300.0 MHz, DMSO) δ 7.34 (s, 0.6 Η), 7.27 (s, 0.4H), 5.90 (d, J = 6.0 Hz, 0.6H), 5.85-5.76 (m, 1.4H), 5.56 (t, J=7.3 Hz, 0.4H), 5.18 (dd, J = 6.4, 8.6

Hz, 0.6H), 3.75-3.35 (m, 7.6H), 3.20-3.09 (m, 0.4H), 2.62-2.53 (m, 1H), 1.98-1.82 (m5 1H), 1.65-1.34 (m, 6H ), 1-32-1.13 (m, 12H), 1.10-1.06 (m, 6H)^ 0.82-0.49 (m, 8H) ppm o Preparation of compound 173 157033.doc •368- 201215604

Cr ο

Nal, K2C03 DMF 80 eC 72%

Compound 173. To a 20 mL microwave vial was fed starting acid (3 〇〇 mg, 0.651 mmol), potassium carbonate (117 mg, 0.847 mmol), sodium iodide (68.3 mg, 18.6 μιη, 0.456 mmol), DMF (10 mL) And chlorodecyl 2-mercaptopropionate (107 mg, 0.782 mmol). Heat 20 minutes at 8 °C in the microwave

The mixture was then partitioned between EtOAc and water (80 mL each). The organic layer was separated, washed sequentially with water and brine (yield: 80 mL), dried (MgSO4), filtered and concentrated. The resulting residue is obtained by MPLC using Isc〇

Purified by Combiflash (40 g column) (0-80% EtOAc/hexanes gradient, 24 column volume, 40 mL/min). The product isolated from the column was dissolved in MeCN (10 mL) and treated with water (8 mL), and then the mixture was lyophilized and lyophilized. 173 (265 mg, 466 466 mmo, 72%) was obtained as a white solid. Analysis by LCMS (60-98% aqueous solution of MeCN, succinic acid modifier, 7 min &apos; C4) ESI-MS m/z calc. 560.292, calc. 561.64 (M+l)+; retention time: 3.41 min. 4 NMR showed the rotation of the isomer. 1H NMR (300.0 MHz, DMSO) δ 7.31 (s, 0.6H), 7.23 (s, 0.4H), 5.90 (d, J = 6.0 Hz, 0.6H), 5.82-5.75 (m, 1-4H), 5.58 (t, J=7.5 Hz, 0.4H), 5.15 (dd, J=6.2, 8.8 Hz, 〇.6H), 3.10 (s, 1.8H), 3.04 (s, 1.2H), 2.85 (s, 1.8H) ), 2.65 (s, 1.2H), 2.63-2.53 (m, 1H), 1.99-1.85 (m, 1H), 1.65-1.32 (m, 6H), 1.32-1.12 (m, 12H), 1.08 (d, J = 7.0 Hz, 6H) and 0.79-157033.doc • 369· 201215604 0.47 (m, 8H) ppm. Preparation of Compound 174 (Predicted) Step 1:

5-(3,3-dimethylbut-1-ynyl)-3-(1-methyl-2-oxooxy-1,2-dihydropyridin-3-ylamino)thiophene-2- Methyl formate. 3-Bromo-5-(3,3-dimethylbut-1-ynyl)thiophene-2-decanoate (594 mg, 3.49 mmol), 3-amino-1-methylpyridine-2 ( 1H)· Ketone (288 mg, 2.32 mmol), Cs2C03 (2.27 g, 6.98 mmol) in a suspension of toluene (15 mL) was purged with a stream of argon for 60 minutes to remove oxygen, followed by the addition of Pd ( OAc) 2 (52.2 mg, 0.232 mmol) and (±) BINAP (144 mg, 0.232 mmol) and purification was continued for another 30 minutes and stirred at 100 ° C for 16 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with EtOAc (l EtOAc) and filtered over EtOAc. The filtrate was washed with water (2×50 mL), brine (2 mL) and dried over Naj. The residue obtained is purified by column chromatography (100-200 mesh EtOAc EtOAc EtOAc/EtOAc) Step 2: 157033.doc • 310· 201215604

Compound 174 methyl ester. To 5-(3,3-dimethylbut-1-ynyl)·3-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl) at 〇 °C a solution of methyl thiophene-2-carboxylate (146 mg, 0.423 mmol), pyridine (6 mL), DMAP (25.8 mg, 0.212 mmol) in dichloroethane (20 mL) Add force? A stock solution of trans-4-methylcyclohexane helium (679 g, 4.23 mmol) in dioxane (5 mL). After the addition, the reaction mixture was at 1 Torr. The mixture was stirred for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with EtOAc (150 mL) and washed with &lt;RTIgt;2N </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; The residue obtained by drying and concentrating was purified by column chromatography (100-200 mesh, EtOAc, 50% EtOAc / pet. Step 3 ··

LiOH*H2(R) (12_3 mg' 〇·291 _〇1) was added to the stirred solution in a 1:1 mixture of water (2 mL) and stirred for 3 hours. The progress of the reaction was monitored by tlc 157033.doc -37!- 201215604. The pH of the reaction mixture was adjusted to ca. 1 using EtOAc (EtOAc) (EtOAc) (EtOAc) (EtOAcjjjjjjj (prediction)

Compound 175 can be prepared according to the procedures described for compounds 107, 112. Preparation of Compound 176 (predicted)

Compound 176 can be prepared according to the procedures described for compounds 95, 128, 144. Preparation of compound 1 预测 (predicted)

Compound 177 can be prepared according to the procedures described for compounds 117, 128, 144. Preparation of compound 17S (predicted) 157033.doc •372- 201215604

Compound 178 can be prepared according to the procedures described for compounds 83, 128, 144. Preparation of Compound 179 (predicted)

#杂7, 2: Steps 1 and 2 can be carried out as described in J.丨 w. C/zem. 1988, 1238. #锵3: Step 3 can be carried out as described for compound 6.

Compound 179. Steps 4-6 can be carried out according to the procedures described for compounds 95, 176. Preparation of Compound 180 (predicted)

#锧7, 2: Steps 1 and 2 can be carried out as described in J. Jw. C/zem. Soc. 1988, 1238. #锧3: Step 3 can be carried out as described for compound 6. 157033.doc -373 - 201215604

Compound 180. Steps 4-6 can be carried out according to the procedures described for compounds 95, 176. Preparation of Compound 181 (predicted)

Compound 181. Steps 1-3 can be carried out according to the procedures described for compounds 14, 179. Preparation of Compound 182 (predicted)

Compound 182. Steps 1-3 can be carried out according to the procedures described for compounds 14, 180. Preparation of Compound 183 (predicted)

Compound 183. Steps 1-3 can be carried out according to the procedures described for compounds 12,179. Preparation of Compound 184 (predicted) 157033.doc - 374- 201215604

Compound 186. Steps 1-3 can be carried out according to the procedures described for compounds 12,180. Preparation of compound predictions)

Compound 185. Steps 1-3 can be carried out according to the procedures described for compounds 13, 179. Preparation of Compound 186 (predicted)

Compound 186. Steps 1-3 can be carried out according to the procedures described for compounds 13, 180. Preparation of compound U7 (predicted)

Compound 187. Steps 1-3 can be carried out according to the procedures described for compounds 83, 91, 92, 179. 157033.doc -375 - 201215604 Preparation of compound 188 (predicted)

Compound 188. Steps 1-3 can be carried out according to the procedures described for compounds 83, 91, 92, 180. Preparation of Compound 189 (predicted)

Compound 189. Steps 1-3 can be carried out according to the procedures described for compounds 117, 179. Preparation of Compound 190 (predicted)

Compound 190. Steps 1-3 can be carried out according to the procedures described for compounds 117, 180. Preparation of Compound 191 (predicted)

# # /, 2 .· Steps 1 and 2 can be performed according to J. Jm. C/zew. *Soc. 1988, 1238. 157033.doc -376- 201215604 #杂3 .· Step 3 can be carried out as described for compound 6 and the like.

Compound 191. Steps 4-6 can be carried out according to the procedures described for compounds 95, 176. Preparation of Compound 192 (predicted)

Compound 192. Steps 1-3 can be carried out according to the procedures described for Compound 14, 181, 191. Preparation of Compound 193 (predicted)

Compound 193. Steps 1-3 can be carried out according to the procedures described for Compounds 12, 181, and 191. Preparation of Compound 194 (predicted)

Compound 194. Steps 1-3 can be carried out according to the procedure described for Compounds 13, 191, 157033.doc -377 - 201215604. Preparation of Compound 195 (predicted)

Compound 195. Steps 1-3 can be carried out according to the procedures described for compounds 83, 91, 92, 191. Preparation of Compound 196 (predicted)

Compound 196. Steps 1-3 can be carried out according to the procedures described for compounds 117, 191. Example 2: PK parameters for certain compounds of the invention To determine the PK parameters of certain compounds of the invention, the compounds can be formulated to 0.5% MC/0.5% Tween 80/99°/. A solution in water was administered to the rats by oral gavage at a dose of 3 mg/kg. The rats were weighed the day before the study. Instech automated blood sampling equipment was used before and at 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours after administration. Rat plasma was sampled. Blood was collected in tubes containing K2-EDTA and 90 pL of plasma was extracted for analysis. Rats were fed ad libitum and standard IACUC and SOP protocols were performed as follows. Plasma samples and dose samples were analyzed using LC/MS/MS. The PK parameters of Compound 160 were measured as described in the previous paragraph, and the number 157033.doc -378 - 201215604 was shown to be converted (more than 50%) to Compound 95. Example 3: HCV Replicon Assay This procedure describes the use of Huh7 hepatoma cell line (hereinafter referred to as cell line ET) containing a highly cell culture-adapted replicon (genotype lb) for HCV replication. Sub-certification. High cell culture adaptive replicon contained in ET cells The l389luc-ubi-neo/NS3-3'/5.1 construct carries a complete copy of the firefly luciferase gene in addition to the neomycin gene (Krieger, N; Lohmann, V; Bartenschlager, R. Enhancement of hepatitis C virus RNA replication by cell culture-adaptive mutations. ·/. Fi&gt;o/· 2001, 75, 4614-4624). A replicon cell line W11.8 containing the genotype of HCV was also used. These two cell lines (genotypes lb and la) allow for the measurement of RNA replication by measuring luciferase activity (for genotype lb) or by measuring NS5A content (for genotype la) by ELISA. Translation. It has been shown that luciferase activity in ET cells is a function of replicon RN A content. The ET cell strain was maintained in the culture at a subconfluent content (&lt;85%). The medium used for cell passage was composed of DMEM (Gibco BRL Laboratories, Mississauga, ON, Canada) supplemented with 10% fetal bovine serum and 1% penicillin/streptavidin, 1 °/. Bran tyrosine, 1% sodium pyruvate, 1% non-essential amino acid, and G418 at a final concentration of 180 pg/ml. B. Measurement of luciferase activity (Luci-ET-lb&gt; To treat cells with test drug, the medium was removed by aspiration from a 175 cm2 T-flask. The cell monolayer was rinsed with 10 mL PBS at room temperature. 1 time. 157033.doc -379· 201215604 Remove PBS by aspiration. Cells were trypsinized using 1 mL trypsin/EDTA. The flask was incubated at 37t (incubator) for 7 minutes. Then add no G418 and no Complete medium of phenol red (9 mL). The cell pellet was fragmented by pipetting up and down several times. The cell suspension was then transferred to a 5 mL mL Falcon polypropylene tube. The cells were then counted several times using a hemocytometer. Cells were diluted to 3 cells/ml with complete DMEM without G418 and no phenol red, and then transferred to a sterile reservoir. Using a multi-injection pipette in each well of a 96-well white opaque microtiter plate Inoculate approximately 3 live cells (100 μ! 〇. Add various concentrations of compound in a 5% C〇2 incubator at a 3 rc for a 24-hour incubation period. The compound under test is 100 mM The reserve concentration is resuspended in DMs. Then, According to the specific template in a sterile 96 deep well plate, dilute at twice the final concentration in the same medium (no G418) described earlier. Then add a volume in each well containing the cells or in the control well without cells (1〇 The dilution of each compound of 〇μΙ〇 “The final drug concentration is generally between 2〇〇 and 〇·_μΜ. Make the ten wells as the positive control well without drug. The cells are in the 5% C〇2 incubator. In the next step, the same concentration of the control compound was used as the internal standard. The four money was incubated, the medium was removed and poured onto a pile of sterile absorbent paper for rapid drying. Then, by using multi-injection pipetting 95 luciferase buffer A was added to lyse the cells, sealed with a T〇pSealTM adhesive sealing film, and the reaction mixture was incubated at room temperature and avoid direct light for at least a minute. The luminometer was read using a luminometer Photozyme count (wai^

MicroBeta Trilux, Perkin ElmerTM, ΜΑ USA) 〇 .I57033.doc • 380· 201215604 Calculate the percent inhibition (double replicate) at each drug concentration tested. A non-linear regression analysis (e.g., GraphPad Software lcn., San Dieg(R), CA, USA) was used to determine the concentration (JC50) necessary to reduce viral replication by 50% based on the reaction curve in the agent. The IC50 values are summarized in Tables 1-3: A: IC5G value (average value) μΜ; Β: 〇-1 μΜ&lt;Ι(:50 value (average) $ι μΜ ; C : 1 kM&lt;IC5G value (average χι〇μΜ ; D: IC5 〇 value (average value) &gt; ι〇μΜ. C· Elisa assay (ELISA W 11.8-la) Detection of HCV replicon cells using ELISA uses a subgenome containing genotype la Replicon replicon cell line wii, 8. Indirectly measure RNA replication in these cell lines in the presence of different concentrations of drug based on the level of NS5A protein content after four days of drug treatment. NS5A is a non-structural protein of HCV and Used as a marker for HCV replication in this assay. To treat cells with test drug, the medium was removed by aspiration from a 175 cm2 T-flask. The cell monolayer was rinsed with 1 〇 2 〇 mL PBS at room temperature. The PBS was removed by aspiration. The cells were trypsinized using 3 mL trypsin (0-25%) / EDTA (0.1%) solution. The flask was incubated at 37 ° C (incubator) for 7 minutes. Complete medium (9 mL) without G418 was added. The cell mass was fragmented by pipetting up and down several times. The suspension was then transferred to a 50 mL Falcon polypropylene tube. The cells were then counted several times using a hemocytometer. The cells were diluted to 50, 〇〇〇 cells/ml with complete DMEM without G41 8 and then transferred to sterile reservoir 157033. .doc • 381- 201215604. Use a multi-injection pipette to inoculate approximately 5,000 viable cells (1 μμΕ) in each well of a 96-well white opaque microtiter plate. At 5% c〇2,|· Various concentrations of compounds were added to the DMS(R) at a stock concentration of 100 mM or 10 mM in a thermostat after a 2-4 hour incubation period at 37 ° C. In some cases (low efficacy) The compound must be diluted to 1 mM or 1 μμ in DMSO as a starting solution in the case of a concentration of the nanomolar concentration. Next, according to the specific template (see attachment) in a sterile 96 deep well plate, described earlier The drug was diluted at twice the final concentration in the same medium (without G418). Then add one volume (1 μμ of each drug dilution) to each well containing the cells. Use 16 wells as a drug-free control well. (〇% suppression). Use 8 Well as a background control well containing 2 μΜ (final concentration) reference compound

(100% inhibition). The reference compound showed about 1% inhibition of NS5A expression at 2 μΜ and was not toxic to cells. The values from the 1% inhibition wells were averaged and used as background values. The cells were in a 5% c〇2 incubator at 37. Further cultivation for 4 days. To speculate on the NS5A protein content, the medium was milked into a suitable waste container by reversing the well plate after a four day incubation period. Remove any residual liquid by gently slamming the absorbent paper several times. The plates were then washed with 150 PBS per well and incubated for 5 minutes on a shaker (500 rpm) at ambient temperature. To each well of the well plate t, 5 〇 is called cold (_2 〇) fixing solution (5 〇 % methanol / acetone mixture) and the plate was incubated at room temperature for 5 minutes. The orifice plate is then inverted and any residual liquid is removed by gently slamming the absorbent paper several times. 157033.doc 201215604 The plates were then washed twice with 150 PBS per well and incubated for 5 minutes at room temperature on a shaker (5 rpm). 150 pL of blocking solution was added to each well of the well plate. Then the T孔pSeaiTM adhesive sealing film was used to seal the well plates and the H was incubated at 37 ° C or at 4. The underarms were incubated overnight to block non-specific sites. Reverse the plate and pour the blocking solution into a suitable waste container. Any residual liquid is removed by gently slamming the absorbent paper several times. The well plates were then washed twice with 150 pL PBS per well and each well was washed once with 15 p pBSTS solution, and each wash was followed by incubation at room temperature for 5 minutes on a shaker (5 。). Add 5 μM of anti-human NS5A antibody (Abl) diluted in blocking solution to each well of the well plate, then seal the well plate with T〇pSeaiTM adhesive sealing film and incubate overnight at 41 The next day, the plate was inverted to pour the solution into a suitable waste container. The plate was gently tapped on the absorbent paper several times to remove residual liquid. The plate was washed five times with 150 μl PBS per well and washed each time. After incubation for 5 minutes at room temperature on a shaker (500 rpm), then add 5 结合 结合 〉 〉 〉 〉 〉 〉 〉 〉 〉 〉 〉 〉 〉 〉 〉 〉 〉 〉 〉 〉 〉 〉 (Ab2). The orifice plate was then sealed with a TopSealTM adhesive sealing film and incubated for 3 hours at room temperature on a shaker (500 rpm). At the end of the 3 hour incubation, a commercially available chemiluminescent substrate was prepared. Connaught ("...(10)... enhancer and equal volume of stable peroxide reagent The composition was stored in the dark. The plate was then inverted to pour the solution into the appropriate waste container A. Any residual liquid was removed by gently slamming the absorbent paper several times. The well plate was washed with 15 PBSTS solution per well. Each well was washed once with 150 μΙ/pBS and every 157033.doc •383-201215604 washes followed by incubation on a shaker (5〇〇rpm) for 5 minutes at room temperature. Add 10 〇 substrate solution. Then seal the plate with TopSeal adhesive sealing film and incubate at room temperature on a shaker (500 rpm) for !!! minutes, then incubate at room temperature for 3 〇 to 6 〇 minutes (protected from light Fluorescence (relative light units) was then read using an Analyst HT plate reader (LJL preset luminescence method). Percent inhibition (dual repeat) at each drug concentration tested by the juice laboratory. Then nonlinear regression analysis was used ( For example, GraphPad Prism Software Version 2.0 (GraphPad Software Inc., San Diego, CA, USA), according to the in-agent reaction curve, confirms the concentration necessary to reduce viral replication by 5% (IC5〇). IC 5 〇 is summarized in In Table 1-3: A: IC5Q value (flat Value) S〇.l μΜ ; Β · 〇· 1 pM&lt;IC5〇(average) $1 μΜ ; C : 1 μΜ&lt;Ι(:5〇(average)si〇μΜ ; D: IC5〇( Mean) &gt;1〇μΜ. Example 4: [3Η] Thymidine combined assay inoculated in a 96-well cluster disk per well in a total of 1 μμM in DMEM (Wisent·, St Bruno, QC) 2 cells, the DMEM supplement has 10 ° /. FBS (Wisent·, St Bruno, QC) and 2 mM branic acid (Life Technologies, Inc. p added penicillin and streptomycin (Life Technologies, Inc.) respectively to a final concentration of 5〇〇u/mI^5 〇pg/mL. Compounds prepared at twice the final concentration were added to the cells after incubation for at least 3 hours at 37 ° C in a 5% C 〇 2 atmosphere. Test 11 consecutive two in double replicate well plates Up to four times diluted drug. After incubation 72 small 157033.doc -384 - 201215604, add 20 pL volume of [3H]methylthymidine (Amersham Life Science, Inc., Arlington Heights, III; 2 Ci/mmol 10 pCi/mL solution in medium, and the plates were incubated for an additional 24 hours at 37. The cells were then washed with phosphate buffered saline (PBS), trypsinized for 2 minutes' and using a Tomtec cell harvester ( Tomtec, Orange, Conn.) was collected on a glass fiber filter. The filter was dried at 37 (1) and placed in a bag with 4.5 mL liquid scintillation cocktail (Wallac Oy, Turku, Finland). Liquid scintillation counter (l450-Microbeta; Wallac Oy) measurement [3H] methyl chest Accumulation of (representing lively replicating cells) Ref. SOP: 265-162-03. For this experiment, the cell line used was: Huh-7 ET (derived from Huh-7 cell line (hepatocellular carcinoma, human)) Cells and contain HCV subgenomic replicon), Molt-4 (peripheral blood, acute lymphoblastic leukemia, human), DU-145 (prostate cancer, metastasis to the brain, human), Hep-G2 (hepatocellular carcinoma, human) And SH-SY5Y (neuroblastoma, human) cells. Six to eight concentrations (three replicates) were used for each compound to determine the 50% cytotoxicity (CC50) of cell toxicity based on the dose response curve. The analysis fits the curve to the data points and uses the GraphPad Prism software version 2.0 (GraphPad Software Inc., San Diego, CA, USA) to interpolate the IC5 依据 value according to the resulting curve. The CC50 values for the compounds of the invention are summarized in the table. 1-3: A: CC5 〇 value (average value weep 100 μΜ; Β: 10 pMSCC5 〇 value (average value) &lt; 100 μΜ; C: CC5 〇 value (average value) £10 μΜ.. 157033.doc • 385 · 201215604 Table 1: IC50, CC of the compounds described in Figure 1. 50, LCMS and NMR data Compound No. HCV-replicon-(Luci-ET) lb IC50 HCV· Replicon-ELISA-la IC50 [3h] thymidine CC50 LCMS fM+ΗΓ LCMS RT NMR 1 AB 419.60 2 AB 447.2 'H NMR (400 MHz, DMSO): 5 7.05 (s, 1H), 5.22 (q, 1H), 3.01 (s, 3H), 2.81 (s, 3H), 1.99 (t, lH), 1.76-1.00 (m, 16H), 0.90 (d, 3H), 0.73 (d, 3H), 0.69-0.35 (m, 2H) 3 AAA 447.43 5.24 4 ABB 480.93 5 AAA 433.54 4.48 6 AAA 459.46 1.62 7 AB 447 8 AA 475.5 5.38 Ή NMR ( 300 MHz, CDC13)S6.62(s,1H), 4.81 (d? 3=6.6 Hz5 1H), 3.65-2.95 (m, 5H), 2.07-0.19 (m, 31H). 9 AA 473.5 5.38 NMR (300 Hz,6,6,6,6,6,6,6,6,6,6 </ RTI> A. J=7.4 Hz, 0.4H), 3.53 (qdd, J=27.8, 20.6, 13.1 Hz, 8H), 3.19-2:99 (m, 0.4H), 1.98 (br, 0.6H), 1.79-1.05 (m , 18H), 0.92-0.38 (m, 8H). 1 3 AAA 461.51 5.28 14 AAA 475.45 5.21 NMR NMR (300 MHz, CDC13) S7.19(s, 1H), 6.90 (s, 1H), 4.68 (d, J=14.7 Hz, 1H), 4.24-3.99 (m, 2H), 3.59 (d, J = 17.3 Hz, 9H), 3.40 (d, J = 3.3 Hz, 3H), 2.18 (d? J = 11.3 Hz, 1H), 2.00 (d, J = 14.4 Hz, OH) , 1.72 (d, J = 12.1 Hzs 1H), 1.63-1.40 (m, 6H), 1.37-1.11 (m, 18H). 386· 157033.doc 201215604

15 AAA 489.4 5.36 Ή NMR (300 MHzs CDC13) S7.49 (s, 1H), 6.72 (s, 2H), 5.39 (q, J = 7.3 Hz, 1H), 5.06 (q, J = 7.5 Hz, 2H) , 4.02-3.55 (m, 21H), 2.06 (dd, J=13.5, 9.8 Hz, 3H), 1.81 (d, J=13.1 Hz, 1H), 1.74-1.41 (m, 12H), 1.34 (d, J =3.2 Hz, 21H), 1.19 (d, J = 7.4 Hz, 4H), 1.05 (d, J = 7.4 Hz, 3H), 0.88-0.59 (m, 12H). 16 AAA 463.36 4.9 lHNMR (300 MHz, DMSO δ 7.25 (s, 0.5H), 7.00 (s? 0.5H) S5.80 (t, 0.5H), 5.35 (t, 0.5H)s 3.48 (d, 1H), 3.42-2.75 (ms 11H), 2.01-1.34 (m, 6H), 1.20 (d, 6H), L25-1.15 (m, 2H), 0.75 (d5 3H), 0.76-0.50 (m, 2H). 17 AAA 461.44 1.87 18 AB 487 3.97 iHNMR ( 300 MHz, CDC13) δ 7.08-6.74 (m, lH), 6.63 (d, J=53.1 Hz, 1H), 4.89-4.56 (m, 1H), 4.19(m, lH), 3.83(m, 1H)S 2.21-1.87 (m, 2H), 1.86-1.54 (ms 8H), 1.52-1.04 (m, 14H), 1.05-0.56 (m,7H)· 19 AA 503 3.2 ]HNMR (300 MHz, CDCI3) δ 6.90 ( S5 1H), 5.39 (s, 1H), 4.44 (m, 1H), 4.12-3.77 (m, 5H), 3.59-3.31 (m, 3H), 2.83 (s, 3H), 2.14-1.74 (m, 4H) ), 1.71-1.14 (m, 15H), 1.09-0.56 (m, 5H). 20 AA 503 2.97 !HNMR(300 MHz, CDCI3) δ 6.61 (s, 1H), 5.08-4.90 (m,1H), 4.04 (s, 1H), 3.95-3.04 (m, 6H), 2.22-1.31 (m, 12H), 1.31-1.14 (m, 10H), 1.10 (t, J=7.9Hz, 2H), 1.02-0.44 (m, 6H). 21 AAA 477.33 4.21 *ΗΝΜΚ(300 MHz, CDC13) δ 7.65 (s, 0.4H), 6.80 (s, 0.6H), 5.60 (dd, 0.4H), 5.20 (t, 0.6H), 3.52-3.00 (m, 11H), 2.1M.90 (m, 1H), 1.85-1.35 (m, 7H), 1.30 (s, 9H), 0.80 (d, 3H)S 0.78-0.60 (m, 2H). 157033.doc 387- 201215604 22 AA 476.78 4.25 'HNMR (300 MHz, CDC13) δ 7.62 ( s, 0.4H), 6.80 (s, 0.6H), 5.61 (dd, 0.4H), 5.23 (ts 0.6H), 3.52-3.00 (m, 11H), 2.1M.90 (m, 1H), 1.85- 1.35 (m, 7H), 1.30 (s, 9H), 0.80 (d, 3H), 0.78-0.60 (m, 2H). 23 AAA 519.35 3.78 'HNMR (300 MHz, DMSO) 6 13.43 (s, 1H)S 7.28 (s, 0.5H)S 7.07 (s, 0.5H), 5.83 (t, J=7.2 Hz, 0.5H), 5.41 (t, J=6.7 Hz, 0.5H), 3.79-2.89 (m, 14H) , 2.11-1.00 (m, 17H), 0.87-0.39 (m, 4H). 24 AA 505.33 3.56 'HNMR (300 MHz, DMSO) 6 13.48 (brs, 1H)S 7.28 (s,0_5H), 7.01 (s, 0.5H), 5.83 (t, 0.5H), 5.46 (t, 0.5H) , 3.70-2.99 (m, 13H), 2.11-0.76 (m, 11H), 1.30 (s, 9H). 25 AA 489.1 3.53 'HNMR (300 MHz, CDC13) 5 6.91 (d, J=l; 7 Hz, lH), 5.11 (d, J = 16.4 Hz, 1H), 4.00 (s, 2H), 3.91-3.80 (m, 1H), 3.77-3.61 (m, lH), 3.59-3.45 (m, 1H), 3.43 -3.19 (m, 3H), 2.32 (t, J = 11.6 Hz, 1H), 2.08-1.81 (m, 3H), 1.60 (dd, J = 17.4, 13.8 Hz, 6H), 1.34 (s, 10H), 0.82 (d, J=6.5 Hz, 4H), 0.75-0.63 (m, 1H). 26 AB 489.1 4.61 NMR (300 MHz, CDCI3) δ 6.92 (dd, J=8.9, 2.1 Hz, 2H), 5.13 ( Dd, J=16.4? 7.0 Hz, 1H), 4.95 (dd, J=16.3, 3.7 Hz, 1H), 4.37 (dd, J=20.2, 13.5 Hz, 2H), 4.07 (dd, J=16.5, 5.5 Hz , 1H), 3.94 (d, J = 16.1 Hz, 3H), 3.58 (d, J = 11.9 Hz, 6H), 3.43-3.22 (m, 3H), 3.08-2.76 (m, 3H), 2.61-2.42 ( m, 1H), 2.38-2.23 (m, 2H), 1.84 (s, 2H)S 1.60 (s, 6H), 1.41 (d, J = 10.9 Hz, 1H), 1.34 (s, 13H), 1.27-1.16 (m, 5H), 0.82 (d, J=6.5 Hz, 5H), 0.71 (dd5 J=18.5, 6.4 Hz, 2H). 388 - 157033.doc 201215604

27 AA 503.1 4.76 lU NMR (300 MHz, CDC13) δ 6.91 (d, J=4.4 Hz, 1H), 5.04 (dds J=20.6, 16.2 Hz, 1H), 3.95 (s, 1H), 3.51 (dd5 5= 152.6, 9.6 Hz, 8H), 2.32 (td, J=ll_9, 3.2 Hz, 1H), 1.87 (d, J=13.3 Hz, 1H), 1.60(s, 4H), 1.41-1.18 (m, 16H), 0.82 (d, J=6.6 Hz, 5H). 28 AA 461.6 3.21 JH NMR (300 MHz, CDC13) δ 6.96 (d, J=9.7 Hz, 1H), 4.80-4.65 (m, 1H)S 4.64-3.82 ( m, 8H), 2.26 (dd, J=11.6, 8.1 Hz, 1H), 1.77 (s, 1H), 1.63 (d, J=11.6 Hz, 4H), 1.34 (s, 11H), 0.82 (dsJ=6.5 Hzs3H), 0.72 (dd, J=17.1, 8.1 Hz, 2H). 29 AA 489.23 3.14 *H NMR (300 MHz, CDC13) 6 6.83 (s,1H), 3.97 (m5 9H), 2.02 (m5 4H), 1.84-1.41 (m, 6H), 1.39-1.09 (m, 12H), 0.78 (t, J=13.0 Hz, 5H). 30 AA 488.99 3.35 *HNMR (300 MHz, CDC13)5 7.19(s, 0.6H) , 6.83 (s, 0.4H), 4.91-4.31 (m, 3H), 4.26-3.59 (m, 4H)? 2.88 (m5 5H), 2.43-1.98 (m, 3H), 1,94-1.45 (m, 5H), 1.45-0.98 (m, 11H)S 0.93-0.46 (m, 4H). 31 AA 517.7 2.99 'H NMR (300 MHz, CDCU) δ 6.98-6.57 (m, 1H), 4.59 (d, J= 7.4 Hz, 1H), 4.29 (d, 5=72 Hz, 1H), 4.05 (q, J=7.2 Hz, 1H), 3.61 (m, 3H), 2.82 (m, 6H), 2.08-1.80 (m, 4H), 1.77-0.98 (m5 15H), 0.86-0.49 (m, 4H) 32 AA 489.62 3.01 33 AA 505.64 2.64 34 AA 463.62 3.16 35 AAB 503.35 3.81 lH NMR (300 MHz, CDCI3) δ 7.65 (s, 0.4H)S 6.80 (s, 0.6H), 5.60 (dd, 0.4H), 5.20 (t, 0.6H), 3.52-3.00 (ms 11H), 2.11-1.90 (m, 1H), 1.85-1.35 (m, 7H), 1.30 (s, 9H), 0.80 (d, 3H)S 0.78- 0.60 (ms 2H). 157033.doc 389· 201215604 36 BA 489.34 3.61 *H NMR (300 MHz, CDC13) δ 7.62 (s, 0.4H), 6.80 (s, 0.6H), 5.61 (dd, 0.4H), 5.23 (t, 0.6H), 3.52-3.00 (m, 11H), 2.11-1.90 (m, 1H), 1.85-1.35 (m, 7H), 1.30 (s, 9H), 0.80 (d, 3H), 0 '78-0.60 (m, 2H). 37 AA 477.1 1.11 NMR (300 MHz, CDC13)5 6.63 (s, 1H), 5.33-4.99 (m,1H), 4.86 (ms 1H)S 4.21-3.43 (m, 4H), 3.32-2.75 (ms 4H), 2.18-0.29 (m, 25H). 38 AA 491.1 1.55 39 AA 503.1 1 'HNMR (300 MHz, CDC13) 5 6.64 (s, 1H), 5.06-4.56 (m, 1H), 3.99 (m,1H), 3.51 (m,5H), 2.87-2.27 (m, 4H), 1.95 (m,3H), 1.78-0.78 (m, 19H), 0.70 (m, 4H)_ 40 AA 517.1 1.77 Old NMR (300 MHz, CDCls) δ 6.80-6.62 (m, 1H), 5.13-4.92 (m, 1H), 3.97-3.25 (m, 7H), 2.91 (s, 3H), 2.16-1.40 (m, 11H)S 1.38-1.03 (m, 16H), 0.99-0.49 (m, 8H). 41 CA 503.1 4.12 Ή NMR (300 MHz, CDC13) δ 7.49 (d, J=8.0 Hz, 1H ), 6.91 (s, 1Η), 4·65 (d, J=16.5 Hz, 1H), 3.82 (d, J=16.5 Hz, 1H), 3.65 (d, J=11.0 Hz, 2H), 2.26 (t , J=ll_5Hz, lH), 1.69 (dd, J=68.0, 56.8 Hz, 9H), 1.47-1.08 (m, 15H), 0.81 (d, J=6.4 Hz, 3H), 0.76-0.61 (m, 2H) 42 AA 474.94 3.34 Ή NMR (300 MHz, CDCI3) δ 6.92 (dd, J=8.9, 3.5 Hz, 1H), 5.07-4.69 (m, 2H), 4.55 (dd, J=25.5S11.3 Hz, lH), 3.92(t, J=19.9 Hzs 2H)s3.58(s, 4H), 2.30 (dd, J=11.95 8.2 Hz, 2H), 2.17-1.91 (m, 2H), 1.84 (d, J= 12.8HZi 1H), 1.73-1.45 (m, 4H), 1.29 (d, J = 19.4 Hz, 10H), 0.80 (d, J = 6.5 Hz, 5H). 43 AA 502.99 3.34 44 AA 502.98 3.5 390- 157033. Doc 201215604

45 474.96 3.8 ]HNMR(300MHz, CDC13)5 6.91 (d, J=21.0 Hz, 1H), 4.82-4.39 (m, 2H), 4.40-3.65 (m, 6H), 3.32 (s, 2H), 2.65 ( s, OH), 2.25 (d, J=11.5 Ηζ, ΙΗ), 1.82 (s, 1H), 1.57 (d, J=13.3 Hz, 3H), 1.45-1.13 (m, 10H), 0.90-0.59 (m , 5H). 46 AA 472.64 3.8 NMR (300 MHz, CDC13) δ 6.88 (s, 1H), 5.20 (ds J=16.3 Ηζ, ΙΗ), 3.86 (d, J=16.3 Hz, 1H), 3.72-3.22 (m, 4H), 2.34 (ts J=11.6 Hz, 1H), 1.90 (d, J=13.4 Hz, 1H), 1.76-1.47 (ms 10H), 1.30 (d, J=19.2 Hz, 11H), 0.82 (d, J=6.5 Hz, 5H). 47 AA 503.6 3.95 48 AB 517.6 3.96 NMR (300 MHz, CDCI3) δ 6.70 (s 1H), 5.15-4.89 (m, 1H), 4.54-4.23 (m, 2H) , 4.05-3.44 (ms 4H), 3.22-2.82 (m, 2H), 2.67-2.22 (m, 2H), 2.21-0.96 (m, 22H), 0.88-0.59 (m, 6H). 49 AA 503.6 3.36 Ή NMR (300 MHz, CDC13) S6.71 (s, lH), 5.15-4.88 (m, 2H), 4.58-4.25 (ms 2H)S 4.10-3.44 (m, 5H), 2.12-1, 95 (m, 2H)S 1.88-0.92 (m,21H)s 0.79Ό.54 (m, 5H). 50 AA 517.6 3.97 Ή NMR (300 MHz, CDC13) 5 6.70 (s, 1H), 5.14-4.88 (m, 1H) , 4.18-3.95 (01,1^, 3.90-3.08 (m, 6H), 2.21-0. 88 (m, 28H), 0.82-0.62 (m5 6H). 51 AA 517.6 3.3 Ή NMR (300 MHz, CDC13) 5 6.73 (s, 1H), 4.88-4.51 (m, 2H), 4.25-3.95 (m, 3H)S 3.65-3.42 (ms3H)s 3.17-3.02 (m, 2H), 2.97-2.80 (m5 3H), 2.21-0.86 (m5 22H), 0.82-0.61 (m, 4H). 52 AA 489.6 3.65 】H NMR (300 MHz, CDC13) 5 6.70 (s, 1H), 4.98-3.83 (m, 8H), 3.42-3.27 (m5 3H), 2.84 (s, 1H), 2.11-1.95 (m, 2H), 1.87- 1.40 (ms 5H)S 1.39-0.91 (m, 12H), 0.86-0.67 (ms 4H). 53 AA 517.6 3.7 54 1 AA 503.6 2.79 157033.doc -391 - 201215604 55 CA 491.39 2.85 JH (300 MHz, d6- DMSO) δ 13.58 (brs, 1H), 7.21 (d, 1H), 4.92 (dd, 1H), 3.85 (dd, 1H); 3.55-3.35 (m, 8H), 2.75-2.60 (m, 1H), 2.30 -2.20 (m, 1H), 1.77-0.38 (m, 19H); 23% of the epimeric alcohol is also present in this mixture of diastereomers: δ 13.58 (brs, 1H), 7.19 (d, 1H), 4·92 (dd, 1H), 3.82 (dd, 1H), 3.55-3.35 (ms 8H), 2.75-2.60 (m, 1H), 2.30-2.20 (m, 1H)S 1.77- 0.38 (m , 19H). 56 AAB 517.36 5.54 'HNMR (300 MHz, DMSO) 5 13.55 (br5 1H), 7.44-6.97 (m, 1H), 5.80-5.06 (m, 1H), 4.36-3. 08 (m, 8H), 2.15-0.95 (m, 20H), 0.89-0.45 (m, 9H). 57 AA 490.97 3.75 58 AA 533.63 4.16 59 AA 477.9 2.51 60 AA 519.58 2.8 61 AAA 533.36 1.47 !HNMR(300 MHz , CDC13) δ 7.50 (s, 0.4H), 6.76 (s, 0.6H), 5.52 (dd, ]=9A, 5.7 Hz, 0.4H), 5.27 (dd, J=10.7, 4.9Hz, 0.6H), 4.09-3.54 (m, 11H), 3.42-3.18 (m, 3H)S 2.14-1.22 (m, 20H), 0.91-0.59 (m, 4H). 62 AA 460 1.92 (DMSO, 300MHz) 0.55-0.72 (2H , m), 0.80 (3H, d), 1.20 (6H, d), 1.20-1.45 (2H, m), 1.50-1.70 (4H, m), 2.15 (lH, t), 2.82 (1H, sept), 3.45 (4H, app s), 3.55 (4H, app s)s3.80(lH, d), 4.89 (1H, d), 7.24 (1H3 s), 13.50 (lH,brs). 63 BB 517.36 1.81 *HNMR (300 MHz, CDCI3) δ 7.64 (s, 0.4H), 6.85 (s, 0.6H), 5.36 (dd, 0.4H), 5.02 (t, 0.6H), 4_00-3.15 (m, 10H), 2.13- </ RTI> </ RTI> <RTIgt; lH), 3.80-3.35 (m, 9H), 2.00-0.50 (m, 29H) 392- 157033.doc 201215604

65 AA 532.99 3.87 'HNMR (300 MHz, CDC13)5 7.95 (d, J=3.5 Hz, 0_lH) 6.80 (d, J=3.1 Hz, 0.9H), 5.57-5.23 (m, 1H), 4.01-3.55 ( m, 9H), 3.54-3.23 (m, 3H), 3.14 (m, 4H), 2.04 (m, lH), 1.67 1.58 (m, 4H), 1.45-1.19 (m, 12H), 1.11-0.96 (m , 1H), 0.91-0.47 (m, 4H). 66 AA 490.97 3.9 67 AA 419.44 3.47 (400 MHz, DMSO) 0.50-0.85 (3H, m), 0.80 (3H, d), 1.19 (6H, d), 1.20-1.69 (6HS m), 2.09 (1H, quin), 2.80 (3H, s), 2.87 (1H, sept), 2.92 (3H, s), 3.85 (lH,d),4_86(lH,d), 7.22 (lH, s), 13.59 (lH, brs). 68 AB 475.33 1.84 JHNMR (300 MHz, CDC13) δ 7.60 (s, 0_4H), 6.74 (s, 0.6H), 5_32 (dd, 0.4H), 5.07 (dd, 0.6H), 3.39 (s, 3H), 3.10-2.94 (m5 4H), 2.14-1.22 (ms 29H). 69 AA 460.24 2.54 (DMSO, 400MHz) 0.55-0.90 (3H, m), 0.81 ( 3H.d), 1.20 (6H,d),1.20-1.39 (2H, m)s 1.50-1.68 (4H, m), 2.14(lH, t)s2.90(lH, sept), 3.10 (4H, br s), 3.59 (4H, brs), 3.88 (lH, d), 5.00 (1H, d), 7.20 (1H, s), 8.90 (lH, brs), 13_58 (1H, br s). 70 AA 405.55 3.27 *H (300 MHz, d6-DMSO) δ 13.80 (brs, 1H), 7.88 (br s, 1H), 7.30 (s, 1H), 4.54 (d, 1H), 3.73 (d, 1H), 2.92 (sept, 1H), 2.58 (d, 3H) , 2.08 (t,1H),1.67-1.51 (m, 4H), 1.52-1.25 (m,4H), 1.25(d,6H),0_85(d,3H), 0.91-0.50 (m, 1H). 71 AA 473.37 3.19 lU (300 MHz, d6-DMSO) δ 13.53 (brs, 1H), 7.22 (d, 1H), 4.68 (d, 4H)S 4.33 (ts lH), 4_30(t,lH), 4.06-4.00 (ms 2H), 3.59-3.55 (m, 2H), 2.82 (sept, 1H), 2.08 (ts 1H), 1.70-1.24 (m, 7H), 1.24 (d, 6H), 0.80 (d, 3H), </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 。 。 。 。 。 。 。 。 。 ), 4.34 (t, J-9.4 Hz, 0.5H), 3.84-3.32 (m, 2H), 2.94 (s, 1.5H), 2.88 (s, 1.5H), 2.60-2.26 (m, 1H), 2.23 -1.97 (m, 1H), 1.94-1.16 (m, 17H) 0.95-0.57 (m, 5H). 84 AB 517 3.85 lU NMR (300 MHz, CDC13) δ 6_75 (s, 1H), 4.92 (m, lH), 3.31 (s, 3H), 3.04 (d, J = 16.6 Hz,3H), 2.83 (m, 2H),2.11-1.91 (m, 3H), 1.84-1.37 (m, 9H), 1.36-1.20 (m, 8H), 1.05-0.54 (m, 10H). 85 AB 517 3.79 86 AB 475 3.65 87 AA 532.9 3.6 88 AA 491 3.6 NMR (300 MHz, CDC13) S6.91 (s, 1H), 5.18-5.12 (m, 1H), 3.54-3.35 (m, 2H), 3.34 -3.23 (ms 3H), 3.13 (m, 4H), 2.03-1.55 (m, 21H), 1.12 (m, 2H), 0.98-0.60 (m, 4H). 89 AA 447 3.8 NMR (300 MHz, CDC13) δ 6.75 (s,1H), 4.92 (m,1H),3_31 (s,3H), 3.07 (s,3H), 3.01 (s,1H), 2.83 (m, 2H)S 2.12-1.91 (m, 2H ), 1.85-1.37 (m, 7H), 1.37-1.20 (m, 6H), 1.09-0.48 (m, 8H). 90 AA 489 3.7 Ή NMR (300 MHz, CDC13) 5 6.78 (s, 1H), 5.20 (m, 2H), 4.02-3.28 (m, 2H), 2.83 (m, 1H), 2.53-2.27 (m, 3H), 2.01 (ms 2H), 1.91-U9 (m, 15H), 1.08-0.56 ( m 、 、 、 、 、 、 、 、 3.64-3.35 (m, 2H), 2.90 (s 1.5H), 2.80 (s, 1'5H), 2.50-2.26 (m, 1H), 2.23-2.02 (m, 1H), 1.84-1.26 (m, 17H), 0.80-0.65 (m, 5H). 394-157033.doc 201215604

92 AA 445.25 4.79 WNMRQOOMHz, CDC13) δ 6.92 (s, 0.5H), 6.90 (s, 0.5H), 5.21 (t, 0.5H), 4.35 (t, 0.5H), 3.66-3.37 (ms 2H), 2.92 (s, 1.5H), 2.82 (s, 1.5H), 2.53-2.24 (ms 1H), 2.26-2.02 (m, 1H), 1.84-1.26 (m, 17H), 0.80-0.65 (m, 5H). 93 AA 515 2.6 94 AAA 514.98 3.1 ^NMRCSOO MHz, CDC13)5 6.98(s,1H)s 4.92-4.15 (m, 5H), 3.65-2.73 (br, 10H), 2.35-2.21 (m, 1H), 1.73 -L50(m; 5H), 1.32 (s, 9H), 1.33-1.22 (m, 2H), 0.85 (d, 3H), 0.80-0.60 (ms 2H). 95 AAB 473.21 1.56 ^HNMR (300 MHz, CDCb ) δ 6.74 (s, 1H), 5.22 (brs, lH), 5.10 (ds J = 10.4 Hz, 1H), 3.99-3.61 (m, 2H)? 3.27 (d, J = = 15.3 Hz, 2H), 3.07 (2xs, 3H), 2.20-1.31 (m, 12H), 1.34 (2xs, 9H)S 0.87-0.57 (m, 5H). 96 AB 461.4 5.31 ^HNMR (300 MHz, DMSO)5 13.53 (s, 1H) , 7.54 (s, 0.65H), 7.32 (s5 0.35H), 4.98 (d, J=6.8 Hz, 0.65H), 4.60 (s, 0.35H), 3.60 (s, 0.65H)? 3.34 (s, 1.35 H), 3.10-2.70 (m, 5H), 2.63-2.34 (m, 2H), 2.10 (dd5 J=15.0, 9.0 Hz, 0.35H), 1.93-1.71 (m, 1.65H), 1.64-1.05 (m , 14H), 0.94-0.44 (m, 6H). 97 AA 489.47 5.3 98 ABA 447.43 5.22 AHNMR (300 MHz, CDC13)6 6.82 (s, 1H), 3.94-3.66 (m, 2H), 3.04 (s, 3H), 2.82 (d, J=18.7 Hz, 3H), 2.73-2.46 (m, 2H), 2.00 (t, J = 11.7 Hz, 1H), 1.65-I.ll (m, 15H), 0.73 (d, J = 6.5 Hz, 5H). 157033.doc -395 - 201215604 99 AB 459.59 2.02 4 NMR (300 MHz, DMSO) S13_5 (br, lH), 7.60 (s, 0.6H), 7.35 (s, 0.4H), 5.01-4.95 (m, 0.6H), 4.65-4.49 (m, 0.4 H), 3.65 (br, 0.4H), 3.25 (br, 0.6H), 3.00 (s, 1.8H), 3.85 (s, 1.2H), 2.80 (s, 1.2H), 2.75 (s, 1.8H) , 2.60-1.75 (m, 2H)S 1.60-1.12 (m, 8H), 1.30 (s, 9H), 0.85 (d, 3H), 0.75 (d, 3H), 0.65-0.50 (m,1H) 100 AA 461.38 1.37 】HNMR (300 MHz, CDC13) δ 7.30 (s, 0.4H), 6.85 (s, 0.6H), 5.03-4.85 (m, 1H), 3.27-2.90 (m, 6H), 2.75 (br, 1H) ), 2.25-1.80 (m, 3H), L75-1.50 (m, 4H), 1.30-1.12 (m, 6H), 1.35 (s, 9H), 0.75 (d, 3H), 0.65-0.50 (m, 1H) 101 AB 487 1.51 'HNMR (300 MHz, DMSO) δ 7.44 (s5 0.6H), 7.32 (s, 0.4H), 4.96 (dd, J = 14.1, 7.0 Hz, 0.6H), 4.61-4.48 (m, 0.4H), 3.70-3.12 (m, 6H)? 2.85 (dd, J=15.4, 5.7 Hz, 0.4H), 2.48-2 .32 (m, 1H), 2.09 (dd, J = 15.3, 8.7 Hz, 0.6H), 1.79 (ddt, J = 12.7, 9.7, 6.6 Hz, 5H), 1.62-1.04 (m, 16H), 0.90 ( d, J = 6.8 Hz, 2H), 0.76 (d, J = 6.5 Hz, 2H), 0.60 (dt, J = 34.5, 11.4 Hz, 2H). 102 AB 487 1.51 'HNMR (300 MHz, DMSO) δ 7.44 (s, 0.6H), 7.32 (s, 0.4H)S 4.96 (dd, J=14.1, 7.0Hz, 0.6H), 4_61-4.48 (m, 0.4H), 3.70· 3.12 (m, 6H), 2.85 (dd, J = 15.4, 5.7 Hz, 0.4H), 2.48-2.32 (m, 1H), 2.09 (dd, J = 15.3, 8.7 Hz; 0.6H), 1.79 (ddt, J = 12.7, 9.7, 6.6 Hz , 5H), 1.62-1.04 (m, 16H), 0.90 (d, J=6.8 Hz, 2H), 0.76 (ds J=6.5 Hz, 2H), 0.60 (dt5 J=34.5S 11.4 Hz, 2H). 396 - 157033.doc 201215604

103 AA 487 1.51 4HNMR (300 MHz, DMSO) δ 7.44 (s5 0.6H), 7.32 (s, 0.4H), 4.96 (dds J=14.1, 7.0 Hz, 0.6H), 4.61-4.48 (m, 0.4^, 3.70-3.12 (m; 6H), 2.85 (dd, 1 = 15.4, 5.7 Hz, 0.4H), 2.48-2.32 (m, 1H), 2.09 (dd, J = 15.3, 8.7 Hz, 0.6H), 1.79 ( Ddt, J=12.7,9.7, 6.6 Hz,5H),1.62-1.04 (m, 16H), 0.90 (d, J=6.8 Hz, 2H), 0.76 (d, J=6.5 Hz, 2H), 0.60 (dt , J=34.5, 11.4 Hz, 2H). 104 AA 503.35 3.63 NMR (300 MHz, CDC13) δ 6.94 (s, 0.5H), 6.80 (s, 0.5H), 4.07-3.95 (m, lH), 3.75 -3.33 (m, 10H), 2.15-2.01 (m5 1H), 1.73-1.40 (m,7H),1_32 (s,9H),1.13-1.02 (m,3H), 0.S0 (d, 3H), 105AA 503 1.36 ]HNMR (300MHzs DMSO) δ 7_54 (s, 0.66H), 7.29 (s, 0.33H), 4.99 (dd, J=14.3, 7.1 Hz, 0.66H), 4.63 (s, 0.33H)S 3.85-3.14 (m, 9H), 2.75-2.10 (m, 5H), 1.76 (s, 1H), 1.64-1.05 (m; 14H), 0.81 (dd, J=32.2, 6.6 Hz, 6H). 106 AA 503 1.36 'HNMR (300 MHz, DMSO) δ 7.53 (s, 0.66H), 7.28 (s, 0.33H), 4.99 (dd, J=14.0, 6.9 Hz, 0.66H), 4.63 (s,0.33H)s 3.79-3.15 (m, 9H)S 2.85-2.10 (m, 5 H), 1.83 (t, J=11.7 Hz, 1H), 1.62-1.02 (m, 14H)S 0.81 (dds J=32.3, 6.6 Hz, 6H). 107 AA 445.25 3.51 *HNMR (300MHzs CDC13) δ 6_84 ( s, 0.5H), 6.80 (s, 0.5H), 5.57-5.34 (m, 0.5H), 4.35-4.23 (ms 0.5H), 3.85-3.61 (m, 1H), 3.33-3.00 (m, 1H) , 3.85-3.60 (m, 6H), 2.15-1.85 (m, 1H), 1.70-1.45 (m, 7H), 1.32 (s, 9H), 0.80-0.60 (m, 5H). 108 AAA 503.35 1.35 ]HNMR (300 MHz, CDCI3) δ 6.94 (s, 0.5H), 6.80 (s, 0.5H)5 4.07-3.95 (m5 1H)S 3.75-3.33 (m, 10H), 2.15-2.01 (m,lH), 1.73 -1.40 (m, 7H), 1.32 (ss 9H), 1.13-1.02 (m, 3H), 0.80 (d, 3H)S 0.80-0.60 (ms 2H). 157033.doc -397- 201215604 109 AA 503.35 1.35 * H NMR (300 MHz, CDC13) δ 6.94 (s, 0.5H), 6.80 (s, 0.5H), 4.07-3.95 (m, 1H), 3.75-3.33 (m, 10H), 2.15-2.01 (m, lH ), 1.73-1.40 (m, 7H), 1.32 (s, 9H), 1.13-1.02 (m, 3H), 0.80 (d, 3H), 0.80-0.60 (m, 2H). 110 AA 516 0.58 JHNMR (300 MHz, DMSO) δ 7.55 (s, 0.65H), 7.30 (s, 0.35H), 4.98 (dd, J=13.9, 6.8Hz5 0.65H), 4.64 (ss 0.35H), 3.65-2.95 (m,7H) , 2.80-2.59 (m, 3H), 2.50-2.20 (m, 7H), 1. 95-1.06 (m, 15H), 0.81 (dd, J = 30.9, 6.6 Hz, 6H). 111 AA 461 1.41 *HNMR (300 MHz, DMSO) δ 7.31 (d, J = 23.9 Hz, 1H) S 5.01 ( d, J=8.6 Hzs 0.65H), 4.69 (s, 0.35H), 3.60 (s, 0.65H)S 3.34 (s, 1.35H), 3.02 (d5 1=12 Hz, 2H), 2.23 (ddd, J =40.9, 20.1, 12.4 Hz, 1H), 1.96-0.44 (τη, 27H). 112 AA 459.5 2.8 113 AA 544 0.58 *HNMR (300 MHz, DMSO) δ 7.51 (s, 0.65H), 7.34 (s, 0.35 H), 5.00 (d5 J=6.7 Hz, 0.65H), 4.50 (dd, J=39.4, 27.1 Hz, 1.35H), 3.55-2.30 (m5 16H), 2.23-1.03 (m,19H), 0.82 (dd , J=36.1, 6.6 Hz, 6H). 114 AA 505 1.47 'H NMR (300 MHz, DMSO) δ 7.52-7.25 (m, 1H), 5.06-4.81 (m, 0.65H)s 4.57 (s, 0.35H ), 3.59-3.12 (m, 8H), 3.10-2.80 (m, 2H)S 2.78 (d, J=5.5 Hz, 1H), 2.60-2.00 (m, 5H), 1.97-0.97 (ms 15H)S 0.96 -0.42 (m, 6H). 115 AA 531 1.54 Ή NMR (300 MHz, DMSO) d 7.56-7.25 (m, 1H), 4.98 (d, J = 4.5 Hz, 0.65H), 4.60 (s, 0.35H) , 3.80-3.60 (m, 2H), 3.46-2.80 (m, 7H), 2.68-2.22 (m, 5H)S 2.18-0.41 (m, 25H). 398- 157033.doc 201215604

116 AA 503 1.32 !HNMR (300 MHz, DMSO) δ 7.40-7.21 (m, 1H), 4.96-4.76 (m, 0.66H), 4.51-3.74 (m, 4.33H), 3.58 (s, 1H), 3.23 -3· 14 (m,3H), 2.78-2.25 (m,lH),2_28(d, J=6.9Hz, 1H), 2.00-0.46 (m, 22H). 117 AA 459.5 1.57 'HNMR(300 MHz, CDCI3) δ 6.83 (d5 J=9.7 Hz, 1H), 5.32 (s, 1H), 3.82-3.51 (m5 2H), 3.28-3.22 (m, 1H), 3.07 (m, 3H), 2.65-2.37 (m , 1H), 2.22-2.18 (m,3H), 1.89-1.38 (m5 9H)S 1.35 (s, 9H)S 0.94-0.76 (m, 4H). 118 A 490.23 2.16 】HNMR (300 MHz, CDC13) 5 6.98 (s, 1H), 4.92-4.15 (m, 5H), 3.65-2.73 (br, 10H), 2.35-2.21 (m, 1H), 1.73-1.50 (ms 5H), 1.32 (s, 9H), 1.33 -1.22 (m, 2H), 0.85 (d, 3H), 0.80-0.60 (m, 2H). 119 A 488.25 2.17 ^NMR (300 MHz, DMSO) 5 7.20 (s, 1H), 3.55-2.71 (m, 8H), 3.45 (s, 3H), 2.75 (s, 2H)S 2.15-2.05 (m, 1H), 1.63-1.50 (ms 5H), 1.32 (s, 9H), 1.33-1.22 (m, 2H), 0.75 (d, 3H)S 0.70-0.60 (ms 2H). 120 B 431.24 1.15 *HNMR (300 MHz, CDCI3) δ 7.04 (s, 1H), 6.59 (d, J = 5.5 Ηζ, ΙΗ), 4.67 (dd , J-14.7, 9.8 Hz, 1H)S 3.97-3.78 (m, 1H), 3.68 (t, J= 8.7 Hz, 1H), 2.90-2.71 (m, 1H), 2.23-1.67 (m, 7H), 1.61-1.38 (m, 2H), 1.32 (s? 9H), 1.03-0.82 (m, 5H). 157033 .doc -399- 201215604 Table 2: ICS0, CCS0 LCMS and NMR data for the compounds described in Figure 2. Compound number HCV-replicon (Luci-ET)-lb IC50 HCV-replicon-ELISA-la IC50 [ 3h] thymidine CC50 LCMS [M+H]+ LCMS RT NMR 121 CA 4.09 (400 MHz, DMSO-d6): 13.42 (brs, interchangeable with D20; H), 7.73-7.72 (m, 2H), 7.57- 7.41 (m, 4H), 4.96 (d, J=16.4 Hz; 1H), 3.93 (d, J=16.8Hz; 1H)S3.55-3.40 (m, 8H), 2.22-2.16 (m, 1H)S1 .75-1.72 (m, 1H), 1.57(brss2H)s 1.42-1.23 (m, 4H), 0.75 (d, J=6 H 122 AA 503.199 5.36 (400 MHz, DMSO-d6): 13.65 (bs, with D20 interchange; 1H), 7.06 (bs, 1H), 5.15 (bs, lH), 3.69-3.44 (m, 8H), 2.08-2.04 (m, 1H), 1.68-1.38 (m, 6H), 1.35-0.87 (m, 12H), 0.85-0.53 (m, 8H). [1], (400 MHz, DMSO-d6): 13.63 (brs, interchangeable with D20; 1H), 13.39 (brs, interchangeable with D20; 1H), 7.26 (br s,1H), 7.14 (br s,lH), 5.56(m,lH), 5.20 (t, J=6.8 Hz; 1H), 3.69-3.41 (m,8H),3.1 (m,0.8H ), 2.68 (s, 1H), 1.99-1.96 (m, 2H), 1.59-1.41 (m, 6H), l 123 AA 489 4.21 (400 MHz, DMSO-d6): 13.47 (brs, interchangeable with D20; lH), 7.37 (d, J=8.4 Hz; 2H), 7.26 (d, J=8.4 Hz; 2H), 7.12 (s, 1H), 5.12-5.08 (m, 1H), 4.24-4.20 (m, 1H), 3.59-3.46 (m , 8H), 1.27(s, 9H). 124 AAA 523 2.73 (400 MHz, DMSO-d6): 13.7 (brs, interchangeable with D20; 1Η), 7.62·7·61 (m, 1H), 7.40-7.38 ( m, 1H), 7.23-7.20 (m, 1H), 7.12 (s, lH), 5.15-5.11 (111, 1H), 4.23-4.19 (m, 1H), 3.58-3.44 (m, 8H), 1.24 ( s, 9H). -400- 157033.doc 201215604

125 BA 4.08 (400 MHz, DMSO-d6): 13.4 (brs, interchangeable with D20; 1H), 7.16-7.06 (m, 5H), 5.11-5.06 m, 1H), 4.21-4.17 (ms 1H), 3.59- 3.46 (m, 8H), 2.25 (s, 3H), 1.26 (s, 9H). 126 BA 4.29 (400 MHz, DMSO-d6): 13.4 (brs, interchangeable with 020; 2H), 7.80-7.71 (m, 2H), 7.50-7.43 (m, 4H), 5.61 (brs, 1H)S 5.29-5.25 (m, 1H), 3.72-3.40 (m, 8H), 2.11-2.05 (m, 1H), 1_85-I. 82(m,1H), 1.71-1.40 (m,6H), 1.32-1.15 (m, 2H)S 0.91-0.81 (m,3H), 0.77-0.5 m 127 AB 491.199 4.85 (400 MHz, DMSO_d6): 13.45 (brs, interchangeable with D20; 1H), 7.21 (s, 1H), 4.90 (d, J = 16.8 Hz; 1H), 3.84 (d, J = 14.4 Hz; 1H), 3.72-3.63 (m, 4H), 2.64-2.59 (m, 4H), 2.12-2.06 (m, 2H), 1.69-1.53 (ms 4H), 1.40-1.33 (m, 11H), 0.77 (d, J = 6.4 Hz; 3H), 0.70-0.61 (m, 2 [ll 128 AA 1.34 (400 MHz, DMSO-d6): 13.45 (brs, interchangeable with D20; lH), 4.91 (d, J = 16.4 Hz; 1H), 3.84 (d, J = 16.4 Hz; 1H)S 3.54-3.53 (m, 4H), 3.39- 3.31 (m, 4H), 2.10-2.05 (m, 1H), 1.68-1.48 (m, 5H)S 1.40- 1.23 (m, 4H), 0.97- 0.92 (m, 2H), 0.88-0.79 (m, 2H), 0. 77 (d, 1=6.4 rn 129 BA 491.47 1.3 (400 MHz, DMSO-d6): 13.62 (brs, interchangeable with D20; 1H), 7_33 (s, 1H), 4.92 (d, J = 16.4 Hz; lH) , 3.87(d, J=16.8Hz; 1H), 3.54-3.40 (m, 8H)S 3.29 (s, 3H), 2.09 (m, 1H)S1.65-1.52 (m, 4H), 1.48 (s, 6H), 1.39-1.23 (m,4H), 0.77 (d, J=6.4 Hz; 3H), 0.68-0.65 m 157033.doc •401 · 201215604 130 BBA 5.44 (400 MHz, DMSO-d6): 13.5 (brs , interchangeable with D20; 1H), 7·22 (s, 1H), 4.91 (d, J=16.8Hz;, 1H), 3.86 (d, J=16.8 Hz;, 1H), 3.34-3.40 (m, 8H ), 2.41 (d, J=6.4Hz; 2H), 2.11-2.06 (m,1H), 1.90-1.83 (ms 1H)S 1.65-1.52 (m,3H), 1.38-1.23 (m,3H),0.99 (s, 3H), m 131 AAA 1.41 400 MHz, DMSO-d6: 13.60 (brs, interchangeable with D20; lH), 7.12 (s, 0.33H), 6.97 (s, 0.65H), 5.50 (t, J= 9.6 Hz; 0.64H), 4.10-4.02 (m, 0.47H) s3.32-3.11 (m, 3H), 3.04-3.00 (s, 1H), 2.41-1.90 (m, 3H), 1.60-1.45 (m , 5H), 1.35-1.01 (m, 11H), 1.01-0.86 (m, 3Η), 0_Π1 132 BA 1.24 400 MHz, DMSO-d6: 13·5 (s, interchangeable with D20; 1H), 7.24 (s, lH), 4.92 (d, J=16.4Hz; 1H), 3_85 (ds J-16.4Hz ; 1H), 3.54-3.53 (m, 4H), 3.39-3.31 (m, 4H), 2.52-2.46 (m, 2H), 2.08-2.05 (m, 1H), 1.65-1.51 (m, 4H), 1.38 -1.23 (m, 3H), 1.16 (t, J=3.6 Hz; 3H), 0.7 m 402- 157033.doc 201215604

133 AAA 489.449 1.85 400 MHz, DMSO-d6: 13.5 (brs, interchangeable with D20; lH), 7.12 (s, 0.3H)S 6.97 (s, 0.7H), 5.56-5.51 (m, 0.7H), 4.14- 4.09 (m, 0.3H), 3.45-3.36 (m, 3H), 3.28- 3.27 (m, 2H), 3.25-3.23 (m, 1H), 3.20-3.16 (m, 2H), 3.13- 3.09 (m, 1H), 2.32- 2.18 (m, 1H), 2.10-1.96 [1], 400 MHz, DMSO-d6: 13.6 (brs, interchangeable with D2O; 0.76H), 7.12 (s, 0.3H), 6.98 (s, (H, 9H) , 1.60-1.42 (m,5H), 1.29- 1.12(m, 11H), 0.77 (d, J=6.4Hz; 3H)? 0.71 134 AAB 487.74 3.94 *ΗΝΜΚ (300 MHz, CDCI3) 6.74 (ss 1H), 5.07 (dd, J=12_0, 1.9 Hz, 1H), 3.81 (dd, J=15.2, 10.7 Hz, 1H), 3.71-3.20 (m, 6H), 2.19-1.37 (ms 7H), 1.34 (d5 J= 3.9 Hz, 9H), 1.17 (q, J=7.2 Hz, 4H), 0.85-0.62 (m, 5H). 135 AA 535.54 3.88 136 AAA 475.65 3.7 137 AAA 521.52 3.76 】HNMR (300 MHz, CDCb) δ 7.43 ( d, J=8.3 Hz, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.28-7.25 (m, 1H), 7.22 (sslH), 7.13 (d, J=1.7Hz, 1H), 6_97 ( s,l H), 5.37 (d, J = 11.3 Hz, 1H), 3.98-3.68 (m, 2H), 3.33 (t, J = 12.6 Hz, 1H), 3.13 ((1, J=6.9 Hz, 3H), 1.86 (s5 6H), 1.33 (dd, J=7.1, 1.7 Hz, 9H). Π1 138 AAA 517.68 3.9 'HNMR(300 MHz, CDC13) δ 6.74 (s,1H), 5.09 (dd, J=12_0, 2.2 Hz , 1H), 3.93-3.41 (m, 6H), 3.35 (d, J=1.9 Hz, 3H), 2.22-1.41 (m, 14H), 1.35 (d, J=3.5 Hz, 9H), 0.82 (dd, J=6.5, 3.0 Hz, 3H)S 0.74 (s, ih). rn 157033.doc -403 - 201215604 139 AAA 475.55 1.7 (DMSO-d6. 400MHz): 13.6 (brs, interchangeable with D20, lH), 7.10 ( s, 0.31H), 6.97 (s, 0.64H), 5.55 (t, J=10Hz; 0.65H), 4.68-4.61 (m, interchangeable with D2〇, 1H), 4.05 (t, J=9.6Hz; 0.30 H), 3.45-3.35 (m, 4H), 3.13-3.03 (m, 4H), 2.19-1.95 (m, 3H), 1.57-1.33 (m, 6H), m 140 AAA 507.04 4.28 in attached DMSO -d6 hNMR (300 MHz, DMSO) δ 7.46 (d, J = 8.2 Hz, 1H), 7.39 (s, 1H), 7.27 (d, 1H), 7.15 (s, 1H), 4.65 (s, 1H), 3.28 (s, 2H), 2.90 (s, 3H), 2.35 (s, 1H), 2.20-2.03 (m, 1H), 1.88 (s, 2H), 1.30 (d, J=3.5 Hz, 9H). m 141 AA 473.19 1.39 400 MHz, DMSO-d6: 13.6 (brs, interchangeable with D20; lH), 7.13 (s, 0.48H, 6.96(s, 1H), 5.48 (t, J=9Hz; 1H), 4.11-4.07 (ms3H)s 3.34-3.31 (m5 0.57H), 3.16-3.10 (m; 1.62H), 2.98-2.93 (m5 1H), 2.32-1.96 (m, 4H), 1.60-1.43 (m, 8H), 1.29 (s, 9H), 1.05 -1.01 (ms6 m 142 AAB 473.19 1.39 400 MHz, DMSO-d6: 13.6 (brs, interchangeable with D20; lH), 7.13 (s, 0.48H, 6.96 (s, 1H), 5.48 (t, J = 9 Hz; 1H ), 4.11-4.07 (m5 3.67 H), 3.36-3.32 (m, 0.83H), 3.16-3.10 (m, 1.8H), 2.97-2.93 (m, 1H), 2.32-1.96 (m, 4H), 1.60 -1.43 (m,8H), 1.29 (s,9H),1.05-1.01 (mm 143 AAB 551.07 3.82 'HNMR (400 MHz, CDC13) δ 7.68 (s, 0.5H), 7.29 (ms 2H)S 7.22-7.04 (m,1H), 6.96 (s, 0.5H), 5.49 (m, 1H), 4.26-3.42 (m, 8H), 1.96-1.45 (m, 2H)S 1.31 (s, 9H), 0.96 (m, 3H). m •404· 157033.doc 201215604

144 AA 2.06 400 MHz, DMSO: 13.45 (s, interchangeable with D20; 1H), 7.21 (s, 1H), 4.91 (d, J = 16.4 Hz; 1H), 3.84 (d, J = 16.4 Hz; 1H) S 3.54-3.53 (m, 4H), 3.39-3.32 (m, 4H)S 2.11-1.98 (m,1H), 1.60-1.51 (m,4H), 1.37-1.34 (m, 2H), 1.31 (s,3H ), 1.19-1.17 (m5 2H), 1.02-1.00 (m, 2rn 145 AB 530.42 2.28 JHNMR (300 MHz, MeOD) δ 7.38 (s, 1H), 5.21 (d, J-11.6 Hz, 1H), 4.41 4.15 (m, 1H), 3.86-3.63 (m, 1H), 3.59-3.35 (m, 3H), 3.00 (d, J = 14.3 Hz, 6H), 2.22-2.20 (m5 1H), 1.74 (dt, J =28.5, 12.7 Hz, 6H), 1.33 (s, 9H), 1.17 (s, 2H), 0.82 (ds J=6.5 Hz, 3H)S 0.77-0.48 (m, 2H). 146 AAB 501.43 2.12 'HNMR ( 300 MHz, CDC13)5 6.65 (s, 1H), 5.00-4.92 (m, 1H), 4.84 (s5 2H)? 3.51-3.27 (m, 2H), 2.28-2.11 (m, 1H), 2.07-1.87 ( m, 3H), 1.86-1.69 (m, 4H)S 1.67-1.44 (m, 4H), 1.49-1.31 (m5 3H), 1.26 (ds J-3.0 Hz, 9H), 1.06 (dt, J=13.7, 6.8 Hz, 6H), 0.81 (s, lH), 0.75-0.69 (m, 3H), 0.66 (s, 2H). 147 BA 523.19 3.51 'HNMR (300 MHz, CDC13) δ 7.64-7.54 (m, 1H) , 7.58 (d, J=7.0 Hz, 1H), 7.33 (s, 1H), 7.27-7.20 ( m, 1H),7,17 (dd, J=8.3S 1.9 Hz, .5H), 7_04 (s,.5H), 4.63 (d, J=11.7 Hzs 1H)S 4.38 (s, 2H), 4.06 ( s, 1H), 3.90 (dd, J=15.2, 10.4 Hz, 1H), 3.69 (s, 1H), 3.31 (ddd, J=33.6, 15.7, 3.4 Hz, 1H), 3.18-3.08 (m, 3H) , 1.34-1.24 (m, 9H). 157033.doc 405- 201215604 148 AAA 473.15 1.61 *H NMR (400 MHz, CDC13) δ 6.76 (s, 1H), 3.68-3.58 (m, 1H), 3.51 (m, lH),3_41(m,2H), 3.18(m,lH), 2.37(dd, J=23.5, 12.2 Hz,1H), 2.08 (m, 2H), 1.95 (d, J=13.6 Hz, 1H), 1.73 (m, 2H)S 1.62-1.41 (m, 4H), 1.26 (s, 9H), 1.12 (m, 5H), 0.73 (d, J = 6.5 Hz, 3H), 0.69-0.57 (m, 2H) 149 AAB 487.17 1 NMR (400 MHz, CDC13) S6.63 (s, 1H), 4.78-4.64 (m, 1H), 3.66-3.47 (m, 1H), 3.21-3.05 (m, 2H), 2.16 ( m, 1H), 2.02-1.80 (m, 4H), 1.61 (m, 1H), 1.36 (m, 3H), 1.16-1.08 (s, 9H), 1.09-0.99 (m, 6H), 0.96-0.90 ( m, 3H), 0.62 (d, J = 6.5 Hz, 3H), 0.54 (m, 2H). 150 AA 503.14 3.71 NMR (400 MHz, CDCI3) δ 6.58 (m, 1H), 3.53-3.39 (m, 2H), 3.35 (m, 2H), 3.26 (m, 3H), 3.12 (ss 3H), 2.23 (ms 1H), 1.91 (m, 2H) ), 1.76 (m, 1H), 1.55 (m, 1H), 1.46-1.24 (m, 4H), 1.10 (s, 6H), 0.98 (s, 5H), 0.57 (d, J = 6.4 Hz, 3H) , 0.51 (m, 3H)· 151 BB 563.039 2.43 (400 MHz, DMSO-d6): 13.3 (brs, interchangeable with D20; 1H), 7.75-7.73 (m, 2H), 7.50 (s, 1H), 7.45- 7.41 (m, 2H), 7.22-7.18 (m, 1H), 7.09-7.07 (4H), 4.95 (d, J = 16.4 Hz; 1H), 3.92 (d, J = 15.6 Hz; 1H), 3.55-3.36 (m, 8H), 2.22-2.16 (m, 1H), 1.75-1.72 (m, 1H), 1.60 152 CB 610.85 2.37 (400 MHz, DMSO-d6): 13.5 (brs, interchangeable with D20; 1H), 7.57 -7.53 (m, 3H), 7.44-7.36 (m, 4H), 7.31-7.29 (m, 1H), 7.21-7.17 (m, 1H), 7.08-7.03 (m, 4H) 55.19-5.15 (m, 1H )S 4.31-4.27 (m,1H), 3.60-3.45 (ms 8H). •406- 157033.doc 201215604

153 AA 473.34 3.87 ^NMR (300 MHz, CDC13)5 7.61 (s3 0.6H), 6.75 (s,0_4H), 5.30 (brs,0.6H), 5.08 (d,J=10.6Hz,0.4H), 4.00- 3.61 (m, 1H), 3.39-3.13 (m, 1H), 3.09 (s, 1.2H), 3.05 (s, 1.8H), 2.23-1.39 (m, 14H), 1.34 (two single peaks, 9H) , 0.75 (m, 5H). ]H NMR (300 MHz, MeOD) δ 8.03-7.92 (m, 1H), 7.45 (s, 1H), 5.28 (d, 1H), 3.89-3.67 (m, 1H), 3.00 (d, J=5.4 Hz, 3H), 2.20-2.02 (m, 1H), 1.99-1.37 (m, 10H), 1.34 (s, 9H), 1.18-0.98 (m, 1H), 0.82 (d, 3H), 0.77-0.56 (m, 2H). 154 A 459.24 1:46 *H NMR (300 MHz, CDC13) δ 6.84 (s, 1H), 3.80-3.48 (m, 2H), 3.36-3.15 (m, 1H), 3.05 (s, 3H), 2.65-2.35 (m, 1H), 2.35-1.93 (m, 4H), 1.93-1.75 (m, 2H), 1.74-1.45 (m, 4H), 1.35 (s, 9H), 0.84 (d, 3H), 0.77-0.63 (m, 1H). Table 3 · ICS0, CC50 LCMS and NMR data for the compound shown in Figure 3. Compound number HCV-replicon (Luci-ET)-1b IC50 HCV-replicon-ELISA-la IC50 [3hi thymidine CC50 LCMS [M+H]+ LCMS RT NMR 156 A 0.004 501.259 1.87 400 MHz, DMSO-d6: 6.85 (s? 0.27H), 6.69 (s,0) . 77H), 5.37-5.33 (ms 0_3Η), 4·58· 4.53 (m, 0.7H), 3.81-3.71 (m, 2H), 3.65-3.54 (m, 2H), 3.32-3.13 (m5lH), 2.83- 2.82(m,lH),2.14-1.98(m,3H), 1.95-1.77(m,3H),1.57-1.50(m,3H), 1.50-1.40(m,lH), 1.27(3,93⁄4 1.23- 1.10 157033.doc -407- 201215604 157 586.6 2.35 *HNMR (300.0 MHz, DMSO) δ 7.52 (s, 1H), 5.23 (d, J=11.5 Hz, 1H), 4.39-4.33 (m, 1H)S 4.29- 4.23 (m, 2H), 3.61 (d, J=3.9 Hz, 1H), 3.54 (t, J=4.5 Hz, 4H), 3.25 (dd, J=4.3, 15.0 Hz, 2H), 2.90 (s, 3H) ), 2.57 (t, J=5.2 Hz, 2H), 2.44-2.38 (m, 4H), 2.02-1.90 (m, 1H), 1.85-1.66 (m, H), 1.64-1.46 (m, 5H), 1.43-1.36 (m, 2H), 1.30 (s, 9H)S 1.23-0.83 (m, 4H), 0.76 (d, J=6.5 Hz, 3H) and 0.70-0.48 (m, 2H) ppm 158 587.62 3.45 ' HNMR (300.0 MHz, DMSO) δ 7.55 (s5 1H)S5.91 (d, J=5.9 Hz, 1H), 5.79 (d, J=5.9 Hz, 1H), 5.21 (d5 J=11.5 Hz, 1H), 3.59 (dd, J=11.2, 15.1Hz, 1H), 3.24 (dd,4.0, 15.0 Hz, 1H), 2.90 (s,3H), 2.01-1.90 (m, 1H), 1.81-1.65 (m, 2H) , 1.63-1.48 (m, 5H), 1.45-1.31 (m, 1H), 1.30 (s, 9H), 1.25-1.15 (m, 2H), 1. 14(s,9H), 1.08-0.84 (m,3H), 0.75 (d, J=6.4 Hz, 3H) and 0.70-0.45 (m, 2H) ppm 408- 157033.doc 201215604

159 589.6 3.06 】HNMR (400.0 MHz, DMSO) δ 7.55 (ss 1H), 5.91 (d, 3=62 Hz, 1H), 5.78 (d, J=6.2 Hz, 1H), 5.23 (dsJ=11.8 Hz, 1H ), 4_81 (qn, J=6.2Hz, 1H), 3.61 (dd, J=11.4, 15.1 Hz, 1H), 3.29-3.22 (m, IH), 2.90 (s, 3H), 1.94 (t, J= 11.6 Hz, 1H), 1.79-1.33 (m, 10H), 1.30(s, 9H), 1.24 (dd, J=1.5S 6.2 Hz, 6H), 1.20-0.90 (m,3H)s 0.76 (d, J = 6.4 Hz, 3H) and 0.73-0.48 (m, 2H) ppm 160 573.61 3.18 'HNMR (300.0 MHz, DMSO) δ 7.55 (s, 1H), 5.91 (d, J = 6.0 Hz, 1H), 5.78 (d , J=6.0 Hz, 1H), 5.21 (d, J=11.5 Hz, 2H), 3.57 (d, J=ll.lHz, 1H)S 3.27 (d, J=2.9 Hz, 1H), 2.90 (s, 3H), 2.60-2.50 (m, 1H), 2.01-1.87 (m, 1H), 1.82-1.33 (m, 9H), 1.30 (s, 9H), 1.29-1_11 (m, 2H), 1_09 (dd, J = 1.2, 7.0 Hz, 6H)S 1.03-0.86 (m, 1H), 0.76 (d, J = 6.4 Hz, 3H) and 0.71· 0.47 (m, 2H) ppm 161 585.57 2.61 ^NMR (300.0 MHz, DMSO δ 7.52 (s, 1H), 5.28-5.08 (m, 3H), 3.61 (dd, J=11.3, 15·1, 1H), 3.29-3.22 (m, 1H)S 2.90 (s, 3H), 2.17 (s,3H)s 2.00-1.31 (m,9H),1.30 (s,9H),1.28-0.85 (m, 5H)S 0.7 5 (d, J=6.5 Hz, 3H) and 0.70-0.46 (ms 2H) ppm 157033.doc 409· 201215604 162 589.6 3.04 iHNMR (300.0 MHz, DMSO) δ 7.27 (s, 1H), 5.89 (d, J= 5.9 Hz, 1H), 5.82 (d, J=5.9 Hz, 1H), 4.92 (d, J=16.7 Hz, 1H), 3.85 (d, J=16.6 Hz, 1H), 3.55 (br s, 4H), 3.41-3.35 (m, 4H), 2.11-1.98 (m, 1H), 1.70-1.34 (m, 6H), 1.30 (s, 9H), 1.28-1.20 (m, 1H), 1.14 (s, 9H), 0.77 (d, J = 6.5 Hz, 3H) and 0.74 - 0.57 (m, 2H) ppm 163 617.56 3.49 fHNMR shows rotamer ^HNMR (300.0 MHz, DMSO) δ 7.34 (s, 0.6H), 7.27 (s , 0.4H), 5.91-5.75 (m, 2H), 5.56 (t; J=7.5 Hz, 0.4H), 5_19 (dd, J=6.4, 8.6 Hz, 0.6H), 3.77-3.39 (m, 7.6H) ), 3.21-3.10 (m, 0.4H), 2.00-1.82 (m, 1H), 1.65-1.35 (m, 6H), 1.34-1.16 (m5 12H)S 1.13 (s, 9H) and 0.80-0.68 (m , 8H) ppm 164 575.59 3.53 fHNMR shows rotamer ^HNMR (300.0 MHz, DMSO) δ 7.31 (s5 0_6H), 7.24 (s, 0_4H), 5.90 (d, J = 6.0 Hz, 0.6H), 5.81 ( d, J=5.0 Hz, 1.4H), 5.58 (t, J=7.5 Hz, 0.4H), 5.16 (dd, J=6.2, 8.8 Hz, 0.6H), 3.10(s, 1.8H), 3.05 (s , 1.2H), 2_85(s, 1 .8H), 2.65 (s, 1.2H), 1.99-1.84 (m, 1H)S 1.66-1.33 (m, 6H), 1.33-1.15 (m, 12H), l_14(s, 9H) and 0.79-0.49 ( m, 8H) ppm -410- 157033.doc 201215604

165 591.59 2.59 *HNMR (300.0 MHz, DMSO) δ 7.27 (s, 1H), 5.84 (dd, J=6_2, 9.7 Hz, 2H) S 4.91 (d, J = 16.7 Hz, 1H), 4.80 (seven peaks, J=6.2 Hz,1H), 3.89 (d, J=16.7Hz, 1H), 3.55 (br s, 4H), 3.45-3.35 (m, 4H), 2.13-1.98 (m, 1H), 1.79-1.33 ( m, 7H), 1.30(s,9H), 1.24 (d, J=6.2 Hz, 6H), 0.77 (d, J=6.4 Hz, 3H) and 0.75-0.57 (m, 2H) ppm 166 619.61 3.02 fHNMR Rotamer <HNMR (300.0 MHz, DMSO) δ 7.36 (s, 0.6H), 7.27 (s, 0.4H), 5.89 (d, J = 6.3 Hz, 0.6H), 5.81-5.74 (m, 1.4H) ), 5.56 (ts J=7_4 Hz, 0.4H), 5.19 (dd, J=6.5, 8.5 Hz, 0.6H), 4.88-4.73 (ms 2H)S3.73-3.35 (m, 7.6H), 3.23- 3.12 (m, 0.4H), 1.97-1.84 (ms 1H), 1.66-1.34 (m, 6H); 1.32-1.07 (m, 17H) and 0.81-0.47 (ms 8H) ppm 167 577.57 3.05 fHNMR shows rotational isomerism Body &quot;HNMR (300.0 MHz, DMSO) δ 7.33 (s, 0.55H), 7.24 (s, 0.45H), 5.89 (d, J = 6.3 Hz, 0.55H), 5.81 (dd, J = 6.3S8.0 Hz, 1H), 5.73 (d, J=6.3 Hz, 0.45H), 5.58 (t, J=7.5 Hz, 0.45H), 5.16 (d, J=2.4 Hz, 0.55H), 4.87-4.85 (m, 1H), 3.11 (s, 1.65H), 3.02 (s, 1.35H), 2.85 (s, 1.65H), 2.63 (s5 1.35H), 1.99-1.86 (m, 1H), 1.67-1.35 (m, 6H)S 1.34-1.08 (m, 18H) and 0.82 -0.51 (m, 8H) ppm 157033.doc •411 - 201215604 168 587.55 2.25 'HNMR (300.0 MHz, DMSO) δ 7.24 (s,1H), 5.18 (d, J=14.1 Hz, 1H), 5.12 (d, J=14.1 Hz, 1H), 4.89 (d, J=16.7 Hz, 1H)S 3.92 (d, J=16.7 Hz, 1H), 3.61-3.48 (m, 4H), 3.47-3.33 (m, 4H), 2_17(s,3H),2_13-2.00 (m, 1H), 1.73-1.33 (m,5H),1.30 (s,9H),1.30-1.15 (m, 2H), 0.77 (d, J=6.5 Hz, 3H) and 0.73-0.55 (m, 2H) ppm 169 615.58 2.61 ]HNMR (300.0 MHz, DMSO) δ 7.31 (s, 0.6H), 7.24 (s, 0.4H), 5.55 (t, J = 7.5 Hz, 0.4 H), 5.25-5.05 (m, 2.6H), 3.78-3.40 (m, 7.6H), 3.09-2.99 (m, 0.4H), 2.17 (s, 3H), 1.98-1.85 (m, 1H), 1.65 -1.33 (m, 6H), 1.32-1.05 (m, 12H) and 0.81 - 0.47 (m, 8H) ppm 170 573.61 2.66 'HNMR (300.0 MHz, DMSO) δ 7.28 (s, 0.6H), 7.21 (ss 0.4 H), 5.55 (t, J=7.5 Hz, 0.4H), 5.24-5.12 (m, 2.2H), 5.02 (ds 1=14.2 Hz5 0.4H), 3.10 (s,1_8H), 3.05 (s,1.2H) ), 2.85(s, 1.8H), 2.64 (s, l_2H), 2.1 7(s,3H), 1.96-1.85 (m, 1H), 1.66-1.33 (m, 6H)S 1.32-1.05 (m, 12H) and 0.79-0.47 (m, SH) ppm 412- 157033.doc 201215604

171 575.59 2.9 'HNMR (300.0 MHz, DMSO) δ 7.26 (s, 1H), 5.85 (dd, J = 5.9, 16.9 Hz, 2H) S4.91 (d, J = 16.7 Hz, 1H), 3.86 (d, J=16.7Hz, 1H), 3.62-3.48 (m, 4H), 3.44-3.33 (m, 4H), 2.65-2.55 (m, 1H), 2.13-1.98 (m, 1H), 1.78-1.35 (m, 5H), 1.30 (s, 9H), 1.29-1.18 (m, 2H), 1.08 (d, J=7.0 Hz, 6H), 0.77 (d, J=6.5 Hz, 3H) and 0.74-0.58 (m, 2H) ) ppm 172 603.68 3.36 々NMR (300.0 MHz, DMSO) δ 7.34 (s, 0.6Ή), 7.27 (s, 0.4H), 5.90 (d, J=6.0 Hz, 0.6H), 5.85-5.76 (ms 1.4H ), 5.56 (t, J-7.3 Hz, 0.4H), 5.18 (dd, J = 6.4, 8.6 Hz, 0.6H), 3.75-3.35 (m, 7.6H), 3.20-3.09 (m, 0.4H), 2.62-2.53 (m, 1H), 1.98-1.82 (m,1H), 1.65-1.34 (m,6H),1.32-1.13 (m,12H),1.10-1.06 (m, 6H)iL0.82-0.49 ( m, 8H) ppm 173 561.64 3.41 !HNMR (300.0 MHz, DMSO) δ 7.3 l(s,0.6H), 7.23 (s,0.4H), 5.90 (d, J=6.0 Hz, 0.6H), 5.82-5.75 (m, 1.4H), 5.58 (t, J = 7.5 Hz, 0.4H), 5.15 (dd, J = 6.2S8.8 Hz, 0.6H), 3.10 (s, 1.8H), 3.04 (s, 1.2H) ), 2.85 (s5 1.8H), 2.65 (s, 1.2H), 2.63-2.53 (m, 1H), 1.99-1.85 (m, 1H), 1.65-1.32 (m,6H), 1.32-1.12 (m, 12H), 1.08 (d, J=7.0 Hz, 6H) and 0.79-0.47 (m, 8H) PPm 157033.doc •413- 201215604 Provided in this article All references are incorporated herein by reference in their entirety. As used herein, all abbreviations, symbols, and conventions are consistent with those used in the scientific literature of the same period. See, for example, Janet s. D〇dd, ACS Style Guide. A Manual for Authors and Editors, 2nd edition Washington, D.C.: American Chemical Society, 1997. It is to be understood that the invention has been described in connection with the embodiments of the invention, and the scope of the invention is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. BRIEF DESCRIPTION OF THE DRAWINGS Figures 1-3 show tables depicting certain compounds of the invention.

157033.doc •414-

Claims (1)

201215604 VII. Patent application scope: 1. A compound represented by structural formula (I), Or a pharmaceutically acceptable salt thereof, wherein: ring A is further substituted with one or more substituents selected from the group consisting of _D, halogen, _cn, Cw leucoyl and Ck from a hospital group; Y is c3 .8 carbocyclic ring, 5-8 membered heterocyclic ring, -(c2 aliphatic group)_R丨, c6•丨〇aryl group or 5-10 membered heteroaryl group, wherein the carbocyclic ring, heterocyclic ring, aryl group and heteroaryl group The groups are each independently substituted by one or more J independently selected from the group consisting of: .CN, -CN, ;6 Schottky, azido, Ra, _s〇2Ra, -ORa, -CORa, -NRRa, -C(0)〇Ra, -〇c(〇)Ra, -NRC(0)Ra, -C(0)NRRa, -NRC(0)NRRa, ·ΝΙΙ(:(0)0Κ/, - 〇CONRRa, -S02NRRa, -NRS02Ra, -NRS02NRRa and -NRC(=NR)NRRa, and wherein the C2 aliphatic group is optionally substituted with one or more substituents selected from the group consisting of halogen, -CN , CN2 alkyl, Cw haloalkyl, hydroxy and decyloxy; R1 is: i) -H, ii) C 1-6 alkyl, optionally substituted by one or more J1 A; iii) C3-1G carbon a ring or a 4-10 membered heterocyclic ring, each optionally substituted by one or more J1B; or iv) a C6-10 aryl group or a 5-10 membered heteroaryl group, Each is optionally substituted by one or more Jlc; R2 is: i) C]-6 aliphatic, optionally substituted by one or more J2A; 157033.doc 201215604 i〇C3, carbocyclic or 4-10 The heterocyclic rings 'each of which is optionally substituted independently by one or more JBs; or the 匸6 1() aryl or 51 杂 heteroaryl groups, each of which is optionally substituted independently by one or more J 2 C; And R4, R5 and R6 are each independently _H, 〇 or a Cw aliphatic group substituted by one or more JDs; R and R8 are each independently i) _H; ii) c丨.6 aliphatic a group, optionally substituted by one or more J, iii) a C3.10 carbocyclic ring or a 4-1 membered heterocyclic ring, each of which is optionally substituted by one or more; or ()) (6 core aryl group) Or 5-1 杂 杂 ' 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Substituting; or when Y is -(C2 aliphatic)-111, R3 and R7, together with the atom to which they are attached, form a 4-10 membered heterocyclic ring, optionally substituted by one or more jE; and R9 is: i)-H ; ii) C丨·6 aliphatic group, as the case may be One or more households are substituted; 111) (: 3_1 () carbocyclic or 4-10 membered heterocyclic rings, each of which is optionally substituted by one or more J9B; or iv) C6.1Q aryl or 5-10 member Heteroaryl groups, each of which is optionally substituted independently by one or more J9C; J, J, J and J are each independently a pendant oxy group (οχο) or Q; or two J1A, two J2A, two j7A And two γ Α respectively form a 3-8 member non-aromatic ring independently of the atom to which they are attached, optionally substituted by one or more JEs; jlB, j2B, jTB and each independently are pendant oxy groups, 卩Or, as the case may be, one or more Q substituted C!·6 aliphatic groups; or two jie, two, two J3B, two J7B and two together with the atom to which they are attached 157033.doc -2- 201215604 Independently form 3-8 non-aromatic rings, optionally substituted by one or more jE; J, J, 1 and j9&lt;: Cl_6 lipids each independently Q or optionally substituted by one or more Q Family base; or two jic, two pcs, two and two J, respectively, independently of the atom to which they are connected, form a 3-8 member non-aromatic ring independently Each j is substituted; each Q is independently selected from the group consisting of: _, cyano, dec, -OR, -SRa, -S(0)Ra, _S02Ra, -NRRa, _c(0)Ra, -C (0) ORa, -0C(0)Ra, -〇c(〇)〇Ra, _NRC(0)Ra, _c(0)NRRa, -NRC(0)NRRa, -NRC(0)0Ra, -NRC( =NR)NRRa, -〇C〇NRRa, -C(0)NRC(0)0Ra, -C(=NR)Ra, -C(=NOR)Ra, -S02NRRa, -NRS〇2Ra, _NRS〇2NRRa, -0P(0)(0Ra)0Ra, a C38 carbon ring substituted by one or more jE, optionally a 4-8 member heterocyclic ring substituted by one or more JE, optionally by one or more J Substituted Ce_ 1Q aryl and 5_ 1 〇 heteroaryl substituted by one or more jF, as appropriate; each 113 is independently: i)-H; ii) Ci·6 aliphatic, as appropriate a plurality of substituents independently selected from the group consisting of: a hydroxyl group, a pendant oxy group, -CN, -OR, -NRRi, -OCOR, -COR&quot;, -C02R, -CONRR, -NRC(0) R, a C3-8 carbocyclic group substituted by one or more JE, optionally a 4-8 membered heterocyclic group substituted by one or more JE, optionally substituted by one or more JFs, Cl 1 〇 Aryl and 5-10 members replaced by one or more jF as appropriate An aryl group; iii) a C3-8 carbocyclic group or a 4-8 membered heterocyclic group, each of which is optionally substituted independently by one or more JE; or iv) a C6.lc aryl group or a 5- to 10-membered heteroaryl group. Each of them may independently take one or more jFs to take 157033.doc 201215604 generations, or R and R and the nitrogen atoms to which they are connected may form 4-8 members of the jade clothing as appropriate, depending on the situation, one or more JE substitution; and each of the Hans independently or, as the case may be, one or more JD substituted Cl. 6 aliphatic groups; each R' is independently _H or optionally substituted by one or more JD d. 6 fats The group ' or R' and R and the nitrogen atom to which they are attached - form a 4-8 membered heterocyclic ring, optionally substituted by one or more JE; each R&quot; is a Cl_6 substituted by one or more JDs as appropriate Aliphatic group; each JD is independently selected from the group consisting of halogen, pendant oxy, -CN, -OH, -NH2, -NH(C丨-C6 alkyl), -N(Ci-C6 alkyl) 2, • OCC^CVCe alkyl), -CCKCVC6 alkyl), _c〇2H, -CCMCV C6 alkyl), -〇 (Ci_C6 alkyl), -〇 (Ci-C; 6_ alkyl), C3.7 Ring-based base, c3_7 ring (haloalkyl) and phenyl; each JE is independently selected a group consisting of: halogen, pendant oxy, ?CN, -OH, -NH2, -NHCCVC^alkylalkyl) 2, -0CCKCVC6 alkyl), -CCKCi-Ce alkyl), -C02H, -ccmcv C6 alkyl), -CKCVC6 alkyl), -CHCVCeii alkyl) and, optionally, one or more JD substituted aliphatic groups; each JF is independently selected from the group consisting of: halogen, -CN, -OH, -NH2, -NH(C丨-C6 alkyl), -N(C!-C6 alkyl)2, -OCCKCi-C^, and -CCKCVC6 alkyl), -C02H, -C〇2 (Ci -C6 alkyl), -oxime (Ci-C6 alkyl), and optionally a CJ-C6 aliphatic group substituted with one or more JD; and 157033.doc -4- 201215604 η is 0 or 1. 2. The compound of claim 1, wherein: each Q is independently selected from the group consisting of halogen, cyano, nitro, -ORa, -SRa, -S(0)Ra, -S02Ra, -NRRa, - C(0)Ra, -C(0)0Ra, -0C(0)Ra, -NRC(0)Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0)ORa, -NRC (=NR)NRRa, -OCONRRa, -C(0)NRC(0)0Ra, -C(=NR)Ra, -C(=NOR)Ra, -S02NRRa, -NRS02Ra, -NRS02NRRa, -0P(0) (0Ra) 0Ra, optionally a C3.8 carbocyclic ring substituted by one or more JE, a 4-8 membered heterocyclic ring substituted by one or more JE, optionally substituted by one or more JF. 1()aryl and 5-10 membered heteroaryl substituted with one or more JF as appropriate. 3. A compound of claim 1 or 2, represented by structural formula (II): Or a pharmaceutically acceptable salt thereof, wherein Ring A is further substituted as appropriate. 4. A compound according to any one of claims 1 to 3, wherein ring A is further substituted by -F as appropriate. The compound of any one of claims 1 to 4, wherein R1 is optionally substituted Cw alkyl or optionally substituted C3.8 carbocyclyl. 6. The compound of claim 5, wherein R1 is optionally substituted Ci-6 alkyl 157033.doc 201215604 or c3-8 cycloalkyl group, each of which is optionally independently selected from one or more selected from the group consisting of Substituent substituent substitution: dentate, pendant oxy, _Cn, -OH, -NH2, -NHd-Cs alkyl), _N(Cl_C6 alkyl)2, -OCCKCrCe), -CCHCVCe alkyl) , -C〇2H, -COKCj C6 alkyl), -CKCi-Ce alkyl), -〇((ν(:6-alkyl), 7-cycloalkyl, 〇3_7 (haloalkyl) and phenyl). 7. The compound of claim 6 wherein R is an optionally substituted Ci6 alkyl group. . . 8. The compound of claim 7, wherein 111 is (:1·6 alkyl, optionally as appropriate - or more And a compound of any one of claims 1 to 8 wherein each q is independently selected from the group consisting of: Halogen; cyano; nitro; - 〇Ra; _SRa; -S(0)Ra; -S02Ra; -NRRa; -C(0)Ra; -C(0)〇Ra; -〇C(0)Ra; -0C(0)0Ra ; -NRC(0)Ra ; -C(0)NRRa ; _NRC(〇)NRRa ; -NRC(0)0Ra ; _N RC( = NR)NRRa ; -OCONRR3 ; -C(0)NRC(0)0Ra ; -C( = NR)Ra ; -C(=NOR)Ra ; -S02NRRa ; -NRS02Ra ; -NRS02NRRa ; (〇Ra)〇Ra; optionally substituted C3 8 carbocyclic group; optionally substituted 4-8 membered heterocyclic group; optionally substituted phenyl; and optionally substituted 5-6 member 10. The compound of claim 9, wherein each Q is independently selected from the group consisting of: halogen; cyano; nitro; _0Ra; _SRa; _s(0)Ra; -S02Ra; -NRRa; C(0)Ra ; -C(0)0Ra ; -0C(0)Ra ; -NRC(0)Ra ; -C(0)NRRa ; 157033.doc -6- 201215604 -NRC(0)NRRa ; -NRC (0)0Ra; -NRC(=NR)NRRa; -OCONRR3; -C(0)NRC(0)0Ra; -C(=NR)Ra ; -C(=NOR)Ra ; -S02NRRa ; -NRS02Ra ; NRS02NRRa; -0P(0)(0Ra)0Ra; optionally substituted C3-8 carbocyclyl; optionally substituted 4-8 membered heterocyclyl; optionally substituted phenyl; and optionally substituted 5-6 members of heteroaryl. 11. A compound according to any one of claims 1 to 10, wherein 1^ is -H, optionally substituted Ci-6 aliphatic, optionally substituted C3.6 carbocyclyl, optionally substituted a 4-8 membered heterocyclic group, optionally substituted phenyl or optionally substituted 5-6 membered heteroaryl; or 1^ together with 11 and the nitrogen atom to which it is attached, optionally formed as appropriate 5-8 member heterocyclic ring. 12. The compound according to any one of claims 1 to 11, wherein: JIA, J2A, J7A and J9A are each independently halogen, pendant oxy, -CN, _ORa, -NRRa, -OCORa, _0C(0)0Ra , _CORa, -C02Ra, -NRC(0)Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0)0Ra ' -OCONRRa, C3_8 cycloalkyl, C3_8 ring (haloalkyl), a substituted 5- to 6-membered heterocyclic group or an optionally substituted phenyl group; JIB, J2B, J7B and J9B are each independently halogen, pendant oxy, -CN, -ORa, -NRRa, -OCORa, -CORa, -C02Ra, -NRC(0)Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0)0Ra, -OCONRRa, or optionally one or more selected from the group consisting of Substituted by a group of substituents (^-(:6 aliphatic group: halogen, pendant oxy group, -CN, -ORa, -NRRa, -OCORa, -CORa, -C02Ra, -NRC(0)Ra, -C( 0) NRRa, NRC(0)NRRa, -NRC(0)0Ra, -OCONRRa, C3-8 cycloalkyl, C3_8 ring (haloalkyl) and phenyl; and 157033.doc 201215604 J1C, J2C, J7C^J9C Each independently is halogen, pendant oxy, -CN, -ORa, -NRRa, -OC(0)Ra, -CORa, -C02Ra, -NRC(0)Ra, -C(0)NRRa, -NRC(0 )NRRa, -NRC(0)0Ra -OCONRRa, or optionally an oxime-oxime group substituted with one or more substituents selected from the group consisting of dentate, pendant oxy, -CN, -ORa, -NRRa, -OCORa, -CORa , -C02Ra, -NRC(0)Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0)0Ra, -OCONRRa, C3.8 cycloalkyl, C3_8 ring (haloalkyl) and 13. A compound according to claim 12, wherein: J1A, J2A, J7A and J9A are each independently halogen, pendant oxy, -CN, -ORa, -NRRa, -OCORa, -CORa, -C02Ra, - NRC(0)Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0)0Ra, -OCONRRa, C3-8 cycloalkyl, C3.8 cyclo(haloalkyl) or phenyl; jlB, j2B, j7B and j9B are each independently halogen, pendant oxy, -CN, -ORa, -NRRa, -OCORa, -CORa, -C02RA, -NRC(0)Ra, -C(0)NRRa, - NRC(0)NRRa, -NRC(0)ORa, -OCONRRa, or optionally an aliphatic group substituted with one or more substituents selected from the group consisting of halogen, pendant oxy, -CN, -ORa , -NRRa, -OCORa, -CORa, -C02Ra, -NRC(0)Ra, -C(0)NRRa, -NRC(0)NRRa, _NRC(0)0Ra, -OCONRRa, C3-8 cycloalkyl, C3.8 ring (haloalkyl) and benzene And jic, j2c, j7c and pc are each independently halogen, pendant oxy, -CN, -ORa, -NRRa, -0C(0)Ra, -CORa, -C02Ra, -NRC(0)Ra, -C (0) NRRa, -NRC(Q)NRRa, -NRC(0)0Ra, -OCONRRa, or optionally substituted by one or more substituents selected from the group consisting of 157033.doc • 8 - 201215604 Base: halogen, pendant oxy, _CN, -ORa, -NRRa, -〇C〇Ra, _CC)Ra, -C02Ra, -NRC(0)Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(〇)〇Ra, -OCONRRa, (:3_8 cycloalkyl, c3-8 ring (haloalkyl) and phenyl. The compound of any one of claims 1 to 13 wherein R 2 is optionally substituted C 6 · 6 aliphatic, optionally substituted C 3 · 8 carbocyclyl, optionally substituted 4 8-membered heterocyclic group, optionally substituted phenyl or optionally substituted 5-6 membered heteroaryl. 15. The compound of claim 14 wherein R2 is a substituted or otherwise substituted phenyl group. 16. The compound of claim 15 wherein the rule 2 is (:5-(:8-cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen; pendant oxy; -CN; -OH; -NH2; -N^CVCs alkyl); -N(Ci-C6 alkyl)2; -OCOCC^-Ce alkyl); -CCKCVCU alkyl); -C02H; _c〇2 (CVc6 alkyl -0 (0,-(:6 alkyl); -CKCVCe dentate); and, optionally, a Cl-C6 aliphatic group substituted with one or more substituents selected from the group consisting of: _ , pendant oxy, _CN, -OH, -NH2, -nh(cvC6 alkyl), _N(Cl_c6 alkyl) 2, _0C0 (Ci_C6 alkyl), -C0 (CVC6 alkyl), _c〇2h, _C〇 2(Cl_c6 alkyl), yl), - oxime (CVC6 haloalkyl), (: 3-7 cycloalkyl, C3-7 cyclo(haloalkyl) and phenyl. 17. The compound of claim 16, Wherein R 2 is optionally substituted cyclohexyl. 18. The compound of claim 17, wherein R 2 is cyclohexyl, optionally substituted by one or the same group of J 2 B selected from the group consisting of: a lignin, 157033. Doc 201215604 -CN, -〇H, -NH2, -NH(Ci-6 alkyl), -N(Ci-6 Base 2, -CKC!.6 alkyl), and optionally C 丨-6 alkyl substituted with one or more substituents selected from the group consisting of halogen, -CN, -OH, -NH2 -NHCCw alkyl), -NCCu alkyl) 2, -CKCu alkyl) and -CKCu haloalkyl). 19. The compound of claim 14 wherein R2 is optionally substituted (:5-(:8-cycloalkenyl. 20. The compound of claim 19 wherein R2 is C5-C8 cycloalkenyl, optionally One or more substituents selected from the group consisting of: halogen; pendant oxy group; -CN; -OH; _ΝΗ2; • Nl^Ci-Ce alkyl); -N (Ci-C6 alkyl) 2; -OCCHCrC^ alkyl); -co(c)-c6 alkyl); -co2H; -C〇2(C]_C6 炫); -〇(Ci-C6 alkyl); hospital base); and optionally a Ci-C6 aliphatic group substituted with one or more substituents selected from the group consisting of: -, a pendant oxy group, -CN, -OH, -2, -Nt^Ci-Ce alkyl), - NCC^-Ce burnt base) 2, -occ^C^-C^ burnt base), -CO (C!-C6 burnt base), -C02H, -COdCVCe burn base), -0 ((^-06 burnt base) ), -CKCVCe haloalkyl), C3_7 cycloalkyl, c3_7 ring (haloalkyl) and phenyl. 21. A compound such as § 青解20, wherein R is optionally substituted cyclohexyl. 22. The compound of claim 21, wherein R2 is cyclohexenyl, optionally substituted with one or more of j2b independently selected from the group consisting of: dentate, -CN, -OH, -NH2, -NHiCu Alkyl), hydrazine ((: ι 6 alkyl, - hydrazine (C1 _ g alkyl), and optionally substituted by one or more substituents selected from the group consisting of 157033.doc -10· 201215604 Cl_6 alkyl: self, _cn,_0H, _NH2, -NHCCu alkyl), _N(Cl_6 alkyl)2, _〇(Ci 6 alkyl) and of! 6 haloalkyl). The compound according to any one of claims 1 to 22, wherein each jY is independently selected from the group consisting of halogen, _CN, nitro, Ra, 〇Ra, _c〇Ra and -NRRa. 24. The compound of claim 23, wherein each jY is independently selected from the group consisting of dentate, _CN, nitro, Cu alkyl, Cl-6 decyl, -OH, -〇 (C -6 -6 alkyl) ), - fluorene (phenyl), _ hydrazine (5-6 membered heteroaryl), - hydrazine 2, - ΝΗβκ alkyl), -Νβυ alkyl)alkyl). 25. The compound of claim 24, wherein each jY is independently selected from the group consisting of: 素, _CN, nitro, (: 丨-6 alkyl, Cl.6l|alkyl, -OH, -〇(Cl_6) Alkyl), _Nh2, _NH(Cl.6 alkyl), hydrazine ((:1.6 alkyl) 2 and -(:(0)((^.6 alkyl). 26. The compound of claim 25] Each is broadly and independently selected from the group consisting of dentate, -CN, nitro, methyl, ethyl, -Cf3, _〇h, -OMe, -NH2, and -C(0)Me. The compound according to any one of items 1 to 26, wherein γ is optionally substituted C3·6 cycloalkyl, optionally substituted 4 4-6 cycloalkenyl, _(C 2 aliphatic)-R1, as the case may be Substituted phenyl or optionally substituted 5-6 membered heteroaryl' and wherein the C2 aliphatic group is optionally substituted. 28. The compound of claim 27, wherein γ is optionally substituted phenyl, as appropriate Substituted thienyl or optionally substituted pyridyl. 157033.doc -11- 201215604 29. The compound of claim 28, wherein γ is optionally substituted phenyl. 30. - the compound of the item, wherein μ α a phenyl group, or optionally substituted phenyl, and wherein the &amp;aliphatic group is substituted as appropriate. The compound of the formula - wherein 丫 is Qianma _ R1, -CHsChH^-c^crI, or as appropriate A substituted phenyl group. The compound of any one of claims 1 to 27, which is optionally substituted C3.6 cycloalkyl or optionally substituted cycloalkenyl. 33. The compound of claim 32, wherein γ is optionally substituted c. The compound of claim 33, wherein γ is optionally substituted cyclohexenyl 0 35. The compound of any one of items 1 to 27, wherein γ is an aliphatic group - R1 ' and wherein the (: 2 aliphatic group is optionally substituted. 36. The compound of claim 35, wherein Y is -CH2 -CH2-R, ·CbCH·R1 or -CscRi. Compound of length 1 or 2 wherein the compound is represented by structural formula (hi): R'7 R1 or a pharmaceutically acceptable salt thereof, wherein Ring A is further substituted as appropriate. 157033.doc •12· 201215604 38. The compound of Kiss 37 is represented by the structural formula (ιν): Substituting -F 39. A compound of claim 37 or 38, wherein the ring is replaced as appropriate. 40. The compound of claim 39 is represented by structural formula (v): Or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 37 to 40, wherein R1 is optionally substituted c u alkyl or optionally substituted c38 carbocyclyl. 42. The compound of claim 41, wherein Ri is optionally substituted alkyl or optionally substituted CM cycloalkyl, each optionally, independently, via one or more substituents selected from the group consisting of Substitution: dentate, pendant oxy, -CN, -OH, -NH2, -NIKCrQ alkyl), alkyl) 2, -OCCKCrCe alkyl), -COCCrC^ alkyl), -C02H, 157033.doc -13 · 201215604 -COJCVC^alkyl), -0((^-(:6 alkyl), -CKCVC6)alkyl, C3-7 cycloalkyl, c3_7 ring (haloalkyl) and phenyl. The compound of claim 42, wherein R1 is optionally substituted (: 1_6 alkyl. 44. The compound of claim 43, wherein R1 is C -6 alkyl, optionally selected from the group consisting of dentate, The compound of any one of claims 37 to 44, wherein each Q is independently selected from the group consisting of halogen; cyano; -0Ra ; -SRa ; -S(0)Ra ; -S02Ra ; -NRRa ; -C(0)Ra ; -C(0)0Ra ; -0C(0)Ra ; -0C(0)0Ra ; NRC(0)Ra ; -C(0)NRRa ; -NRC(0)NRRa ; -NRC(0)0Ra ; -NRC(=NR)N RRa ; -0C0NRRa ; -C(0)NRC(0)0Ra ; -C(=NR)Ra ; -C(=N0R)Ra ; -S02NRRa ; -NRS02Ra ; -NRS02NRRa ; -0P(0)(0Ra)0Ra Substituted as appropriate (: 3-8 carbocyclyl; optionally substituted 4-8 membered heterocyclyl; optionally substituted phenyl; and optionally substituted 5-6 membered heteroaryl. The compound of claim 45, wherein each Q is independently selected from the group consisting of: iS; cyano; nitro; - 〇Ra; -SRa; -S(0)Ra; -S02Ra; -NRRa; (0)Ra ; -C(0)0Ra ; -0C(0)Ra ; -NRC(0)Ra ; -C(0)NRRa ; -NRC(0)NRRa ; -NRC(0)0Ra ; -NRC( =NR)NRRa ; -OCONRR3 ; -C(0)NRC(0)0Ra ; -C(=NR)Ra ; -C(=N0R)Ra ; -S02NRRa ; -NRS02Ra ; -NRS02NRRa ; -0P(0)( 0Ra)0Ra; optionally substituted C3_8 carbocyclic group; optionally substituted 4-8 membered heterocyclic group; optionally substituted phenyl; and optionally substituted 5-6 membered heteroaryl. The compound of any one of claims 37 to 46, wherein Ra is -Η, optionally substituted Cu aliphatic group, optionally substituted c3.6 carbocyclic group, Optionally substituted 4-8 membered heterocyclyl, optionally substituted phenyl or optionally substituted 5-6 membered heteroaryl; or Ra optionally formed together with R and the nitrogen atom to which it is attached The 5-8 member heterocyclic ring was replaced by the situation. The compound according to any one of claims 37 to 47, wherein: JIA, J2A, J7A and J9A are each independently halogen, pendant oxy, -CN, -ORa, -NRRa, _〇CORa, -OC ( 0) ORa, -CORa, -C02Ra, _-NRC(0)Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0)0Ra, OCONRRa, C3_8 cycloalkyl, C3-8 ring (haloalkyl), optionally substituted 5-6 membered heterocyclic group or optionally substituted phenyl; JIB, J2B, J7B&amp;J9B are each independently halogen, pendant oxy, -CN, -ORa, -NRRa, -OCORa, -CORa, -C02Ra, -NRC(0)Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0)0Ra, -OCONRRa, or as the case may be one or more a c丨-c6 aliphatic group substituted with a substituent selected from the group consisting of halogen, pendant oxy, -CN, -ORa, -NRRa, -OCORa, -CORa, -C02Ra, -NRC(0) Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0)0Ra, -OCONRRa, (:3_8 cycloalkyl, C3.8 ring (haloalkyl) and phenyl; and jic, j2c :, j7C and j9c are each independently halogen, pendant oxy, -CN, -ORa, -NRRa, -OCORa, -CORa, -C02Ra, -NRC(0)Ra, -C(0)NRRa, -NRC( 0) NRRa, -NRC(0)0Ra, -OCONRRa Or, optionally, a CrCfi aliphatic group substituted with one or more substituents selected from the group consisting of halogen, pendant oxy, -CN, -ORa, -NRRa, -OCORa, -CORa, -C02Ra, -NRC (0)Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0)0Ra, 157033.doc -15- 201215604 •OCONRRa, C3.8 cycloalkyl, C3_8 ring (haloalkyl) And a phenyl group. The compound of claim 48, wherein: J1A, J2A, J7A and J9A are each independently halogen, pendant oxy, -CN, -ORa, -NRRa, -OCORa, -CORa, -C02Ra, -NRC(0)Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0)ORa, -0C0NRR3, C3_8 cycloalkyl, C3_8 ring (haloalkyl) or phenyl; jlB, j2B , j7B and j9B are each independently halogen, pendant oxy, -CN, -ORa, -NRRa, -OCORa, -CORa, -C02Ra, -NRC(0)Ra, -C(0)NRRa, -NRC(0 NRRa, -NRC(0)0Ra, -OCONRRa, or optionally a Κ6 aliphatic group substituted with one or more substituents selected from the group consisting of halogen, pendant oxy, -CN, -ORa, - NRRa, -OCORa, -CORa, -C02Ra, -NRC(0)Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0)0Ra, -OCONRRa, C3.8 cycloalkyl, C3 -8 (haloalkyl) and phenyl; and J1C, J2C, J7C and J9C are each independently halogen, pendant oxy, -CN, -ORa, -NRRa, -OCORa, -CORa, -C02Ra, -NRC(0) Ra, -C(0)NRRa, -NRC(0)NRRa, -NRC(0)ORa, -OCONRRa, or, optionally, a CrCe aliphatic group substituted with one or more substituents selected from the group consisting of: Halogen, pendant oxy, -CN, -ORa, -NRRa, -OCORa, -CORa, -C02Ra, -NRC(0)Ra, -C(0)NRRa, NRC(0)NRRa, -NRC(0)0Ra , -OCONRRa, C3_8 cycloalkyl, (: 3.8 ring (||alkyl) and phenyl. The compound of any one of claims 37 to 49, wherein R2 is an optionally substituted CN6 aliphatic group, optionally substituted C3_8 carbocyclic group, optionally substituted 157033.doc •16·201215604 A 4-8 membered heterocyclic group, optionally substituted phenyl or optionally substituted 5-6 membered heteroaryl. 51. The compound of claim 50, wherein R2 is optionally substituted (: 5-(8:8-alkyl or optionally substituted phenyl. 52. The compound of claim 51 wherein R2 is C5- a C8 cycloalkyl group, optionally substituted with one or more substituents selected from the group consisting of: alkoxy; pendant oxy; -CN; -OH; -NH2; alkyl); -NCCVCealkyl)2; -OCCKCrCe alkyl); -CCKCi-Ce alkyl); -C02H; -COWCi-Ce alkyl); -CHCVCe alkyl); -CKCVC6 dentate alkyl); and optionally one or more selected from the group consisting of a group of substituted Ci-C6 aliphatic groups: halogen, pendant oxy, -cn, -OH, _NH2, •N^CVG alkyl), -Ν((^-(:6 alkyl)2 _0C0 (Cl_C6 alkyl), -CCKCVC^alkyl), -C02H, -COdCVCe alkyl), -CKC^-Ce alkyl), -CKCVCe haloalkyl, C3-7 cycloalkyl, c3-7 ring (haloalkyl) and phenyl. 53. The compound of claim 52 wherein R2 is optionally substituted cyclohexyl. 54. The compound of claim 53, wherein R2 is cyclohexyl, optionally substituted with one or more of j2b independently selected from the group consisting of: dentate, -CN, -OH, -NH2, -NH^Cu Alkyl), _N(Cl 6 alkyl) 2, -CKC!.6 alkyl), and, optionally, one or more substituents selected from the group consisting of: , -CN, -OH, -NH2, -NHiCw alkyl), alkyl)2, -〇(Cb6 alkyl) and 〇(Ci 6_alkyl). 55. The compound of claim 54, wherein J2B comprises a Cl_6 alkyl group optionally substituted with one or more substituents selected from the group consisting of: halogen, • CN, -OH, _NH2 , _NH (Ci 6 alkyl), _N (Ci 6 alkyl, • ◎ (Cm alkyl) and · 0 ((: 1 6 alkyl). 56. The compound of claim 55, wherein j2B includes _ 57. A compound according to any one of claims 37 to 56, wherein γ is optionally substituted C3·6 cycloalkyl, optionally substituted CM cycloalkenyl, _((: 2 aliphatic And the optionally substituted phenyl or the optionally substituted 5-6 membered heteroaryl, wherein the C2 aliphatic group is optionally substituted. 5 8. The compound of any one of claims 1 to 57, Wherein γ, γ, R5 and R6 are each independently -H or an optionally substituted Cw alkyl group; or R3, together with R7 and the atom to which it is attached, form, as the case may be, a 4-1 member heterocyclic ring which is optionally substituted. The compound of any one of claims 1 to 58, wherein r3, R4, R5 and R6 are each independently -Η or optionally substituted CN6 alkyl; and R7 and R are each independently Optionally substituted Cw aliphatic, optionally substituted 3-8 carbocyclyl or optionally substituted 4-8 membered heterocyclyl, or R7 and R8 together with the nitrogen atom to which they are attached, as appropriate The compound of any one of claims 1 to 58, wherein: R3, R4, R5 and R6 are each independently _H or optionally one or more selected from the group consisting of a substituted group of substituted C1-6 alkyl groups: halogen, pendant oxy, -CN, -OH, -NH2, -Nl^Ci-C^alkyl), -N(CVC6 alkyl)2, - OCCKCVCe alkyl), -CO(CVC6 alkyl), -C02H, 157033.doc • 18 · 201215604 -ccMq-Q alkyl), -o(Ci-c6 alkyl), alkyl), c3-7 naphthenic a group, a c3_7 ring (haloalkyl) and a phenyl group; and R7 and R8 are each independently -H; C!·6 alkyl, optionally substituted with one or more substituents selected from the group consisting of: , side oxy, -CN, -OH, -NH2, -NP^CVCe alkyl), -N(CVC6 alkyl)2, -OCCKCrCe alkyl), -CCHCVC^alkyl), -C02H, -COXCV C6 burnt base), -〇 (C!-C6 burnt base), -〇 (C!-C6_ burnt base), C3-7 ring a C3-7 ring (haloalkyl) and a phenyl group; or a &lt;:3-8 carbocyclic group or a 4-8 membered heterocyclic group, each of which is optionally independently selected from one or more selected from the group consisting of Group substituent substitution: li, side oxy, -CN, -OH, -NH2, -NH (Ci_C6 alkyl), -N (Ci_C6 alkyl) 2, -〇CO (Ci_C6), -CO (Ci_C6 alkyl), -CO2H, -C〇2 (Ci_C6 alkyl), -0 (Ci-C6), -〇((:!-(:6-tooth alkyl) and optionally one or more CrC6 alkyl substituted with a substituent selected from the group consisting of: halogen, pendant oxy, -CN, -OH, -NH2, alkyl), alkyl) 2, -OCO (Ci_C6), -CO (Ci_C6 alkyl), -CO2H, -C〇2 (Ci-C6 alkyl), -〇 (Ci-C6 thio), -0 (Ci-C6 functional thiol), C3-7 cycloalkyl, C3 -7 ring (haloalkyl) and phenyl; or R7 and R8, together with the atom to which they are attached, form a 4-10 membered heterocyclic ring, optionally substituted with one or more substituents selected from the group consisting of: Halogen, pendant oxy, -CN, -OH, -NH2, -NHd-Ce^), -N (Ci-C6 alkyl) 2, -OCO (Ci-C6 alkyl), -CO (Ci-C6) ;)^ base), -C O2H, -C〇2 (Ci-C6), -0 (Ci-C; 6 alkyl), -0 ((^.C6 haloalkyl), and optionally one or more selected from the group consisting of Group 157033.doc •19· 201215604 Substituted CrCe alkyl: halogen, pendant oxy, -CN, -〇H, -NH2, alkyl), -NCCrC^ alkyl)2, -OCCKCVCe alkyl ), -CO(C-C6 alkyl), -C02H, -COdCrC^alkyl), -0 ((^-(Ι:6 alkyl), -CKCVCj alkyl), c3.7 cycloalkyl, C3.7 a cyclo(haloalkyl) group and a phenyl group; or R3 and R7, together with the atom to which they are attached, form a 4-10 membered heterocyclic ring, optionally substituted with one or more substituents selected from the group consisting of: : _, side, oxy, -CN, -OH, -NH2, yl), alkyl) 2, -OCCKCVQ alkyl, -(^((^-(^)), -C02H, -COJCVCe a group of -C-CVCe alkyl), -〇((:,-ce haloalkyl), and optionally a Ci-C6 alkyl group substituted with one or more substituents selected from the group consisting of halogen, side oxygen Base, _CN, -OH, -NH2, -Nl^CVCe alkyl), -N(C丨-C6 alkyl) 2, -0(:0((:1-(:6)), -CCHC^ -Ce alkyl), _ Co2h, -CCMC^-Cfi alkyl), - fluorene (CrCe alkyl), - hydrazine (C "C6ii alkyl"), (: 3.7 cycloalkyl, C3_7 ring (haloalkyl) and phenyl. 61. The compound of claim 60, wherein: R3, R4, R5 and R6 are each independently -Η or optionally substituted C6 alkyl; and R7 and R8 are each independently _H or optionally substituted Cl 6 alkyl, optionally substituted (: 3 · 8 carbocyclyl or optionally substituted 4-8 heterocyclyl ' or R 7 and R 8 together with the atom to which they are attached, optionally substituted 4 - A compound of claim 60. 62. The compound of claim 60, wherein: 157033.doc -20- 201215604 R3, R4, R5 and R6 are each independently - or optionally one or more selected from the group consisting of Group substituted by (3!-6 alkyl: halogen, -CN, -OH, -NH2, -NHCCu alkyl), -NCCu alkyl) 2, -CKCw alkyl) and -CKCw haloalkyl) And R7 and R8 are independently -H or optionally substituted by one or more substituents selected from the group consisting of: halogen, -CN, -OH, -NH2, -N^ Cm alkyl), -N(C!-6 alkyl)2, -CHCu alkyl) and -〇(Ci-6 dentate alkyl); R7 and R8, together with the atom to which they are attached, form a 4_1 member heterocyclic ring as the case may be substituted by one or more substituents selected from the group consisting of: -, -, -, -, - -, - - Alkyl), -NCCw alkyl) 2 - hydrazine (Ci. 6 alkyl) and - hydrazine (C丨_6 dentate). 63. The compound of claim 61 or 62, wherein R7 and R8, together with the atom to which they are attached, form a optionally substituted heterocyclic ring. 64. The compound of claim 63, wherein the heterocyclic ring formed by the ruthenium 7 and r8 is a bridged or spiro ring. 65. The compound of claim 60, wherein: RR, Μ and R8 are each independently -Η or optionally substituted c, 6 alkyl; and 'R and R are taken together with the original + to which they are attached, as appropriate Replace the 10 member heterocyclic ring. 66. The compound of claim 65, wherein R4 is selected from the group consisting of, R5, R6, and R8夂R are independently substituted with _H or, as the case may be, a substituent of the group consisting of: .6 alkyl: or more halogens, 157033.doc •21· 201215604 -CN, -OH, -NH2, -NHiCu alkyl), -NiCu alkyl) 2, -0 (Ci_6 alkyl) and -〇 ( Ci-6 functional group); and R3 and R7 together with the atom to which they are attached form a 4-10 membered heterocyclic ring, optionally substituted with one or more substituents selected from the group consisting of dentate, -CN, -OH, -NH2, -NHiCw alkyl), -Νγυalkyl) 2, -CHCw alkyl) and -OCCm haloalkyl). 67. The compound of claim 65 or 66, wherein the heterocyclic ring formed by R3 and R7 is selected from the group consisting of: Wherein the rings D1-D7 are each independently substituted as appropriate. 68. A compound according to any one of clauses 37 to 67, wherein: R is 匸! • 6 alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, 2 〇H and alkyl; C16 aliphatic &amp; substituted as appropriate Carbocyclyl, m-substituted forest 8M miscellaneous m replaced by 157033.doc -22- 201215604 Phenyl money substituted by 5.6-membered heteroaryl; R, R and R6 are each independently _Η or a substituted Cl 6 alkyl group; and R and R are each independently _H, optionally substituted Cw aliphatic group, optionally substituted q8 carbocyclic group; or R together with the atom to which it is attached The formation of a 4-1 member heterocyclic ring which is optionally substituted; or R and R, together with the nitrogen atom to which they are attached, form a optionally substituted 4-1 member heterocyclic ring. 69. A compound according to any one of items 37 to 68, which is represented by the structural formula (νι) Or a pharmaceutically acceptable salt thereof, wherein Ring B is substituted with one or more J2B as appropriate. 70. The compound of claim 69, wherein: 28 is halo, _cn, -OH, -NH2, alkyl), -Νβυalkyl), ·0 ((: 1-6 alkyl), or as appropriate One or more 〇1.6 alkyl groups substituted with a substituent selected from the group consisting of: _, - 〇], -1, -1, ^, -1^11 ((: 1-6 alkyl), -Nfu burnt base) 2, _ 〇 (Ci_6 alkyl) and - 〇 ((^.6_ alkyl). 71. The compound of claim 70, wherein ^ is 烷基 "alkyl or - 〇 ((:!. 6 alkane 157033.doc -23- 201215604 base). The compound of formula (VII) is shown in Table 72. The compound of any one of claims 37 to 71 is shown: Or a pharmaceutically acceptable salt thereof. The compound of _72, wherein the carbonyl group at position 1 of the cyclohexyl group to which J2B is attached is in a trans form. 74. The compound according to any one of claims 72 or 73, wherein the radical is 75. The compound of claim 74, wherein γ Β is a methyl group. 76. A compound according to any one of claims 37 to 75, wherein the compound is a compound of claim 76, wherein the compound is a tertiary butyl group or a different The compound of any one of claims 1 to 77, wherein R3, μ, r5 and R are each independently -H or, as the case may be, substituted by one or more substituents selected from the group consisting of Cu alkyl: halogen, _CN, _〇H, •nh2, —NH(Cl.6 alkyl), —N(Cl.6 alkyl) 2, _0(Ci 6 alkyl), and —◦ (Cw teeth The compound of any one of claims 1 to 78, wherein R3, R4, R5 and R6 are each independently -Η or optionally one or more _0 (Ci 6 haloalkyl) The compound of any one of claims 1 to 78, wherein R3, R4, R5 and R6 are each independently -Η, -CH3, -CH2CH3, -CH2CH2CH3, -CH2 - 〇CH3, -CH2CH2-OCH3, -CH2CH2-OCH2CH3 or -CH2ch2-och2ch3. The compound of any one of claims 1 to 30, wherein the compound is represented by the formula (VIII): Or a pharmaceutically acceptable salt thereof, wherein Rings A and P are each independently substituted as appropriate. 82. The compound of claim 81 wherein the compound is represented by the formula (ι): Or a pharmaceutically acceptable salt thereof, wherein the cyclic oxime and ρ are each independently substituted as appropriate. 83 such as ▲ main i • % of the compound of formula 82, wherein the compound is represented by the structural formula (X): 157033.doc •25- 201215604 Depending on the situation or its pharmaceutically acceptable salt, the ring p is replaced by a separate step. Wherein the compound is represented by the formula (XI): Table 8. 4. The compound of claim 8 3: Or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 81 to 84, wherein: R2 is optionally substituted C5_C8 cycloalkyl or optionally substituted phenyl', each of which is optionally independently selected from one or more selected from Substituents of the following composition are substituted: a functional element; a pendant oxy group: -CN; -OH; -NH2; -NK^CVC^alkyl); ·NCCrCg alkyl)2; -OCCKCVC^ alkyl); -C0 (C丨-C6 alkyl); -C02H; -CCMCrCe alkyl); -CKCi-Ce alkyl); -0(0^-(^haloalkyl); and optionally one or more selected from the following Substituent substituted Ci-Cfi aliphatic group of the constituent group: halogen, pendant oxy group, -CN, -OH, -NH2, -NHCC^-CU alkyl group, -NfrCe alkyl group) 2, -0C0 (C -C6 alkyl), -CCHCi-C^alkyl), -co2h, 157033.doc -26- 201215604 -COKCVCe alkyl), -CHC^-Ce alkyl), haloalkyl), (:3- a 7-cycloalkyl group, a C3_7 ring (haloalkyl group), and a phenyl group; R3, R4, and r5ar6 are each independently _H or, as the case may be, Ci.6 alkane substituted with one or more substituents selected from the group consisting of: Base: halogen, pendant oxy, -CN, -OH, -NH2, -Ni^CVCe alkyl), -NCCVC6 alkane Base) 2, -OCCKCi-C^ alkyl), -CCKCi-C^ alkyl), -C02H, -CCMCVCe alkyl), -CKCVQ alkyl, -CKCVC6 alkyl, C3_7 cycloalkyl, C3_7 Ring (haloalkyl) and phenyl; R7 and R8 are each independently -H; Cu alkyl, optionally substituted with one or more substituents selected from the group consisting of dentate, pendant oxy, - CN, -OH, -NH2, -NI^CVC^alkyl), -N(Ci-C6 alkyl)2, OCCHCVCe alkyl), -C0(C丨-C6 alkyl), -C02H, -ccmcv c6 Alkyl), -0((^-(:6 alkyl), -CKC^-Ce haloalkyl), C3-7 cycloalkyl, C3-7 cyclo(haloalkyl) and phenyl; or C3- 8 carbocyclyl or 4-8 membered heterocyclyl, each optionally substituted with one or more substituents selected from the group consisting of halogen, pendant oxy, -CN, -OH, -NH2 - ΝΗ ((ν(:6 alkyl), -Nfi-Ce alkyl) 2, -OCCKCVCe alkyl), -CCKCi-Ce alkyl), -C02H, -COKCVC^alkyl), alkyl), - OCCi-Ce haloalkyl) and, optionally, a CrCe alkyl group substituted with one or more substituents selected from the group consisting of halogen, pendant oxy, -CN, -OH, -NH2 -NHCC^-Q alkyl), -NCCi-C^alkyl)2, -OCCKCrCe alkyl), -CCKCVC^alkyl), -C02H, -COJCV c6 alkyl), -CKCi-C^ alkyl) , -0((^-(:6^ alkyl), c3.7 cycloalkyl, c3.7 cyclo(haloalkyl) and phenyl; or 157033.doc -27· 201215604 R7 and R8 are attached thereto The atoms together form a 4-10 membered heterocyclic ring, optionally substituted with one or more substituents selected from the group consisting of halogen, pendant oxy, -CN, -OH, -NH2, -NHCCi-C^ Alkyl), alkyl) 2, -〇CO(Ci-C6 alkyl), -(^((^-(^)), -CO2H, -C〇2 (Ci-C6 alkyl), -0 (Ci-C6 alkyl), -oxime (Ci-c6 haloalkyl) and optionally substituted by one or more substituents selected from the group consisting of halogen, pendant oxy, -CN, - OH, -ΝΗ2, alkyl), -N(Ci-C6 alkyl)2, ·OCOCCrQ alkyl)'-CO(C!-C6 alkyl), -CO2H, -C〇2 (Ci-C6 alkyl) ), -OCCVC6 alkyl), -CKCi-Ce haloalkyl), C3-7 cycloalkyl, (: 3-7 ring (haloalkyl) and phenyl. 86. The compound of claim 85, wherein: R3, R4, R5 and R6 are each independently _H or optionally substituted with one or more substituents selected from the group consisting of: halogen, - CN, ·〇Η, -NH2, -NH(C 丨·6 alkyl), -Νπυ alkyl) 2, -〇(C丨_6 alkyl) and -〇(Ci.6 haloalkyl); R7 and R8 are independently -H or, as the case may be, substituted by one or more substituents selected from the group consisting of: (., .6 alkyl: halogen, -CN, -OH, ^112, -&gt; ((:1.6 alkyl), -> 1 ((: 1-6 alkyl) 2, -0 ((:1.6 alkyl) and -Οβκ), or R7 and R8 together with the atom to which they are attached Forming a 4-10 membered heterocyclic ring as appropriate [optionally substituted with one or more substituents selected from the group consisting of: halogen, -CN, -OH, -NH2, -NP^Cu alkyl), -ISKCu Base) 2, -CHCw alkyl) and -CKCw functional alkyl). 157033.doc -28 - 201215604 87. The compound of any one of claims 81 to 86, which is represented by structural formula (XII): Or a pharmaceutically acceptable salt thereof, wherein Ring B is substituted with one or more J2B as appropriate. 88. The compound of claim 87, wherein: [28 is halogen, _CN, -OH, -NH2, -NHCCk alkyl), -N(Cb6 alkyl) 2, -(XCu alkyl), or optionally One or more Cu alkyl groups substituted with a substituent selected from the group consisting of halogen, _CN, _〇H, -ΝίΪ2, _NH(Ci 6 alkyl), -ncCm alkyl) 2, _〇 (Ci 6 Alkyl) and _〇 (〇16_ alkyl). 89. The compound of claim 88, wherein jZB is Ci6 alkyl or 〇(Cl6 alkyl). 9. The compound of any one of claims 81 to 89, which is represented by the structural formula (XIII): Or a pharmaceutically acceptable salt thereof. For example, a compound of the formula 89, wherein J2B is trans to the carbonyl group at position 1 of the ring of 157033.doc -29-201215604 linked to J2B. The compound of any one of claims 90 or 91, wherein: [28 is a Cw alkyl group. 93. The compound of claim 92, wherein j2B is methyl. The compound according to any one of claims 84 to 93, wherein R3, R4, R5 and R6 are each independently -H or optionally substituted by one or more substituents selected from the group consisting of: Base: halogen, -CN, -OH, -ΝΗ2, -ΝΗγυ alkyl), alkyl)2, -CXCw alkyl) and 〇(Ci-6 haloalkyl). The compound according to any one of claims 84 to 93, wherein R3, R4, R5 and R6 are each independently a C-alkyl group substituted by -H or optionally one or more -CKCm-functional alkyl groups. The compound of any one of claims 84 to 93, wherein R3, R4, R5 and R6 are each independently -H, -CH3, -CH2CH3, -CH2CH2CH3, -CH2-OCH3, -CH2CH2-OCH3, - CH2CH2-OCH2CH3 or -CH2CH2-OCH2CH3. The compound of any one of claims 1 to 96, wherein r9 is _H or optionally substituted with one or more substituents selected from the group consisting of: 丨_6 alkyl: i, Side oxy, -CN, -OH, -NH2, -NHCCi-C^alkyl), alkyl)2, -OC(0)(Ci-C6 alkyl), -OCCCOOd-Cs alkyl), -CCKCi -Ce alkyl), -C02H, -COdCrQ alkyl), -CKCrCe alkyl), -CKCi-C^haloalkyl), C3.7 cycloalkyl, c3-7 (haloalkyl), phenyl, and 5-157033.doc -30-201215604 6-membered heterocyclic ring optionally substituted with one or more substituents selected from the group consisting of pendant oxy groups and alkyl groups. 98. The compound of claim 97, wherein r9 is η or, as the case may be, one or more C 1 -6 alkyl groups substituted with a substituent selected from the group consisting of dentate, fluorenyl, -CN, - OH, -NH2, -NH(C,-C6 alkyl), alkyl) 2, -0 (: (0) ((:, - (: 6 alkyl), -CCKCrh alkyl), -C02H, - COdCVC^alkyl), -CKCVCe alkyl), -CKCVC6 haloalkyl, C3.7 cycloalkyl, c3.7 cyclo(haloalkyl) and phenyl. The compound of any one of claims 1 to 98, wherein the compound is a compound of any one of claims 1 to 98, wherein the compound is a compound of any one of claims 1 to 98. And a compound of any one of items 1 to 98, wherein R9 is a compound of the formula (1). Is a compound of any one of claims 1 to 98, wherein R9 is _H. 103. The compound of claim 102, wherein the compound is pharmaceutically acceptable The compound of any one of claims 1 to 3, wherein ng〇e 1〇5. The compound of claim 1 or 2 is represented by structural formula (XX): Or a pharmaceutically acceptable salt thereof, wherein: R is 匸..6 alkyl, optionally selected from the group consisting of halogen, 157033.doc •31·201215604-CN, -OH and -CKCrCe alkyl) Substituted by a group of substituents; R8 is -H or optionally substituted with one or more substituents selected from the group consisting of: halogen, hydroxy, -CKCm alkyl), -NH2 -NI^Cw alkyl) and -N(C!_4 alkyl)2; R9 is -H or optionally substituted by one or more substituents selected from the group consisting of halogens, side oxygen Base, -CN, -OH, -NH2, -NHCCi-C^ alkyl), -NCCVCe alkyl)2, -OCCHCVCe alkyl), -0(:(0)0((:,-(:6) Base, -co(c)-c6 alkyl), -co2h, -COKCVCe alkyl), -CHCi-C^alkyl), -CKCVC6 dentate alkyl, c3_7 cycloalkyl, c3_7 ring (haloalkyl) a phenyl group, and optionally a 5-6 membered heterocyclic ring substituted with one or more substituents selected from the group consisting of pendant oxy groups and alkyl groups; ring B optionally substituted with one or more J2B; C is a 5-7 membered heterocyclic ring, optionally substituted with one or more selected from the group consisting of: Substituted with: halo, hydroxy, -0 ((^ --4 alkyl), -NH2, -NI ^ Cu-alkyl) and -New alkyl) 2. 106. The compound of claim 1 , wherein R 9 is -H or optionally substituted by one or more substituents selected from the group consisting of halogen, pendant oxy, -CN , -OH, -NH2, -NHCC^-Ce alkyl), -N(C-C6 alkyl)2, -OCCKCVCe alkyl), -CCKCi-C^ alkyl), -C02H, -CCMCVQ alkyl ), -CKCVC6 alkyl), -〇((^-(:6 haloalkyl), C3.7 cycloalkyl, (:3_7 ring (decyl)) and phenyl. 107. as claimed in claim 106 or 107 a compound wherein: R1 is a third butyl or isopropyl group; 157033.doc -32-201215604 R8 is -Η or optionally substituted by one or more Cw alkyl groups selected from the group consisting of: Element, hydroxyl, -〇(ch3), -o(c2h5), -NH2, -NH(CH3) and -N(CH3)2; and J2Ba halogen, -CN, -OH, -NH2, -ΝΗβκ alkyl , -Nfw alkyl) 2, -0 ((:!-6 alkyl), or optionally Ci.6 alkyl substituted by one or more substituents selected from the group consisting of: halogen, -CN , -OH, _NH2, -NP^Cw alkyl), -NCCw alkyl) 2, -〇(C丨.6 alkyl), and -O (C 1.6 functional * base). #108. A compound of claim 106 or 107, wherein R8 is -HSCw alkyl. 109. The compound of any one of claims 1 to 5, wherein the rule 9 is 4. 110. The compound of any one of claims 1 to 5, wherein j2b is _CH3 or -〇(CH3). The compound of any one of claims 105 to 110, wherein the compound is represented by the structural formula (XXI): Or a pharmaceutically acceptable salt thereof, wherein q is. ,... 112. The compound of claim U1, wherein the compound is a pharmaceutically acceptable salt, 113. A compound selected from the group consisting of α τ, which is given in Figure 1, or a pharmaceutical thereof A salt that is acceptable for learning. A compound selected from any one of the structural formulae of the green color in Fig. 2 or Fig. 3 or a pharmaceutically acceptable salt thereof. 157033.doc -33 - 201215604. A compound selected from any one of the compounds 1 to 12, 121 to 154, 156 to 173, and 174 to 191, or a pharmaceutically acceptable salt thereof. 116. A pharmaceutical composition, as set forth in the claims 1 to 115, and a pharmaceutically acceptable remedy or excipient. 117. A method of inhibiting or reducing polymerase activity in an in vitro biological sample, which comprises administering to the sample an effective amount of a compound according to any one of claims 1 to 3. 118. A method of treating an HCV infection in an individual, comprising administering to the individual a therapeutically effective amount of a compound of any one of claims 丨 to 115. 119. A method of inhibiting or reducing Hcv polymerase activity in an individual, comprising administering to the individual a therapeutically effective amount of a compound of any one of claims 1-5 to 115. 120. The method of claim 118 or 119, further comprising co-administering one or more other therapeutic agents to the individual. 121. The method of claim 120, wherein the other therapeutic agent comprises an anti-HCV drug. 122. The method of claim 121, wherein the anti-HCv drug is an hCV protease inhibitor. 123. The method of claim 122, wherein the HCV protease inhibitor is an Hcv NS3 inhibitor. 124. The method of claim 121 wherein the anti-HCV drug is an HCV NS5A inhibitor. 125. The method of claim 121 wherein the anti-HCV drug is a nucleoside or nucleoside 157033.doc-34-201215604 acid HCV polymerase inhibitor. 126. The method of any one of claims 120 to 125, wherein co-administered with interferon and/or viral beta (ribavirin). 127. The method of claim 126, wherein the interferon is a pegylated interferon. The method of claim 127, wherein the pegylated interferon is polyethylene glycolated interferon alpha. 129. The method of claim 127, wherein the pegylated interferon is polyethylene glycolated interferon a2a or pegylated interferon a2b. The method of any one of items 118 to 129, wherein the Hcv is genotype 1. The method of any one of claims 118 to 129, wherein the 11 (: ¥ is a genotype la or a genotype lb. 132) is a compound represented by the structural formula (j) or a pharmaceutically acceptable compound thereof A method of accepting a salt wherein the variables of the structural formula are each independently as claimed in any one of claims 1 to 115, and wherein the method comprises reacting the compound (ig) with the compound (lh) to form the structural formula (I) Steps for the compound: Wherein the variables of the compounds (lg) and (lh) are each independently as described for structural formula (I) and X is a suitable leaving group; and optionally further comprises -C of the compound of formula (I) 〇) C) R9 157033.doc • 35· 201215604 The step of hydrolyzing to form $_C〇〇H under suitable hydrolysis conditions. 133. The method of claim 13, wherein the compound prepared by the method of the formula is represented by the formula (II) or a pharmaceutically acceptable salt thereof: The variables of the structural formula (II) are each independently as described in the request item 针对32 for the structural formula (I). 134. The method of claim 132, wherein the compound prepared by the method is represented by structural formula (III) or a pharmaceutically acceptable salt thereof: *, The variables of the structural formula (ΙΪΙ) are each independently as described in the request item 132 for the structural formula (I). 135. The method of claim 132 wherein the compound prepared by the method is represented by structural formula (IV) or a pharmaceutically acceptable salt thereof: 157033.doc -36· 201215604 wherein the variables of the structural formula (ιν) are each independently as described for the structural formula (I) in the request item i32. 36. A method of preparing a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof, which causes the variables of the structural formula (1) to be independently as claimed in any one of claims 1 to 115. Said, and wherein the method comprises the step of reacting compound (lp) with compound (1f): XC(0)R2 to form a compound of formula (1): R7 Ο 丫kR8 % 备 s (I) dp) wherein the variables of the compound (lp) are each independently as described for the structural formula (1), and X is a suitable leaving group; and, as the case may be, further comprises a compound of the formula (1) The step of _c(〇)〇R9 is hydrolyzed under suitable hydrolysis conditions to form -COOH. 137. The method of claim 136, wherein the compound prepared by the method is represented by structural formula (II) or a pharmaceutically acceptable salt thereof: The variables of structural formula (II) are each independently as described in claim 136 for the formula (I). 157033.doc • 37· 201215604 138. The method of claim 136, wherein the compound prepared by the method is represented by the structural formula (m) or a pharmaceutically acceptable salt thereof: The variables of structural formula (III) are each independently as described in claim 136 for structure (I). 139. The method of claim 136, wherein the compound prepared by the method is represented by structural formula (IV) or a pharmaceutically acceptable salt thereof: The variables of the structural formula (11) are each independently as described in the claim 丨36 for the structuring (I). β 157033.doc 38-