EA012389B1 - Macrocyclic compounds as inhibitors of viral replication - Google Patents

Abstract

The embodiments provide compounds of the general formulas I-XIX, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating flaviviral infection, including hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.

Description

The application for this invention is a partial continuation of the application for US patent No. 11/064445, filed February 23, 2005, which is a continuation of PCT / I804 / 33970, filed October 13, 2004, having priority in accordance with 35 Code of Laws of the United States §119 (e) on provisional application for US patent No. 60/511541, filed October 14, 2003, and provisional application for US patent No. 60/612460, filed September 22, 2004; this application also has priority on provisional application for US patent No. 60/612381, filed September 22, 2004; provisional application for US patent No. 60/562418, filed April 14, 2004; and provisional application for US patent No. 60 / 558,161, filed March 30, 2004, a description of each of which is fully incorporated into this description by reference.

The scope of the invention

FIELD OF THE INVENTION

The present invention relates to compounds, methods for their synthesis, pharmaceutical compositions and methods for treating flavivirus infections, such as viral hepatitis C (HCV). In particular, the present invention discloses novel peptide analogues, pharmaceutical compositions containing such analogues, and methods for using these analogues in the treatment of flavivirus infections.

Description of the prior art

In the United States, hepatitis C virus (HCV) is the most common chronic blood-borne infection. Although the number of new infections has declined, the number of chronic patients is significant, and according to the Centers for Disease Control and Prevention in the United States, there are approximately 3.9 million (1.8%) infected people. Chronic liver disease is the tenth leading adult cause of death in the United States, with approximately 25,000 deaths annually, or approximately 1% of all deaths. Studies show that 40% of chronic liver diseases are associated with hepatitis C virus, resulting in approximately 80,000,000 deaths each year. Hepatitis C virus-related end-stage liver disease is the most common cause of liver transplant in adults.

Antiviral therapy for chronic hepatitis C has evolved dynamically over the past decade with significant improvements in treatment efficacy. However, even with combined treatment using interferon-alpha conjugated with PEG plus ribavirin, treatment was not successful in 40-50% of patients, i.e. patients showed either no therapeutic effect or relapse of the disease. To date, there has been no effective treatment alternative for these patients. In particular, patients with advanced liver fibrosis or cirrhosis detected by biopsy have a significant risk of developing complications of advanced liver diseases, including ascites, jaundice, varicose bleeding, encephalopathy, and progressive liver dysfunction, and the risk of hepatocellular carcinoma also significantly increases.

The widespread prevalence of chronic hepatitis C virus infection has serious public health consequences, in the form of the immediate burden of chronic liver disease in the United States. Data from the National Research Service for Health and Nutrition (ΝΗΑΝΕ8 III) indicate that a significant increase in the number of infections occurred in the late 60s and early 80s, especially among people aged 20 to 40. It is approximately estimated that the number of people with a protracted form of HS virus infection of 20 years or more can increase 4 times over the period from 1990 to 2015. from 750,000 to over 3 million. A proportional increase in the number of people infected within 30 or 40 years could be even greater. Since the risk of chronic liver disease associated with HCV is associated with the duration of infection, the risk of cirrhosis is gradually increasing for people infected for more than 20 years, this can lead to a significant increase in diseases associated with cirrhosis and mortality among patients infected between 1965- 1985 years

HCV is a virus of the flavivirus family with a twisted strand of RNA of positive polarity. The HCV genome is represented by a single RNA strand with a length of about 9,500 nucleotides and contains a single open reading frame (OKE) that carries information about the only large virus-specific polyprotein with a size of about 3,000 amino acid residues. In infected cells, this polyprotein is cleaved into numerous sites by cellular and viral proteases to produce structural and non-structural (N8) proteins of the virus. In the case of HCV, the formation of mature non-structural proteins (N82, N83, N84, Ν84Α, Ν84Β, Ν88Α and Ν85Β) is carried out by two viral proteases. The first viral protease cleaves the Ν82-Ν83 polyprotein bond. The second viral protease is a serine protease containing the N-terminal portion of N83 (hereinafter referred to as N83 protease). The N83 protease is the mediator of all subsequent cleavages at sites below the N83 position in the polyprotein (i.e., sites located between the C-terminus of N83 and the C-terminus of the polyprotein). Ν83 protease is active both in the cis position during cleavage of the Ν83-Ν84 site and in the trans position for the remaining Ν84Α-Ν84Β, Ν84Β-Ν85Α and Ν85Α-Ν85Β sites. Ν84Α protein is believed to be a multifunctional polyprotein and promotes

- 1 012389 activity of N83 protease and possibly involved in membrane localization of N83 and other viral replicase components. Obviously, the formation of a complex between N83 and Ν84Α is necessary for processes mediated by N83, and improves proteolytic efficacy in all areas recognized by N83. Protease N83 also exhibits nucleoside triphosphatase and RNA helicase activity. N856 is an RNA-dependent RNA polymerase involved in HCV RNA replication.

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Urabandai, Fukishima, Japan (1996) (Apyu1ga1 Keeeagsy, (1996), 30: 1, A23 (abstract 19));

- 2 012389

81 bags A1., Vueyesh., 37: 8899-8905;

1pdaShpe11a e! A1., Vueyesh., 37: 8906-8914.

where O is a central ring selected from

where the central ring may be unsubstituted or substituted by halogen, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, phenyl, thiazolyl, C (O ^ HCH ₂ CH ₃ , C (O) OH, OCH ₂ CH ^ H (C _1-3 alkyl), OCH ₂ CH ^ (C _1-3 alkyl) ₂ , C ₂ -alkoxy containing imidazolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, CH ₂ CH ^ (CH ₃ ) as a substituent ₂ , C (O) OCH ₂ CH ₃ , spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl or spirocyclic cyclohexyl, or

O represents K / -K ² , where K ¹ represents phenyl, pyridine, furan, thiophene, thiazole, pyrazole, naphthyl, quinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole or benzimidazole, each of which may contain substituents from one to three ΝΚ ⁶ Κ ⁷ , halogen atoms, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl, possibly substituted up to 5 fluorine atoms, or C _1-6 alkoxy, possibly substituted up to 5 fluorine atoms; and K ² represents H, or phenyl, or imidazole, each of which may contain from one to three halogen atoms as substituents;

K ⁴ represents H;

K ⁵ represents H, C (O) No. ⁶ K ⁷ , -C (O) K ⁸ , C (O) OK ⁸ or (CO) SNK ² ^ H (CO) K ²² ;

K ⁶ and K ⁷ each independently represent H, C _1-6 alkyl, C _3-7 cycloalkyl or phenyl, said phenyl may contain from one to three halogen, cyano, C _1-6 alkyl, C atoms as substituents _1-6 alkyls, possibly substituted with up to 5 fluorine atoms, or C _1-6 alkoxy, which can be substituted with up to 5 fluorine atoms; or

K ⁶ and K ⁷ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

K ⁸ represents C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, wherein said C _1-6 alkyl may contain phenyl as a substituent; or

K ⁸ is C _1-6 alkyl, optionally substituted with up to 5 groups containing fluorine; or

K ⁸ represents a tetrahydrofuran ring bonded through the positions of the C3 or C4 tetrahydrofuran ring; or

K ⁸ is a tetrahydropyran ring linked through position

C4 tetrahydropyran ring;

Υ represents a sulfonimide group of the formula —C (O ^ H8 (O) ₂ K ⁹ , where K ⁹ represents C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, or K ⁹ represents phenyl or naphthyl, each of which may contain up to three substituents selected from halogen, cyano, nitro, C _1-6 alkyl or C _1-6 alkoxy; or K ⁹ represents C _1-6 alkyl, optionally substituted with up to 5 fluorine-containing groups, G ⁶ K ⁷ or G ^1a K ^1b ; or K ⁹ is a monocyclic heteroaromatic ring containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, cat one may be substituted up to two times with halogen; or Υ represents a carboxyl group or a pharmaceutically acceptable salt, solvate or prodrug thereof;

where K ^1a and K ^1b , each independently, are H, C _1-6 alkyl or C _3-7 cycloalkyl, which may be substituted one to three times by cyano, or

K ^1a and K ^1b each independently represent H, C ₆ aryl, which may contain from one to three halogen atoms, cyano, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 alkyl as substituents possibly substituted with up to 5 fluorine atoms, or

K ^1a and K ^1b , each independently, are H or 5-, 6- or 7-membered saturated or

- 3 012389 unsaturated heterocyclic molecule containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, or

CC ^1a To ^1b is an alkyl cyclic secondary amine containing from 3 to 6 members, which may contain in the ring from one to three heteroatoms selected from the group consisting of nitrogen and oxygen;

p is 0 or 1;

V is selected from O, 8 or ΝΗ;

when V is selected from O or 8, is selected from O or ΝΚ ¹⁵ ;

when V represents ΝΗ, represents ΝΚ ¹⁵ , where K ¹⁵ represents Η;

dashed line indicates a possible double bond;

K ²¹ represents C _1-6 alkyl or C _3-7 cycloalkyl and

K ²² represents C _1-6 alkyl;

provided that the compounds having the formula I do not include the compound having the formula II, III

C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl or C _1-6 alkyl, optionally substituted with up to 5 fluorine atoms , C _1-6 alkoxy, optionally substituted with up to 5 fluorine atoms, C ₆ or C ₁₀ -aryl, pyridinyl, pyrimidinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, 8Ο ₂ ΝΚ ⁶ Κ ⁷ , ΝΗ ^ Ο) ΝΚ ⁶ Κ ⁷ , Ν№ (8) ΝΚ ⁶ Κ ⁷ , PODO, ΝΚ ⁶ Κ ⁷ , C (O) K ⁸ , C (O) OK ⁸ , MUOG, ΝΗ ^ Ο) ΟΚ ⁸ , ⁸ Out of ⁸ , Ν ^ Ο ) ^ ⁸ , (BSC ^ K ⁶ K ⁷ , O (BSC ^ K ⁶ K ⁷ or BSC ⁹ ; where K ⁹ is imidazolyl or pyrazolyl; indicated thienyl, pyrimidinyl, furanyl, thiazolyl and oxazolyl in the definition of K ¹ and K ² may contain, from one to two halogen atoms, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyls, C4-10 alkylcycloalkyls, C2-6 alkenyls, C1-6 alkoxy, hydroxy-C1-6 alkyls, C1-6 alkyls as substituents possibly substituted by up to 5 fluorine atoms, or C1-6 alkoxy, possibly substituted by up to 5 fluorine atoms; said C6 or C10-aryl, pyridinyl, phenoxy and thiophenoxy in the definition of K ¹ and K ² may contain from one to three halogen atoms as substituents , cyano, nitro, hydroxy, C1-6alkyl, _C3-7 cycloalkyls, _C4-10 alkylcycloalkyls, _C2-6 alkenyl c, C _1-6 alkoxy, hydroxyC _1-6 alkyl, C _1-6 alkyl optionally substituted with up to 5 fluorine atoms, or C _1-6 alkoxy optionally substituted with up to 5 fluorine atoms;

(b) m = 0, 1 or 2;

(c) K ⁴ represents Η, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, phenyl or benzyl, said phenyl or benzyl may contain from one to three halogen, cyano, nitro atoms as substituents , hydroxy, C _1-6 alkyl, C _3-7 cycloalkyls, C _4-10 alkylcycloalkyls, C _2-6 alkenyls, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl, possibly substituted up to 5 fluorine atoms, or C _1-6 alkoxy, possibly substituted with up to 5 fluorine atoms;

(b) K ⁵ is Η, C ^ alkyl, CO \ U, O8) \ U. -C (O) K ⁸ , C (O) OK ⁸ , 8 (LK ⁸ or ΧΟΧΗ ^ ΝΗΧΟ ^ ²² ;

(e) K ⁶ and K ⁷ each independently represent Η, C _1-6 alkyl, C _3-7 cycloalkyl, C4-10 alkylcycloalkyl or phenyl, said phenyl may contain from one to three halogen, cyano, nitro, hydroxy, _C1-6 alkyls, C3-7 cycloalkyls, C4-10 alkylcycloalkyls, C _2-6 alkenyls, hydroxy-C _1-6 alkyls or C _1-6 alkyls, possibly substituted with up to 5 fluorine atoms, C _1-6 alkoxy, possibly substituted up to 5 fluorine atoms; or

- 4 012389

B ⁶ and B ⁷ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

(I) B ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _{4-1 0} alkylcycloalkyl, each of which may be substituted one to three times by halogen, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl; or

B ⁸ represents C ₆ or C ₁₀ aryl, which may contain from one to three halogen atoms, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C ₄₁₀ alkylcycloalkyl, C _2- as substituents ₆ alkenyls, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl, possibly substituted up to 5 fluorine atoms, or C _1-6 alkoxy, possibly substituted up to 5 fluorine atoms; or

B ⁸ represents C _1-6 alkyl optionally substituted with up to 5 fluorine-containing groups; or

B ⁸ is a tetrahydrofuran ring bonded through the positions of the C3 or C4 tetrahydrofuran ring; or

B ⁸ is a tetrahydropyran ring bonded through position

C4 tetrahydropyran ring;

(e) Υ represents a sulfonimide group of the formula C (O) XH8 (O) ₂ B ⁹ , where

B ⁹ represents C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, each of which may be substituted one to three times by halogen, cyano, nitro, hydroxy, C1-6 alkoxy or phenyl; or

B ⁹ represents C ₆ or C ₁₀ aryl, which may contain, from one to three halogen, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl atoms as substituents _2-6 alkenyls, C _1-6 alkoxy, hydroxy-C _1-6 alkyl or C _1-6 alkyl, possibly substituted up to 5 fluorine atoms, C1-6 alkoxy, possibly substituted up to 5 fluorine atoms; or

B ⁹ is C _1-6 alkyl, optionally substituted with up to 5 fluorine-containing groups, PV ⁶ B ⁷ or (CO) OH; or

B ⁹ represents a heteroaromatic ring, possibly substituted up to two times by halogen, cyano, nitro, hydroxyl or C _1-6 alkoxy; or

Υ represents a carboxyl group or a pharmaceutically acceptable salt, solvate or prodrug thereof;

(II) B ¹⁰ and B ¹¹ each independently represent H, C _1-6 alkyl, C _3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or C10-aryl, hydroxy- _C1-6 alkyl, _C1-6 alkyl, optionally substituted up to 5 fluorine atoms, (С11Д.ХВВ. (СН2) пС (О) ОВ ¹⁴ , where

B ¹⁴ represents H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, each of which may be substituted one to three times by halogen, cyano, nitro, hydroxy, C1-6 alkoxy or phenyl; or

¹⁴ represents C6 or C10-aryl, which may contain as substituents from one to three halogen atoms, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyls, C4-10 alkylcycloalkyls, C2-6 alkenyls, C1 -6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl, possibly substituted up to 5 fluorine atoms, or _C1-6 alkoxy, possibly substituted up to 5 fluorine atoms; the specified C ₆ or C ₁₀ aryl in the definition of B ¹⁰ and B ¹¹ may contain from one to three halogen atoms, cyano, nitro, hydroxy, C1-6 alkyls, C3-7 cycloalkyls, C4-10 alkylcycloalkyls, C2-6 alkenyls, C1 -6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl, possibly substituted with up to 5 fluorine atoms, or C1-6 alkoxy, possibly substituted with up to 5 fluorine atoms; or B ¹⁰ and B ^11, together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or B ¹⁰ and B ¹¹ together represent O;

(ί) p = 0 or 1;

(ί) B ¹² and B ¹³ each independently represent H, C _1-6 alkyl, C _3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or C10-aryl, hydroxy- _C1-6 alkyl, _C1-6 alkyl, optionally substituted up to 5 fluorine atoms, (СН) пив ⁶ В ⁷ , (СШ) пС (О) ОВ ¹⁴ , where

B ¹⁴ represents H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, each of which may be substituted one to three times by halogen, cyano, nitro, hydroxy, C _1-6 alkoxy or phenyl , or

¹⁴ represents C6 or C10-aryl, which may contain as substituents from one to three atoms of halogen, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy C1-6alkyl, C1-6alkyl, optionally substituted with up to 5 fluorine atoms, or C1-6alkoxy, optionally substituted with up to 5 fluorine atoms; the specified C6 or C10-aryl in the definitions of B ¹² and B ¹³ may contain as substituents from one to three halogen atoms, cyano, nitro, hydroxy, C1-6 alkyls, C3-7 cycloalkyls, C4-10 alkylcycloalkyls, C2-6 alkenyls, C1-6 alkoxy hydroxy-C1-6alkyls, C1-6alkyls optionally substituted with up to 5 fluorine atoms, or C1-6alkoxy optionally substituted with up to 5 fluorine atoms; or B ¹² and B ¹³ together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or B ¹² and B ¹³ each independently represent C _1-6 alkyl, optionally substituted with (CH ₂ ) _p OB ⁸ ;

(k) In ²⁰ represents H, C1-6 alkyl, C3-7 cycloalkyl, S4-10alkiltsikloalkil, C6 or C10 aryl, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted by up to 5 fluorine atoms, (CH2) ⁶ PVC ⁷ , (CH2) _p C (O) OV ¹⁴ ,

- 5 012389 where B ¹⁴ represents H, C1-beam. C3_7cycloalkyl; C4-10alkylcycloalkyl. each of which can be substituted from one to three times by halogen. cyano, nitro. hydroxy. C1-balkoxy or phenyl. or B ¹⁴ is Cb or C ₁₀ aryl. which may contain from one to three halogen atoms as substituents. cyano. nitro. hydroxy. C _1-b alkyl. With _3-7 cycloalkyls. C _4-10 alkylcycloalkyls. With _2- balkenyls. C _1- alkoxy. hydroxy-C _1-b alkyl. C _1-b alkyl. possibly substituted up to 5 fluorine atoms. C _1- alkoxy. possibly substituted up to 5 fluorine atoms; said C _b or C ₁₀ aryl in the definition of B ¹² and C ¹³ may contain from one to three halogen atoms as substituents. cyano. nitro. hydroxy. C _1-b alkyl. With _3-7 cycloalkyls. C _4-10 alkylcycloalkyls. C _2- alkenyl. C _1- alkoxy. hydroxy-C _1-b alkyl. C _1-b alkyl. possibly substituted up to 5 fluorine atoms. C _1- alkoxy. possibly substituted up to 5 fluorine atoms;

(1) n = 1-4;

(t) V is selected from O. 8 or KH;

(o) when V is O or 8. is selected from O. KB ¹⁵ or CB ¹⁵ ;

when V is KN. choose from KB ¹⁵ or CB ¹⁵ . where In ¹⁵ represents N. With _1-b alkyl. C _3-7 cycloalkyl. C _4-10 alkylcycloalkyl or C _{1 -b} alkyl. possibly substituted up to 5 fluorine atoms;

(o) dashed line means a possible double bond;

(p) B ²¹ represents C _{1 -b} alkyl. C _3-7 cycloalkyl. C _4-10 alkylcycloalkyl. each of which can be substituted from one to three times by halogen. cyano. nitro. hydroxy. C _1- alkoxy. With _1-b alkyl. possibly substituted up to 5 fluorine atoms. or phenyl; or

B ²¹ is C _b or C ₁₀ aryl. which may contain from one to three halogen atoms as substituents. cyano. nitro. hydroxy. C _1-b alkyl. With _3-7 cycloalkyls. C _4-10 alkylcycloalkyls. C _2- alkenyl. C _1- alkoxy. hydroxy-C _1-b alkyl. C _1-b alkyl. possibly substituted up to 5 fluorine atoms. C _1- alkoxy. possibly substituted up to 5 fluorine atoms; or

At ²¹ is pyridinyl. pyrimidinyl. pyrazinyl. thienyl. furanyl. thiazolyl. oxazolyl. phenoxy. thiophenoxy; and (c |) B ²² is C ₁ -balkyl. C _3-7 cycloalkyl. C _4-10 alkylcycloalkyl. each of which can be substituted from one to three times by halogen. cyano. nitro. hydroxy. With _1-b alkyl. possibly substituted up to 5 fluorine atoms. or phenyl.

(d) Ζ represents a system of fused or bonded aryl or heteroaryl rings.

The present invention also provides a compound. having the formula XI th ^{2 ν =} <

νν

Yu

XI where a) B ^1a and B ^1b . each independently. are N. C _{1 -b} alkyl or C _3-7 cycloalkyl. each of which can be substituted from one to three times cyano. or

B ^1a and B ^1b . each independently. represent N. With _b- aryl. which may contain from one to three halogen atoms as substituents. cyano. C _1-b alkyl. C _{1 b} alkoxy or C _{1 b} alkyl. possibly substituted up to 5 fluorine atoms. or

B ^1a and B ^1b . each independently. represent H or 5-. a b- or 7-membered saturated or unsaturated heterocyclic molecule. containing from one to four heteroatoms. selected from the group. consisting of nitrogen. oxygen and sulfur. or

KB ^1a B ^1b is an alkyl cyclic secondary amine. containing from 3 to 6 members. which may contain from one to three heteroatoms in the ring. selected from the group. including nitrogen and oxygen;

b) represents O or KH;

c) V is selected from O. 8 or KH;

j) when V is selected from O or 8. is selected from O or KB ¹⁵ ;

when V is KN. represents KV ¹⁵ . where B ¹⁵ represents H;

e) K ² is a bicyclic secondary amine structure

where K ²¹ and K ²² each independently represent H, halogen, cyano, hydroxy, C1_6 alkyl, C1_6 alkoxy, C1-6 alkyl, possibly substituted with up to 5 fluorine atoms, thiazolyl, C (O) CC ⁶ K ⁷ , ΝΚ ⁶ Κ ⁷ , C (O) OK ⁸ or ΝΗί '.' (Ο) Β ⁸ : the specified thiazolyl in the definition of K ²¹ and K ²² may contain C1-6 alkyl as a substituent;

K ¹⁰ and K ¹¹ each independently represent H or C _1-6 alkyl; or

K ¹⁰ and K ^11, together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

p is 0 or 1;

K ¹² and K ¹³ each independently represent H or (CH ₂ ) ^ K ⁶ K ⁷ ;

K ²⁰ represents H;

n = 0-4;

K ⁶ and K ⁷ each independently represent H, C _1-6 alkyl or C _3-7 cycloalkyl; or K ⁶ and K ^7, together with the nitrogen to which they are attached, form piperidinyl, piperazinyl or morpholinyl; or

K ² represents K ^2a K ^2b when Α = Ν4 and Y = O, where

K ^2a represents phenyl, pyridine, furan, thiophene, thiazole, pyrazole, naphthyl, quinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole or benzimidazole, each of which may contain from one to three ΝΕ ^ β as substituents. ²² , halogen atoms, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl, possibly substituted up to 5 fluorine atoms, or C _1-6 alkoxy, possibly substituted up to 5 fluorine atoms;

K ^2b represents H, phenyl or imidazole, each of which may contain from one to three halogen atoms as substituents;

said K ^2c and K ²² each independently represent H or C _1-6 alkyl or K ^2c and K ²² together with the nitrogen to which they are attached form morpholinyl;

ί) K ⁴ represents H;

d) K ⁵ represents H, C (O ^ K ⁶ K ⁷ , -C (O) K ⁸ or C (O) OK ⁸ ;

11) K ⁸ represents C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkylcycloalkyl, wherein said C _1-6 alkyl may contain phenyl as a substituent; and

ί) A dashed line indicates a possible double bond.

The present invention provides a compound of formula XVIII

where a) K ¹ represents phenyl, pyridine, furan, thiophene, thiazole, pyrazole, naphthyl, quinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole or benzimidazole, each of which may contain from one to three NK ⁵ K as substituents ⁶ , halogen atoms, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl, possibly substituted up to 5 fluorine atoms, or C _1-6 alkoxy, possibly substituted up to 5 fluorine atoms;

B) K ² represents H, phenyl, which may contain up to three halogen atoms or imidazole as substituents;

c) K ³ represents H;

2) K ⁴ represents C (O ^ K ⁵ K ⁶ , -C (O) K ⁷ or C (O) OK ⁷ ;

e) K ⁵ and K ⁶ each independently represent H, C _1-6 alkyl or C _3-7 cycloalkyl or K ⁵ and K ⁶

- 7 012389 together with the nitrogen to which they are attached form morpholinyl;

ί) K ⁷ represents C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, wherein said C _1-6 alkyl may be substituted with phenyl;

d) To ⁸ represents C _1-3 alkyl, C _3-4 cycloalkyl or phenyl which may be substituted by one to two halo, cyano, C1 _-3 alkyl or C1 _-3 alkoxy; and

d) the dotted line means a possible double bond;

or a pharmaceutically acceptable salt of said compound.

In addition, the present invention provides a compound of the formula

where a) Ζ is a group capable of forming a hydrogen bond with an imidazole fragment of Ηί§57 N83 protease and forming a hydrogen bond with a nitrogen atom of C1u137 N83 protease;

b) P ₁ 'is a group capable of participating in non-polar interaction with at least one fragment 81' of the N83 protease pocket selected from the group consisting of L3'136, C1u137, 8eg139, δι _δ 57, C1u58, 8eg42 and Pye43;

c) b represents a linker group containing from 1 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen and sulfur;

ά) P _{2 is} selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclyl, and substituted heterocyclyl; the position of P _{2 is} determined by L with the formation of non-polar interaction with at least one fragment 82 of the N83 protease pocket selected from the group consisting of Ηί _δ 57, Agd155, Wa1178, Azr79, C1p80 and Azr81;

f) dashed line means a possible double bond;

ί) K ^{5 is} selected from the group consisting of Η, C (O) NK ⁶ K ⁷ and C (O) OK ⁸ ;

e) K ⁶ and K ⁷ each independently represent Η, C _1-6 alkyl or C _3-7 cycloalkyl and

j) K ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkylcycloalkyl, wherein said C _1-6 alkyl may be substituted with phenyl; or

K ⁸ is C _1-6 alkyl optionally substituted with up to 5 fluorine-containing groups; or

K ⁸ represents a tetrahydrofuran ring bonded through the positions of the C3 or C4 tetrahydrofuran ring; or

K ⁸ is a tetrahydropyran ring linked through position

C4 tetrahydropyran ring;

with the proviso that said compound does not include a compound of formula II, III or IV as defined above; and provided that the compound does not include a compound of the formula

- 8 012389

- 9 012389

The present invention also provides a compound of formula ν

11 where K ⁴ represents H;

K ⁵ represents ϋ (Ο) ΝΚ ⁶ Κ ⁷ , -C (O) K ⁸ , C (O) OK ⁸ or (CO) SNK ² ^ H (CO) K ²² ;

K ⁶ and K ⁷ each independently represent H, C _1-6 alkyl, C _3-7 cycloalkyl or phenyl, said phenyl may contain from one to three halogen, cyano, C _1-6 alkyl, C atoms as substituents _1-6 alkyl, possibly substituted up to 5 fluorine atoms, or C _1-6 alkoxy, possibly substituted up to 5 fluorine atoms; or

K ⁶ and K ⁷ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

K ⁸ represents C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, wherein said C _1-6 alkyl may be substituted with phenyl; or

K ⁸ is C _1-6 alkyl optionally substituted with up to 5 fluorine-containing groups; or

K ⁸ is a tetrahydrofuran ring bonded through C ₃ or

- 10 012389

C _4- tetrahydrofuran ring; or

K ⁸ is a tetrahydropyran ring linked through position

C _4- tetrahydropyran ring;

Υ represents a sulfonimide group of the formula —C (O) YN8 (O) ₂ K ⁹ , where K ⁹ represents C _1-3 alkyl, which may contain 1 to 3 halogen atoms, C _3-7 cycloalkyl or phenyl as substituents which may contain from one to two halogen, cyano, nitro, C _1-3 alkyl or C _1-3 alkoxy atoms as substituents, or Υ represents a carboxyl group;

V is selected from OH or ΝΗ ₂ ;

dashed line indicates a possible double bond;

K ²¹ represents C _1-6 alkyl or C _3-7 cycloalkyl and

K ²² represents C _1-6 alkyl;

provided that the specified compound does not include a compound of the formula

The present invention provides a compound of the formula

where O represents a Central ring selected from:

where the central ring may be unsubstituted or substituted by halogen, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, phenyl, thiazolyl, C (O) INCH ₂ CH ₃ , C (O) OH, OCΗ ₂ CΗ ₂ NΗ (C _1-3 -alkyl), OCH ₂ CH ^ (C _1-3 -alkyl) ₂ , C ₂ -alkoxy containing imidazolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, CH ₂ CH ^ (CH ₃ ) ₂ , C (O) OCH ₂ CH ₃ , spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl or spirocyclic cyclohexyl, or

P represents K ¹ -K ² , where K ¹ represents phenyl, pyridine, furan, thiophene, thiazole, pyrazole, naphthyl, quinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole or benzimidazole, each of which may contain substituents one to three ΝΒ. ^6/7, halo, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl optionally substituted with up to 5 fluorine atoms, or C _1-6 alkoxy optionally substituted with up to 5 fluorine atoms; and K ² represents H, phenyl or imidazole, each of which may contain from one to three halogen atoms as substituents;

K ⁴ represents H;

K ⁵ represents C (O) M < ⁶ 1 < ⁷ , —C (O) K ⁸ , C (O) OK ⁸ or (CO) SNK ²¹ KN (CO) K ²² ;

_K 6 and K ⁷ each independently represent H, C _1-6 alkyl, C _3-7 cycloalkyl or phenyl, said phenyl may contain from one to three halogen, cyano, C _1-6 alkyl, C atoms as substituents _1-6 alkyl, possibly substituted up to 5 fluorine atoms, C _1-6 alkoxy, possibly substituted up to 5 fluorine atoms; or K ⁶ and K ⁷ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

K ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, wherein said C 1-6 alkyl may be substituted with phenyl; or

- 11 012389

I ⁸ represents C1_alkyl, possibly substituted with up to 5 fluorine-containing groups; or

I ⁸ represents a tetrahydrofuran ring bonded through the positions of the C ₃ or C ₄ tetrahydrofuran ring; or

I ⁸ is a tetrahydropyran ring linked through position

C4 tetrahydropyran ring;

Υ represents COOA ⁹ , where I ⁹ represents C _1-6 alkyl; or

Υ represents a sulfonimide group of the formula —C (O) XH8 (O) ₂ I ⁹ , where I ⁹ represents C _1-3 alkyl, C _3-7 cycloalkyl or phenyl, which may contain from one to two halogen atoms as substituents , cyano, nitro, C _1-3 alkyl or C _1-3 alkoxy; or

Υ represents a carboxyl group;

V represents O or 8 and represents O or ΝΗ;

dashed line indicates a possible double bond;

I ²¹ represents C _1-6 alkyl or C _3-7 cycloalkyl and

I ²² represents C _1-6 alkyl.

The present invention also provides pharmaceutical compositions comprising preferred compounds and pharmaceutically acceptable carriers.

The invention also provides a method for treating a patient with hepatitis C virus infection, comprising administering to said patient an effective amount of preferred compounds.

The present invention also provides a method for treating liver fibrosis in a patient, comprising administering to said patient an effective amount of preferred compounds.

In addition, the present invention provides a method for increasing liver function in a patient with hepatitis C virus infection, comprising administering to said patient an effective amount of preferred compounds.

The chemical formulas characterizing the compounds presented in the present description also include pharmaceutically acceptable salts, solvates, esters and prodrug derivatives of the proposed compounds.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Definitions.

As used here, the term “hepatic fibrosis”, used interchangeably with the term “liver fibrosis”, refers to the growth of scar tissue in the liver that occurs in a chronic form of hepatitis virus infection.

The terms "individual", "virus carrier", "subject" and "patient" are used interchangeably and refer to mammals, including, but not limited to, primates, including monkeys and humans.

As used herein, the term “liver function” refers to normal liver function, including, but not limited to, synthetic function, including, but not limited to, synthesis of proteins such as whey proteins (eg, albumin, blood coagulation factors, alkaline phosphatase, aminotransferases (e.g. alanine transaminase, aspartame transaminase), 5'-nucleosidase, γ-glutaminyl transpeptidase, etc.), bilirubin synthesis, cholesterol synthesis and bile acid synthesis; metabolic function of the liver, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormonal metabolism, and lipid metabolism; detoxification of exogenous drugs; hemodynamic function, including visceral and portal dynamics of blood circulation, etc.

As used herein, the terms “N83 protease inhibitor of HCV” and “N83 protease inhibitor” refer to any agent that inhibits the protease activity of the Ν83 / Ν84Α HCV complex. At least, unless otherwise indicated, the term “N83 inhibitor” is used interchangeably with the terms “N83 protease inhibitor of HCV” and “N83 protease inhibitor”.

As used here, the term "polyol" means a hydrocarbon containing at least two hydroxyl groups attached to a carbon atom, including sugars (reducing and non-reducing sugars), sugar alcohols and sugar acids. Polyols may include other functional groups.

Examples of polyols include sugar alcohols such as mannitol and trehalose and polyesters. “Reducing sugar” is a sugar that contains a semi-acetal group that can restore metal ions or covalently interact with lysine and other amino groups in proteins, and “non-reducing sugar” is a sugar that does not have the characteristics of a reducing sugar.

Examples of reducing sugars include fructose, mannose, maltose, lactose, arabinose, xylose, ribose, ramnose, galactose and glucose. Mannitol, xylitol, erythritol, threitol, sorbitol and glycerol are examples of sugar alcohols. In relation to sugar acids, they include L-gluconate and metal salts.

- 12 012389

The term "polyester", as used here, means a hydrocarbon containing at least three ether bonds. Polyesters may include other functional groups. Polyesters include polyethylene glycol (PEG).

The term “sustained viral response” (8UV; also referred to as “sustained response” or “sustained response”), as used herein, refers to a patient's response to a hepatitis C virus infection treatment program based on serum HCV titer. Typically, a “sustained viral response” refers to the absence (not detection) of HCV RNA (for example, less than 500, less than 200 or less than 100 genomic copies per 1 ml of serum) in a patient's serum for a period of at least one month, at least at least two months, at least three months, at least four months, at least five months, at least six months after discontinuation of treatment.

The term non-treatable patients, as used herein, refers generally to patients infected with HCV who do not have a therapeutic effect after prior treatment for HCV (referred to as “patients with no therapeutic effect”) or who initially responded to treatment but who the therapeutic effect is not saved (referred to as "patients with relapse"). Typically, pre-treatment may include monotherapy with α-interferon or combination therapy with α-interferon and some antiviral agent, such as ribavirin.

As used here, the terms "treatment" and "therapy", etc. relate to obtaining the desired pharmacological and / or physiological effect. The effect can be prophylactic, based on the fully or partially prevented disease or its symptoms and / or can be therapeutic, based on the partial or complete elimination of the disease and / or adverse damage inherent in the disease. “Treatment”, as used herein, encompasses any treatment of a disease in a mammal, namely a human, and includes (a) preventing a disease in a patient who may be predisposed to the disease, but diagnosing that the disease is absent;

(b) suppressing the disease, i.e. stopping its development; and (c) relief from the disease, i.e. disease regression.

The terms “individual,” “carrier organism of the virus,” “subject,” and “patient” are used interchangeably and refer to mammals, including, but not limited to, mice, monkeys, humans, mammals, and animals from farmers and hunters and domestic mammals.

As used here, the term "pirphenidone" refers to 5-methyl-1-phenyl-2- (1H) pyridone. As used herein, the term “pirfenidone analogs” refers to any compound of formula I, ΙΙΑ or ΙΙΒ in the section entitled “Pirfenidone and its analogues” below. The “specific analog of pirfenidone” and all its grammatical variants are related and limited to each and every analog of pirfenidone shown in the table. 1, in the section entitled “Pirfenidone and its analogues”, presented below.

As used herein, an “interferon-type receptor agonist» type "refers to any ligand of the human interferon receptor Ι type of natural origin or non-natural origin that binds and causes signal transduction through the receptor. Ι type interferon receptor agonists include interferons encompassing naturally occurring interferons, modified interferons, synthetic interferons, PEG modified interferons, a compound protein comprising interferon, heterologous interferons, mixed interferons; antibodies specific for interferon receptors; non-peptide chemical agonists, etc.

As used here, the term "type interferon receptor agonist" refers to any ligand of the human interferon receptor ΙΙ type of natural origin or non-natural origin, which binds and causes signal transduction through the receptor. Type II interferon receptor agonists include natural human interferon-γ, representatives of recombinant interferon-γ, representatives of glycosylated interferon-γ, representatives of PEG conjugated interferon-γ, modified or changed representatives of interferon-γ, interferon-γ hybrid proteins, antibody agonists, receptor-specific non-peptide agonists, etc.

As used here, the term "type interferon receptor agonist" refers to any ligand of the human 1L-28 receptor ("1L-28K.") Of natural origin or non-natural origin, the amino acid sequence of which is described by Sheppard et al. Below and which binds and causes signal transduction through the receptor.

As used herein, the term “interferon receptor agonists” refers to any of the interferon type Ι receptor agonists, interferon type тора receptor agonists, or interferon type рецеп receptor agonists.

The term "dosed administration" as used herein refers to the administration of an antiviral agent to a patient in need thereof, wherein administration may include one or more doses of an antiviral agent from a drug administration device. Thus, the term "dosage administration",

- 13 012389 as used here, includes, but is not limited to, the installation of a continuous administration system (eg, a pump or other controlled injection device); single subcutaneous injection after installation of the system for continuous administration.

“Continuous delivery,” as used herein (for example, in the following context, “continuous delivery of a compound to a tissue”), means moving a drug to a delivery site, such as a tissue, in some way that will deliver the desired amount of substance to the tissue over a selected period of time where approximately the same amount of the drug is received by the patient every minute for a selected period of time.

“Controlled release”, as used herein (for example, in the following context, “controlled release of a drug”), includes the release of a compound (eg, an interferon type I or type II receptor agonist, for example interferon alpha) at a selected or otherwise controlled rate, interval and / or quantity, which is largely not affected by the conditions of use. “Controlled release” thus encompasses, but is not necessarily limited to, substantially continuous delivery and systematic delivery (eg, intermittent delivery over a period of time that is interrupted by regular or irregular time intervals).

“Systematic” or “temporary” delivery, as used in the context of drug delivery, means the delivery of a drug systematically, especially according to a regular schedule, over a pre-selected period of time (for example, other than the period associated with the injection of a shock dose of a substance). A “systematic” or “temporary” drug delivery includes drug delivery at an increasing, decreasing, constant or pulsating speed or speed range (for example, the amount of the drug per unit time or the volume of the dosage form per unit time) and also includes the delivery, which is continuous or substantially continuous or constant.

The term “controlled drug delivery device” encompasses any device where the release (eg, speed, release time) of a drug or other desired substance contained therein is controlled by or determined by the device itself and is not affected by environmental conditions of use or where release occurs at a rate that is reproducible in the environment of use.

“Constantly significant”, as used herein in the following context, “substantially constant infusion” or “substantially constant delivery” refers to the delivery of a drug in a manner that does not interrupt for a pre-selected time interval where the amount of drug received by the patient during any 8-hour interval in a pre-selected period of action will never drop to zero. Moreover, “substantially constant” delivery may also include drug delivery at a constant, pre-selected speed or speed range (for example, the amount of drug per unit time or the volume of the dosage form per unit time) that is not violated during the pre-selected delivery period medicines.

“A condition that is largely stable,” as used here in the context of a biological parameter that can vary as a function of time, means that this biological parameter has a constant value over a period of time, such that the area under the curve defined by the values biological parameter as a function of time during any 8-hour interval in the period of action (OPK8h), not more than 20% more or 20% less or preferably no more than 15% more or 15% less and more it is preferably not more than 10% larger or 10% smaller than the average area under the curve of the biological parameter over an 8-hour period during the operation period (OPK8ch average). OPK8h average is defined as the quotient (s. |) From the area under the curve of the biological parameter for the total duration of the action (total OPK), divided by the number of 8-hour intervals for the period of action (number / 3 days), i.e. p. | = (total defense industry) / (number / 3 days). For example, the concentration in the serum of the drug remains stable during the period of action of the drug, when the area under the curve of the concentration of the drug in serum during any 8-hour interval over the duration of the action (OPK8h) is not more than 20% or 20% less than the average area under the curve of the concentration of the drug in serum for any 8-hour interval during the action (OPK8h average), i.e. OPK8ch no more than 20% more or 20% less than OPK8ch average for the concentration of the drug in serum over the duration of the drug.

As used herein, a “hydrogen bond” refers to the attractive force between an electronegative atom (such as oxygen, nitrogen, sulfur or halogen) and a hydrogen atom that is covalently bonded to another electronegative atom (such as oxygen, nitrogen, sulfur or halogen). See, for example, 81guyeg et al. Βίοοίκιηίδΐιγ. Εάίΐίι Εάίΐίοη 2002, Egeetap & Co. Ν.Υ. Usually a hydrogen bond is formed between a hydrogen atom and a lone pair of electrons of another atom. A hydrogen bond between hydrogen and an electronegative atom non-covalently bonded to it can exist when

- 14 012389 a hydrogen atom is located at a distance of about 2.5 to 3.8 angstroms from a non-covalently bound electronegative atom, and the angle formed by these three atoms (electronegative atom covalently bonded to hydrogen, hydrogen and an electronegative atom non-covalently bonded to hydrogen) deviates from 180 ° by approximately 45 ° or less. The distance between the hydrogen atom and the non-covalently bonded electronegative atom is referred to herein as the “hydrogen bond length”, and the angle formed by three atoms (electronegative atom covalently bonded to hydrogen, hydrogen and the electronegative atom non-covalently bonded to hydrogen) is referred to here as the “hydrogen angle communication. " In some cases, stronger hydrogen bonds may form when the length of the hydrogen bond is shorter; moreover, in some cases, the length of the hydrogen bond may vary from 2.7 to about 3.6 angstroms, or from about 2.9 to about 3.4 angstroms. In some cases, stronger hydrogen bonds are formed when the angle of the hydrogen bond is close to linear; moreover, in some cases, the angle of the hydrogen bond may deviate from 180 ° by approximately 25 ° or less, or by approximately 10 ° or less.

As used herein, “non-polar interaction” refers to the proximity of non-polar molecules or fragments, or the proximity of molecules or fragments with a low polarity sufficient for Van der Waals interaction between fragments and / or sufficient to exclude molecules of polar solvents such as water molecules. See, for example, 81gueg et al. VusyeshShgu, Iy йοη 2002, Rgeetai & Co. Ν.Υ. Typically, the distance between atoms (excluding hydrogen atoms) of non-polar interacting fragments can vary from about 2.9 to about 6.0 angstroms. In some cases, the space separating non-polar interacting fragments is smaller than the space that could accommodate a water molecule. As used here, a non-polar fragment or a fragment with a low polarity refers to fragments with a low dipole moment (usually a dipole moment less than the dipole moments of the O-H bond in the H ₂ O molecule and the Ν-H bond in ΝΗ ₃ ) and / or fragments, which usually do not participate in the formation of hydrogen bonds or electrostatic interactions.

Examples of low polarity fragments are alkyl, alkenyl and unsubstituted aryl fragments.

As used here, the N83 protease pocket fragment 81 ′ refers to the N83 protease fragment that interacts with the first amino acid of the C-terminus of the cleavage site of the суб83 protease cleaved polypeptide (e.g., например83 protease fragments that interact with amino acid 8 in the OEUUT-8TAUY polypeptide) .

Examples of fragments include, but are not limited to, the atoms of the peptide backbone or side chain of the amino acids Li8136, 61y137, 8g139, Hk57, 61u58, 61i41, 8g42 and Pye43, see Υαο et al., 81gisige 1999, 7, 1353.

As used here, the Ν83 protease pocket fragment 82 refers to the Ν83 protease fragment that interacts with the second amino acid of the Ν-terminus of the cleavage site of the polypeptide substrate cleaved by the Ν83 protease (e.g., Ν83 protease fragments that interact with amino acid V in the OEUUT-8TAUYU polypeptide).

Examples of fragments include, but are not limited to, atoms of the peptide backbone or side chain of the amino acids Hk57, Lgd155, να1178, Lp79, 61i80 and Lp81, see Υαο et al., 81gisig 1999, 7, 1353.

As used here, the expression "the second fragment determines the position of the first fragment" when the spatial orientation of the first fragment is determined by the properties of the second fragment with which the first atom or fragment is covalently bonded. For example, phenyl carbon can determine the location of an oxygen atom bound to phenyl carbon in a spatial position such that the oxygen atom forms a hydrogen bond with a hydroxyl moiety in the Ν83 active region.

Before the present invention will be described in more detail, it should be noted that this invention is not limited to the presented specific embodiments of the invention, in fact, of course, they may vary. It is also understood that the terminology used herein is for the purpose of describing particular embodiments of the invention not meant to be limiting, since the scope of the present invention may be limited only by the appended claims.

Where a range of values is presented, it is understood that each intermediate value, up to one decimal place in units of the lower boundary value, at least, unless indicated otherwise, between the upper and lower boundary values of this range and any other claimed range or intermediate value in this claimed range is covered by this invention. The upper and lower bounds of these smaller ranges can also be independently included in these smaller ranges and are also covered by the present invention, provided that any bounds in the claimed range are excluded. Where the claimed range includes one or both of the boundary values, ranges excluding either one or both of the boundary values are also included in the scope of the present invention.

- 15 012389

At least, unless otherwise indicated, all technical or scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practical part or studies of the present invention, preferred methods and materials are still described here. All publications used herein are incorporated by reference for the purpose of describing and disclosing the methods and / or materials in connection with which the publications are cited.

It should be noted that, as used herein and in the appended claims, the singular forms include the plural, at least unless otherwise indicated. Thus, for example, reference to some “method” includes many such methods and reference to “any dose” includes reference to one or more doses and their equivalents known to those skilled in the art, etc.

The publications discussed here are publications disclosed prior to the filing date of the application for this invention. Nothing presented herein is considered as an assumption that the present invention does not give the right to retroactively date such a publication based on an earlier invention. Also, the published publication dates may differ from the actual publication date, which may need to be independently verified.

The invention discloses compounds of the formulas Ι-ΧΙΧ, also pharmaceutical compositions and forms containing any compound of the structural formulas Ι-ΧΙΧ. The claimed compound is useful for the treatment of flavivirus infection, such as HCV infection and other diseases, as discussed below.

Compositions.

Various preferred embodiments of the compositions are described below. For ease of discussion, the description of these embodiments is divided into sections A, B, C, I, and E. Various conditions that can be defined in a particular section are considered to be applicable only within that section and also applicable elsewhere when referenced to a specific section. Similarly, any reference within a section to a specific number or designation should be understood in the context of the corresponding numbering or designation of symbols used within this section, as opposed to the context of possibly similar or identical numbering or designation of symbols used in another section, unless otherwise indicated.

Section A.

Preferred embodiments of section A disclose compounds having the general formula I

where the central ring may be unsubstituted or substituted by H, halogen, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy C _1-6 alkyl, C _1-6 alkyl, substituted C _1-6 alkyl, C _1-6 alkoxy, substituted C _1-6 alkoxy, C ₆ or C ₁₀ aryl, pyridinyl, pyrimidinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulfonamido, urea, thiourea, amido, keto, carboxyl, carbamide, sulfide, sulfoxide, sulfone, amino, alkoxyamino, alkyloxyheterocyclyl m, alkylamino, alkylcarboxy, carbonyl, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or spirocyclic cyclohexyl, or represents K ¹ -K ^2, where R ¹ represents C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, each quinoxaline, benzothiazole, may, be replaced by one about three

- 16 012389 substituents ΝΉ ^ ⁷ , halogen, cyano, nitro, hydroxy, C | -6 alkyl. C3_7cycloalkyls, C4_10alkylcycloalkyls, C2-6alkenyls, C1-6alkoxy, hydroxy-C1_6alkyls or C1-6alkyls optionally substituted with up to 5 fluorine atoms, C1-6alkoxy, possibly substituted with up to 5 fluorine atoms; and K ² represents H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, or benzimidazole, each of which may be substituted by one to three substituents Ν ^ Β ^7, halogen, cyano, nitro, hydroxy, C 1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C ₂ - ₆ alkenyl, S1_ ₆ alkoxy, hydroxy-S1_ ₆ alkyl S1_ ₆ alkyl optionally substituted with up to 5 fluorine atoms, C1 _-6 alkoxy, optionally deputy fluorine atoms up to 5;

K ⁴ represents H, C1 _-6 alkyl, C _3-7 cycloalkyl, C _4- yualkiltsikloalkil, phenyl or benzyl, said phenyl or benzyl can be substituted with from one to three halogen atoms, cyano, nitro, hydroxy, C1 _-6 alkyl C _3-7 cycloalkyl, C _4- 1 ₀ alkylcycloalkyl, _C2-6 alkenyl, C1 _-6 alkoxy, hydroxyC _1-6 alkyl, C _1-6 alkyl optionally substituted with up to 5 fluorine atoms, C _1-6 alkoxy, possibly substituted up to 5 fluorine atoms;

K ⁵ represents H, C1-6 alkyl, C (O ^ K ⁶ K ⁷ , C (8) NΒ ⁶ K ⁷ , -C (O) K ⁸ , C (O) OK ⁸ , 8 (O) 2K ^8, or (CO) SNK ²¹ XN (CO) K ²² ;

K ⁶ and K ⁷ each independently represent H, C _1-6 alkyl, C _3-7 cycloalkyl, C4-10 alkylcycloalkyl or phenyl, said phenyl may be substituted with one to three atoms of halogen, cyano, nitro, hydroxy, C1 -6alkyls, C3-7cycloalkyls, C4-10alkylcycloalkyls, C2-6alkenyls, C1-6alkoxy, hydroxy-C1-6alkyls, C1-6alkyls, possibly substituted with up to 5 fluorine atoms, C1-6alkoxy possibly substituted with up to 5 fluorine atoms; or K ⁶ and K ⁷ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

K ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, all of which can be substituted one to three times with halogen, cyano, nitro, hydroxy, C1-6 alkoxy or phenyl; or

K ⁸ is C ₆ or C ₁₀ aryl, which may be substituted by one to three halogens, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyls, C _4-10 alkylcycloalkyls, C _2-6 alkenyls, C1-6 alkoxy, hydroxy-C1-6 alkyls, C1-6 alkyls, possibly substituted with up to 5 fluorine atoms, or C1-6 alkoxy, possibly substituted with up to 5 fluorine atoms; or

K ⁸ is C1-6 alkyl optionally substituted with up to 5 fluorine groups; or

K ⁸ represents a tetrahydrofuran ring linked through the positions of the C3 or C4 tetrahydrofuran ring; or

K ⁸ is a tetrapyranyl ring bonded through the position of the C4-tetrapyranyl ring;

Υ represents a sulfonamide group of the formula —C (O) XH8 (O) ₂ K ⁹ , where

K ⁹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, all of which can be substituted one to three times with halogen, cyano, nitro, C _1-6 alkoxy or phenyl, or

K ⁹ represents C ₆ or C ₁₀ aryl, which is optionally substituted with one to three atoms of halogen, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _{2- 6} alkenyls, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl, possibly substituted with up to 5 fluorine atoms, C1-6 alkoxy, possibly substituted with up to 5 fluorine atoms; or

K ⁹ is C _1-6 alkyl, optionally substituted with up to 5 groups with fluorine, NΒ ⁶ K ⁷ , NΒ ^1a K ^1b , or (CO) OH; or

K ⁹ represents a heteroaromatic ring, possibly substituted up to two times by halogen, cyano, nitro, hydroxyl or C _1-6 alkoxy; or

Υ represents a carboxyl group or a pharmaceutically acceptable salt, solvate or prodrug thereof, where

K ^1a and K ^1b , each independently, are H, C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkylcycloalkyl, all of which may be substituted with one to three halogens, cyano, nitro, C _1-6 alkoxy , amido, or phenyl, or K ^1a and K ^1b each independently represent H, C ₆ or C ₁₀ aryl, which is optionally substituted with one to three halogen atoms, cyano, nitro, hydroxy, C1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, _C1-6 alkyl, optionally substituted with up to 5 fluorine atoms, _C1-6 alkoxy, possibly substituted fluorine atoms up to 5, or

K ^1a and K ^1b each independently represent H, a heterocycle that is a 5-, 6- or 7-membered saturated or unsaturated heterocyclic molecule containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, or

NΒ ^1a K ^1b is an alkyl cyclic secondary amine containing from 3 to 6 members, which may have one to three heteroatoms included in the ring, and which may be substituted by one to three halogens, cyano, nitro, C _1-6 alkoxy, amido, phenyls, or

NΒ ^1a K ^1b is heteroaryl selected from the group consisting of

- 17 012389

where B ^1c represents H, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, ΝΟ 2, Ν (Β ^{1 ά} ) 2, MH (CO) B ^s or KN (CO) KNV ^1a , where each B ^1a independently represents H, C _1-6 alkyl or C _3-6 cycloalkyl, or

B ^1c represents ΝΗ ^ Ο) ΟΒ ¹⁶ , where B ^1e represents C _1-6 alkyl, C _3-6 cycloalkyl;

p is 0 or 1;

V is selected from O, 8 or ΝΗ;

when V is selected from O or 8, is selected from O, ΝΒ ¹⁵ or CB ¹⁵ ;

when V is ΝΗ, choose from ΝΒ ¹⁵ or CB ¹⁵ , where B ¹⁵ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl or C _1-6 alkyl, optionally substituted with up to 5 atoms fluorine;

dashed line indicates a possible double bond;

B ²¹ represents C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, each of which may be substituted one to three times by halogen, cyano, nitro, hydroxy, C _1-6 alkoxy, C _{1- 6 by} alkyl, possibly substituted with up to 5 fluorine atoms, or phenyl; or

B ²¹ represents C ₆ or C ₁₀ aryl, which may be substituted by one to three halogen atoms, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _{2- 6} alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl, possibly substituted with up to 5 fluorine atoms, C1-6 alkoxy, possibly substituted with up to 5 fluorine atoms; or

B ²¹ represents pyridinyl, pyrimidinyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy or thiophenoxy; and

B ²² is C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkylcycloalkyl, all of which can be substituted one to three times with halogen, cyano, nitro, hydroxy, C _1-6 alkyl, optionally substituted with up to 5 fluorine atoms, or phenyl.

In preferred embodiments of the invention, embodiments of the section disclose compounds having the general formula I, wherein the central ring is

In preferred embodiments of the invention, embodiments of the section disclose compounds having the general formula I, wherein the central ring is

In preferred embodiments of the invention, the embodiments of the section disclose compounds having the general formula I, wherein the central ring is (

/ '

In preferred embodiments of the invention, embodiments of the section disclose compounds having the general formula 1a

In preferred embodiments of the invention, embodiments of the section disclose compounds having the general formula 1b

- 18 012389

In preferred embodiments of the invention, compounds of the general formula 1c disclose embodiments of section A

implementation section

In preferred embodiments of the invention, the options

In preferred embodiments of the invention, the variants disclose compounds having the general formula 1e of the implementation section

V /

In preferred embodiments of the invention, embodiments of section A disclose compounds having the general formula 11 ′

- 19 012389

In preferred embodiments, compounds of the general formula are disclosed! E section embodiments

In preferred embodiments of the invention, compounds of the general formula III are disclosed. Sectional Embodiments

In preferred embodiments, compounds of the general formula Σι are disclosed.

- 20 012389 embodiments of the section

In preferred embodiments, compounds of the general formula I] are disclosed.

options disclose compounds having the General formula Σζ implementation section

section embodiments

In preferred embodiments, compounds of the general formula I are disclosed in which Υ is a sulfonamide group of the formula ^ (^ ΝΗΒζΟδΒ ⁹ , where K ^{9 is} selected from the group consisting of C1-6 alkyl, C3-7 cycloalkyl, C4-1oalkylcycloalkyl, and NI ^ ¹³ K where K ^1a and R ^1b each independently represent Η, C 1-6 alkyl or C _3- 7tsikloalkil.

In preferred embodiments of the invention, the embodiments of section A disclose compounds having the general formula I, in which the C13-C14 double bond is cis-configured.

In preferred embodiments of the invention, embodiments of section A disclose compounds having the general formula I, wherein the C13-C14 double bond has a trans configuration.

In some embodiments, the compounds of general formula I do not include the compounds described in PCT / I804 / 33970. For example, in some embodiments, compounds of general formula I do not include compounds of formulas II, III, IV, presented in section B below.

Section B.

Embodiments of the invention of section B disclose compounds having the general formulas II, III, IV

- 21 012389 where I ¹ and K ² each independently represent H, halogen, cyano, nitro, hydroxy, C1-6 alkyl, C3_7 cycloalkyl, C4.10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1_6 alkyl, C1_6 alkyl, possibly substituted with up to 5 fluorine atoms, C1-6 alkoxy, possibly substituted with up to 5 fluorine atoms, C6 or C10-aryl, pyridinyl, pyrimidinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, 8Ο2ΝΚ ⁶ Κ ⁷ , \ 11C (O) \ I``I. \ Ns (8) \ I am I. C (O) \ I Am. \ 0, C (O) I ⁸ , C (O) OA ⁸ , 1CHNS (O) I ⁸ , 1CHNS (O) OY ⁸ , 8NO ⁸ , ΝΙ 1YA (O). I ⁸ . S11.JAJA. EASTER'S or EARTH ⁹ ; where I ⁹ represents imidazolyl or pyrazolyl; the indicated thienyl, pyrimidinyl, furanyl, thiazolyl and oxazolyl in the definition of I ¹ and I ² can be substituted with one to two halogens, cyano, nitro, hydroxy, C1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _{2 -6} alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl, possibly substituted up to 5 fluorine atoms, C _1-6 alkoxy, possibly substituted up to 5 fluorine atoms; the indicated C ₆ or C ₁₀ aryl, pyridinyl, phenoxy and thiophenoxy in the definition of I ¹ and I ² can be substituted with one to three halogens, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _{4- 10} alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl, possibly substituted with up to 5 fluorine atoms, C _1-6 alkoxy, possibly substituted with up to 5 fluorine atoms;

t is 0, 1 or 2;

I ⁴ represents H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl or phenyl or benzyl, said phenyl or benzyl may be substituted with one to three atoms of halogen, cyano, nitro, hydroxy, C _{1 -6} alkyls, C _3-7 cycloalkyls, C _4-10 alkylcycloalkyls, C _2-6 alkenyls, C _1-6 alkoxy, hydroxy-C1-6 alkyls, C1-6 alkyls, possibly substituted with up to 5 fluorine atoms, C1-6 alkoxy, possibly substituted up to 5 fluorine atoms;

I ⁵ represents H, C ^ alkyl, C (O) \ I Am. C ^ IIA'I ⁷ , -C (O) I ⁸ , C (O) OA ⁸ , 8 (O) _; 1Я or (СО) СНЫ ²¹ ХН (СО) Я ²² ;

I ⁶ and I ⁷ , each independently, are H, C _1-6 alkyl, C _3-7 cycloalkyl, C4-10 alkylcycloalkyl or phenyl, said phenyl is optionally substituted with one to three atoms of halogen, cyano, nitro, hydroxy, C1- 6alkyls, C3-7cycloalkyls, C4-10alkylcycloalkyls, C2-6alkenyls, hydroxy-C1-6alkyls, C1-6alkyls, possibly substituted with up to 5 fluorine atoms, C1-6alkoxy, possibly substituted with up to 5 fluorine atoms; or

I ⁶ and I ⁷ together with the nitrogen to which they are attached form indolyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

I ⁸ represents C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, all of which can be substituted one to three times with halogen, cyano, nitro, hydroxy, C1-6 alkoxy or phenyl; or

I ⁸ represents C6 or C10 aryl, which may be substituted by one to three halogens, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyls, C4-10 alkylcycloalkyls, C2-6 alkenyls, C _1-6 alkoxy, hydroxy- C _1-6 alkyl, C _1-6 alkyl, possibly substituted up to 5 fluorine atoms, C _1-6 alkoxy, possibly substituted up to 5 fluorine atoms; or

I ⁸ represents C _1-6 alkyl, optionally substituted with up to 5 groups with fluorine; or

I ⁸ represents a tetrahydrofuran ring bonded through the positions of the C ₃ or C4 tetrahydrofuran ring; or

I ⁸ represents a tetrapyranyl ring bonded through the position of the C4-tetrapyranyl ring;

Υ represents a sulfonamide group of the formula —C (O) XH8 (O) ₂ Z ⁹ , where

I ⁹ represents C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, all of which can be one to three times halogen, cyano, nitro, C _1-6 alkoxy, amido or phenyl, or

I ⁹ represents C6 or C10 aryl, which may be substituted by one to three atoms of halogen, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyls, C _4-10 alkylcycloalkyls, C _2-6 alkenyls C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted with up to 5 fluorine atoms, C _1-6 alkoxy optionally substituted with up to 5 fluorine atoms; or

I ⁹ represents C _1-6 alkyl, optionally substituted with up to 5 groups with fluorine, XY ⁶ I ⁷ or (CO) OH, or

I ⁹ represents a heteroaromatic ring, possibly substituted up to two times by halogen, cyano, nitro, hydroxyl or C1-6 alkoxy; or

Υ represents a carboxyl group or a pharmaceutically acceptable salt, solvate or prodrug thereof;

I ¹⁰ and I ¹¹ , each independently, are H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or C10-aryl, hydroxy-C1-6 alkyl, C1-6 alkyl, optionally substituted with up to 5 fluorine atoms, (CH2 ) ^ I ⁶ I ⁷ , (CH2) _P C (O) OA ¹⁴ , where I ¹⁴ represents H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, all of which can be substituted one to three times by halogen, cyano , nitro, hydroxy, C1-6 alkoxy or phenyl, or I ¹⁴ represents C6 or C10-aryl, which may be substituted by one to three halogen atoms, cyano, nitro, hydroxy, C1-6 alkyl, C _3-7 cycloalkyl mi, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl, possibly substituted with up to 5 fluorine atoms, C _1-6 alkoxy, possibly substituted with 5 fluorine atoms; the specified C ₆ or C ₁₀ -aryl in the definition of I ¹⁰ and I ¹¹ may be substituted by one to three

- 22 012389 by a halogen atom. cyano. nitro. hydroxy. With _1-b alkyl. C. _3- 7tsikloalkilom. With _4-10 alkylcycloalkyl. With _2- alkenyl. C _1- alkoxy. hydroxy-C ₁ -b alkyl. With _1-b alkyl. possibly substituted up to 5 fluorine atoms. C _1- alkoxy. possibly substituted up to 5 fluorine atoms; or

B ¹⁰ and B ¹¹ together with a carbon atom. to which they are attached. form cyclopropyl. cyclobutyl. cyclopentyl or cyclohexyl; or

B ¹⁰ and B ¹¹ are combined in O;

p is 0 or 1;

B ¹² and B ¹³ . each independently. represent N. C1-beam. C3-7cycloalkyl. C4-10 alkylcycloalkyl. Sat or C10 aryl. hydroxy-C1 -alkyl. C1-beam. possibly substituted up to 5 fluorine atoms. (CH2) ^b The PCI ^7. (CH2) _p C (O) OB ¹⁴ . where In ¹⁴ represents N. C1-beam. C3-7cycloalkyl. C4-10 alkylcycloalkyl. which all can be substituted one to three times with halogen. cyano. nitro. hydroxy. C1-balkoxy or phenyl. or B ¹⁴ is Cb or C ₁₀ aryl. which may be substituted by one to three halogen atoms. cyano. nitro. hydroxy. C _1-b alkyl. With _3-7 cycloalkyls. C _4-10 alkylcycloalkyls. C _2- alkenyl. C _1- alkoxy. hydroxy-C _1-b alkyl. C _1-b alkyl. possibly substituted up to 5 fluorine atoms. C _1- alkoxy. possibly substituted up to 5 fluorine atoms; said C _b or C ₁₀ aryl in the definition of B ¹² and C ¹³ may be substituted with one to three halogen atoms. cyano. nitro. hydroxy. C _1-b alkyl. With _3-7 cycloalkyls. C _4-10 alkylcycloalkyls. C _2- alkenyl. C _1- alkoxy. hydroxy C1-beams. C1-beam. possibly substituted up to 5 fluorine atoms. C1-balkoxy. possibly substituted up to 5 fluorine atoms; or

B ¹² and B ¹³ together with a carbon atom. to which they are attached. form cyclopropyl. cyclobutyl. cyclopentyl or cyclohexyl; or

B ¹² and B ¹³ . everyone. are C _{1 -b} alkyl. possibly substituted (CH ₂ ) _p OB ^{8 with a} substituent;

At ²⁰ represents N. C1-beam. C3-7 cycloalkyl. C4-10 alkylcycloalkyl. Sat or C10 aryl. hydroxy-C1 -alkyl. C1-beam. possibly substituted up to 5 fluorine atoms. (CH2) ^b The PCI ^7. (CH2) _p C (O) OB ¹⁴ . Where

B ¹⁴ is H. C _{1 -b} alkyl. C _3-7 cycloalkyl. C _4-10 alkylcycloalkyl. which all can be substituted one to three times with halogen. cyano. nitro. hydroxy. With _1- alkoxy or phenyl. or

B ¹⁴ is Cb or C10 aryl. which may be substituted by one to three halogen atoms. cyano. nitro. hydroxy. C1-beam. C3-7 cycloalkyls. C4-10 alkylcycloalkyls. C2-balkenyls. C1-balkoxy. hydroxy-C1-beams. C1-beam. possibly substituted up to 5 fluorine atoms. C1-balkoxy. possibly substituted up to 5 fluorine atoms; said Cb or C10-aryl in the definition of B ¹² and B ¹³ may be substituted with one to three halogen atoms. cyano. nitro. hydroxy. C1-beam. C3-7cycloalkyl. With _4-10 alkylcycloalkyl. With _2- alkenyl. C _1- alkoxy. hydroxy-C ₁ -b alkyl. C1-beam. possibly substituted up to 5 fluorine atoms. C1-balkoxy. possibly substituted up to 5 fluorine atoms;

n = 1-4;

V is selected from O. 8 or KH;

when V is O or 8. is selected from O. KB ¹⁵ or CB ¹⁵ ;

when V is KN. choose from KB ¹⁵ or CB ¹⁵ . where In ¹⁵ represents N. With _1-b alkyl. C _3-7 cycloalkyl. C _4-10 alkylcycloalkyl or C _{1 -b} alkyl. possibly substituted up to 5 fluorine atoms;

dashed line indicates a possible double bond;

B ²¹ is C ₁ -balkyl. C _3-7 cycloalkyl. C _4-10 alkylcycloalkyl. each of which can be substituted from one to three times by halogen. cyano. nitro. hydroxy. C _1- alkoxy. With _1-b alkyl. possibly substituted up to 5 fluorine atoms. or phenyl; or

B ²¹ is C _b or C ₁₀ aryl. which may be substituted by one to three halogen atoms. cyano. nitro. hydroxy. C _1-b alkyl. With _3-7 cycloalkyls. C _4-10 alkylcycloalkyls. C _2- alkenyl. C _1- alkoxy. hydroxy-C _1-b alkyl. C _1-b alkyl. possibly substituted up to 5 fluorine atoms. C _1- alkoxy. possibly substituted up to 5 fluorine atoms; or

At ²¹ is pyridinyl. pyrimidinyl. pyrazinyl. thienyl. furanyl. thiazolyl. oxazolyl. phenoxy. thiophenoxy and

B ²² is C ₁ -balkyl. C _3-7 cycloalkyl. C _4-10 alkylcycloalkyl. each of which can be substituted from one to three times by halogen. cyano. nitro. hydroxy. C1-beam. possibly substituted up to 5 fluorine atoms. or phenyl.

- 23 012389

Embodiments of the invention of section B disclose compounds having the general formula II

where R ¹ represents H, halogen, cyano, nitro, hydroxy, C1 _-6 alkyl, C _3-7 cycloalkyl, C _4- 1 ₀ alkylcycloalkyl, _C2-6 alkenyl, C1 _-6 alkoxy, hydroxy-C1 _-6 alkyl C1 _-6 alkyl optionally substituted with up to 5 fluorine atoms, C 1 _-6 alkoxy optionally substituted with up to 5 fluorine atoms;

K ² represents H, OCIηNK ⁶ K ⁷ , OCHPK ¹⁶ , halogen, cyano, nitro, hydroxy, C1-6alkyl, C3-7cycloalkyl, C4-10alkylcycloalkyl, C2-6alkenyl, C1-6alkoxy, hydroxy-C1-6alkyl, C1- 6alkyl, possibly substituted with up to 5 fluorine atoms, C1-6 alkoxy, possibly substituted with up to 5 fluorine atoms; the specified K ⁶ and K ⁷ in the definition of K ² each independently denotes H, C1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkylcycloalkyl; or the indicated K ⁶ and K ⁷ in the definition of K ² together with the nitrogen to which they are attached form indolyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

n = 1-3;

K ⁴ represents H;

K ⁵ represents H, C (O) NK ⁶ K ⁷ , C (O) OK ⁸ , where the indicated K ⁶ and K ⁷ in the definition of K ⁵ are each independently H, C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkylcycloalkyl;

K ⁸ represents C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, each of which may be substituted one to three times by halogen, cyano, nitro, hydroxy, C _1-6 alkoxy or phenyl; or

K ⁸ is C _1-6 alkyl optionally substituted with up to 5 fluorine groups; or

K ⁸ is a tetrahydrofuran ring bonded through the positions of a C ₃ or C4 tetrahydrofuran ring; or

K ⁸ is a tetrapyranyl ring bonded through the position of the C4-tetrapyranyl ring;

Υ represents a sulfonamide group of the formula —C (O) KH8 (O) ₂ K ⁹ , where K ⁹ represents C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, all of which can be substituted from one to three times with halogen, C1-6 alkoxy or phenyl;

K ¹⁰ , K ¹¹ , K ¹² , K ¹³ are H;

p is 0 or 1;

Y = O and choose from O, ΝΚ or CH ₂ .

In preferred embodiments of the invention, embodiments of section B disclose compounds having general formulas II, III, IV, where p may be 0. In preferred embodiments of the invention, embodiments of section B disclose compounds having general formulas II, III, IV where p may be equal to 1.

In preferred embodiments of the invention, section B embodiments of the invention disclose compounds having the general formulas II, III, IV, wherein one or both of K ¹ , K ² are H. In some embodiments, p is 0. In others, p is 1.

In preferred embodiments of the invention, embodiments of section B disclose compounds having the general formulas II, III, IV, wherein neither K ¹ nor K ² are H. In some embodiments, p is 0. In others, p is 1.

In preferred embodiments of the invention, section B embodiments of the invention disclose compounds having the general formulas II, III, IV, wherein K ² is OCI η NK ⁶ K ⁷ , OCHPK ¹⁶ .

In preferred embodiments of the invention, section B embodiments disclose compounds having the general formulas II, III, IV, wherein K ⁹ is alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, all of which may be substituted from one to three times halogen

24 012389 nom, cyano, nitro, hydroxy, C _1-6 alkoxy or phenyl.

In preferred embodiments of the invention, section B embodiments of the invention disclose compounds having the general formulas II, III, IV, wherein K ⁹ is C ₆ or C ₁₀ aryl, which may be substituted with one to three halogen, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl, optionally substituted with up to 5 fluorine atoms, C _1-6 alkoxy, possibly substituted with up to 5 fluorine atoms.

In preferred embodiments of the invention, embodiments of section B disclose compounds having the general formulas II, III, IV, wherein K ⁹ is a heteroaromatic ring which may be substituted one to two times by halogen, cyano, nitro, hydroxy, C _{1- 6} alkoxy.

In preferred embodiments of the invention, section B embodiments of the invention disclose compounds having the general formulas II, III, IV, wherein K ⁹ is C _1-6 alkyl, optionally substituted with up to 5 fluoro groups; ΝΚ ⁶ Κ ⁷ or (CO) OH.

In preferred embodiments of the invention, embodiments of section B disclose compounds having the general formulas II, III, IV, where the dashed line in formulas (II), (III) or (IV) represents a single bond.

Embodiments of the invention of section B disclose compounds having the general formula II

where K ¹ and K ² each independently represent H, halogen, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1- 6 alkyl, possibly substituted with up to 5 fluorine atoms, C1-6 alkoxy, possibly substituted with up to 5 fluorine atoms, C6 or C10-aryl, pyridinyl, pyrimidinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, 8Ο2ΝΚ ⁶ Κ ⁷ , ANN (O ) LK ⁶ K ⁷ , N 1+ (8) +10+, + (0) + 1 + 1 +, ΝΚ ⁶ Κ ⁷ , C (o) to ⁸ , C (O) OK ⁸ , NNS (O) K ⁸ , ONS (O) OK ⁸ , 8OtK ⁸ , IN8 (O) 2K ⁸ , SNPC ⁶ K ⁷ , SNPC ⁶ K ⁷ or SNPC ¹⁶ ; where K ¹⁶ represents imidazolyl or pyrazolyl; the indicated thienyl, pyrimidinyl, furanyl, thiazolyl and oxazolyl in the definition of K ¹ and K ² are optionally substituted one to two times by halogen, cyano, nitro, hydroxy, C1-6alkyl, C3-7cycloalkyl, C4-10alkylcycloalkyl, C2-6alkenyl, C1 -6alkoxy, hydroxy-C1-6alkyl, C1-6alkyl, optionally substituted with up to 5 fluorine atoms, C1-6alkoxy, optionally substituted with up to 5 fluorine atoms; the specified C6 or C10-aryl, pyridinyl, phenoxy and thiophenoxy in the definition of K ¹ and K ² can be substituted with one to three halogens, cyano, nitro, hydroxy, C1-6 alkyl, C _3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2- 6alkenyls, C1-6alkoxy, hydroxy-C1-6alkyls, C1-6alkyls, possibly substituted with up to 5 fluorine atoms, C1-6alkoxy, possibly substituted with up to 5 fluorine atoms;

t is 0, 1 or 2;

K ⁴ represents H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl or phenyl or benzyl, said phenyl or benzyl may be substituted with one to three atoms of halogen, cyano, nitro, hydroxy, C _{1 -6} alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl, optionally substituted with up to 5 fluorine atoms, C _1-6 alkoxy, optionally substituted with up to 5 fluorine atoms;

K ⁵ represents H, C1-6 alkyl, C (O) NK ⁶ K ⁷ , C (8) NK ⁶ K ⁷ , -C (O) K ⁸ , C (O) OK ⁸ , 8 (O) 2K ^8, or (CO) SNK ²¹ OH (CO) K ²² ;

_K 6 and K ⁷ each independently represent H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl or phenyl, said phenyl may be substituted with one to three halogen atoms, cyano, nitro, hydroxy, C1-6 alkyl, C3 -7cycloalkyl, C4-10alkylcycloalkyl, C2-6alkenyl, hydroxy-C1-6alkyl, C1-6alkyl, possibly substituted with up to 5 fluorine atoms, C1-6alkoxy, possibly substituted with up to 5 fluorine atoms; or _K 6 and K ⁷ together with the nitrogen to which they are attached form indolyl, pyrrolidinyl, piperis

25 012389 dinyl, piperazinyl or morpholinyl;

B ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, all of which can be substituted one to three times with halogen, cyano, nitro, hydroxy, C _1-6 alkoxy or phenyl; or

B ⁸ is C ₆ or C ₁₀ aryl, which may be substituted by one to three halogens, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyls, C4-10 alkylcycloalkyls, C2-6 alkenyls, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl, possibly substituted up to 5 fluorine atoms, C _1-6 alkoxy, possibly substituted up to 5 fluorine atoms; or

B ⁸ is C1-6 alkyl optionally substituted with up to 5 fluorine groups; or

B ⁸ is a tetrahydrofuran ring bonded through the positions of the C3 or C4 tetrahydrofuran ring; or

B ⁸ is a tetrapyranyl ring bonded through the position of the C4-tetrapyranyl ring;

Υ represents a sulfonamide group of the formula —C (O) XH8 (O) ₂ B ⁹ , where

B ⁹ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, all of which can be substituted one to three times with halogen, cyano, nitro, C _1-6 alkoxy, amido or phenyl, or

B ⁹ represents C6 or C10 aryl, which may be substituted by one to three atoms of halogen, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyls, C _4-10 alkylcycloalkyls, C _2-6 alkenyls C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted with up to 5 fluorine atoms, C _1-6 alkoxy optionally substituted with up to 5 fluorine atoms; or

B ⁹ is C _1-6 alkyl, optionally substituted with up to 5 groups with fluorine, ΝΚ ⁶ ^ ⁷ , or (CO) OH; or

B ⁹ represents a heteroaromatic ring which may be substituted up to two times with halogen, cyano, nitro, hydroxyl or C _1-6 alkoxy; or

Υ represents a carboxyl group or a pharmaceutically acceptable salt, solvate or prodrug thereof;

B ¹⁰ and B ¹¹ each independently represent H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or C10-aryl, hydroxy-C1-6 alkyl, C1-6 alkyl, optionally substituted with up to 5 fluorine atoms, (CH2 ) pV ⁶ V ⁷ , (CH2) pC (O) OB ¹⁴ , where B ¹⁴ is H, C1-6 alkyl, C _3-7 cycloalkyl, C4-10 alkylcycloalkyl, all of which can be substituted one to three times with halogen, cyano , nitro, hydroxy, C1-6 alkoxy or phenyl, or B ¹⁴ represents C6 or C10-aryl, which may be substituted by one to three halogen atoms, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-1 Alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl, possibly substituted with up to 5 fluorine atoms, C1-6 alkoxy, possibly substituted with up to 5 fluorine atoms; the specified C6 or C10-aryl in the definition of B ¹⁰ and B ¹¹ may be substituted by one to three halogen atoms, cyano, nitro, hydroxy, C1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl, possibly substituted with up to 5 fluorine atoms, C _1-6 alkoxy, possibly substituted with up to 5 fluorine atoms; or

B ¹⁰ and B ¹¹ together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or B ¹⁰ and B ¹¹ are combined in O;

p is 0 or 1;

B ¹² and B ¹³ each independently represent H, C _1-6 alkyl, C _3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or C10-aryl, hydroxy- _C1-6 alkyl, _C1-6 alkyl, optionally substituted with up to 5 atoms fluorine, (C1 IAABB. (CH2) pC (O) OV ¹⁴ , where

¹⁴ represents H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, all of which can be substituted one to three times with halogen, cyano, nitro, hydroxy, C1-6 alkoxy or phenyl; or

¹⁴ represents C6 or C10 aryl, which may be substituted by one to three halogen atoms, cyano, nitro, hydroxy, C1-6alkyl, C3-7cycloalkyl, C4-10alkylcycloalkyl, C2-6alkenyl, C1-6alkoxy, hydroxy-C1 -6alkyl, C1-6alkyl, possibly substituted up to 5 fluorine atoms, C1-6alkoxy, possibly substituted up to 5 fluorine atoms; the specified C6 or C10-aryl in the definition of B ¹² and B ¹³ may be substituted by one to three halogen atoms, cyano, nitro, hydroxy, C1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl, possibly substituted with up to 5 fluorine atoms, C _1-6 alkoxy, possibly substituted with up to 5 fluorine atoms; or B ¹² and B ¹³ together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or B ¹² and B ¹³ each represents C1-6 alkyl optionally substituted with (CH2) pOB ⁸ ;

B ²⁰ represents H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or C10-aryl, hydroxy-C1-6 alkyl, C1-6 alkyl, optionally substituted with up to 5 fluorine atoms, (Ο ^ ηΝΕ. ⁶ ^, (CH2) _p C (O) OV ¹⁴ , where

¹⁴ represents H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, all of which can be substituted one to three times by halogen, cyano, nitro, hydroxy, C _1-6 alkoxy or phenyl; or

B ¹⁴ is C ₆ or C ₁₀ aryl, which may be substituted by one to three halogen atoms, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _{2- 6} alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl, optionally substituted with up to 5 fluorine atoms

- 26 012389 pa, C1 _-6 alkoxy optionally substituted with up to 5 fluorine atoms; said C ₆ or C ₁₀ aryl in the definition of K ¹² and K ¹³ may be substituted with one to three halogen atoms, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl, optionally substituted with up to 5 fluorine atoms, C _1-6 alkoxy, possibly substituted with up to 5 fluorine atoms;

n = 0-4;

V is selected from O, 8 or N11;

when V is O or 8, A is selected from O, NK ¹⁵ or SK ¹⁵ ;

when V is NΗ, A is selected from NK ¹⁵ or CK ¹⁵ , where K ¹⁵ is Η, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl or C _1-6 alkyl, optionally substituted with up to 5 fluorine atoms;

dashed line indicates a possible double bond;

K ²¹ represents C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, each of which can be substituted one to three times by halogen, cyano, nitro, hydroxy, C _1-6 alkoxy, C _{1- 6 by} alkyl, possibly substituted with up to 5 fluorine atoms, or phenyl; or

K ²¹ represents C ₆ or C ₁₀ aryl, which may be substituted by one to three halogen atoms, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C2-6 alkenyl C1-6alkoxy, hydroxy-C1-6alkyl, C1-6alkyl, optionally substituted with up to 5 fluorine atoms, C1-6alkoxy, optionally substituted with up to 5 fluorine atoms; or

K ²¹ represents pyridinyl, pyrimidinyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy; and

K ²² represents C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, each of which can be substituted from one to three times by halogen, cyano, nitro, hydroxy, C1-6 alkyl, possibly substituted by up to 5 fluorine atoms, or phenyl.

Embodiments of the invention of section B disclose compounds having the general formula Pa

where K ¹ and K ² each independently represent Η, halogen, cyano, hydroxy, C _1-3 alkyl,

C1-3 alkoxy;

K ⁵ represents SSC ^ K ⁶ ^, C (O) K ⁸ or C (O) OK ⁸ ;

K ⁶ and K ⁷ each independently represent Η, C _1-6 alkyl, C _3-7 cycloalkyl, C4-10 alkylcycloalkyl or phenyl;

K ⁸ is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl or 3-tetrahydrofuryl;

Υ represents a sulfonamide group of the formula —SCH ^ LJ ^ K ⁹ , where K ⁹ represents C _1-3 alkyl, C _3-7 cycloalkyl, or phenyl, which may be substituted by one to two halogen atoms, cyano, nitro, hydroxy C _1-3 alkyl, C _3-7 cycloalkyl, C _1-3 alkoxy, or

Υ represents a carboxyl group or a pharmaceutically acceptable salt, solvate or prodrug thereof;

_TO ¹⁰ _and

K ¹¹ , each independently, is Η or C _1-3 alkyl, or K ¹⁰ and K ¹¹ together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

A is selected from O, NΗ, and the dashed line indicates a possible double bond.

- 27 012389

Embodiments of the invention of section B disclose compounds having the general formula 111a

where I ¹ and I ² each independently represent H, halogen, cyano, hydroxy, C _1-3 alkyl, C _1-3 alkoxy;

I ⁴ represents H;

I ⁵ represents H, C (O) F ⁶ I ⁷ , C (O) I ⁸ , C (O) OA ⁸ ;

I ⁸ represents C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl or 3-tetrahydrofuryl;

Υ represents a sulfonamide group of the formula -C (O) \ 118 (Ό) ₂ Κ ⁹ , where I ⁹ represents C _1-3 alkyl, C _3-7 cycloalkyl, or phenyl, which may be substituted by one to two halogen atoms , cyano, nitro, hydroxy, C _1-3 alkyl, C _3-7 cycloalkyl, C _1-3 alkoxy, or

Υ represents a carboxyl group or a pharmaceutically acceptable salt, solvate or prodrug thereof;

selected from O, NΗ and the dashed line indicates a possible double bond.

Embodiments of the invention of section B disclose compounds having the general formula 1Hb

where I ¹ and I ² each independently represent H, halogen, cyano, hydroxy, C _1-3 alkyl, C _1-3 alkoxy;

I ⁵ represents H, C (O) OA ⁸ or C (O ^ I ⁸ ;

I ⁸ represents C _1-6 alkyl, C _5-6 cycloalkyl or 3-tetrahydrofuryl;

I ⁹ represents C _1-3 alkyl, C _3-4 cycloalkyl or phenyl, which may be substituted by one to two halogen atoms, cyano, hydroxy, C _1-3 alkyl, C _1-3 alkoxy;

I ¹⁰ and I ¹¹ , each independently, represent H, C _1-3 alkyl, or I ¹⁰ and I ¹¹ together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohex;

selected from O or NΗ and the dotted line indicates a possible double bond.

- 28 012389

Embodiments of Section B disclose compounds having the general formula SH

where K ¹ and K ² each independently represent H, halo, cyano, hydroxy, C1 _-3 alkyl, C1 _-3 alkoxy;

K ⁵ represents H, C (O) OK ⁸ , ϋ (Ο) ΝΚ ⁸ ;

K ⁸ is C _1-6 alkyl, C _5-6 cycloalkyl or 3-tetrahydrofuryl;

K ⁹ represents C _1-3 alkyl, C _3-5 cycloalkyl or phenyl, which may be substituted by one to two halogen atoms, cyano, hydroxy, C _1-3 alkyl, C _1-3 alkoxy;

K ¹⁰ and K ¹¹ each independently represent H, C _1-3 alkyl or C _4-5 cycloalkyl;

W is selected from O or ΝΗ and the dashed line indicates a possible double bond.

Embodiments of the invention of section B disclose compounds having the general formula 11c

u and

Ps where K ¹ and K ² each independently represent H, chloro, fluoro, cyano, hydroxy, C _1-3 alkyl, C _1-3 alkoxy;

K ⁵ represents C (O) OK ⁸ , C (O) IR. ⁸ ;

K ⁸ represents C _1-6 alkyl, C _5-6 cycloalkyl;

K ⁹ represents C _1-3 alkyl, C _3-4 cycloalkyl or phenyl, which may be substituted by one to two halogen atoms, cyano, hydroxy, C _1-3 alkyl, C _1-3 alkoxy;

(e) K ¹⁰ and K ¹¹ each independently represent H, C _1-3 alkyl, or K ¹⁰ and K ¹¹ together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl;

(ί) A dashed line indicates a possible double bond.

- 29 012389

Embodiments of Section B disclose compounds having the general formula

where K ¹ and K ² each independently represent Η, chloro, fluoro, cyano, hydroxy, C1 _-3 alkyl, C1 _-3 alkoxy;

K ⁵ represents Η, C (O) OK ⁸ or ϋ ^ ΝΒ ⁸ ;

K ⁸ is C _1-6 alkyl or C _5-6 cycloalkyl;

K ⁹ represents C | _-3 alkyl, C _3-4 cycloalkyl or phenyl which may be substituted with one to two halogen atoms, cyano, hydroxy, C1 _-3 alkyl, C1 _-3 alkoxy;

the dotted line indicates a possible double bond.

Embodiments of Section B disclose compounds having the general formula Hb

where K ¹ and K ² each independently represent Η, halogen, cyano, hydroxy, C1 _-3 alkyl or C1 _-3 alkoxy;

K ⁴ represents Η;

K ⁵ represents Η, C ^ NCC ⁷ , C (O) OK ⁸ or C (O) Mk ⁸ ;

K ⁸ is C _1-6 alkyl or C _3-7 cycloalkyl, C _{4-1 0} alkylcycloalkyl or 3-tetrahydrofuryl;

Υ represents a sulfonamide group of the formula -C (Ο) \ Η8 (Ο) 2Κ ^9, where R ⁹ represents C 1 _-3 alkyl, C _3-7 cycloalkyl, or phenyl which may be substituted by one to two halo, cyano, , nitro, hydroxy, C1 _-3 alkyl, _C3-7 cycloalkyl, C1 _-3 alkoxy, or

Υ represents a carboxyl group or a pharmaceutically acceptable salt, solvate or prodrug thereof;

K ¹⁰ and K ¹¹ each independently represent Η, C1 _-3 alkyl, or K ¹⁰ and K ¹¹ together with the carbon atom to which they are attached form cyclopropane, cyclobutyl, cyclopentyl or cyclohexyl;

To ²⁰ represents Η, C1 _-6 alkyl, C _3-7 cycloalkyl, C _4- 1 ₀ alkylcycloalkyl, C ₆ or C _{| 0} aryl, hydroxy-C1 _-6 alkyl, C1 _-6 alkyl which may be substituted by up to 5 fluorine atoms, (SNARK ⁷ , (SI2) pC (O) OK ¹⁴ , where

- 30 012389

K ¹⁴ represents H, C ₁ . ₆ alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, each of which may be substituted one to three times by halogen, cyano, nitro, hydroxy, C _1-6 alkoxy or phenyl, or

K ¹⁴ represents C6 or C10 aryl, which may be substituted by one to three atoms of halogen, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyls, C4-10 alkylcycloalkyls, C2-6 alkenyls, C1-6 alkoxy, hydroxy-C1 -6 alkyl, C1-6 alkyl, possibly substituted up to 5 fluorine atoms, C1-6 alkoxy, possibly substituted up to 5 fluorine atoms; the specified C6 or C10-aryl in the definition of K ¹² and K ¹³ may be substituted by one to three atoms of halogen, cyano, nitro, hydroxy, C1-6 alkyls, C3-7 cycloalkyls, C _4-10 alkylcycloalkyls, C _2-6 alkenyls, C _1-6 alkoxy, hydroxy-C _1-6 alkyls, C _{1 6} alkyls, possibly substituted up to 5 fluorine atoms, C1-6 alkoxy, possibly substituted up to 5 fluorine atoms;

selected from O or ΝΗ and the dotted line indicates a possible double bond.

Embodiments of the invention of section B disclose compounds having the general formula 1Aa

where K ¹ and K ² each independently represent H, halogen, cyano, hydroxy, C _1-3 alkyl or C1-3 alkoxy;

K ⁴ represents H;

K ⁵ represents H, C (Ο) NK ⁶ K ⁷ , C (O) OK ⁸ or € (Θ) ΝΗ ⁸ ;

K ⁸ is C _1-6 alkyl or C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl or 3-tetrahydrofuryl;

Υ represents a sulfonamide group of the formula —C (O) NH8 (O) ₂ K ⁹ , where K ⁹ represents C _1-3 alkyl, C _3-7 cycloalkyl, or phenyl, which may be substituted by one to two halogen atoms, cyano, nitro, hydroxy, C _1-3 alkyl, C _3-7 cycloalkyl, C _1-3 alkoxy, or

Υ represents a carboxyl group or a pharmaceutically acceptable salt, solvate or prodrug thereof;

_K ¹⁰ and K ¹¹ each independently represent H, C _1-3 alkyl, or K ¹⁰ and K ¹¹ together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

K ²⁰ represents H, C1-6 alkyl, C3-7cycloalkyl, C4-10 alkylcycloalkyl, C6 or C10-aryl, hydroxy-C1-6 alkyl, C1-6 alkyl, possibly substituted with up to 5 fluorine atoms, (CH2) ηNK ⁶ K ⁷ , ( CH2) _p C (O) OK ¹⁴ , where

K ¹⁴ represents H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, each of which may be substituted one to three times by halogen, cyano, nitro, hydroxy, C _1-6 alkoxy or phenyl ; or

K ¹⁴ represents C ₆ or C ₁₀ aryl, which may be substituted by one to three halogen atoms, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C2-6 alkenyl C1-6alkoxy, hydroxy-C1-6alkyl, C1-6alkyl, optionally substituted with up to 5 fluorine atoms, C1-6alkoxy, optionally substituted with up to 5 fluorine atoms; the specified C6 or C10-aryl in the definition of K ¹² and K ¹³ may be substituted by one to three halogen atoms, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy C1-6alkyl, C1-6alkyl, optionally substituted with up to 5 fluorine atoms, C1-6alkoxy, optionally substituted with up to 5 fluorine atoms;

selected from O or N4 and the dotted line indicates a possible double bond;

Ζ represents a fused or connected aryl heteroaryl ring

- 31 012389 system.

Section C.

Embodiments of the invention of section C disclose compounds having the general formula XI

where K ^1a and K ^1b each independently represent Η, C _1-6 alkyl, C _3-7 cycloalkyl, or C4-10 alkylcycloalkyl, each of which may be substituted by one to three halogens, cyano, nitro, C _{1- 6} alkoxy, amido, or phenyl; or

K ^1a and K ^1b each independently represent Η, C ₆ or C ₁₀ aryl, which may be from one to three halogen atoms, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C _4-10 alkylcycloalkyl , C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl, possibly substituted with up to 5 fluorine atoms, C _1-6 alkoxy, possibly substituted with up to 5 fluorine atoms; or

K ^1a and K ^1b each independently represent Η, a heterocycle that is a 5-, 6- or 7-membered saturated or unsaturated heterocyclic molecule containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; or

IR ^1a K ^1b is an alkyl cyclic secondary amine containing from 3 to 6 members, which may have from one to three heteroatoms included in the ring, and which is optionally substituted by from one to three halogens, cyano, nitro, C _1-6 alkoxy, amido, phenyl; or

HC. ^1a K ^1b is heteroaryl selected from the group consisting of

where R ^1c represents Η, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, S3-6tsikloalkoksi, ΝΟ2, Ν (Κ ^1ά) 2 CI (CO) ^N or K ΝΗ ^ Ο) ΝΗΚ ^1ά, wherein each K ^1a independently represents Η, C _1-6 alkyl or C _3-6 cycloalkyl; or

K ^1c is CI (CO) OK ^1e , where K ^1e is C _1-6 alkyl, C ₃ -cycloalkyl;

A represents O or ΝΗ;

V is selected from O, 8 or ΝΗ;

when V is selected from O or 8, A is selected from O, ΝΚ ^15, or SK ¹⁵ ;

when V is ΝΗ, A is selected from ΝΚ ¹⁵ or CK ¹⁵ , where K ¹⁵ is Η, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-1 alkyl alkyl cycloalkyl, or C _1-6 alkyl, possibly substituted to 5 fluorine atoms;

K ² is a bicyclic secondary amine with a structure

where K ²¹ and K ^{2 2} each independently represent Η, halogen, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1 -6 alkyl, possibly substituted with up to 5 fluorine atoms, C1-6 alkoxy, possibly substituted with up to 5 fluorine atoms, C6 or C10-aryl, pyridinyl, pyrimidinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, 8Ο; ΝΙ \ Ί \ ⁷ , N11 ( '(Ο) ΝΙ \ Ί \ ^7, HIS (8) x ^b K ^7, C (O) \ 1G1 ^<7 HC ^b to ^7, C (O) K ^8, C (O) OK ^8, HIS (O) K ^8, HIS (O) OK ⁸ 8OtK ⁸ (m = 0, 1 or 2), HI8 (O) 2R ^8, said thienyl, pyrimidinyl, furanyl, thiazolyl and oxazolyl in the definition ELENITE K ²¹ and K ²² can be substituted with one to two halogen, cyano, nitro, hydroxy, C 1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, _C2-6 alkenyl, _C1-6 alkoxy, hydroxy -C _1-6 alkyl, _C1-6 alkyl, possibly substituted up to 5 fluorine atoms, C1-6 alkoxy, possibly substituted up to 5 fluorine atoms; said C ₆ or C ₁₀ -aryl, pyridinyl, phenoxy and thiophenoxy in the definition of K ²¹ and K ²² can be substituted by one to three halogens, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _{1- 6} al sludges, C1-6alkyl optionally substituted with up to 5 fluorine atoms, or C1-6 alkoxy optionally substituted with up to 5 ato

- 32 012389 mov of fluorine;

B ¹⁰ and B ¹¹ each independently represent H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or C10-aryl, hydroxy-C1-6 alkyl, C1-6 alkyl, optionally substituted with up to 5 fluorine atoms, (CH ^^ WB ^ ⁷ , (CH2) _P C (O) OB ¹⁴ , where B ¹⁴ is H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, each of which can be substituted one to three times with halogen, cyano , nitro, hydroxy, C1-6 alkoxy or phenyl, or B ¹⁴ represents C6 or C10-aryl, which may be substituted by one to three atoms of halogen, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C _4-10 alkylcycloalkyls, C _2-6 alkenyls, C _1-6 alkoxy, hydroxy-C _1-6 alkyls, _C1-6 alkyls, possibly substituted with up to 5 fluorine atoms, C1-6 alkoxy, possibly substituted with up to 5 fluorine atoms; indicated C ₆ or C ₁₀ -aryl in the definition of B ¹⁰ and B ¹¹ can be substituted by one to three atoms of halogen, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyls, C _4-10 alkylcycloalkyls, C2-6 alkenyls , C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl, possibly substituted with up to 5 fluorine atoms, _C1-6 alkoxy, possibly substituted with up to 5 fluorine atoms; or B ¹⁰ and B ^11, together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or B ¹⁰ and B ¹¹ are combined in O;

where p = 0 or 1;

where B ¹² and B ¹³ each independently represent H, C _1-6 alkyl, C _3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or C10-aryl, hydroxy- _C1-6 alkyl, _C1-6 alkyl, optionally substituted with up to 5 fluorine atoms, (CBDpBBv ⁷ , (CH2) p (O) OB ¹⁴ , where

B ¹⁴ represents H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, each of which may be substituted one to three times by halogen, cyano, nitro, hydroxy, C1-6 alkoxy or phenyl, or

B ¹⁴ represents C6 or C10 aryl, which may be substituted by one to three atoms of halogen, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyls, C4-10 alkylcycloalkyls, C2-6 alkenyls, C1-6 alkoxy, hydroxy-C1 -6 alkyl, C1-6 alkyl, possibly substituted up to 5 fluorine atoms, C1-6 alkoxy, possibly substituted up to 5 fluorine atoms; the specified C6 or C10-aryl in the definitions of B ¹² and B ¹³ may be substituted by one to three atoms of halogen, cyano, nitro, hydroxy, C1-6 alkyl, C _3-7 cycloalkyls, C _4-10 alkylcycloalkyls, C _2-6 alkenyls C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl, optionally substituted with up to 5 fluorine atoms, C _1-6 alkoxy optionally substituted with up to 5 fluorine atoms; or B ¹² and B ¹³ together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

B ²⁰ represents H, C1-6 alkyl, C3-7cycloalkyl, C4-10 alkylcycloalkyl, C6 or C10-aryl, hydroxy-C1-6 alkyl, C1-6 alkyl, optionally substituted with up to 5 fluorine atoms, (CH2), CV ⁶ B ⁷ , (CH2) _P C (O) OV ¹⁴ , where

B ¹⁴ represents H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, each of which may be substituted one to three times by halogen, cyano, nitro, hydroxy, C1-6 alkoxy or phenyl, or

¹⁴ represents C6 or C10-aryl, which may be substituted by one to three atoms of halogen, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloapkyls, C2-6 alkenyls, C1-6 alkoxy, hydroxy- C1-6alkyl, C1-6alkyl, possibly substituted up to 5 fluorine atoms, C1-6alkoxy, possibly substituted up to 5 fluorine atoms; the specified C6 or C10-aryl in the definitions of B ¹² and B ¹³ may be substituted by one to three atoms of halogen, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyls, C _4-10 alkylcycloalkyls, C _2-6 alkenyls, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, _C1-6 alkyl, possibly substituted up to 5 fluorine atoms, C1-6 alkoxy, possibly substituted up to 5 fluorine atoms;

where n = 0-4;

where B ⁶ and B ⁷ each independently represent H, C _1-6 alkyl, C _3-7 cycloalkyl, C4-10 alkylcycloalkyl or phenyl, said phenyl may be substituted with one to three atoms of halogen, cyano, nitro, hydroxy, C1-6alkyls, C3-7cycloalkyls, C4-10alkylcycloalkyls, C2-6alkenyls, hydroxy-C1-6alkyls, C1-6alkyls, possibly substituted up to 5 fluorine atoms, C1-6alkoxy possibly substituted up to 5 fluorine atoms; or B ⁶ and B ⁷ together with the nitrogen to which they are attached form indolyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; or

B ² is B ^2a B ^2b when \ Y = XH and ν ^, where

B ^2a represents C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinine quinoxaline, benzothiazole, benzothiophene, benzofuran, indole or benzimidazole, each may be substituted with one to three substituents ΝΒ ^2σ Β ^2ά , halogen, cyano, nitro, hydroxy, C1-6 alkyl, C _3-7 cycloalkyls, C _4-10 alkylcycloalkyls, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, or C _1-6 alkyl optionally substituted with up to 5 atoms fluoro, _C1-6 alkoxy optionally substituted with up to 5 fluorine atoms;

In ^2b represents H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each of which may be

- 33 012389 is substituted by one to three substituents XK ^2c K ²⁴ , halogens, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyls, C _4-10 alkylcycloalkyls, C _2-6 alkenyls, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl, possibly substituted up to 5 fluorine atoms, C _1-6 alkoxy, possibly substituted up to 5 fluorine atoms;

said K ^2c and K ²⁴ each independently represent H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl or phenyl, said phenyl may be substituted with one to three halogen, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyls, C _4-10 alkylcycloalkyls, C _2-6 alkenyls, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl, possibly substituted up to 5 fluorine atoms, C _1-6 alkoxy, optionally substituted with up to 5 fluorine atoms; or

K ^2c and K ²⁴ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

K ⁴ represents H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl or phenyl, said phenyl may be substituted with one to three halogen, cyano, nitro, hydroxy, C _1-6 alkyl atoms, C _3-7 cycloalkyls, C _4-10 alkylcycloalkyls, C _2-6 alkenyls, C _1-6 alkoxy, hydroxy-C _1-6 alkyls, _C1-6 alkyls, possibly substituted with up to 5 fluorine atoms, C1-6 alkoxy, possibly substituted with 5 fluorine atoms;

K ⁵ represents H, C1-6 alkyl, C (Ο) NK ⁶ K ⁷ , C (8) NK ⁶ K ⁷ , -C (O) K ⁸ , C (O) OK ⁸ or 8 (O) 2K ⁸ ;

K ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, all of which can be substituted one to three times with halogen, cyano, nitro, hydroxy, C _1-6 alkoxy or phenyl; or

K ⁸ is C ₆ or C ₁₀ aryl, which may be substituted with one to three halogens, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyls, C _4-10 alkylcycloalkyls, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl, possibly substituted up to 5 fluorine atoms, C _1-6 alkoxy, possibly substituted up to 5 fluorine atoms;

the dotted line indicates a possible double bond.

Embodiments of the invention of section C disclose compounds having the general formula XII wherein K ^1a and K ^1b are each independently

represent H, C _1-6 alkyl, C _3-7 cycloalkyl, or C4-10 alkylcycloalkyl, all of which can be substituted by one to three halogens, cyano, nitro, C1-6 alkoxy, amido, or phenyl,

K 1a and

consisting of

K ^1b each independently represents H or heteroaryl selected from the group

where R ^1c represents H, halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, S3-6tsikloalkoksi, NΟ2, ^ K ¹⁴⁾ 2, NH (SΟ) ¹⁴ K, or NH (SΟ) NHK ^14, wherein each K ¹⁴ independently represents H, C _1-6 alkyl, or C3-6 cycloalkyl, or XE. ^1a K ^1b is an alkyl cyclic secondary amine containing from 3 to 6 members, which may have from one to three heteroatoms included in the ring, and which may be substituted by one to three halogens, cyano, nitro, alkoxy, amido, phenyls where K ²¹ and K ²² each independently represent H, halogen, cyano, hydroxy, C _1-3 alkyl, C _1-3 alkoxy,

K ⁵ represents H, C (Ο) NK ⁶ K ⁷ , C (O) K ⁸ or C (O) OK ⁸ ;

where K ⁶ and K ⁷ each independently represent H, C _1-6 alkyl, C _3-7 cycloalkyl,

- 34 012389

C ₄ . ₁₀ alkylcycloalkyl or phenyl;

I ⁸ represents C _1-6 alkyl, C ₃ . ₇ cycloalkyl, C ₄ . ₁₀ alkylcycloalkyl or 3-tetrahydrofuryl;

I ¹⁰ and I ¹¹ , each independently, are H, halogen or C _1-3 alkyl, or

I ¹⁰ and I ¹¹ together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

I ¹² and I ¹³ , each independently, represent H, halogen, C _1-6 alkyl, C ₃ . ₇ cycloalkyl, C ₄ . ₁₀ alkylcycloalkyl, C ₆ or C ₁₀ aryl, hydroxy-C ₁ . ₆ alkyl, C _1-6 alkyl, optionally substituted with up to 5 fluorine atoms;

the dotted line indicates a possible double bond.

Embodiments of the invention of section C disclose compounds having the general formula HCHH

where I ^1a and I ^1b , each independently, represent H, C _1-6 alkyl, C ₃ . ₇ cycloalkyl, or C ₄ . ₁₀ alkylcycloalkyl, each of which may be substituted by one to three halogens, cyano, nitro, alkoxy, amido or phenyl, or

I ^1a and I ^1b , each independently, are H or heteroaryl selected from the group consisting of

Ο ^ Ν ΗΝ ^Χ Ο ^ Ν ° Ν Рц /% \ = | ^ / \ = | = / \ = | = /, ' ^Ν .пай Ν — Ν _К 1С _К 1С' н ^1с 'to ^1с К ¹⁰ .

where I ^1c represents H, halogen, C1-6 alkyl, C3.6 cycloalkyl, C1-6 alkoxy, C3.6 cycloalkoxy, NO2, I ^1a ) 2, IN (CO) I ^1a or IN (CO) ME ^1a , where each I ^1a independently represents H, C _1-6 alkyl, or C _3-6 cycloalkyl; or

NYa ^{1a to 1b} is an alkyl cyclic secondary amine containing from 3 to 6 members, which may have from one to three heteroatoms included in the ring and which is optionally substituted by from one to three halogens, cyano, nitro, C _1-6 alkoxy, amido phenyl;

I ²¹ and I ²² , each independently, represent H, halogen, cyano, hydroxy, C _1-3 alkyl, C _1-3 alkoxy,

I ⁵ represents H, C (O ^ I ⁶ I ⁷ , C (O) I ⁸ or C (O) OA ⁸ ;

I ⁶ and I ⁷ , each independently, represent H, C _1-6 alkyl, C ₃ . ₇ cycloalkyl, C ₄ . ₁₀ alkylcycloalkyl or phenyl;

I ⁸ represents C _1-6 alkyl, C ₃ . ₇ cycloalkyl, C ₄ . ₁₀ alkylcycloalkyl or 3-tetrahydrofuryl; the dotted line indicates a possible double bond.

- 35 012389

Embodiments of the invention of section C disclose compounds having the general formula XIV

where R ^1a and R ^1b each independently represent H, C _1-6 alkyl, C _3- 7tsikloalkil or C _4-10 alkylcycloalkyl, each of which may be substituted by one to three halogen, cyano, nitro, C _{1- 6} alkoxy, amido or phenyl, or

K ^1a and K ^1b each independently represent H or heteroaryl selected from the group consisting of δ ^ Ν Ο ^ Ν ΗΝ '% c / H | ΚΝ ^ Ν \ r: | = /, \ r | x / \ = | = / Ν = Ρ, _{) 3Π} ά ν ⁼ Ν _К 1с _К 1с ' _К 1с' _К 1с К ^1с .

where K ^1c is H, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, NΟ2, Ν (Η ^1ά ) 2, KH (CO) K ^1a or NΗ (CΟ) NΗK ^1a , where each K ^1a independently represents H, C _1-6 alkyl, or C _3-6 cycloalkyl, or

^{XK 1a} To ^1b is an alkyl cyclic secondary amine containing from 3 to 6 members, which may have from one to three heteroatoms included in the ring and which may be substituted by from one to three halogens, cyano, nitro, C _1-6 alkoxy, amido phenyls,

K ^2a is C6 or C10-aryl, optionally substituted with one to three substituents ΝΗ ^ Η ²⁰ , halogen, cyano, nitro, hydroxy, C1-6 alkyl, C _3-7 cycloalkyls, C _4-10 alkylcycloalkyls, C _2-6 alkenyl, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, or C _1-6 alkyl, optionally substituted with up to 5 fluorine atoms, C _1-6 alkoxy optionally substituted with up to 5 fluorine atoms;

said K ^2c and K ^2a each independently represent H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl or phenyl, said phenyl may be substituted with one to three halogen, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyls, C _4-10 alkylcycloalkyls, C _2-6 alkenyls, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl, possibly substituted up to 5 fluorine atoms, C _1-6 alkoxy, optionally substituted with up to 5 fluorine atoms; or K ^2c and K ^2a, together with the nitrogen to which they are attached, form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

K ^2a is an unsaturated 5- or 6-membered heteroaryl, or such a specific heteroaryl fused to another ring, heterocycle or other ring;

K ⁵ represents H, C (Ο) NK ⁶ K ⁷ , C (O) K ⁸ or C (O) OK ⁸ ;

K ⁶ and K ⁷ each independently represent H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl or phenyl;

K ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl or 3-tetrahydrofuryl and the dotted line indicates a possible double bond.

- 36 012389

Embodiments of the invention of section C disclose compounds having the general formula XV

where K ¹ and K ² each independently represent Η, chloro, fluoro, cyano, hydroxy, C1 _-3 alkyl, C1 _-3 alkoxy;

To ⁵ represents C (O) OK ⁸ , C (O) NK. ⁸ ;

K ⁸ is C _1-6 alkyl, C _5-6 cycloalkyl or 3-tetrahydrofuryl;

K ⁹ represents C _1-3 alkyl, C _3-5 cycloalkyl, or phenyl, which may be substituted by one to two halogen atoms, cyano, hydroxy, C _1-3 alkyl, C _1-3 alkoxy;

K ¹⁰ and K ¹¹ each independently represent Η, C _1-3 alkyl or C _4-5 cycloalkyl;

A represents O or ΜΗ and the dotted line indicates a possible double bond.

Embodiments of the invention of section C disclose compounds having the general formula XVI

where K ¹ and K ² each independently represent Η, chloro, fluoro, cyano, hydroxy, C _1-3 alkyl, C1-3 alkoxy;

To ⁵ represents C (O) OK ⁸ , C (O) NK. ⁸ ;

K ⁸ represents C _1-6 alkyl, C _5-6 cycloalkyl;

K ⁹ represents C _1-3 alkyl, C _3-4 cycloalkyl or phenyl, which may be substituted by one to two halogen atoms, cyano, hydroxy, C1-3 alkyl, C1-3 alkoxy;

_K 10 and K ¹¹ each independently represent Η, C _1-3 alkyl, or _K 10 and K ¹¹ together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl;

the dotted line indicates a possible double bond.

- 37 012389

Embodiments of the invention of section C disclose compounds having the general formula XVII

where K ¹ and K ² each independently represent H, chloro, fluoro, cyano, hydroxy, C _1-3 alkyl, C _1-3 alkoxy;

K ⁵ represents C (O) OK ⁸ , C (O) IR. ⁸ ;

K ⁸ represents C _1-6 alkyl, C _5-6 cycloalkyl;

K ⁹ represents C _1-3 alkyl, C _3-4 cycloalkyl or phenyl, which may be substituted by one to two halogen atoms, cyano, hydroxy, C _1-3 alkyl, C _1-3 alkoxy;

the dotted line indicates a possible double bond.

Section Ό.

Embodiments of the invention of section Ό disclose compounds having the general formula XVIII

where K ¹ represents C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinine , quinoxaline, benzothiazole, benzothiophene, benzofuran, indole or benzimidazole, each may be substituted by one to three substituents XK_ ⁵ K ⁶ , halogen, cyano, nitro, hydroxy, C1-6 alkyl, C _3-7 cycloalkyls, C _4-10 alkylcycloalkyls , C2 _-6 alkenyls, C _1-6 alkoxy, hydroxy-C _1-6 alkyl or C _1-6 alkyl, possibly substituted up to 5 atoms in fluorine, C _1-6 alkoxy, optionally substituted with up to 5 fluorine atoms;

K ² represents H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiazole, benzotiazole, benzot benzimidazole, each of which can be substituted by one to three substituents XK_ ⁵ K ⁶ , halogens, cyano, nitro, hydroxy, C _1-6 alkyls, C _3-7 cycloalkyls, C _4-10 alkylcycloalkyls, C2 _-6 alkenyls, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl, possibly substituted with up to 5 fluorine atoms, C _1-6 alkoxy, possibly substituted up to 5 fluorine atoms;

K ³ represents H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, phenyl or benzyl, said phenyl or benzyl may be substituted with one to three atoms of halogen, cyano, nitro, hydroxy, C _{1 -6} alkyls, C _3-7 cycloalkyls, C _4-10 alkylcycloalkyls, C _2-6 alkenyls, C _1-6 alkoxy, hydroxyC1-6 alkyls, C1-6 alkyls, possibly substituted with up to 5 fluorine atoms, C1-6 alkoxy, possibly substituted with 5 fluorine atoms;

- 38 012389

In ⁴ represents N. C1-beam. C (O) HF ⁵ V ^b . C (8) HF ⁵ V ^b . -C (O) B ⁷ . C (O) OB ⁷ . 8 (O) 2B ⁷ ;

B ⁵ and B ^b . each independently. represent N. With _1-b alkyl. C _3-7 cycloalkyl. C _{4-1 0} alkylcycloalkyl or phenyl. said phenyl may be substituted with one to three halogen atoms. cyano. nitro. hydroxy. C1- _balkyl . With _3-7 cycloalkyls. C _{4-1 0} alkylcycloalkyl. C _2- alkenyl. C1-balkoxy. hydroxy-C1-beams. C1-beam. possibly substituted up to 5 fluorine atoms. C1-balkoxy. possibly substituted up to 5 fluorine atoms; or _B 5 and B ^b together with nitrogen. to which they are attached. form indolinyl. pyrrolidinyl. piperidinyl. piperazinyl or morpholinyl;

V ⁷ represents a C1 _-B alkyl. C _3-7 cycloalkyl. C _{4-1 0} alkylcycloalkyl. each of which can be substituted from one to three times by halogen. cyano. nitro. hydroxy. C1 _-b alkoxy or phenyl; or

In ⁷ represents C _b or C | _0- aryl. which may be substituted by one to three halogens. cyano. nitro. hydroxy. C1- _balkyl . With _3-7 cycloalkyls. C _{4-1 0} alkylcycloalkyl. C _2- alkenyl. C1-balkoxy. hydroxy-C1-beams. C1-beam. possibly substituted up to 5 fluorine atoms. or C1-baloxy. possibly substituted up to 5 fluorine atoms;

B ⁸ is C1-3 alkyl. C3-4cycloalkyl or phenyl; which is possibly substituted by one to two halogens. cyano. hydroxy. C1-3alkyl or C1-3alkoxy; and the dotted line indicates a possible double bond.

Section E.

Embodiments of the invention of section E disclose compounds. having the general formula XIX

where Ζ is a group. capable of forming a hydrogen bond with an imidazole H1 §57 K83 protease fragment and forming a hydrogen bond with a C1u137 K83 protease nitrogen atom;

P ₁ ′ represents a group. capable of participating in nonpolar interaction with at least one fragment 81 'of the K83 protease pocket. selected from the group. consisting of b8bb. C1u137. 8eg139. H1z57. C1u58. 8eg42 and Rye43;

B represents a linker group. containing from 1 to 5 atoms. selected from the group. consisting of carbon. oxygen. nitrogen. hydrogen and sulfur;

P _{2 is} selected from the group. consisting of unsubstituted aryl. substituted aryl. unsubstituted heteroaryl. substituted heteroaryl. unsubstituted heterocyclyl and substituted heterocyclyl; the position of P _{2 is} determined by L in order to create non-polar interaction with at least one fragment 82 of the K83 protease pocket. selected from the group. consisting of H1z57. Agd 155. Va1178. Azr79. C1p80 and Azr81;

dashed line indicates a possible double bond;

⁵ select from the group. consisting of N. C (O) KB ^b B ⁷ and C (O) OB ⁸ ;

^B and ^{C 7} . each independently. represent N. C1- _balkyl . C _3-7 cycloalkyl. C4-10 alkylcycloalkyl or phenyl. said phenyl may be substituted with one to three halogen atoms. cyano. nitro. hydroxy. C1-beam. C3-7 cycloalkyls. C4-10 alkylcycloalkyls. C2-balkenyls. hydroxy-C1-beams. C1-beam. possibly substituted up to 5 fluorine atoms. C1-balkoxy. possibly substituted up to 5 fluorine atoms; or _B b and C ⁷ together with nitrogen. to which they are attached. form indolyl. pyrrolidinyl. piperidinyl. piperazinyl or morpholinyl;

At ⁸ represents alkyl C1 _-b. C _3-7 cycloalkyl. C _{4-1 0} alkylcycloalkyl. each of which can be substituted from one to three times by halogen. cyano. nitro. hydroxy. C1 _-b alkoxy or phenyl; or

B ⁸ is C _b or C ₁₀ aryl. which may be substituted by one to three halogens. cyano. nitro. hydroxy. C1- _balkyl . With _3-7 cycloalkyls. C _{4-1 0} alkylcycloalkyl. C _2- alkenyl. Sc balkoxy. hydroxy-C1-beams. C1-beam. possibly substituted up to 5 fluorine atoms. C1-balkoxy. possibly substituted up to 5 fluorine atoms; or

B ⁸ is C1-beam. possibly substituted up to 5 groups with fluorine; or

B ⁸ is a tetrahydrofuran ring. linked through C3 or

- 39 012389

C _4- tetrahydrofuran ring; or

K ⁸ is a tetrapyranyl ring bonded through the position of the C ₄ -tetrapyranyl ring.

As used herein, a “hydrogen bond” refers to an attractive force between an electronegative atom (such as oxygen, nitrogen, sulfur or halogen) and a hydrogen atom that is covalently bonded to another electronegative atom (such as oxygen, nitrogen, sulfur or halogen). See, for example, 81guyeg et al. Vusyetschru, 5th ed., 2002, Egeetap & Co. New York. Usually a hydrogen bond is formed between a hydrogen atom and a lone pair of electrons of another atom. A hydrogen bond between hydrogen and an electronegative atom non-covalently bonded to it can exist when the hydrogen atom is located at a distance of about 2.5 to 3.8 angstroms from the non-covalently bonded electronegative atom and the angle formed by these three atoms (electronegative atom, covalently bound to hydrogen, hydrogen and an electronegative atom non-covalently bound to hydrogen) deviates from 180 ° by about 45 ° or less. The distance between the hydrogen atom and the non-covalently bonded electronegative atom is referred to herein as the “hydrogen bond length”, and the angle formed by three atoms (electronegative atom covalently bonded to hydrogen, hydrogen and the electronegative atom non-covalently bonded to hydrogen) is referred to here as the “hydrogen angle communication. " In some cases, stronger hydrogen bonds may form when the length of the hydrogen bond is shorter; moreover, in some cases, the length of the hydrogen bond may vary from 2.7 to about 3.6 angstroms, or from about 2.9 to about 3.4 angstroms. In some cases, stronger hydrogen bonds are formed when the angle of the hydrogen bond is close to linear; moreover, in some positions, the angle of the hydrogen bond may deviate from 180 ° by approximately 25 ° or less, or by approximately 10 ° or less.

As used herein, “non-polar interaction” refers to the proximity of non-polar molecules or fragments, or the proximity of molecules or fragments with a low polarity sufficient for Van der Waals interaction between fragments and / or sufficient to exclude molecules of polar solvents such as water molecules. See, for example, 81guyeg et al. VusyetSchGu, 5th ed., 2002, Egeetap & Co. New York. Typically, the distance between atoms (excluding hydrogen atoms) of non-polar interacting fragments can vary from about 2.9 to about 6 angstroms. In some cases, the space separating non-polar interacting fragments is smaller than the space that could accommodate a water molecule. As used here, a non-polar fragment or a fragment with a low polarity refers to fragments with a low dipole moment (usually the dipole moment is less than the dipole moments of the O-H bond in the H2O molecule and the Ν-H bond in + H ₃ ) and / or fragments that usually do not participate in the formation of hydrogen bonds or electrostatic interactions.

Examples of low polarity fragments are alkyl, alkenyl and unsubstituted aryl fragments.

As used here, the '83 protease pocket fragment 81 ′ refers to the Ν83 protease fragment that interacts with the first amino acid of the C-terminus of the cleavage site of the Ν83 protease cleaved polypeptide (for example, Ν83 protease fragments that interact with amino acid 8 in the OEEUUT-8T \ UUBU).

Examples of fragments include, but are not limited to, the atoms of the peptide backbone or side chain of the amino acids Lyu136, O1u137, 8eg139, HE57, O1u58, O1n41, 8eg42 and Pye43, see Υαο et al., 81Gis1ige 1999, 7, 1353.

As used here, the 8283 protease pocket fragment 82 refers to the Ν83 protease fragment that interacts with the second amino acid of the Ν-terminus of the cleavage site of the polypeptide substrate cleaved by the Ν83 protease (e.g., Ν83 protease fragments that interact with amino acid V in the PIEUT-8TAUSU polypeptide).

Examples of fragments include, but are not limited to, atoms of the peptide backbone or side chain of amino acids HE57, Agd155, Va1178, Axr79. O1i80 and Arg81, see Υαο et al., 81gis1ige 1999, 7, 1353.

As used here, the expression of the second fragment “determines the position” of the first fragment when the spatial orientation of the first fragment is determined by the properties of the second fragment with which the first atom or fragment is covalently bonded. For example, phenyl carbon can determine the location of an oxygen atom bound to phenyl carbon in a spatial position such that the oxygen atom forms a hydrogen bond with a hydroxyl moiety in the Ν83 active region.

Also disclosed are compounds containing fragments capable of interacting with specific sites, specific amino acid residues, or specific Ν83 protease atoms. Some of the compounds presented here contain one or more fragments capable of forming a hydrogen bond with a Ν83 protease at a specific site, amino acid residue or atom. Some of the compounds presented here contain one or more fragments capable of participating in nonpolar interaction with the Ν83 protease at a specific amino acid site

- 40 012389 residue or atom. For example, a compound having the general formula XIX may contain one or more fragments that form a hydrogen bond with peptide backbone atoms or side chain fragments located on an N83 protease pocket that binds the substrate. In another example, a compound having the general formula XIX may contain one or more fragments that are involved in nonpolar interaction with peptide backbone atoms or side chain fragments located on the N83 protease pocket that binds the substrate. In the compound of formula XIX, the dashed line between 13 and 14 carbon atoms can be a single bond or a double bond.

As represented in the compound having the formula XIX, Ζ is capable of forming a hydrogen bond with the atoms of the peptide backbone or side chain fragments located on the N83 protease pocket that binds the substrate, including, but not limited to, the H1e57 imidazole fragment of the N83 protease and the nitrogen atom of the C1u137 N83 protease . In some compounds, Ζ is capable of forming a hydrogen bond with both the H1e57 imidazole fragment of the N83 protease and the nitrogen atom of the C1u137 N83 protease.

The P ₁ ′ group of a compound having general formula XIX is capable of participating in nonpolar interaction with peptide backbone atoms or side chain moieties located on an N83 protease pocket that binds a substrate, including, but not limited to, amino acid residues that form an 81 ′ N83 pocket proteases. For example, the P ₁ ′ group is able to participate in nonpolar interaction with at least one amino acid selected from Lb1313, C1b137, 8b139, H1e57, C1u58, 8b42 and Pb43.

A P ₂ group of a compound having general formula XIX is capable of participating in nonpolar interaction with peptide backbone atoms or side chain fragments located on a N83 protease pocket that binds a substrate, including, but not limited to, amino acid residues that form 82 N83 protease pocket. For example, the P ₂ group is able to participate in nonpolar interaction with at least one amino acid selected from H1e57, Agd155, Va1178, Aep79, C1p80 and Aper81. The P ₂ group is also capable of forming a hydrogen bond with peptide backbone atoms or side chain fragments located on the N83 pocket of the protease binding substrate, including, but not limited to, amino acid residues that form 82 N83 protease pocket. In some embodiments, P2 may be selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic radical, and substituted heterocyclic radical.

In some embodiments, the position of the P2 group is determined by linker b. For example, the P ₂ position is determined by the L linker to participate in nonpolar interaction with peptide backbone atoms or side chain fragments located on the N83 protease pocket that binds the substrate, including, but not limited to, amino acid residues that form 82 N83 protease pocket. For example, the position of the P ₂ group is determined by the L linker to participate in nonpolar interaction with at least one amino acid selected from H1e57, Agd155, Va1178, Aep79, C1p80 and Aper81. In another example, the position of the P ₂ group is determined by linker L to form a hydrogen bond with the atoms of the peptide backbone or side chain fragments located on the N83 protease pocket that binds the substrate, including, but not limited to, amino acid residues that form 82 N83 protease pocket.

For example, the position of the P ₂ group is determined by the linker b for the formation of a hydrogen bond with at least one amino acid selected from H1e57, Agd155, Va1178, Aep79, C1p80 and Aper81. In some embodiments, the position of P2 can be determined both to participate in nonpolar interaction and to form a hydrogen bond with the atoms of the peptide backbone or side chain fragments located on the N83 protease pocket that binds the substrate, such as amino acids selected from H1e57, Agd155, Va1178 , Aer79, C1p80 and Aer81. Such a hydrogen bond and non-polar interaction can occur with the same amino acid residues or with different amino acid residues on the 82 pocket of the N83 protease.

As presented in the compound having the formula XIX, b may be a linker group that binds P ₂ to the heterocyclic base of the compound of the formula XIX. Linker L may contain any of a variety of atoms and fragments suitable for placing P ₂ on the pocket N83 of the prosthesis connecting the substrate. In one embodiment of the invention, b may contain from 1 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen and sulfur. In another embodiment, b may contain from 2 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen and sulfur. For example, b may contain a group having the formula - \ - C (= ^, where V or \ are each individually selected from O, 8 or N4. Specific examples of groups for b include, but are not limited to, esters, amides, carbamates, thioethers and thioamides.

The compound of formula XIX may also contain a K ⁵ group, where the K ⁵ group may contain a carboxyl fragment.

- 41 012389

Examples of carboxyl fragments of K ⁵ include C (O ^ K ⁶ K ⁷ and C (O) OK ⁸ , where

By ⁶ and R ⁷ each independently represent H, C1 _-6 alkyl, C 7tsikloalkil _{3-, 4-} C 1 ₀ alkylcycloalkyl or phenyl, said phenyl may be substituted by one to three halogen atoms, cyano, nitro, hydroxy, C1 _-6 alkyl, C 7tsikloalkilov _{3-, 4-} C 1 ₀ alkylcycloalkyl, C2 _-6 alkenyl, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally substituted with up to 5 fluorine atoms; or _K 6 and _K ⁷ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

K ⁸ represents C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, each of which may be substituted one to three times by halogen, cyano, nitro, hydroxy, C1-6 alkoxy or phenyl; or

K ⁸ is C6 or C10-aryl, which can be substituted by one to three halogens, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyls, C4-10 alkylcycloalkyls, C2-6 alkenyls, C1-6 alkoxy, hydroxy-C1- 6 alkyl, C1-6 alkyl, possibly substituted up to 5 fluorine atoms, or _C1-6 alkoxy, possibly substituted up to 5 fluorine atoms; or

By ⁸ is C1 _-6 alkyl optionally substituted with up to 5 fluoro groups; or

K ⁸ represents a tetrahydrofuran ring linked through the positions of the C3 or C4 tetrahydrofuran ring; or

K ⁸ is a tetrapyranyl ring bonded through the position of the C4-tetrapyranyl ring.

In some embodiments, several bonds of a compound of formula XIX may have a certain chirality.

Preferred embodiments of section E of the invention disclose compounds wherein the substituents at the C13-C14 double bond are in the cis position. Preferred embodiments of section E of the invention disclose compounds wherein substituents at the C13-C14 double bond are in the trans position.

Preferred embodiments of section E of the invention disclose compounds having the general formula XIX, wherein b consists of 2-5 atoms.

Preferred embodiments of section E of the invention disclose compounds having the general formula XIX, where b includes the group -Ά- € (= ν) -, where V and each are individually selected from O, 8 or N11.

Preferred embodiments of section E of the invention disclose compounds having the general formula XIX, wherein b is selected from the group consisting of ether, amide, carbamate, thioester and thioamide.

Preferred embodiments of section E of the invention disclose compounds having the general formula XIX, wherein the position of the P ₂ group is determined by a linker L to form a hydrogen bond with at least one fragment 82 of the N83 protease pocket, consisting of H1857, Agd155, να1178, Azr79, Olp80 and Azr81 .

Preferred embodiments of section E of the invention disclose compounds having the general formula XIXa

Preferred embodiments of section E of the invention disclose compounds having the general formula XIXa, where b consists of 2-5 atoms.

Preferred embodiments of section E of the invention disclose compounds having the general formula XIXa, where b includes the group -Ά- ((= ν) -, where V and each are individually selected from O, 8 or N11.

Preferred embodiments of section E of the invention disclose compounds having the general formula XIXa, wherein b is selected from the group consisting of ether, amide, carbamate, thioester and thioamide.

- 42 012389

Preferred embodiments of section E of the invention disclose compounds having the general formula XCHa, where the position of the P ₂ group is determined by a linker L to form a hydrogen bond with at least one fragment 82 of the Ν83 protease pocket, consisting of Hlz57, Agd155, Wa1178, Azr79, Pnp80 and Azr81 .

Preferred embodiments of section E of the invention disclose compounds having the general formula XIX, wherein P ₂ is

Preferred embodiments of section E of the invention disclose compounds having the general formula XEX

Preferred embodiments of section E of the invention disclose compounds having the general formula xxx, where b consists of 2-5 atoms.

Preferred embodiments of section E of the invention disclose compounds having the general formula XEX, where b includes the group - ^ - C (= Y) -, where V and each are individually selected from O, 8 or ΝΗ.

Preferred embodiments of section E of the invention disclose compounds having the general formula XBC, where b is selected from the group consisting of ether, amide, carbamate, thioether and thioamide.

Preferred embodiments of section E of the invention disclose compounds having the general formula XEX, where the position of the P ₂ group is determined by a linker L to form a hydrogen bond with at least one moiety 82 of the Ν83 protease pocket, consisting of Hlz57, Agd155, Wa1178, Azr79, Pnp80 and Azr81 .

Preferred embodiments of section E of the invention disclose compounds having the general formula HXa, wherein the substituents at the C13-C14 double bond are in the cis position.

Preferred embodiments of section E disclose compounds having the general formula X £ Xa, where the substituents at the C13-C14 double bond are in the trans position.

Compounds of formula X £ X can be prepared in the same manner as compounds of formula I-XVII.

In some embodiments, compounds of the general formula X £ X do not include the compounds disclosed in PCT / I804 / 33970. For example, in some embodiments, the compounds of general formula I do not include compounds of formulas II, III IV described in section B.

Pharmaceutical formulations.

The present invention also discloses compositions comprising pharmaceutical formulations containing compounds of the general formula EXK and their salts, esters or other derivatives. The pharmaceutical composition described herein includes a compound of the invention and a pharmaceutically acceptable excipient. A wide variety of pharmaceutically acceptable excipients (excipients) are well known in the art and need not be discussed in detail here. Pharmaceutically acceptable carriers (excipients) have been described in numerous publications including, for example, A. Peppago (2000), op Kettd: Be 8s1epse APB RgasIse RBagtasu about £ 20 esShyup ^1b, 1rr1psoy, LHShatz, &AEktz;! Republican State University of Economics and Public Relations of the Republic of Bashkortostan Apze1 e! A1., ebz., 7 ^{1b eb} ., EfrtsoI, A'X Shatz, &AX11stz; apb Iapbook about £ РБагтасее Еса1 ЕхсщюПз (2000), A.I. K1bie e! a1., ebz., 3 ^GB fucked. ATEG. RB Bagtaseis 1 Azzos.

Pharmaceutically acceptable excipients such as diluents, adjuvants, carriers or solvents are readily available for public use. Moreover, pharmaceutically acceptable excipients, such as regulatory PI, buffering agents, regulatory concentration

- 43 012389 tion agents, stabilizers, moisturizers, etc., are readily available for public use.

Examples of suitable embodiments of the pharmaceutical compositions and methods for their preparation are described in more detail below.

Inhibition of enzymatic activity of flavivirus.

In most embodiments, the compound inhibits the enzymatic activity of flavivirus. Whether a compound of the invention will inhibit flavivirus can be easily determined using any known method. Flavivirus infections include infections caused by flaviviruses, including, but not limited to, hepatitis C virus, West Nile virus, CB virus, Japanese encephalitis, Dengue virus, and yellow fever virus. In most embodiments, the compound of the invention inhibits the enzymatic activity of hepatitis C virus protease N83 (HCV). Whether compound N83 inhibits HCV can be easily determined by known methods. Conventional methods include determining whether the HCV polyprotein or other polypeptide, including the N83 recognition site, is cleaved by the N83 protease in the presence of an agent. In most embodiments of the invention, the described compound inhibits N83 enzymatic activity by at least about 10%, at least

about on fifteen%, by extreme least about on twenty%, by extreme least about on 25% by extreme least about on thirty%, by extreme least about on 40% by extreme least about on fifty%, by extreme least about on 60% by extreme least about on 70% by extreme least

about 80%, at least about 90% or more compared to the enzymatic activity of N83 in the absence of compound.

In many embodiments, the compound of the invention inhibits the enzymatic activity of the N83 HCV protease with 1C ₅₀ less than 50 μM, for example, the compound of the invention inhibits the enzymatic activity of the N83 HCV protease with 1C ₅₀ less than 40 μM, less than 25 μM, less than 10 μM, less than 1 μM, less than 100 nm, less than 80 nm, less than 60 nm, less than 50 nm, less than 25 nm, less than 10 nm or less than 1 nm or less.

In many embodiments, the compound described herein inhibits HCV replication. For example, a compound of the invention inhibits HCV replication at least

at least approximately on 10%, at least about 15% by extreme least about on twenty%, by extreme least about on 25% by extreme least about on thirty%, by extreme least about on 40% by extreme least about on fifty%, by extreme least about on 60% by extreme least about on 70% by extreme least about on 80% by extreme least

approximately 90% or more compared with HCV replication in the absence of compound. Whether the compound inhibits HCV replication can be determined by methods known in the art, including testing for virus replication νίΐτο.

Treatment for flavivirus infection.

The methods and compositions described herein are commonly used to treat flavivirus infection.

Whether the method according to the invention is effective in treating flavivirus infection can be determined by a decrease in viral load, a decrease in seroconversion time (the virus is not detected in the patient’s serum), an increase in the rate of a prolonged viral response to treatment, a decrease in morbidity or mortality in clinical cases, or another indicator of response to disease.

Typically, an effective amount of a compound of Formulas Ι-ΧΙΧ, and optionally with one or more additional antiviral agents, is an amount that is effective in reducing the viral load or improving the long-term viral response to therapy.

Whether the method of the invention is effective in treating flavivirus infection can be determined by measuring viral load or measuring parameters associated with flavivirus infection, including, but not limited to, liver fibrosis, increased serum transaminase concentration, and non-inflammatory activity in the liver. Indicators of liver fibrosis are discussed in detail below.

The method comprises administering an effective amount of a compound of the formula Ι-ΧΙΧ, possibly in combination with an effective amount of one or more additional antiviral agents. In some embodiments, an effective amount of a compound of Formulas Ι-ΧΙΧ and optionally one or more additional antiviral agents is an amount effective to reduce the titer of the virus to an undetectable level, for example, from about 1000 to 5000, from 500 to 1000, or from 100 to 500 genomic copies / ml of serum. In some embodiments, an effective amount of a compound of Formulas Ι-ΧΙΧ, and optionally with one or more additional antiviral agents, is an amount effective to reduce the viral load to below 100 genomic copies / ml of serum.

- 44 012389

In some embodiments, an effective amount of a compound of formulas LXHX, and optionally with one or more additional antiviral agents, is an amount effective to achieve a reduction of 1.5-1od, 2-1od, 2.5-1od, 3-1od, 3, 5-1od, 4-1od, 4.5-1od or 5-1od of the titer of the virus in the patient's serum.

In some embodiments, an effective amount of a compound of the formula [-XIX. and optionally, with one or more additional antiviral agents, represents an amount effective to improve the “sustained viral response”, for example, the absence (not detection) of HCV RNA (eg, less than 500, less than 400, less than 200 or less than 100 genomic copies / ml of serum) in the patient’s serum for a period of at least one month, at least two months, at least three months, at least four months, at least five months, at least six months after discontinuation of treatment.

Whether the method of the invention is effective in treating flavivirus infection can be determined, as noted above, by measuring parameters associated with flavivirus infection, such as liver fibrosis. Methods for determining the degree of liver fibrosis are discussed in detail below. In some embodiments, the concentration of serum liver fibrosis markers in serum indicates its degree.

As one non-limiting example, the serum alanine aminotransferase (ALT) concentration is measured using standard assays. Typically, ALT concentrations of less than approximately 45 international units (IU) are considered normal. In some embodiments, an effective amount of a compound of Formulas I-XIX, and optionally with one or more additional antiviral agents, is an amount effective to lower the ALT concentration lower than 45 IU / ml of serum.

A therapeutically effective amount of a compound of formulas I-XIX, and optionally with one or more additional antiviral agents, is an amount effective

to reduce concentration markers liver fibrosis in serum by extreme least about on 10%, by extreme least about on fifteen%, by extreme least about on twenty%, by extreme least about on 25% by extreme least about on thirty%, by extreme least about on 40% by extreme least about on fifty%, by extreme least about on 60% by extreme least about on 70% by extreme least about on 80% by extreme least

approximately 90% or more compared to the concentration of markers in a patient without treatment or a patient receiving a placebo. Methods for measuring markers in serum include immunological methods, for example, enzyme-linked immunosorbent assay (EIA), radioimmunoassay, etc., using antibodies specific for this marker in serum.

In many embodiments, an effective amount of a compound of Formulas I-XIX and optionally one or more additional antiviral agents is a synergistic amount. As used herein, a “synergistic combination” or “synergistic amount” of a compound of formulas and an additional antiviral agent is a combined dose that is more effective in the therapeutic or prophylactic treatment of a HS virus infection than a gradual improvement as a result of treatment that is expected or expected only from an additional combination: ί) the therapeutic or prophylactic benefit of the compound of formulas I-XIX when it is administered at the same dose as monotherapy; and, (ίί) the therapeutic or prophylactic benefit of the additional antiviral agent when it is administered at the same dose as monotherapy.

In some embodiments, a selected amount of a compound of formulas I-XIX and a selected amount of additional antiviral agent are effective when used in combination therapy for treating a disease, but a selected amount of a compound of formulas I-XIX and / or a selected amount of additional antiviral agent is ineffective when used in monotherapy to treat a disease. Thus, the invention encompasses (1) modes in which a selected amount of an additional antiviral agent improves the therapeutic benefit of a selected amount of a compound of formulas I-XIX when they are used in combination therapy to treat a disease, and the selected amount of an antiviral agent does not provide therapeutic benefit when used in monotherapy to treat a disease; (2) modes in which a selected amount of a compound of formulas I-XIX improves the therapeutic benefit of a selected amount of an additional antiviral agent when used in combination therapy to treat a disease, and the selected amount of a compound of formulas does not provide therapeutic benefit when used in monotherapy for treatment diseases (3) modes in which a selected amount of a compound of formulas I-XIX and a selected amount of an additional antiviral agent provide therapeutic benefit when used in combination therapy to treat a disease, each of the selected amounts of a compound of formulas I-XIX and an additional antiviral agent, respectively , does not bring therapeutic benefits when they are used in monotherapy to treat a disease. How to use

- 45 012389 is here, the “synergistically effective amount” of the compound of the Ι-ΧΙΧ formulas and the additional antiviral agent and their grammatical equivalents should be considered included in any mode covered by modes (1) - (3) listed above.

Treatment of hepatitis viral infection.

The methods and compositions described herein are typically used to treat hepatitis C virus infection.

Whether the method according to the invention is effective in the treatment of hepatitis C virus infection can be determined by a decrease in viral load, a decrease in seroconversion time (the virus is not detected in the patient’s serum), an increase in the rate of a prolonged viral response to treatment, a decrease in morbidity or mortality in clinical cases, or other indicator response to the disease.

Typically, an effective amount of a compound of Formulas Ι-ΧΙΧ, and optionally with one or more additional antiviral agents, is an amount that is effective in reducing the viral load or improving the long-term viral response to therapy.

Whether the method of the invention is effective in the treatment of hepatitis C virus infection can be determined by measuring the viral load or measuring parameters associated with HCV infection, including, but not limited to, liver fibrosis, increased serum transaminase concentration and non-inflammatory activity in the liver. Indicators of liver fibrosis are discussed in detail below.

The method comprises administering an effective amount of a compound of the formulas Ι-ΧΙΧ possibly in combination with an effective amount of one or more additional antiviral agents. In some embodiments, an effective amount of a compound of Formulas Ι-ΧΙΧ and optionally one or more additional antiviral agents is an amount effective to reduce the titer of the virus to an undetectable level, for example from about 1000 to 5000, from 500 to 1000, or from 100 to 500 genomic copies / ml serum. In some embodiments, an effective amount of a compound of Formulas Ι-ΧΙΧ, and optionally with one or more additional antiviral agents, is an amount effective to reduce the viral load to below 100 genomic copies / ml of serum.

In some embodiments, an effective amount of a compound of formula Ι-ΧΙΧ, and optionally with one or more additional antiviral agents, is an amount effective to achieve a reduction of 1.5-1 od, 2-1 od, 2.5-1 od. 3-1od, 3.5-1od. 4-1 od, 4.5-1 od or 5-1 od virus titer in the patient's serum.

In some embodiments, an effective amount of a compound of Formulas Ι-ΧΙΧ, and optionally with one or more additional antiviral agents, is an amount effective to improve a “sustained viral response”, for example, the absence (not detection) of HCV RNA (eg, less than 500, less 400, less than 200 or less than 100 genomic copies / ml of serum) in the patient's serum for a period of at least one month, at least two months, at least three months, at least four months, in cr yney least five months, at least six months after the cessation of treatment.

Whether the method of the invention is effective in the treatment of hepatitis C virus infection can be determined, as noted above, by measuring parameters associated with HCV infection, such as liver fibrosis. Methods for determining the degree of liver fibrosis are discussed in detail below. In some embodiments, the concentration of serum liver fibrosis markers in serum indicates its degree.

As one non-limiting example, the serum alanine aminotransferase (ALT) concentration is measured using standard assays. Typically, ALT concentrations of less than approximately 45 international units (IU) are considered normal. In some embodiments, an effective amount of a compound of Formulas Ι-ΧΙΧ, and optionally with one or more additional antiviral agents, is an amount effective to lower ALT concentration lower than 45 IU / ml serum.

A therapeutically effective amount of a compound of the formulas Ι-ΧΙΧ, and optionally with one or more additional antiviral agents, is an amount effective to reduce the concentration of liver fibrosis markers in serum by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least riblizitelno 70%, at least about 80%, at least about 90% or more compared with the concentration of markers in a patient without treatment or patient receiving placebo. Methods for measuring markers in serum include immunological methods, for example, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay, etc., using antibodies specific for this marker in serum.

- 46 012389

In many embodiments, an effective amount of a compound of the formula Σ-ΧΓΧ, and optionally with one or more additional antiviral agents, is a synergistic amount. As used here, a “synergistic combination” or “synergistic amount” of a compound of the formulas Σ-ΧΓΧ and an additional antiviral agent is a combined dose that is more effective in the therapeutic or prophylactic treatment of a viral infection of the HS than a gradual improvement as a result of treatment that is expected only the additional combination is expected: ί) therapeutic or prophylactic benefit of the compound of the formulas Σ-ΧΣΧ when it is administered in the same dose as a monotone rapies and, (ίί) the therapeutic or prophylactic benefit of an additional antiviral agent when administered in the same dose as monotherapy.

In some embodiments, a selected amount of a compound of formulas [-XIX and a selected amount of additional antiviral agent are effective when used in combination therapy to treat a disease, but a selected amount of a compound of formulas RXH and / or a selected amount of additional antiviral agent is ineffective when used in monotherapy to treat a disease. Thus, the invention encompasses (1) modes in which a selected amount of an additional antiviral agent improves the therapeutic benefit of a selected amount of a compound of the formulas of IACS when they are used in combination therapy to treat a disease, and the selected amount of an antiviral agent does not provide therapeutic benefit when used in monotherapy to treat a disease; (2) modes in which a selected amount of a compound of the formulas of IACS improves the therapeutic benefit of a selected amount of an additional antiviral agent when used in combination therapy to treat a disease, and the selected amount of a compound of formulas of IACC does not provide therapeutic benefit when used in monotherapy to treat a disease ; (3) modes in which a selected amount of a compound of formulas of RXHC and a selected amount of an additional antiviral agent provide therapeutic benefit when used in combination therapy to treat a disease, each of the selected amounts of a compound of formulas of RXH and an additional antiviral agent, respectively, does not bring a therapeutic benefit when they are used in monotherapy to treat a disease. As used here, the “synergistically effective amount” of the compound of the RXH formulas and the additional antiviral agent and their grammatical equivalents should be considered included in any mode covered by modes (1) to (3) listed above.

Fibrosis treatment.

The present invention provides methods of treating liver fibrosis (including forms of liver fibrosis resulting from or associated with a hepatitis C virus infection), which typically include administering a therapeutic amount of a compound of the formulas LEX, and possibly with one or more additional antiviral agents, as well as dosage regimens, as discussed below. The effective number of compounds of the RXH formulas with one or more additional antiviral agents or without them, as well as dosage regimens, are discussed below.

Whether treatment is a compound of the formulas LEXX, and possibly with one or more additional antiviral agents, is effective in reducing liver fibrosis, any of a number of well-known techniques for measuring liver fibrosis and liver function is determined. A reduction in liver fibrosis is determined by analysis of a sample of liver tissue obtained by biopsy. Analysis of a liver biopsy includes an assessment of two main characteristics: a non-inflammatory process, assessed by "degree" to measure the severity of the disease and the current activity of the disease, and damage by fibrosis and parenchymal or vascular changes to assess the "stage" as a reflection of the long-term development of the disease. See, for example, Βιυηΐ (2000), Ηеρаΐο1. 31: 241-246 and ΜΕТΑVΣК (1994), ρеρаΐο1οд 20: 15-20. Based on an analysis of a liver biopsy, indices are established. There are various standard gradation systems that quantify the degree and severity of fibrosis. They include ΜΕТΑVΣК, КпобеП, 8с Нейег. Liytad and Sh1a1s gradation systems.

The ΜΕΤΑν ^ gradation system is based on an analysis of various signs of a liver biopsy, including fibrosis (portal fibrosis, central lobe fibrosis, and cirrhosis); necrosis (partial and lobular necrosis, acidophilic retraction and ballooning dystrophy); inflammation (inflammation of the portal tracts, portal lymphoid accumulation and the spread of portal inflammation); changes in the bile ducts; Knodell index (KpobeP) (stage of periportal necrosis, lobular necrosis, portal inflammation, fibrosis and the full degree of disease activity). The definition of each stage in the ΜΕΤΑνΊΗ system is as follows:

stage 0, no fibrosis;

stage 1, stellate growth of the portal tract, but without the formation of septa;

stage 2, lengthening of the portal tract with a slight formation of septa;

stage 3, numerous septa without cirrhosis and stage 4, cirrhosis.

- 47 012389

Knodell's gradation system (Kpobe11), also referred to as the histological activity index (IG A), classifies the degree of disease activity based on stages in four categories of histological features:

I) periportal and / or bridge necrosis;

Ii) intralobular degeneration and focal necrosis;

Iii) portal inflammation;

Iv) fibrosis.

In the Knodell Gradation System (Kpobe11), the stages are as follows:

stage 0, no fibrosis;

stage 1, mild fibrosis (spread of portal fibrosis);

stage 2, moderate fibrosis;

stage 3, severe fibrosis (bridge fibrosis) and stage 4, cirrhosis.

The higher the stage of the disease, the more seriously damaged liver tissue. Kpobe11 (1981) Nera! O1. 1: 431.

In the grading system, the 8th and 10th stages are as follows:

stage 0, no fibrosis;

stage 1, elongated fibro-altered portal tracts;

stage 2, periportal or portoportal septa, but untouched architectonics; stage 3, fibrosis with a violation of architectonics, but the absence of obvious cirrhosis; stage 4, probable or definite cirrhosis. 8cGeyeg (1991), I. Nera! O1. 13: 372.

The Ishak gradation system (IHak) is described in [zhak (1995), I. Nera! O1. 22: 696-699: stage 0, no fibrosis;

stage 1, fibrosis of some portal tracts with or without short fibrous septa; stage 2, fibrosis of most portal tracts with or without short fibrous septa; stage 3, fibrosis of most portal tracts with rare portoportal septa (bridge-like fibrosis);

stage 4, fibrosis of the portal tracts with pronounced bridge-like fibrosis (portal or port-central septa);

stage 5, pronounced bridge-like fibrosis (portoportal or portocentral septa) with single nodes (early cirrhosis);

stage 6, cirrhosis, probable or detectable cirrhosis.

The beneficial effects of treating fibrosis can also be measured and evaluated using the Child-Pugh Criteria System (SYI-ReedG), which includes a multicomponent system of criteria that are based on impaired serum bilirubin, albumin, prothrombin time, the presence and severity of ascites, the presence and severity encephalopathy. Based on the identification and severity of the violation of these criteria, patients can be assigned to one of three categories according to the increasing severity of the disease: A, B or C.

In some embodiments, a therapeutically effective amount of a compound of Formula I, and optionally with one or more additional antiviral agents, is an amount that changes one or more units in the fibrosis stage based on prior and post treatment biopsy of the liver. In specific embodiments, a therapeutically effective amount of a compound of the formulas HCH, and optionally with one or more additional antiviral agents, reduces liver fibrosis by at least one unit in METLUEC gradation systems, Kpobe11, 8c11eyeg. Bshushch or GGak.

Secondary or indirect indices of liver function can also be used to evaluate the effectiveness of treatment with the compound of the formulas HCH. A morphometric computerized semi-automatic evaluation of liver fibrosis based on specific staining with collagen and / or serum markers of liver fibrosis can also be measured as an indicator of the effectiveness of the described treatment method. Secondary liver function indices include, but are not limited to, serum transaminase levels, prothrombin time, bilirubin, platelet counts, portal pressure, albumin levels, and Child-Pugh criteria (CH14-Read).

A therapeutically effective amount of a compound of the formulas HCH, and optionally with one or more additional antiviral agents, is an amount effective to increase the liver function index by at least about 10%, at least

about on twenty%, by extreme least about on 25% by extreme least about on thirty%, by extreme least about on 35% by extreme least about on 40% by extreme least about on 45% by extreme least about on fifty%, by extreme least about on 55% by extreme least about on 60% by extreme least about on 65% by extreme least about on 70% by extreme least about on 75% by extreme least

about 80%, at least about 85% or more compared to the index

- 48 012389 liver function in a patient without treatment or a patient receiving a placebo. One of skill in the art can easily measure such liver function indices using standard research methods, many of which are commercially available, and which are commonly used in a clinical setting.

Serum markers of liver fibrosis can also be measured as an indicator of the effectiveness of the described method of treatment. Serum markers include, but are not limited to, hyaluronate, Ν-terminal procollagen III peptide, 78 type IV collagen domain, C-terminal procollagen I peptide and laminin. Additional biochemical markers of liver fibrosis include α-2 macroglobulin, haptoglobulin, γ-globulin, apolipoprotein A and γ-glutamyl transpeptidase.

A therapeutically effective amount of a compound of the HCBH formulas, and optionally with one or more additional antiviral agents, is an amount effective to reduce the concentration of serum liver fibrosis markers by at least about 10%,

by extreme least about on fifteen%, by extreme least about on twenty%, by extreme least about on 25% by extreme least about on thirty%, by extreme least about on 40% by extreme least about on fifty%, by extreme least about on 60% by extreme least about on 70%

at least about 80%, at least about 90% or more compared to the concentration of markers in a patient without treatment or a patient receiving a placebo. One of skill in the art can easily measure such serum markers of liver fibrosis using standard research methods, many of which are commercially available and which are commonly used in a clinical setting. Methods for measuring markers in serum include immunological methods, for example enzyme-linked immunosorbent assay (EIA). radioimmunoassay and the like, using antibodies specific for a given marker in serum.

Quantitative tests of liver functional reserves can also be used to evaluate the effectiveness of treatment with interferon and pirfenidone receptor agonists (or pirfenidone analogues). These include the excretion of Indocyanine green DSS), the ability to remove galactose (CEC), the aminopyrine breath test (ABT), the excretion of antipyrine, the excretion of monoethyl glycine silidide (MEC-X) and the excretion of caffeine.

As used herein, “a complication associated with cirrhosis of the liver” refers to diseases that are consequences of decompensation diseases of the liver, that is, either occur after, or result from the development of liver fibrosis, and include, but are not limited to, the development of ascites , varicose bleeding, portal hypertension, jaundice, progressive liver failure, encephalopathy, hepatocellular carcinoma, lack of liver function, requiring its transplantation, and fatal outcome associated liver diseases.

A therapeutically effective amount of a compound of the formulas GEX, and possibly with one or more additional antiviral agents, is an amount effective to reduce the degree (for example, the likelihood that the patient will develop a disease) of cirrhosis disorders by at least about 10% at least about 20%

by extreme least about on 25% by extreme least about on thirty%, by extreme least about on 35% by extreme least about on 40% by extreme least about on 45% by extreme least about on fifty%, by extreme least about on 55% by extreme least about on 60% by extreme least about on 65% by extreme least about on 70%

at least about 80% or more compared to untreated patients or placebo-treated patients.

Whether treatment with a compound of the formulas GEX, and possibly with one or more antiviral agents, is effective in reducing the extent of disorders associated with cirrhosis of the liver can be easily determined by those skilled in the art.

Decreased liver fibrosis increases liver function. Moreover, the invention provides methods for increasing liver function, usually including the introduction of a therapeutically effective amount of a compound of the formulas GEX, and possibly with one or more additional antiviral agents. Liver functions include, but are not limited to, a synthetic function, including, but not limited to, the synthesis of proteins such as whey proteins (e.g., albumin, blood coagulation factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartame transaminase), 5'- nucleosidase, γ-glutaminyl transpeptidase, etc.), bilirubin synthesis, cholesterol synthesis and bile acid synthesis; metabolic function of the liver, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormonal metabolism, and lipid metabolism; detoxification of exogenous drugs; hemodynamic function, including visceral and portal dynamics of blood circulation; etc.

Whether liver function increases is easily ascertained by those skilled in the art using well-tested liver function tests. Moreover, the synthesis of liver function markers, such as albumin, alkaline phosphatase, alanine transaminase, aspartame transaminase, bilirubin, etc., can be determined by measuring the level of markers in serum using standard immunological and enzymatic studies. Internal circulation and portal hemodynamics can be measured by portal wedging pressure and / or resistance using standard methods. Metabolic functions can be measured by determining serum ammonia levels.

Whether the concentration of whey proteins normally excreted by the liver falls into the normal range can be determined by measuring the level of such proteins using standard immunological and enzymatic studies. The person skilled in the art knows the normal ranges for such whey proteins. The following are non-limiting examples. The usual concentration of alanine transaminase is about 45 IU / ml serum. The usual concentration of aspartame transaminase is 5 to 40 IU / ml serum. Bilirubin is measured by standard studies. Normal bilirubin levels are usually less than 1.2 mg / dl. Serum albumin concentration is measured using standard studies. Normal serum albumin levels range from 35 to 55 g / L. The duration of prothrombin time is also measured using standard studies. Normal prothrombin time lasts less than 4 s compared to the control.

A therapeutically effective amount of a compound of formulas G-HHC, and optionally with one or more additional antiviral agents, is an amount effective to increase liver function by at least about 10%, at least about at least about at least about at least at least about 70%, at least about 80% or more.

For example, a therapeutically effective amount of a compound of formula G, and optionally or more additional antiviral agents, is an amount effective to reduce the elevated concentration of serum markers of liver function by at least approximately by liver function to a normal range.

A therapeutically effective amount of a compound of formula G, and optionally with one or more additional antiviral agents, is an amount effective to increase the decreased concentration of serum markers of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or olee or increasing the concentration of serum markers of liver function to a normal range.

Interferon G type receptor agonists.

In any of the above methods, in some preferred embodiments of the invention, type G interferon receptor agonists are administered. Interferon G type receptor agonists include interferon (IFN) -a; IFN-β; IFN-τ; IFN-ω; antibody agonists specific for type G interferon receptors; and any other type G interferon receptor agonist, including the nonpeptide 30%, according

50%, at least approximately at least approximately

on twenty%, on 40% on 60% , from one

10%, at least about 20%, at least about 30%, at least about 40%, at least about 60%, at least about 80% or more, or at least a decrease in the concentration of serum markers approximately 50%, at least approximately 70%, agonists.

Interferon alfa.

Any known IFN-α can be used in the present invention. The term "interferon-alpha" refers to a family of related polypeptides that inhibit viral replication and cell proliferation, and regulate the immune response. The term “IFN-α” includes IFN-α of natural origin, synthetic IFN-α, derivatives of IFN-α (for example, IFN-α conjugated to PEG, glycosylated IFN-α, etc.) and analogues of natural origin or synthetic IFN -α; basically any IFN-α that has antiviral properties, as described for IFN-α of natural origin.

Suitable α-interferons include, but are not limited to, IFN-α of natural origin (including, but not limited to, natural origin of IFN ^^ a, IFN - "- 2b); recombinant interferon-alpha-2b, such as GI1goi-A interferon, available from 8c11spgp Sogrogyai, Ksp0 ^ a1H. N.1 .; recombinant interferon-alpha-2a, such as YaoHegop interferon, available from Neutapp-ba Yaosie, No. 11eu, N.1 .; recombinant interferon-alpha-2c, such as VegoGog interferon-2, available from Wojeppdeg GpdeShe1t Ryagtaseeysa1, Gps., Yaadeiaea, Sopp .; interferon-alpha-p1, a purified mixture of natural interferons, such as 8itGegop, available from 8tyoto, 1aray, or also ^ MeHGegop interferon α-p! (ANN), available from C1axo-Me11sote b1a., Bopa, Cgea! Vyat; and interferon alfa

- 50 012389 p3 mixture of natural α-interferons made by 1p1sgGsgop 8s1epse8 and available from Rigbye Egebepsk Co., Νοπν; · ι11 <. Sopp., Under the A1Gegop trademark.

The term “interferon alpha” also encompasses consensus IFN-α. Consensus IFN-α (also referred to as "CIF" and "IFN-con" and consensus interferon) include, but are not limited to, the amino acid sequences designated ΙΕΝ-com (IFN-con ₁ ), ΙΕΝ-com (IFN-con ₂ ) and ΙΕΝ-coma (IFN-con ₃ ), which are disclosed in US patent No. 4695623 and 4897471; and consensus interferon to determine the consensus sequence of interferons-alpha of natural origin (for example, 1nGegdep®, 1n1gMipe, 1ps., Bnkap, Ca11G.). ΙΡΝ-social (IFN-con ₁ ) is a consensus interferon agent in the product 1pGegdep® A1Gasop-1. The product of the consensus interferon 1nGegdep® is hereinafter referred to by its brand (1nGegdep®) or by its general name (interferon-alpha-con ₁ ). The DNA sequence encoding IFN-con can be synthesized as described in the above patents or other standard methods. The use of KIFN is of particular interest.

Hybrid polypeptides including IFN-α and a heterologous polypeptide are also suitable for use in the present invention. Suitable IFN-α fusion polypeptides include, but are not limited to A1bshop-a1prya ™ (Albuyeron-α) (a hybrid product of human albumin and IFN-α; Nitap Sepote 8c1epse8; see, for example, Okboge e! A1. (2002) 1. Ragtaco1 Exp. Tiegar. 303: 540-548). Genetically mixed forms of IFN-α are also suitable for use in the present invention. See, for example, Mac e! a1. (2003), Sigg. Opso1. Yaer. 5: 108-113.

Interferon-alpha conjugated to PEG.

The term "IFN-α" also covers derivatives of IFN-α, which are transformed (for example, are chemically modified) to change some of their properties, such as the half-life of serum. Thus, the term "IFN-α" includes glycosylated IFN-α; IFN-α conjugated to polyethylene glycol ("IFN-α with PEG", "PEGylated IFN-α"), etc. PEGylated IFN-α and methods for its preparation are discussed in US Pat. Nos. 5,382,657; 5981709 and 5951974. PEGylated IFN-α encompasses PEG conjugates of any of the above IFN-α molecules, including, but not limited to, PEG conjugated interferon-alpha2a (YaoGegop, NoGGtap Ga-Yaosye, No. 11еу, Ν.Γ), interferon- alpha-2b (1n1gop, 8syegsd-P1oid, Maykop, Ν.Γ), interferon-alpha-2s (VegoGog A1rya, Voeyppdeg 1pdeShe1t, 1pdeShe1t, Segtapu) and consensus interferon by definition of the consensus sequence 1 of nature 1 , 1ps., Vnkbape, SaGP).

Any of the aforementioned IFN-α polypeptides can be modified with one or more polyethylene glycol fragments, i.e. conjugated to PEG. The polyethylene glycol molecule of the pegylated IFN-α polypeptide conjugates to one or more amino acid side chains of the IFN-α polypeptide. In some embodiments, the PEGylated IFN-α contains PEG fragments on only one amino acid. In other embodiments, the PEGylated IFN-α contains PEG fragments on two or more amino acids, for example, IFN-α contains PEG fragments attached to 2, 3, 4, 5, 6, 7, 8, 9, or 10 different amino acid residues.

IFN-α can be coupled to PEG directly (i.e., without linking groups) through an amino group, a sulfhydryl group, a hydroxyl group or a carboxyl group.

In some embodiments, the PEGylated IFN-α is conjugated to PEG at or near the amino terminus (Ν-terminus) of the IFN-α polypeptide, for example, the PEG fragment is conjugated to the IFN-α polypeptide at one or more amino acid residues from amino acid 1 via amino acid 4 or from amino acid 5 through amino acid 10.

In other embodiments, the PEGylated IFN-α is conjugated to PEG at one or more amino acid residues from about 10 to about 28.

In some embodiments, the PEGylated IFN-α is conjugated to PEG at or near the carboxyl terminus (C-terminus) of the IFN-α polypeptide, for example, one or more amino acids 156-166 or amino acids 150 to 155.

In other embodiments, the PEGylated IFN-α is conjugated to PEG on one or more amino acid residues of amino acids 100-114.

Conjugation of polyethylene glycol with amino acid residues at or near receptor-binding and / or active sites of IFN-α protein domains can disrupt the functioning of these domains. In some embodiments, amino acids on which PEG conjugation is avoided include amino acid residues from amino acids 30-40 and amino acid residues from amino acids 113-149.

In some embodiments, the PEG is attached to IFN-α via a linking (linker) group. A linker group is any biocompatible linking group, where "biocompatibility" indicates that the compound or group is not toxic and

- 51 012389 may be used w νίίτο or w νίνο without harm. causing disease. diseases. of death. Suitable biocompatible groups include. but not limited to. ether group. amide group. imide group. carbamate group. carboxyl group. hydroxyl group. carbohydrates. a succinimide group (including, for example, succinimidyl succinate (88A). succinimidyl propionate (8PA). succinimidyl butanoate (8BA). succinimidyl carboxymethylate (8CM). succinimidyl succinamide (88A) or K-hydroxy Succinim). epoxy groups. hydroxycarbonylimidazole group (including, for example, carbonyldimidazole (COI)). nitrophenyl group (including, for example, nitrophenyl carbonate (cattle) or trichlorophenyl carbonate (TPC)). trisylate group. aldehyde groups. isocyanate group. vinyl sulfone group. tyrosine group. cystine group. a histidine group or a primary amine.

Methods for producing succinimidyl propionate (8PA) and succinimidyl butanoate (8BA) - esters. activated PEG. described in US patent No. 5b72bb2 (Nagpk. e! A1.) and AO 97 / 0310b.

Methods of attaching PEG to an IFN-α polypeptide are known in the art and any known method can be used. See .. for example. Ragk et al. Apksapseg Vek .. 1: 373-37b (1981); ΖαρΙίρκΚν and bj. Ро1уе! Ku1epe C1uso1 SketkRu: Vyu! Esksshsa1 apy Vyuteyuua1 ArrksaRopk. Hm. Natk. her .. P1epit Rgekk. KU. chapter 21 (1992); US patent No. 59852b5; 5b72bb2 (Nat. E! A1.) And AO 97 / 0310b.

PEGylated IFN-α and methods for its preparation. are being discussed. eg. US Pat. No. 5,382b57; 5,981,709; 59852b5 and 5951974. PEGylated IFN-α encompasses PEG conjugates of any of the above IFN-α molecules. including. but not limited to. PEG-conjugated interferon-alpha-2a (VoGegop. NogGtap ba Voske. Ki! 1eu. CE.). where the pegylated WoGegop is known as Edyuk (NogGtap ba Voske); interferon-alpha-2b (1n! gop. 8skegsd-R1oidk. Maykop. K.G.). where pegylated ΙπΡόπ is known as RES-1pRop (8skegsd-P1oid); interferon-alpha-2c (VegoGog A1rka. Voekszdeg 1pde1ke1t. 1pde1ke1t. Segtapu) and consensus interferon for determining the consensus sequence of interferon-alpha of natural origin (1pGegdep®. 1n! eMMipe. 1pc. where pegylated 1pGegdep is known as RES-1pGegdep.

In many embodiments, the PEG is a monomethoxypolyethylene glycol molecule. which interacts with the primary amine group of the IFN-α polypeptide. Methods for modifying monomethoxy-PEG polypeptides by reductive alkylation are known in the art. See .. for example. Scatote e! a1. (1994) Vyusoi). Sket. 5: 133-140.

In one. not limiting the scope of claims. In the example, PEG is conjugated to IFN-α via a linker - succinimidyl propionate (8PA). The 8PA and PEG esters and methods for their preparation are described in US Pat. No. 5b72bb2. 8PA bonds provide a compound with the free amino groups of the IFN-α polypeptide.

For example. the PEG molecule is covalently linked through a bond. which includes an amide bond between the propionyl group of the PEG fragment and the ε-amino group of the lysine residue protruding on the surface in the IFN-α polypeptide. Such a connection can be formed. eg. upon condensation of the activated PEG ester and α-methoxy. ω-propanoic acid (t-PEG-edge).

In one. not limiting the scope of claims. An example is a conjugate of one mono-PEGylated KIFN. preferred for use here. has a linear PEG fragment of about 30 kDa. attached via a covalent bond to a CIFN polypeptide. where the covalent bond is an amide bond between the propionyl group of the PEG fragment and the ε-amino group of the lysine residue protruding on the surface in the CIFN polypeptide. where protruding on the surface of the lysine residue selected from 1uk ³¹ . 1uk ⁵⁰ . 1uk ⁷¹ . 1uk ⁸⁴ . 1uk ¹²¹ . 1uk ¹²² . 1uk ¹³⁴ . 1uk ¹³⁵ and 1uk ^1ba . and the amide bond is formed by condensation of the activated ester of the PEG fragment and α-methoxy. ω-propanoic acid.

Polyethylene glycol.

Polyethylene glycol (PEG). suitable for conjugation with any IFN-α polypeptide. soluble in water at room temperature and has the general formula B (O-CH ₂ -CH ₂ ) _p O-B. where represents hydrogen or a protective group. such as alkyl or alkanoyl. and where n is an integer from 1 to 1000. If B represents a protecting group. then it usually contains from 1 to 8 carbon atoms.

In many embodiments, the PEG has at least one hydroxyl group. for example, a terminal hydroxyl group. wherein the hydroxyl group is modified to form a functional group for reaction with an amino group. for example, the ε-amino group of the lysine residue. a free amino group at the K-terminus of the polypeptide or any other amino group. such as the amino group of asparagine. glutamine. arginine or histidine.

In other embodiments, the PEG is transformed as follows. that he himself enters into a chemical reaction with the IFN-α polypeptide. for example, a free carboxyl group at the carboxyl terminus of an IFN-α polypeptide. Suitable PEG derivatives. which are capable of interacting with the free carboxyl group at the carboxyl terminus of the IFN-α polypeptide include. but not limited to. PEG amines and hydrazine derivatives of PEG (e.g.

- 52 012389

PEG-CN-CN ₂ ).

In other embodiments, the PEG is transformed so that it includes a terminal thiocarboxyl group, —CO 8 H, which selectively reacts with amino groups to form amide derivatives. Due to the chemical nature of thioacids, the selectivity of some amino groups improves compared to others. For example, -8H is a good leaving group in reaction with the Ν-terminal amino group at corresponding pH values such that the ε-amino groups in lysine residues are protonated and remain non-nucleophilic. On the other hand, reactions at suitable pH values may facilitate selective interaction of from about about to about to about to about about kDa, from kDa, from kDa, from kDa, from about about about to to to about about about about kDa, kDa, kDa, kDa, of the available lysine residues.

In other embodiments, the PEG comprises a reactive ester, such as Ν-hydroxy succinimidate at the end of the PEG chain. Such a Ν-hydroxy succinimidate containing a PEG molecule interacts with a selective amino group at specific pH values, such as neutral 6.5-7.5. For example, the Ν-terminal amino groups can be selectively modified at neutral pH values. However, if the reactivity of the reagents would be ultra-high, the available H ₂ groups of lysine could also react.

PEG can be directly conjugated to the IFN-α polypeptide or via a linker. In some embodiments, a linker is attached to an IFN-α polypeptide to form a linker-modified IFN-α polypeptide. Such linkers provide various functional groups, for example chemically active groups, such as a sulfhydryl, amino or carboxyl group for connecting the PEG reagent with a modified IFN-α polypeptide linker.

In some embodiments, the PEG conjugated to the IFN-α polypeptide is linear. In other embodiments, the PEG conjugated to the IFN-α polypeptide is branched. Branched PEG derivatives, such as those described in US Pat. Nos. 5,643,575, “star-shaped PEGs” and highly branched PEGs, such as those described in Geologic Ploetega 5, Cc. Catalog "Derivatives of Polyethylene Glycol" 1997-1998. "Star PEGs" are described in the prior art, including, for example, US patent No. 6046305.

PEG has a molecular weight of from about 2 kDa to about 100 kDa, where the term “approximately” as applied to PEG indicates that in the production of polyethylene glycol, some molecules have a greater weight, some less than the claimed molecular weight. For example, a PEG suitable for conjugation with IFN-α has a molecular weight of from about 2 to about 5 kDa, from about 5 to about 10 kDa, from about 10 to about 15 kDa, from from about 80 to about 90 kDa , from about 90 to about 100 kDa.

Obtaining conjugates of PEG-IFN-α.

As discussed above, PEG fragments can be attached directly or via a linker to amino acid residues at or near the окончания-terminus, inside, or at or near the C-terminus of the IFN-α polypeptide. Conjugation can be carried out in solution or in solid phase.

Ν-terminal connection.

Methods for attaching PEG fragments to amino acid residues at or near the Ν-terminus of the IFN-α polypeptide are known in the art. See, for example, US patent No. 5985265.

In some embodiments of the invention, known methods are used for the selective preparation of Ν-terminal chemically modified IFN-α. For example, a method for modifying proteins by reductive alkylation can be used that utilizes the different reactivity of different types of primary amino groups (lysine versus)-termination) available for transformation of specific proteins. Under suitable reaction conditions, the selective transformation of the protein at the Ν-terminus with the carbonyl group containing the polymer is improved. The reaction is carried out at a pH at which the difference in pKa between the ε-amino groups of the lysine residues and the α-amino groups of the Ν-terminal protein residue can be used. By such selective transformation, the attachment of the PEG fragment to IFN-α is controlled: conjugation with the polymer takes place mainly on the Ν-terminal residue of IFN-α, and significant modification of other chemically active groups, such as amino groups of lysine side chains, does not occur.

C-terminal compound.

Methods of a Ν-terminal specific compound, such as those described in US Pat. No. 5,985,265, provide predominantly mono-PEGylated products. However, purification methods aimed at removing excess reagents and minor multiple PEGylated products remove Ν-terminally protected polypeptides. Under the conditions of therapy, such processes will lead to a significant increase in production costs. For example, the study of the structure

- 53 012389 of the characterized sequence of the Shegdei A1 amino acids Asoi-1 KIFN of the polypeptide demonstrates that the cut-off (restriction) represents approximately 5% at the carboxyl terminus and thus there is only one basic C-terminal sequence. Thus, in some embodiments, Ν-terminally PEGylated IFN-α is not used; instead, IFN-α polypeptide conjugated to PEG at the C-terminus is used.

Thus, an effective synthetic and also therapeutic approach for producing mono-PEGylated Shegdean products is presented as follows.

A PEG reagent that is selective for C termination can be prepared with or without spacers. For example, polyethylene glycol modified as methyl ether at one end and having an amino group at the other end can be used as starting material.

The preparation or preparation of water-soluble carbodiimide as a condensing agent can be carried out. The coupling of IFN-α (for example, Shetdep ABasop-1 KIFN or consensus interferon) with a carbodiimide dissolved in water as a condensing agent is usually carried out in an aqueous medium with a suitable buffer system at an optimal pH to obtain an amide bond. A high molecular weight PEG can be covalently attached to a protein to increase molecular weight.

The reagents chosen will depend on the process optimization studies.

An example of a suitable reagent that does not limit the scope of claims is EOAC or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide. The solubility of EELS in water allows direct addition to the reaction without the need for preliminary dissolution in an organic solvent. Excess reagent and isourea formed as a by-product of the intermolecular bond formation reaction are water soluble and can easily be removed by dialysis or gel filtration. A concentrated solution of EEAC in water is prepared to facilitate the addition of a small molar amount to the reaction mixture. A stock solution is prepared and used immediately, taking into account the instability of the reactants in water. Most synthetic protocols in the literature offer an optimal reaction medium at a pH range between 4.7 and 6.0. However, the condensation reaction proceeds without significant loss in output to a pH value of 7.5. Water can be used as a solvent. Considering the intended use of Shegdep, the preferred medium will be a buffer solution of 2- (L-morpholino) ethanesulfonic acid, previously titrated to a pH between 4.7 and 6.0. However, 0.1 M phosphate at pH 7-7.5 can also be used, taking into account the fact that the product is in the same buffer. The ratio of PEG amine to IFN-α molecule is selected in such a way that the C-terminal (e) carboxyl (e) residue (s) are selectively conjugated to PEG to produce a mono-PEGylated derivative (s).

Even when using the PEG amine, which was mentioned above by name or structure, such derivatives are given by way of example only, and other groups, such as hydrazine derivatives of PEG -XN-XH ₂ , which will also be condensed with the carboxyl group of IFN-α, can be used. In addition to the aqueous phase, reactions can also be carried out in the solid phase. Polyethylene glycol can be selected from the list of compounds with a molecular weight in the range of 300-40000. The choice of various polyethylene glycols can also be dictated by the binding efficiency and biological characteristics of the purified derivatives of νίίτο and νίνο, i.e. circulation time and antiviral activity, etc.

Additionally, suitable spacers can be added to the C-terminus of the protein. Spacers may contain chemically active groups such as 8H, ΝΉ ₂ or COOH to bind to the corresponding PEG reagent to produce IFN-α derivatives with high molecular weight. The combined solid / dissolved phase technique can be developed to produce C-terminal PEGylated interferons. For example, the C-terminus of IFN-α is placed on the solid phase using a C1u-C1u-Suc-MH ₂ spacer and then mono-PEGylated in solution using an activated dithiopyridylPEG reagent of the corresponding molecular weight. Since the binding at the C-terminus does not depend on the protection of the окончания-termination, the presented processes and products will be cost-effective (a third of the protein is not consumed compared to the methods of Ν-terminal PEGylation) and contributes to savings in the treatment of viral infection.

There may be more reactive carboxyl groups of amino acid residues somewhere else in the molecule to interact with the PEG reagent and lead to mono-PEGylation at this site or to multiple PEGylation when IFN-α is added to COOH at the C-terminus. It is clear that these reactions will be minimal with steric freedom at the end of the molecule and steric hindrances imposed by carbodiimides and PEG reagents, as in branched chains of the molecule. Thus, this is the preferred method of PEG modification for [pTsgdsp and such similar proteins, natural or obtained recombinantly, which may have Ν-terminus protection to change the degree of improvement in efficiency and support

- 54 012389 desire for higher biological activity ΐη νίνο.

Another method for improving C-terminal PEGylation is as follows. The selectivity of C-terminal PEGylation is improved with sterically hindered reagents that exclude reactions on carboxyl residues that are hidden in helices or inside IFN-α. For example, one such reagent could be a branched chain PEG with a molecular weight of ~ 40 kDa and this agent could be synthesized as follows:

ΟΗ ₃ С- (СΗ2СΗ2Ο) _η -СΗ2СΗ2NΗ2 + Glutamic acid, i.e. 11OCO-C11 ₂ C11 ₂ C11 (ΛΊ 1 ₂ ) -COO11 is condensed with a suitable agent, for example dicyclohexyl carbodiimide or water-soluble BOC, to obtain a branched chain of the PEG agent OH ₃ C- (CH ₂ CH2O) _p -CH2CH2 \ НСОСН (\ Н2) CH ₂ OCH ₃ | (; ₂ n () (H ₂₎ ..- ( 'n ₂ (.'N ₂ \ H (.' O ( 'n · o..

II

H ₃ C — O— (CH ₂ CH ₂ O) _p —CH ₂ CH ₂ CN ₂ + BUT C — CH ₂ CH ₂ CH — COOH DCH ₂ BOAS I

H ₃ C-O- (CN ₂ CH ₂ O) _n -CH ₂ CH ₂ CO-MH οηνη _{2 (CH2)} 2

H ₃ C — O— (CH ₂ CH ₂ O) _p —CH ₂ CH ₂ No. 1-CO

This reagent can be used in excess to connect the amino group with the free and available carboxyl group of IFN-α to form a peptide bond.

If desired, PEGylated IFN-α is separated from unPEGylated IFN-α using known methods including, but not limited to, ion exchange chromatography, size exclusion chromatography, and combinations thereof. For example, where the conjugate of PEG and IFN-α is mono-PEGylated IFN-α, the products are first separated by ion exchange chromatography to obtain a material having the charging characteristics of a mono-PEGylated material (another multi-PEGylated material having the same apparent charges may be present), and then the mono-PEGylated material separated using size exclusion chromatography.

MonoPEGylated (30 kDa, linear) IFN-α.

PEGylated IFN-α, which is suitable for use in embodiments of the invention, includes a mono-PEGylated Consensus Interferon (CIFN) molecule comprising a single CIFN polypeptide and a single polyethylene glycol (PEG) fragment, where the PEG fragment is linear and has a molecular weight of 30 kDa and directly or indirectly, through a stable covalent bond, is linked either to the Ν-terminal residue in the CIFN polypeptide or to the lysine residue in the CIFN polypeptide. In some embodiments, the mono-PEGylated (30 kDa, linear) IFN-α is a mono-PEGylated (30 kDa, linear) consensus IFN-α.

In some embodiments, the PEG moiety is linked either to the α-amino group of the Ν-terminal residue in the CIFN polypeptide, or to the ε-amino group of the lysine residue in the CIFN polypeptide. In other embodiments, the bond is an amide bond between the PEG moiety and / or the α-amino group of the термина-terminal residue or the ε-amino group of the lysine residue of the KIFN polypeptide. In still other embodiments, the bond is an amide bond between the propionyl group of the PEG moiety and / or the α-amino group of the Ν-terminal residue or the ε-amino group of the lysine residue of the KIFN polypeptide. In further embodiments, the amide bond is formed by condensation of the activated α-methoxy, ω propanoic acid ester of the PEG fragment and / or the α-amino group of the Ν-terminal residue or the ε-amino group of the lysine residue of the CIFN polypeptide, thereby forming a hydrolytically stable bond between the PEG fragment and KIFN polypeptide.

In some embodiments, the PEG moiety is linked to the Ν-terminal residue in the CIFN polypeptide. In other embodiments, the PEG fragment is linked to the α-amino group of the Ν-terminal residue of the CIFN polypeptide. In other embodiments, the bond is an amide bond between the PEG moiety and the α-amino group of the Ν-terminal residue of the CIFN polypeptide. In still other embodiments, the bond is an amide bond between the propionyl group of the PEG moiety and

- 55 012389 by the α-amino group of the terminal residue of the CIFN polypeptide. In further embodiments, an amide bond is formed by condensation of the activated ester of α-methoxy, ω propanoic acid of the PEG fragment and the α-amino group of the terminal residue of the CIFN polypeptide.

In some embodiments, the PEG moiety is linked to a lysine residue in the CIFN polypeptide. In some embodiments, the PEG moiety is linked to the ε-amino group of the lysine residue in the CIFN polypeptide. In other embodiments, the bond is an amide bond between the PEG moiety and the ε-amino group of the lysine residue of the CIFN polypeptide. In still other embodiments, the bond is an amide bond between the propionyl group of the PEG moiety and the ε-amino group of the lysine residue of the CIFN polypeptide. In further embodiments, an amide bond is formed by condensation of the activated ester of α-methoxy, ω propanoic acid of the PEG fragment and the ε-amino group of the lysine residue of the KIFN polypeptide.

In some embodiments, the PEG moiety binds to a surface-acting lysine residue of the CIFN polypeptide. In other embodiments, the PEG moiety is coupled to the ε-amino group of a surface-acting lysine residue in the CIFN polypeptide. In other embodiments, the bond is an amide bond between the PEG moiety and the ε-amino group of the CIFN polypeptide protruding on the surface of the lysine residue. In still other embodiments, the bond is an amide bond between the propionyl group of the PEG moiety and the ε-amino group of the CIFN polypeptide protruding on the surface of the lysine residue. In further embodiments, the amide bond is formed by condensation of the activated ester of α-methoxy, ω propanoic acid of the PEG fragment and the ε-amino group of the KIFN polypeptide protruding on the surface of the lysine residue.

In some embodiments, the PEG moiety binds to a lysine selected from 1U8 ³¹ , 1U8 ⁵⁰ , 1U8 ⁷¹ , 1U8 ⁸⁴ , 1U8 ¹²¹ , 1U8 ¹²² , 1U8 ¹³⁴ , 1UV ¹³⁵ and 1UV ¹⁶⁵ KIFN. In other embodiments, the PEG moiety is linked to the ε-amino group of the lysine residue selected from 1 § ³¹ , 1 8 ⁵⁰ , 1 ⁷¹ , 1 8 ⁸⁴ , 1 ¹²¹ , 1 ¹²² , 1 ¹³⁴ , 1 ¹³⁵ and 1 ¹⁶⁵ in the CIFF polypeptide. In other embodiments, the bond is an amide bond between the PEG moiety and the ε-amino group of the selected lysine residue of the CIFN polypeptide. In still other embodiments, the bond is an amide bond between the propionyl group of the PEG fragment and the ε-amino group of the selected lysine residue of the CIFN polypeptide. In further embodiments, the amide bond is formed by condensation of the activated ester of α-methoxy, ω propanoic acid of the PEG fragment and the ε-amino group of the selected lysine residue of the KIFN polypeptide.

In some embodiments, the PEG moiety binds to a lysine selected from lu8 ¹²¹ , l1§ ¹³⁴ , l3 ¹³⁵ and l3 ¹⁶⁵ CIFN. In other embodiments, the PEG moiety is linked to the ε-amino group of the lysine residue selected from 1 ¹²¹ , 1 8 ¹³⁴ , 1 ¹³⁵ and 1 ¹⁶⁵ in the CIFN polypeptide. In other embodiments, the bond is an amide bond between the PEG moiety and the ε-amino group of the selected lysine residue of the CIFN polypeptide. In still other embodiments, the bond is an amide bond between the propionyl group of the PEG fragment and the ε-amino group of the selected lysine residue of the CIFN polypeptide. In further embodiments, the amide bond is formed by condensation of the activated ester of α-methoxy, ω propanoic acid of the PEG fragment and the ε-amino group of the selected lysine residue of the KIFN polypeptide.

In connection with the above-described mono-PEGylated CIFN molecules, the invention also includes variants of each such molecule where the CIFN polypeptide is selected from interferon-alpha-cop ₁ , interferon-alpha-cop ₂ and interferon-alpha-cop ₃ , where the amino acid sequence of such KIFN polypeptides is disclosed in the patent US No. 4,695,623.

IFN-α populations.

In addition, any of the methods of the invention may employ a pegylated IFN-α composition that includes a population of mono-PEGylated IFN-α molecules, where the population consists of one or more types of mono-PEGylated IFN-α molecules, as described above. The specified composition includes a population of modified IFN-α polypeptides, each with one PEG molecule, associated with one amino acid residue of the polypeptide.

In some embodiments, the population includes a mixture of the first IFN-α polypeptides linked to the PEG molecule on the first amino acid residue; and at least a second IFN-α polypeptide linked to the PEG molecule at the second amino acid residue, where the first and second IFN-α polypeptides are the same or different and where the location of the first amino acid residue in the amino acid sequence of the first IFN-α polypeptide is not the same that the position of the second amino acid residue in the second IFN-α polypeptide. As one non-limiting example of the claims, the composition includes a population of PEG-modified IFN-α polypeptides, a population comprising the IFN-α polypeptide is bound to

3%

twenty%,

40%

60%

80%, approximately approximately approximately approximately approximately

4%,

25%

45%

65%

85%, approximately approximately approximately approximately approximately

10%,

thirty%,

fifty%,

70%

90%, approximately approximately approximately approximately approximately approximately

2%

fifteen%,

35%

55%

75%

95% yielded by its amino terminus to a linear PEG molecule; and IFN-α polypeptide linked to a linear PEG molecule by a lysine residue.

In general, these modified species represent from 0.5 to 99.5% of the total population of mono-PEGylated Ifn-α polypeptide molecules in a population, for example, these modified species represent approximately 0.5%, approximately 1%, approximately approximately approximately approximately approximately 99%, or approximately 99.5% of the total population of mono-PEGylated IFN-α polypeptide molecules in the population. In some embodiments, the composition comprises a population of mono-PEGylated IFN-α polypeptides, wherein the population comprises at least about 70%, at least 80%, at least about 90%, at least about 95%, or at least about 99 % IFN-α polypeptides associated with PEG in the same region, for example, ^ terminal amino acid.

In specific embodiments of the invention of interest, said composition comprises a population of mono-PEGylated CIFN molecules, the population consists of one or more types of molecules, where each type of molecule, characterized by one CIFN polypeptide linked directly or indirectly by covalent bond, with one linear PEG moiety with a molecular weighing 30 kDa, and where binding occurs with either the lysine residue of the polypeptide, CIFN or the terminal amino acid residue of the CIFN polypeptide.

The amino acid residue to which PEG is attached in many embodiments is a terminal amino acid residue. In other embodiments, a PEG moiety is attached (either directly or via a linker) to a lysine residue protruding on the surface. In further embodiments, a PEG moiety is attached (either directly or via a linker) to a lysine residue selected from 1ue ³¹ , 1ue ⁵⁰ , 1ue ⁷¹ , 1ue ⁸⁴ , 1ue ¹²¹ , 1UE ¹²² , 1UE ¹³⁴ , 1UE ¹³⁵ and 1UU ^{165 of the} KIFN polypeptide. In other embodiments, the PEG moiety is attached (either directly or via a linker) to a lysine residue selected from 1ue ¹²¹ , 1ue ¹³⁴ , 1ue ¹³⁵ and 1ue ^{165 of the} CIFN polypeptide.

As an example, this composition includes a population of mono-PEGylated CIFN molecules, consisting of the first types of mono-PEGylated CIFN polypeptides characterized by a PEG fragment linked to the terminal amino acid residue of the first CIFN polypeptide, and second types of mono-PEGylated CIFN polypeptides, characterized by a PEG fragment linked to the first lys the remainder of the second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different. The specified composition may also include at least one additional type of molecules of mono-PEGylated CIFN polypeptides that differ in the PEG fragment associated with the lysine residue of the CIFN polypeptide, where the location of the binding site for each additional type of mono-PEGylated CIFN polypeptide does not coincide with the position of the binding site for any other species. In all species in this example, the PEG moiety is a linear moiety having an average molecular weight of about 30 kDa.

Each of the above populations of mono-PEGylated CIFN molecules consists of the first types of mono-PEGylated CIFN polypeptides differing in the PEG fragment associated with the terminal amino acid residue of the first CIFN polypeptide, and the second types of mono-PEGylated CIFN polypeptides molecules differing in the PEG fragment linked to the first protruding surface a second CIFN polypeptide, wherein the first and second CIFN polypeptides are the same or different. The specified composition may also include at least one additional type of molecules of mono-PEGylated CIFN polypeptides, characterized by a PEG fragment associated with a protruding lysine residue of the CIFN polypeptide, where the location of the binding site for each additional type of mono-PEGylated CIFN polypeptide does not coincide with the position of the binding site in any other kind of. In all species in this example, the PEG moiety is a linear moiety having an average molecular weight of about 30 kDa.

As another example, said composition includes a population of mono-PEGylated CIFN molecules consisting of the first types of mono-PEGylated CIFN polypeptides characterized by a PEG fragment linked to the terminal amino acid residue of the first CIFN polypeptide, and the second types of mono-PEGylated CIFN polypeptides molecules differing in the PEG fragment associated with the first a lysine residue selected from 1ue ^{31, 50} 1ue, 1ue ⁷¹ 1ue ⁸⁴ 1ue ¹²¹ 1ue ¹²² 1ue ^{134, 135} and 1ue 1ue ¹⁶⁵ KIFN second polypeptide, wherein the first and second polypeptides KI H are the same or different. The composition may also include a third type of molecule.

- 57 012389 mono-PEGylated CIFN polypeptides characterized by a PEG fragment linked to a second lysine residue selected from 1 § ³¹ , 1 § ⁵⁰ , 1 § ⁷¹ , 1 ⁸⁴ , 1 ¹²¹ , 1 8 ¹²² , 1 ¹³⁴ , 1 ^{135 135} and 1y ¹⁶⁵ CIFN of the third CIFN polypeptide, where the third CIFN polypeptide is the same or different from the first and second CIFN polypeptide, where the second lysine residue is located at the amino acid sequence of the third CIFN polypeptide, which is not the same as the position of the first lysine residue of the second amino acid sequence of the KIFN polypeptide. The composition may also include at least one additional type of mono-PEGylated CIFN polypeptide molecules characterized by a PEG fragment associated with one of 1 § ³¹ , 1 § ⁵⁰ , 1 8 ⁷¹ , 1 8 ⁸⁴ , 1 ¹²¹ , 1 ¹²² , 1 ¹³⁴ , 1y§ ¹³⁵ and 1y§ ¹⁶⁵ , where the location of the binding site for each additional type of mono-PEGylated CIFN polypeptide does not coincide with the position of the connecting area for any other species. In all species in this example, the PEG moiety is a linear moiety having an average molecular weight of about 30 kDa.

As another example, said composition includes a population of mono-PEGylated CIFN molecules consisting of the first types of mono-PEGylated CIFN polypeptides characterized by a PEG fragment linked to the термина-terminal amino acid residue of the first CIFN polypeptide, and the second types of monoPEGylated CIFN polypeptides that differ in the PEG fragment the first lysine residue selected from 1x ¹²¹ . 1 §§ ¹³⁴ , 1 § ¹³⁵ and 1 § ^{165 of the} second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different. Said composition may also include a third type of mono-PEGylated CIFN polypeptide molecules characterized by a PEG fragment linked to a second lysine residue selected from 1U8 ¹²¹ , 1U§ ¹³⁴ , 1U§ ³⁵ and 1U§ ¹⁶⁵ CIFN of the third CIFN polypeptide, where the third CIFN polypeptide is the same or different from one of the first and second CIFN polypeptide, where the second lysine residue is located at the position of the amino acid sequence of the third CIFN polypeptide, which is not the same as the position of the first amino acid lysine residue slotnoy KIFN second polypeptide sequence. The specified composition may also include at least one additional type of molecules of mono-PEGylated CIFN polypeptides characterized by a PEG fragment associated with one of 1U8 ¹²¹ , 1U§ ¹³⁴ , 1U§ ¹³⁵ and 1U§ ¹⁶⁵ , where the location of the binding site for each additional type of mono-PEGylated CIFN polypeptide does not coincide with the position of the binder in any other species. In all species in this example, the PEG moiety is a linear moiety having an average molecular weight of about 30 kDa.

As another non-limiting example, this composition includes a population of mono-PEGylated CIFN molecules consisting of the first types of mono-PEGylated CIFN polypeptides characterized by a PEG fragment linked to the first lysine residue of the first CIFN polypeptide and the second types of molecules of mono-PEGylated CIFN polypeptide that differ in PEG with a second lysine residue of the second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different and where the first lysine residue is in the position of the amino acid sequence of the first CIFN polypeptide, which does not coincide with the position of the second lysine residue in the amino acid sequence of the second CIFN polypeptide. The specified composition may also include at least one additional type of molecules of mono-PEGylated CIFN polypeptides that differ in the PEG fragment associated with the lysine residue of the CIFN polypeptide, where the location of the binding site for each additional type of mono-PEGylated CIFN polypeptide does not coincide with the position of the binding site for any other species. In all species in this example, the PEG moiety is a linear moiety having an average molecular weight of about 30 kDa.

As another non-limiting example, this composition includes a population of mono-PEGylated CIFN molecules consisting of the first types of mono-PEGylated CIFN polypeptides characterized by a PEG fragment linked to the first lysine residue selected from 1 § ³¹ , 1 Cl ⁵⁰ , 1 Cl ⁷¹ , 1 Cl ⁸⁴ , 1y ¹²¹ , 1y ¹²² , 1y ¹³⁴ , 1y ¹³⁵ and 1y ^{165 of the} first CIFN polypeptide, and of the second types of mono-PEGylated CIFN polypeptides, characterized by a PEG fragment associated with a second lysine residue selected from 1y ³¹ , 1y§ ⁵⁰ , 1у8 ⁷¹ , 1у§ ⁸⁴ , 1u8 ¹²¹ , 1u§ ¹²² , 1u8 ¹³⁴ , 1u§ ¹³⁵ and 1u§ ^{165 of the} second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different and where the second lysine residue is in the position of the amino acid sequence of the second CIFN polypeptide, which does not coincide with the position the first lysine residue in the amino acid sequence of the first CIFN polypeptide. The specified composition may also include at least one additional type of molecules of mono-PEGylated CIFN polypeptides characterized by a PEG fragment associated with one of 1U8 ³¹ , 1U ⁵⁰ , 1U ⁷¹ , 1U ⁸⁴ , 1U8 ¹²¹ , 1U ¹²² , 1U8 ¹³⁴ , 1UZ ¹³⁵ and 1 § ¹⁶⁵ , where the location of the binder site for each additional type of monoPEGylated KIFN polypeptide does not coincide with the position of the binder site for any other species. In all species in this example, the PEG moiety is a linear moiety having an average molecular weight of about 30 kDa.

As another non-limiting example of the claims, this composition includes a population of mono-PEGylated CIFN molecules, consisting of the first types of mono-PEGi molecules

58 012389 liquefied CIFN polypeptides characterized by a PEG fragment linked to the first lysine residue selected from 1 ¹²¹ , 1 ¹³⁴ , 1 ¹³⁵ and 1 ^{165 165 of the} first CIF polypeptide, and second types of mono-PEGylated CIF polypeptides, characterized by a PEG fragment associated with the second lysine residue selected from 1uk ¹²¹ 1uk ^{134, 135} and 1uk 1uk ¹⁶⁵ KIFN second polypeptide, wherein the first and second polypeptides KIFN are identical or different and wherein second lysine residue in position of the amino acid sequence of the second polyp ptida KIFN which does not coincide with the position of the first lysine residue in the amino acid sequence of the first polypeptide KIFN. The specified composition may also include at least one additional type of molecules of mono-PEGylated CIFN polypeptides, characterized by a PEG fragment associated with one of 1uk ¹²¹ , 1uk ¹³⁴ , 1uk ¹³⁵ and 1uk ¹⁶⁵ , where the location of the binding site for each additional type of mono-PEGylated KIFN polypeptide does not coincide with the position of the binder in any other species. In all species in this example, the PEG moiety is a linear moiety having an average molecular weight of about 30 kDa.

As another non-limiting example, this composition includes a population of mono-PEGylated CIFN molecules consisting of the first types of mono-PEGylated CIFN polypeptides, characterized by a PEG fragment associated with the first lysine residue protruding on the surface of the first CIFN polypeptide, and the second types of molecules of mono-PEGylated CIFN polypeptides, different from CIFF polypeptides a fragment associated with the second protruding on the surface of the lysine residue of the second CIFN polypeptide, where the first and second poly the CIFN peptides are the same or different and where the first lysine residue is in the position of the amino acid sequence of the first CIFN polypeptide, which does not coincide with the position of the second lysine residue in the amino acid sequence of the second CIFN polypeptide. The specified composition may also include at least one additional type of molecules of mono-PEGylated CIFN polypeptides, characterized by a PEG fragment associated with a protruding lysine residue of the CIFN polypeptide, where the location of the binding site for each additional type of mono-PEGylated CIFN polypeptide does not coincide with the position of the binding site in any other kind of. In all species in this example, the PEG moiety is a linear moiety having an average molecular weight of about 30 kDa.

In connection with the above populations of mono-PEGylated CIFN molecules, the invention also includes variants when the molecules in each such population include a CIFN polypeptide selected from interferon-alpha-com, interferon-alpha-cop ₂ and interferon-alpha-cop ₃ .

In some embodiments, a product is defined that is produced by reacting a CIFN polypeptide with α-methoxy, ω-propionylpoly (ethylene glycol) succinimidyl ester (t-PEG-edge), which is linear and has a molecular weight of about 30 kDa, where the reactants are initially taken in a molar ratio of from 1: 1 to 1: 5 KIFN: t-PEG-kra and where the reaction is carried out at a pH of from 7 to 9, followed by recovery of the mono-PEGylated reaction product. In one embodiment of the invention, the reactants are initially present in a molar ratio of 1: 3 KIFN: t-PEG-edge and the reaction is carried out at a pH of about 8. In other embodiments of the invention, where the product is formed according to the scaling procedure required for toxicological and clinical studies, the reactants take in a molar ratio of 1: 2 KIFN: t-PEGC and the reaction is carried out at a pH of about 8.0.

In connection with the above populations of mono-PEGylated CIFN molecules, the invention also includes variants wherein the CIFN reactant is selected from interferon-alpha-co1, interferon-alpha-co2 and interferon-alpha-co3.

IFN-β.

The term interferon beta ("IFN-β") includes IFN-β polypeptides, which are naturally occurring polypeptides; non-natural origin and analogues of IFN-β polypeptides of natural and non-natural origin, which retain the antiviral activity of related IFN-β polypeptides of natural and non-natural origin.

Any of a variety of beta interferons can be delivered by the continuous delivery method of the present invention. Suitable beta interferons include, but are not limited to, IFN-β of natural origin; IFNph-1a, for example Auopeh® (Wüdep, Sch.), And Keb® (8egopo, 8A); IFNph-1b (Be1acegop®; Veg1ex) and the like.

IFN-β forms may include Ν-protected species, where the Ν-terminal amino acid is acylated by acyl groups such as formyl group, acetyl group, malonyl group, and the like. Consensus IFN-β is also suitable.

IFN-β polypeptides can be obtained by known methods. DNA sequences encoding IFN-β can be synthesized using standard methods. In many embodiments, IFN-β polypeptides are expression products of the obtained DNA sequences transformed or transfected into bacterial host cells, for example E.co11, or eukaryotic host cells (e.g. yeast, mammalian cells, such

- 59 012389 as ί, ΉΘ cells, etc.). In these embodiments, IFN-β is a recombinant IFN-β. When the host cell is a bacterial host cell, IFN-β is modified by the incorporation of terminal methionine.

It is understood that the IFN-β described herein may include one or more modified amino acid residues, for example, by glycosylation, chemical modifications, and the like.

IFN-τ.

The term interferon-tau includes IFN-τ polypeptides, which are polypeptides of natural origin; non-natural origin and analogues of IFN-τ polypeptides of natural and non-natural origin, which retain the antiviral activity of related IFN-τ polypeptides of natural and non-natural origin.

Suitable tau interferons include, but are not limited to, IFN-τ of natural origin; TaiTegop® (Rerdep Comp.) And the like.

IFN-τ may include an amino acid sequence as set forth in any one of the SepWap Catalog No. P15696; P56828; P56832; P56829; P56831; P29429; P28595; P28594; 808072; P08071; P08070; P08053; P56830; P28169; P28172; and P28171. The sequence of any known IFN-τ polypeptide can be changed in various ways known in the art to create targeted changes in the sequence. The variety of the polypeptide will usually be substantially similar to the sequences presented here, that is, it will differ by at least one amino acid and can differ by at least two, but not more than ten amino acids. Sequence changes can be substitutions, insertions, exceptions. Conservative amino acid substituents typically include substituents in the following groups: glycine, alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid; asparagine, glutamine; serine, threonine; lysine, arginine or phenylalanine, tyrosine.

Modifications of interest that may or may not alter the primary amino acid sequence include chemical transformation of the polypeptides, for example acetylation or carboxylation; changes in the amino acid sequence that introduce or exclude glycosylation sites; changes in the amino acid sequence that make the protein susceptible to pegylation, etc. Also include glycosylation modifications, for example, those performed by modifying glycosylation patterns of a polypeptide during its synthesis and processing, or further processing steps, for example, exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylation or deglycosylation enzymes. Also include sequences that have phosphorylated amino acid residues, for example, phosphotyrosine, phosphoserine or phosphotreonine.

IFN-τ forms may include N-protected species, where the terminal amino acid is acylated with acyl groups such as formyl group, acetyl group, malonyl group, etc. Consensus IFN-τ is also suitable.

IFN-τ polypeptides can be obtained by known methods. DNA sequences encoding IFN-τ can be synthesized using standard methods. In many embodiments, IFN-τ polypeptides are expression products of the obtained DNA sequences transformed or transfected into bacterial host cells, for example E.co11, or eukaryotic host cells (e.g. yeast, mammalian cells, such as CIO cells, etc. .). In these embodiments, the IFN-τ is a recombinant IFN-τ. When the host cell is a bacterial host cell, IFN-τ is modified by the incorporation of terminal methionine.

It is understood that the IFN-τ described herein may include one or more modified amino acid residues, for example by glycosylation, chemical modifications, and the like.

IFN-ω.

The term interferon-omega ("IFN-ω") includes IFN-ω polypeptides, which are polypeptides of natural origin; non-natural origin and analogues of IFN-ω polypeptides of natural and non-natural origin, which retain the antiviral activity of related IFN-ω polypeptides of natural and non-natural origin.

Any known omega-interferon can be delivered by the continuous delivery method of the present invention. Suitable IFN-ω include, but are not limited to, IFN-ω of natural origin; recombinant IFN-ω, for example Vyuteb 510 (VyuMebktek); and the like.

IFN-ω may include an amino acid sequence as set forth in any one of the SepWap Catalog No. 002168 or AAA70091. The sequence of any known IFN-ω polypeptide can be changed in various ways known in the art to create targeted changes in the sequence. The type of polypeptide will usually be substantially similar to the sequences presented here, that is, it will differ by at least one amino acid and may differ by at least two, but not more than ten amino acids. Treason

- 60 012389 sequences may be substitutions, insertions, exclusions. Conservative amino acid substituents typically include substituents in the following groups: glycine, alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid; asparagine, glutamine; serine, threonine; lysine, arginine or phenylalanine, tyrosine.

Modifications of interest that may or may not alter the primary amino acid sequence include chemical transformation of the polypeptides, for example acetylation or carboxylation; changes in the amino acid sequence that introduce or exclude glycosylation sites; changes in the amino acid sequence that make the protein susceptible to pegylation, etc. Also include glycosylation modifications, for example, those performed by modifying glycosylation patterns of a polypeptide during its synthesis and processing, or further processing steps, for example, exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylation or deglycosylation enzymes. Also include sequences that have phosphorylated amino acid residues, for example, phosphotyrosine, phosphoserine or phosphotreonine.

IFN-ω forms may include Ν-protected species, where the Ν-terminal amino acid is acylated by acyl groups such as formyl group, acetyl group, malonyl group, and the like. Consensus IFN-ω is also suitable.

IFN-ω polypeptides can be obtained by known methods. DNA sequences encoding IFN-ω can be synthesized using standard methods. In many embodiments, IFN-ω polypeptides are expression products of the obtained DNA sequences transformed or transfected into bacterial host cells, for example E. coi, or eukaryotic host cells (for example, yeast, mammalian cells, such as CHO cells, etc.) . In these embodiments, the IFN-ω is a recombinant IFN-ω. When the host cell is a bacterial host cell, IFN-ω is modified by the inclusion of a Ν-terminal methionine.

It is understood that the IFN-ω described herein may include one or more modified amino acid residues, for example, by glycosylation, chemical modifications, etc.

Type III interferon receptor agonists.

In any of the above methods, an interferon receptor agonist is, in some embodiments, an type III interferon receptor agonist (for example, a “type III interferon agonist"). Type III interferon agonists include the [I-28b polypeptide; and ^ -28; ·! polypeptide; and GE-29 (interleukin-29) polypeptide; receptor antibodies specific for type III interferon receptors; and any other type III interferon receptor agonist, including non-polypeptide agonists.

^ -28: -1, [B-28b and [I-29 (hereinafter referred to as "type III interferons" or "IFN III") are described in 8 hyperrag4 eG a1. (2003) No. 1ig 4: 63-68. Each polypeptide binds a heterodimeric receptor, consisting of a Yu-Yu (interleukin) β chain receptor and a ^ -283 receptor. 8errag4 eG a1. (2003), supra. The amino acid sequences EE-28a, EE-28b and ^ -29 were found in the SeiVaik catalog No. 742150, No. 742151 and No. 42152, respectively.

The amino acid sequence of IFN type III polypeptide can be changed in various ways known in the art to create targeted changes in the sequence. The variety of the polypeptide will usually be substantially similar to the sequences presented here, that is, it will differ by at least one amino acid and may differ by at least two, but not more than ten amino acids. Sequence changes can be substitutions, insertions, exceptions. Scanning mutations that typically introduce alanine or other residues can be used to identify key amino acids. Specific amino acid substituents of interest include conservative and non-conservative changes. Conservative amino acid substituents typically include substituents in the following groups: glycine, alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid; asparagine, glutamine; serine, threonine; lysine, arginine or phenylalanine, tyrosine.

Modifications of interest that may or may not alter the primary amino acid sequence include chemical transformation of the polypeptides, for example acetylation or carboxylation; changes in the amino acid sequence that introduce or exclude glycosylation sites; changes in the amino acid sequence that make the protein susceptible to pegylation, etc. Also include glycosylation modifications, for example, those performed by modifying glycosylation patterns of a polypeptide during its synthesis and processing, or further processing steps, for example, exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylation or deglycosylation enzymes. Also include sequences that have phosphorylated amino acid residues, for example phosphotyrosine, phosphoserine or phosphotreonine.

- 61 012389

The invention includes polypeptides that have been modified using conventional chemical techniques to improve their resistance to proteolytic degradation, optimize solubility, or make them more suitable as therapeutic agents. For example, the peptide backbone may be cyclized to improve stability (see Epebel et al. (2000) 1. Vu1. Sb. 275: 23783-23789). Analogs that include residues other than naturally occurring L-amino acids, for example L-amino acids or synthetic non-naturally occurring amino acids, can be used. Protein can be conjugated to PEG to improve stability. The polypeptides may be coupled with albumin.

Polypeptides can be prepared by the ίη ugo method using conventional methods known in the art, prepared by recombinant methods, or can be isolated from forced or protein producing cells by nature. The specific sequence and method of preparation is determined by the opportunity, economic benefits, required purity, etc. If desired, various groups can be introduced into the polypeptide during synthesis or expression, which is permissible for binding to other molecules or to the surface. Moreover, cysteines can be used to obtain thioethers, histidines for binding metal-ion complexes, carboxyl groups for the formation of amides or esters, amino groups for the formation of amides, etc.

Type II interferon receptor agonists.

Type II interferon receptor agonists include any naturally occurring or non-naturally occurring type II human interferon receptor ligand that binds and causes signal transduction through the receptor. Type II interferon receptor agonists include naturally-occurring interferons, modified interferons, synthetic interferons, PEG conjugated interferons, fusion proteins comprising interferon and some heterologous protein, mixed interferons; antibodies specific for interferon receptors, non-peptide chemical agonists, and the like.

A specific example of type II interferon receptor agonists is IFN-γ and its variants. Since the present invention illustrates the use of IFN-γ polypeptide, it is easy to understand that any type II interferon receptor agonist can be used in the described method.

Interferon-gamma.

Nucleic acid sequences encoding IFN-γ can be accessed from open databases, for example Peppap, journal publications, etc. Since various mammalian IFN-γ polypeptides are of interest, human protein will usually be used to treat human diseases. The sequence encoding human IFN-γ can be found in Sep. no. X13274; U00543 and ΝΜ000619. Corresponding genomic sequences can be found in Sep. no 100219; M37265 and U00536. See, for example, Sgau e! a1. (1982), Miige 295: 501 (Sep. Nos. X13274) and Krzegegkpes, et al. (1984), 1. B.C. 259: 6790.

IFN-γ-Φ (Asbttipe®; human interferon) is a single chain polypeptide of 140 amino acids. It is produced recombinantly in E. soi and glycosyl groups are removed. Vshbegkpesy! et al. (1984) 1. Vu1. Sb. 259: 6790-6797. Recombinant IFN-γ, as discussed in US patent No. 6497871, is also suitable for use here.

IFN-γ for use in the methods of the invention may be any of the natural IFN-γ, recombinant IFN-γ, and their derivatives having IFN-γ activity, namely, human IFN-γ activity. Human IFN-γ exhibits the antiviral and antiproliferative properties of interferons, as well as various other immunomodulatory activities, as is known in the art. Although IFN-γ is determined by the sequences as described above, the production of protein and proteolytic treatment can result in its technological options. The raw sequence presented by Sgau et al. Above consists of 166 amino acids (aa). Although the recombinant IFN-γ produced in E. soi originally contained 146 amino acids (starting at 20 amino acids), it was subsequently found that natural human IFN-γ is cleaved after residue 23 to produce 143 aa protein or 144 aa if terminal methionine is present as necessary for expression in bacteria. During purification, the finished protein can be further cleaved at the C-terminus after residue 162 (referring to the sequence of Sgau et al.) To obtain a protein of 139 amino acids or 140 amino acids if the starting methionine is present, for example, if required for bacterial expression. The термина-terminal methionine is an artifact encoded by mRNA with a translational “start” AIS signal, which is not processed in the specific case of E. Soi expression. In other microbiological systems or eukaryotic expression systems, methionine can be removed.

In the methods of the invention, any of the natural IFN-γ peptides, variants and modifications thereof, or a combination of one or more peptides can be used. IFN-γ peptides of interest include fragments and can be differently trunked at the carboxyl terminus with respect to the complete sequence. Such fragments continue to show character.

- 62 012389 properties of human gamma-interferon, as long as amino acids from 24 to about 149 are present (numbering of the residues of the untreated polypeptide). External sequences can be replaced by an amino acid sequence following amino acid 155 without loss of activity. See, for example, US patent No. 5690925. Natural IFN-γ fragments include molecules in various ways, extending from amino acid residues 24-150; 24-151, 24-152; 24-153, 24-155 and 24-157. Any of these options and other options known in the prior art and with IFN-γ activity can be used in the presented methods.

The amino acid sequence of the IFN-γ polypeptide can be changed in various ways known in the art to create targeted changes in the sequence. The variety of the polypeptide will usually be substantially similar to the sequences presented here, that is, it will differ by at least one amino acid and may differ by at least two, but not more than ten amino acids. Sequence changes can be substitutions, insertions, exceptions. Scanning mutations that typically introduce alanine or other residues can be used to identify key amino acids. Specific amino acid substituents of interest include conservative and non-conservative changes. Conservative amino acid substituents typically include substituents in the following groups: glycine, alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid; asparagine, glutamine; serine, threonine; lysine, arginine or phenylalanine, tyrosine.

Modifications of interest that may or may not alter the primary amino acid sequence include chemical transformation of the polypeptides, for example acetylation or carboxylation; changes in the amino acid sequence that introduce or exclude glycosylation sites; changes in the amino acid sequence that make the protein susceptible to pegylation, etc. In one embodiment, the invention contemplates the use of IFN-γ variants with one or more non-naturally occurring glycosylation and / or PEGylation sites that are designed to provide glycosyl and / or PEG conjugated transformed polypeptides with reduced serum purification, such as IFN variants -γ polypeptides described in international patent application \ ¥ O 01/36001. Also include glycosylation modifications, for example, those performed by modifying glycosylation patterns of a polypeptide during its synthesis and processing, or further processing steps, for example, exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylation or deglycosylation enzymes. Also include sequences that have phosphorylated amino acid residues, for example phosphotyrosine, phosphoserine or phosphotreonine.

The invention includes polypeptides that have been modified using conventional chemical techniques to improve their resistance to proteolytic degradation, optimize solubility properties, or make them more suitable as therapeutic agents. For example, the main chain of a peptide can be cyclized to improve stability (see Epheg e! A1. (2000) I. Vu1. Sg. 275: 23783-23789). Analogs that include residues other than naturally occurring L-amino acids, for example L-amino acids or synthetic non-naturally occurring amino acids, can be used. Protein can be conjugated to PEG to improve stability. The polypeptides may be coupled with albumin.

Polypeptides can be prepared by the ίη νίΙΐΌ method using conventional methods known in the art, prepared by recombinant methods, or can be isolated from forced or protein producing cells by nature. The specific sequence and method of preparation is determined by the opportunity, economic benefits, required purity, etc. If desired, different groups can be introduced into the polypeptide during synthesis or expression, which is permissible for binding to other molecules or to the surface. Moreover, cysteines can be used to obtain thioethers, histidines for binding metal-ion complexes, carboxyl groups for the formation of amides or esters, amino groups for the formation of amides, etc.

Polypeptides can also be isolated and purified in accordance with conventional recombinant synthesis methods. The lysate can be prepared by gene expression and the lysate is purified using HPLC, size exclusion chromatography, gel electrophoresis, affinity chromatography or other purification methods. Most of the compositions that are used include at least about 20 wt.% The desired product, more usually at least 75 wt.%, Preferably at least 95 wt.% And for therapeutic purposes, usually at least about 99.5 wt.% in relation to pollutants related to the receipt of the product and its purification. Typically, percentages are based on the total protein content.

- 63 012389

Pirfenidone and its analogues.

Pirfenidone (5-methyl-1-phenyl-2- (1H) pyridone) and specific analogues of pirfenidone are described for the treatment of fibrotic conditions. A “fibrotic condition” is what is to be treated by the administration of a compound having antifibrotic activity.

Description of the substituents K _b K ₂ , X.

K ₁ : carbocyclic (saturated and unsaturated), heterocyclic (saturated and unsaturated), alkyls (saturated and unsaturated). Examples include phenyl, benzyl, pyrimidyl, naphthyl, indolyl, pyrrolyl, furyl, thienyl, imidazolyl, cyclohexyl, piperidyl, pyrrolidyl, morpholinyl, cyclohexenyl, butadienyl and the like.

K1 may also include substituents in carbocyclic and heterocyclic moieties with substituents such as halogen, nitro, amino, hydroxyl, alkoxy, carboxyl, cyano, thio, alkyl, aryl, hetroalkyl, heteroaryl, and combinations thereof, for example 4-nitrophenyl, 3-chlorophenyl , 2,5-dinitrophenyl, 4-methoxyphenyl, 5-methylpyrrolyl, 2,5-dichlorocyclohexyl, guanidinylcyclohexinyl and the like.

K2: alkyl, carbocycyl, aryl, heterocyclyl.

Examples include methyl, ethyl, propyl, isopropyl, phenyl, 4-nitrophenyl, thienyl, and the like.

X: may be any number of substituents (1 to 3) in a carbocyclic or heterocyclic ring. Substituents may be the same or different. Substituents include hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, halogen, nitro, carboxyl, hydroxyl, cyano, amino, thio, alkylamino, haloaryl and the like.

Substituents can in turn be substituted by 1-3 substituents from the group consisting of alkyl, aryl, nitro, alkoxy, hydroxyl and halogen. Examples include methyl, 2,3-dimethylphenyl, phenyl, p-tolyl, 4-chlorophenyl, 4-nitrophenyl, 2,5-dichlorophenyl, furyl, thienyl, and the like.

Specific examples include the compounds listed in the table. one.

- 64 012389

Table 1

PA PV

5-methyl-1 - (2 ’-pyridyl) -2- (1 N) pyridine 6-methyl-1-phenyl-3- (1 N) pyridone 6-methyl-1-phenyl l-2- (1 N) pyridone 5-methyl-1-p-toly l-2- (1 N) pyridone 5-methyl-3-phenyl-1 - (2’-thienyl) -2- (1H) pyridone 5-methyl-1 - (2 ’-naphthyl) -3 - (1 N) pyridone 5-methyl-1-p-tolyl-2- (1 N) pyridone 5-methyl-1-phenyl-3 - (1 N) pyridone 5-methyl-1 - (G-naphthyl) -2- (1 N) pyridone 5-methyl-1 - (2 ’-quinolyl) -3 - (1 N) he pyrid 5-ethyl-1-phenyl-2- (1 N) pyridone 5-ethyl-1-phenyl-3 - (1 H) pyridone 5-methyl-1 - (5 ’-quino lyl) -2- (1 N) pyridone 5-methyl-1 - (4 ’-methoxyphenyl) -3 (1H) pyridone 5-methyl-1 - (4 ’-quinolyl) -2- (1 N) pyridone 5-methyl-1 - (3 ’-pyridyl) -3 - (1 N) pyridone 5-methyl-1 - (4 ’-pyridyl) -2- (1 N) pyridone 5-methyl-1 - (2 ⁵ -thienyl) -3- (1 N) pyridone 5-methyl-1-phenyl-2- (1 N) pyridone 5-methyl-1 - (2 ’-pyridyl) -3 - (1 N) pyridone 5-methyl-1 - (4 ’-methoxyphenyl) -2- (1H) pyridone 5-methyl-1 - (2 ’-quinolyl) -3 - (1 N) he pyrid 1-phenyl-2- (1H) pyridone 1-phenyl-2- (1H) pyridone 1,3-diphenyl-2- (1 N) pyridone 1- (2’-furyl) -5-methyl-2- (1H) pyridone 1,3-diphenyl-5-methyl-2- (1 N) pyridone 1 - (4 ’-chlorophenyl) - 5-methyl-3 - (1 N) pyridine 5-methyl-1 - (3 ’-trifluoromethylphenyl) -2- (1H) pyridone 3-ethyl-1-phenyl-2- (1 N) pyridone 5-methyl-1 - (3 ’-pyridyl) -2- (1 N) pyridone 5-methyl-1 - (3-nitrophenyl) -2- (1 N) pyridone 3- (4 ’-chlorophenyl) -5-methyl-1-phenyl-2 - (1H) pyridone 5-methyl-1 - (2 ’-thienyl) -2- (1 N) pyridone 5-methyl-1 - (2 ’-thiazolyl) -2- (1 N) pyridone 3,6-dimethyl-1-phenyl-2- (1 N) pyridone 1 - (4 ’-chlorophenyl) -5-methyl-2- (1 N) pyridone 1 - (2’-imidazolyl) -5-methyl-2- (1H) pyridone 1 - (4 ’-nitrophenyl) -2- (1 N) pyridone 1 - (2 ’-furyl) -5-methyl-2- (1 N) pyridone 1-phenyl-3- (4 ’-chlorophenyl) -2- (1 N) pyridine

U.S. Patent Nos. 3,974,281; 3,839,346; 4,042,699; 4,052,509; 5,310,562; 5,518,729; 5716632 and 6090822 describe methods for the synthesis and forms of pirfenidone and specific analogues of pirfenidone in pharmaceutical compositions suitable for use in the methods of the invention.

Thymosin-α.

Thymosin-α (/ ac1axm ™; available from 8c1C1ope Ryagtasei11ca18, Yc., 8ap Ma1eo, CΑ) is a synthetic form of thymosin-a1, a hormone found in nature in the blood circulation and produced by the thymus gland. Thymosin-α increases the activity of T cells and the activity of natural cell killers. 2a4ax1p in the subcutaneous injection form is a purified sterile lyophilized form of chemically synthesized thymosin α1 identical to human thymosin α1. Thymosin-A1 is an acetylated polypeptide having the following sequence: Ac-Zeg-Azr-Ak-Ak ^ abAzr-Tyg-Zeg-Zeg-OY-Ie-Tyg-Tyr-Luz-Azr-Lye-Luz- OY-LZ-LYZ-OYV-1-Va1-Θ1i-Θ1i-Α1a-Θ1i-Α8η-ΟΗ and having a molecular weight of 3.108 Da. The lyophilized form contains 1.6 mg of synthetic thymosin-α, 50 mg of mannitol and phosphate buffer to adjust the pH to 6.8.

Ribavirin

Ribavirin, 1-3-B-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, is a nucleoside analogue available from Κ Ν Ь Ь Ь Ь аг та та та се се Н Н Н,, 1 ps., Co1a Mesa, CaEG. and described in the Megsk Catalog, compound No. 8199, 11th ed. Its manufacture and dosage forms are described in US Pat. No. 4,211,771. The invention also contemplates the use of ribavirin derivatives (see, for example, US Pat. No. 6,277,830). Ribavirin can be administered orally in the form of a capsule or tablet. Of course, other types of ribavirin administration, as far as they are available, are considered, such as nasal spray, transdermal administration, suppositories, long-acting dosage form, etc.

Any form of administration will work as long as the dosage forms themselves are delivered without destroying the active ingredient.

Ribavirin is usually administered in an amount in the range of from 400 to about 1200 mg, from about 600 to 1000 mg, or from 700 to 900 mg per day. In some embodiments, ribavirin is administered throughout the course of the Ν83 inhibitory therapy.

Levovirin.

Levovirin is the B-enantiomer of ribavirin and exhibits properties that improve the TM immune response over the T112 immune response. Levovirin is produced by Κ Ν Ь аг та та се се.

Levovirin has the following structure:

Viramidine.

Viramidine is a 3-carboxamidine derivative of ribavirin and acts as a prodrug of ribavirin. It is effectively converted to ribavirin by adenosine deaminase.

Viramidine has the following structure:

Nucleoside analogues.

Nucleoside analogues that are suitable for use in the combination therapy of the invention include, but are not limited to, ribavirin, levovirin, viramidine, isatoribine, B-ribofuranosyl nucleoside, as described in US Pat. No. 5,559,101 and described by Formula I of US Pat. No. 5,559,101 (e.g., 1 Z-B-ribofuranosyl uracil, 1-Z-B-ribofuranosyl-5-fluorouracil, 1-Z-B-ribofuranosylcytosine, 9-Z-B-ribofuranosyladenine, 9-Z-B-ribofuranosylhypoxanthin,

9-b-ribofuranosylguanine, 9-3-B-ribofuranosyl-6-thioguanine, 2-amino-α - ^ - ribofuran [1 ', 2': 4,5] oxazoline, Ο ² , Ο ² -anhydro 1-α - ^ - ribofuranosyl-uracil, 1-α - ^ - ribofuranosyl-uracil, 1- (2,3,5-tri-Obenzoyl-α-ribofuranosyl) -4-thiouracil, 1-α-B-ribofuranosylcytosine, 1 -α- ^ -ribofuranosyl-4thiouracil, 1-α - ^ - ribofuranosyl-5-fluorouracil, 2-amino-3-B-aribinofurano [1 ', 2': 4,5] oxazoline, O ² , O ² anhydro-3-L -arabinofuranosyl uracil, 2'-deoxy-3-B-uridine, 3 ', 5'-di-O-benzoyl-2'-deoxy-4-thio-3-Buridine, 2'-deoxy-b-cytidine, 2'-deoxy-β-Ε-4-thiouridine, 2'-deoxy-3-B-thymidine, 2'-deoxy-3-B-5 fluoruridine, 2 ', 3'-dideoxy-3-L uridine, 2'-deoxy-3-B-5-fluorouridine and 2'-deoxy-3-B-inosine); the compound as disclosed in US patent No. 6423695 and is covered by formula I of US patent No. 6423695; the compound as disclosed in US patent publication No. 2002/0058635 and is covered by formula 1 of US patent publication No. 2002/0058635; nucleoside analogue as disclosed in S0 01/90121 A2

- 66 012389 (Yeshh); a nucleoside analog as disclosed in AO 02/069903 A2 (Vusguk! Ryagtaseijsak Ys); a nucleoside analog as disclosed in AO 02/057287 A2 or AO 02/057425 A2 (both Megsk / Lk) and the like.

Antagonists of tumor necrosis factor (TNF).

In some embodiments, the method of the invention comprises administering an effective amount of a Ν83 inhibitor and an effective amount of a tumor necrosis factor antagonist α (TNF-α). Suitable antagonists for use herein include agents that reduce the synthesis of TNF-α, agents that block or inhibit the binding of TNF-α to TNF-α receptors (TNF-P), and agents that block the mediated TNF-P signal transduction. At least, unless clearly indicated otherwise, each reference to a “TNF-α antagonist” or “TNF-antagonist” will mean a TNF-α antagonist other than pirfenidone or its analogues.

As used herein, the terms “TNF-R receptor polypeptide” and “TNF-R polypeptide” refer to polypeptides derived from TNF-R (from any species) that are capable of binding TNF-R. Two different cell surfaces of TNF-R are described: type II TNF-R (or p75 TNF-R or TNF-RP) and type I TNF-R (or p55 TNF-R or TNF-RC Full-length mature human p75 TNF-R represents a glycoprotein having a molecular weight of approximately 75-80 kDa.

The full-length mature human p75 TNF-P is a glycoprotein having a molecular weight of approximately 55-60 kDa. Typical TNF-P polypeptides are derived from TNF-P type I and / or TNF-P type II. Soluble TNF-R includes p75 TNF-P polypeptide; fusion of p75 TNF-P with heterologous incorporating components, for example the Pc region of immunoglobulin.

TNF-R polypeptides may be intact TNF-R or a suitable TNF-R fragment. US Pat. No. 5,605,690 provides examples of TNF-R polypeptides, including soluble TNF-R polypeptides suitable for use in the present invention. In many embodiments, the TNF-R polypeptide comprises the extracellular domain of TNF-R. In some embodiments, the TNF-R polypeptide is a hybrid polypeptide comprising the extracellular domain of TNF-R linked to the constant domain of an immunoglobulin molecule. In other embodiments, the TNF-P polypeptide is a hybrid polypeptide comprising the extracellular domain of p75 TNF-P linked to the constant domain C61 of the molecule. In some embodiments, when administration to a human is contemplated, some C used for fusion proteins is human, such as human tdO1.

Monovalent and multivalent forms of TNF-R polypeptides can be used in the present invention. Multivalent forms of TNF-R polypeptides have more than one TNF binding site. In some embodiments, TNF-R is a bivalent or dimeric form of TNF-R. For example, as described in US Pat. No. 5,605,690 and in Moyeg et al., 1993, 1. Tttipoc, 151: 1548-1561, a chimeric antibody polypeptide with TNF-R extracellular domains for the variable domains of one or both immunoglobulin heavy or light chains will provide TNF-A P polypeptide for the present invention. Typically, when such a chimeric TNF-R: antibody polypeptide is produced by cells, it forms bivalent molecules through disulfide bridges between the immunoglobulin domains. Such a chimeric TNF-P: antibody polypeptide is referred to as TNF-P: Pc.

In one embodiment, the method of the invention comprises administering an effective amount of soluble TNF-P ΕΝΒΡΕΕ®. ΕΝΒΡΕΕ® is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kDa (p75) TNF-P bound to the Pc portion of human TDC1. The PC component EIBBE® contains the CH2 domain, the CH3 domain and the hinge region, but not the CH1 domain of ΕΝΒΡΕΕ® is produced in the mammalian Chinese hamster ovary expression system (CHO). It consists of 934 amino acids and has a molecular weight of approximately 150 kDa. 8th et al. (1990) 8c1epse 248: 1019-1023; Moyeg et al. (1993), Σ. ] ttypo1. 151: 1548-1561; US patent No. 5395760 and US patent No. 5605690.

Monoclonal antibodies that bind TNF-α are also suitable for use. Monoclonal antibodies include humanized murine monoclonal antibodies; chimeric antibodies; monoclonal antibodies that are at least about 80%, at least 90%, at least 95% or 100% human in amino acid sequence and the like. See, for example, AO 90/10077; AO 90/04036 and AO 92/02190. Suitable monoclonal antibodies include antibody fragments such as Ρν, P (aB ') ₂ and PaB; synthetic antibodies; artificial antibodies; phage display antibodies and the like.

Examples of suitable monoclonal antibodies include TrhhmbA (KEMGSAPE®, CeOsog) and AynthIb (IMKA ™, ABOi). KEMGSAPE® is a chimeric monoclonal anti-TNF-α that comprises approximately 25% of the murine amino acid sequence and about 75% of the human amino acid sequence. KEMGSAOE® contains variable regions of a murine monoclonal anti-TNF-α antibody coupled to a constant region of human ^ 61. Yeshoy et al. (1993), AgYpik Kieit. 36: 1681-1690; Yeshoy et al. (1994), yaps! 344: 1105-1110; Wai, et al. (1999), Ca81noe1od 116: 22-28. IIMKA ™ is a human monoclo

- 67 012389 full length native antibody that has been identified using phage imaging technology. P1a8s1k (2003), 1. At. Ryagt. Azkos. 43: 327-328.

Stress-activated protein kinase inhibitors (8APK) are also included in the term “TNF antagonist”, and thus are suitable for use in the method described herein. 8APK inhibitors are known in the art and include, but are not limited to, 2-alkylimidazoles described in US Pat. No. 6,548,520; 1,4,5-substituted imidazole compounds as described in US Pat. No. 6,489,325; 1,4,5-substituted imidazole compounds as described in US Pat. No. 6,569,871; heteroarylaminophenyl ketones, which are described in published patent application US No. 2003/0073832; pyridylimidazole compounds that are disclosed in US Pat. No. 6,288,089 and heteroarylaminobenzophenones that are disclosed in US Pat. No. 6,432,962. Also of interest are compounds described in US patent application No. 2003/0149041 and US patent No. 6214854. Stress-activated protein kinase is a member of the mitogen-activated protein kinase family that are activated in response to stress irritation. 8APKs include, but are not limited to, p38 (Le et al. (1994), No. 1 Schrö 372: 739) and a c-linked terminal kinase (1K).

Methods for assessing the activity of TNF antagonists are known in the art and are exemplified here. For example, the activity of a TNF antagonist can be assessed using studies of cellular competitive binding. In such a study, TNF labeled with a radioactive isotope is mixed with sequentially diluted TNF antagonists and cells exhibiting binding to the TNF-R cell membrane. Part of the suspension is centrifuged to separate free and bound TNF and the amount of radioactivity in the free and bound fractions is determined. TNF antagonist activity is assessed by inhibition of TNF binding to cells in the presence of a TNF antagonist.

As another example, TNFα antagonists can be tested for their ability to inhibit TNFα νίΡΌ activity in bioassays using cells susceptible to TNFα cytotoxic activity as target cells. In such a study, target cells grown with TNF are treated with various amounts of TNF antagonist and then examined for cytolysis. The activity of TNF antagonists is assessed by a decrease in TNF-induced cytolysis of target cells in the presence of TNF antagonists.

Inhibitors Zh5V.

In some embodiments, the invention provides a method comprising administering an effective amount of an N83 inhibitor of the invention and an effective amount of an HCV non-structural protein inhibitor-5 (N85; RNA-dependent RNA polymerase) to a patient in need thereof. Suitable No. 5B inhibitors include, but are not limited to, the compounds described in US Pat. No. 6,479,508 (Voeyppdeg-Gdedeht); a compound as described in any of the international patent applications PCT / CA02 / 01127, PCT / CA02 / 01128 and PCT / CA02 / 01129, all filed June 18, 2002. Voenppdeg GpdeSche1t; the compound described in US patent No. 6440985 ^ yoRNagta); the compound described in MO 01/47883, for example TGK-003 (1arap Tobasso); dinucleotide analogues, as described in Ζίκοΐβ et al. (2003). Adepp SNetoSheg. 47: 2674-2681; benzothiadiazine compounds, as described in ENapack et al. (2002), 1. VI1 SNet. 277 (41) 38322-7; W5B inhibitor as described in MO 02/100846 A1 or MO 02/100851 A2 (both 8Hr); Zh5B inhibitor, as described in MO 01/85172 A1 or MO 02/098424 A1 (both C1axo 8thyK1te); W5B inhibitor, as described in MO 00/06529 or MO 02/06246 A1 (both Megsk); G5B inhibitor, as described in MO 03/000254 (1arab Tobasso), G5B inhibitor, as described in EP 1256628 A2 (Adoigop); 1TK-002 (1arap Tobasso); TTK-109 (1arap Tobasso), etc.

In many embodiments, N85 inhibitors that are specific N85 inhibitors are of interest, for example, N85 inhibitors that inhibit N85 RNA-dependent RNA polymerase and lack a significant inhibitory effect on other RNA-dependent RNA polymerase and DNA-dependent RNA polymerase.

Additional antivirus agents.

Additional antiviral therapeutic agents that can be administered in combination with the N83 inhibitory compounds of the invention include, but are not limited to, inosine monophosphate dehydrogenase inhibitors (1MREN); ribozymes that are complementary to viral nucleotide sequences; antisense RNA inhibitors, etc.

Inhibitors 1MREN.

GMRON inhibitors that are suitable for use in the combination therapy of the invention include, but are not limited to, νΧ-497 ((8) -№3- [3- (3-methoxy-4-oxazole-5ylphenyl) ureido] benzylcarbamic acid tetrahydrofuran- 3-yl ether); Vе ^ ιеx РНагтасеиОсаЕ; see, for example, Magkapa et al. (2000), Apytugo. Adep18 is NOTHING. 44: 859-866; ribavirin; levovirin (H1barkagt; see, for example, Ma1§op (2002), Sigg Ort G ^ eShd Aegid5 3 (5) 680-3); Viramidine (YALarkagt), etc.

- 68 012389

Ribozymes and antisense compounds.

Ribozymes and antisense antiviral agents that are suitable for use in combination therapy include, but are not limited to, Ζ8Ζ8 14803 (Ζ8Ζ8 RyagtaseiBsa1k / E1ap SogrogogaBop; see, for example, Abyege11 (2001), Sgt Ort νпνекί ^ 2 Эгид. 1523-9); Ίерίаζутте ™, etc.

In some embodiments, an additional antiviral agent is administered throughout the course of treatment with N83 inhibitory compounds. In other embodiments, an additional antiviral agent is administered over a period of time that overlaps with the treatment with N83 inhibitor compounds, for example, treatment with an additional antiviral agent can begin before treatment with N83 inhibitor compounds and ends before treatment with N83 inhibitor compounds; treatment with an additional antiviral agent can begin after the start of treatment with N83 inhibitor compounds and end after treatment with N83 inhibitor compounds; treatment with an additional antiviral agent can begin after treatment with N83 inhibitor compounds begins and ends before treatment with N83 inhibitor compounds or treatment with an additional antiviral agent can begin before treatment with N83 inhibitor compounds and ends after treatment with N83 inhibitor compounds.

Doses, dosage forms and routes of administration.

In the method of the invention, the active agent (s) (for example, compounds of formula I, and optionally with one or more additional antiviral agents) can be administered to a patient using any suitable means capable of producing the desired therapeutic effect. Moreover, the agent can be included in various dosage forms for therapeutic administration. More specifically, the agents of the present invention can be formulated in combination with appropriate pharmaceutically acceptable carriers or diluents, and can be formulated in solid, semi-solid liquid or gaseous forms, such as tablets, capsules, powder, granules, ointments, solutions , suppositories, injections, inhalers and aerosols.

Dosage Forms.

The active agent (s) discussed above can be formulated using well-known reagents and methods. The compositions are presented in combination with pharmaceutically acceptable excipients. A wide variety of pharmaceutically acceptable excipients are known in the art and need not be discussed in detail here. Pharmaceutically acceptable excipients are widely described in a variety of publications, for example, A. Seppago (2000), KettUyp: Thie 8s1epse apb PrgasBse oT Ryagtasu, 20th ed., Irr1pso11, A1Shatk, &APtc; RyagtaseiBsa1 Eokade Yogtk apb Aegid OeBueguu 8uk1etk (1999), ShS. Apke1 et al., Ebk., 7th ed., IrrsoI A1Shatk &APktk; and Η б б Ь о Т Т Р аг та се се 1 1 1 1 с с с (2000), Λ.Η. Klbie et al., Ebk., 3rd ed. ATEG. RPhtaseiBsa1 Akkos.

Pharmaceutically acceptable excipients, such as excipients, carriers or diluents, are readily available for public use. Moreover, pharmaceutically acceptable excipients, such as p-regulating and buffering agents, concentration-regulating agents, stabilizers, humectants, etc., are readily available for public use.

In some embodiments of the invention, the agent is introduced into the composition of the aqueous buffer. Suitable aqueous buffers include, but are not limited to, acetate, succinate, citrate, and phosphate buffers, varying in strength from 5 to 100 mM. In some embodiments, the aqueous buffer includes reagents that provide isotonicity of the solution. Such reagents include, but are not limited to, sodium chloride and sugars such as mannitol, dextrose, sucrose, and the like. In some embodiments, the aqueous buffer also includes non-ionic surfactants, such as Polysorbate 20 or 80. Dosage forms may also include preservatives. Suitable preservatives include, but are not limited to, benzyl alcohol, phenol, chlorobutanol, benzaalkonium chloride, and the like. In many cases, the forms are stored at a temperature of about 4 ° C. The forms can also be lyophilized, in which case they usually include cryoprotective substances such as sucrose, trehalose, lactose, maltose, mannitol and the like. Lyophilized forms can be stored for a long period of time even at room temperature.

Essentially, the administration of agents can be improved in various ways, including oral, trans buccal, rectal, parenteral, intraperitoneal, intradermal, subcutaneous, intramuscular, transdermal, intratracheal, etc. method of administration. In many embodiments, administration is by bolus injection, for example, subcutaneous bolus injection, intramuscular bolus injection, and the like.

The pharmaceutical compositions of the invention can be administered orally, parenterally or via an implantable container. Oral administration or administration by injection is preferred.

Subcutaneous administration of the pharmaceutical composition is carried out using standard methods and devices, for example, a needle and syringe or a portal delivery system for subcutaneous injection and the like, see, for example, US Pat. Nos. 3,547,119; 4,755,173; 4,531,937; 4311137 and 6017328. The combination of a subcutaneous injection port and a device for administering the pharmaceutical composition of the invention to a patient

- 69 012389 through the specified port is referred to here as the "system for portal delivery of subcutaneous injection." In many embodiments, subcutaneous administration is improved by bolus delivery with a needle and syringe.

In pharmaceutical dosage forms, the agents may be administered in the form of their pharmaceutically acceptable salt, or they may also be used alone or in appropriate combination with other pharmaceutically active compounds. The following methods and excipients are illustrative and do not limit the scope of the claims.

For oral forms, the agents can be used individually or in combination with appropriate additives to obtain tablets, powders, granules or capsules, for example with conventional additives such as lactose, mannitol, corn starch; with binders such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch or gelatin; with disintegrants (breakers) such as corn starch, potato starch or sodium carboxymethyl cellulose; with lubricants such as talc or magnesium stearate; or if desired with diluents, buffering agents, moisturizers, preservatives and flavorings.

Agents can be formulated for injection by dissolving, suspending or emulsifying them in an aqueous or non-aqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol, and, if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.

Moreover, agents can be introduced into suppositories by mixing a base, such as an emulsifying base or a water soluble base. The compounds of the invention can be administered rectally through a suppository. A suppository may include excipients, such as cocoa butter, paraffin and polyethylene glycols, which melt at body temperature and remain solid at room temperature.

Unit dosage forms for oral or rectal administration, such as syrups, elixirs and suspensions, can be provided where each dosage unit, for example a teaspoon, tablespoon, tablet or suppository, contains a certain amount of a composition containing one or more inhibitors. Similarly, unit dosage forms for injection or intravenous administration may include inhibitor (s) in the composition in the form of a solution in sterile water, normal saline or another pharmaceutically acceptable carrier.

The term "unit dosage form" as used herein refers to a physically isolated unit suitable as a unit dose for a human or animal, each unit containing a certain amount of a compound of the present invention, calculated in an amount sufficient to produce the desired effect in conjunction with a pharmaceutically an acceptable diluent, carrier or excipient. The technical requirements for the new unit dosage forms of the invention depend on the particular compound employed and the effect that can be improved, and the pharmacodynamics associated with each compound in the patient.

Pharmaceutically acceptable excipients, such as excipients, carriers or diluents, are readily available for public use. Moreover, pharmaceutically acceptable excipients, such as pH regulating and buffering agents, concentration regulating agents, stabilizers, humectants, and the like, are readily available for public use.

Other antivirus agents.

As discussed above, the method of the invention was carried out by administering an N83 inhibitor, such as a compound of formula Ι, and optionally with one or more additional antiviral agent (s).

In some embodiments, the method also comprises administering one or more interferon receptor agonists. Interferon receptor agonists are described above.

In other embodiments, the method comprises administering pirfenidone or pirfenidone analogues. Pirfenidone and its analogues are described above.

Additional antiviral agents that are suitable for use in combination therapy include, but are not limited to, nucleotide and nucleoside analogues.

Non-limiting examples include azidothymidine (ΑΖΤ) (zidovudine), its analogues and derivatives; 2 ', 3'-dideoxyinosine (ΌΌΙ) (didanosine), its analogues and derivatives; 2 ', 3'-didehydro-2', 3'-dideoxythymidine (Ό4Τ) (stavudine), its analogues and derivatives; combivir; abacavir; adefovir; dipoxyl; cidofovir; ribavirin; its analogues, etc.

In some embodiments, the method comprises administering ribavirin. Ribavirin, 1-3-O-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, is a nucleoside analogue available from ICN Pbactasei11ca1k, 1ps., Socba Meca, Ca11G. and described in the Megsk catalog, compound 8199, 11th ed. Its manufacture and dosage forms are described in US Pat. No. 4,211,771. The invention also contemplates the use of ribavirin derivatives (see, for example, US Pat. No. 6,277,830). Ribavirin can be administered orally in the form of a capsule or tablet. Of course others

- 70 012389 types of administration of ribavirin, as far as they are available, are considered, such as nasal spray, transdermal administration, suppositories, long-acting dosage form, etc. Any form of administration will work as long as the dosage forms themselves are delivered without destroying the active ingredient.

In some embodiments, an additional antiviral agent is administered throughout the course of treatment with N83 inhibitory compounds. In other embodiments, an additional antiviral agent is administered over a period of time that overlaps with the treatment with N83 inhibitor compounds, for example, treatment with an additional antiviral agent can begin before treatment with N83 inhibitor compounds and ends before treatment with N83 inhibitor compounds; treatment with an additional antiviral agent can begin after the start of treatment with N83 inhibitor compounds and end after treatment with N83 inhibitor compounds; treatment with an additional antiviral agent can begin after the start of treatment with N83 inhibitor compounds and end before treatment with N83 inhibitor compounds; or treatment with an additional antiviral agent may begin before treatment with N83 inhibitor compounds and end after treatment with N83 inhibitor compounds.

The compounds of the invention N83 inhibitors are suitable for use in dosage forms that require good solubility in water. For example, the compounds of the invention can be used in dosage forms that do not contain sugar alcohols and polyols, such as three or more basic sugar alcohols, for example glycerol, erythritol, glycerol, arabitol, xylitol, sorbitol and mannitol, and do not contain other alcohols, such as propylene glycol and polyethylene glycol (PEG) or other agents used to compensate for insufficient solubility in water. In one aspect, embodiments disclose a compound of the invention an N83 inhibitor in capsules, tablets or capsule-shaped tablets, where capsules, tablets or capsule-shaped tablets provide sufficient bioavailability due to the high water solubility of the compound. In some embodiments, the solubility of said compounds allows for administration of doses equivalent to or greater than 1 mg of the drug compound / kg of patient body weight.

Ways of treatment.

Monotherapy.

The compound of the invention an N83 inhibitor can be used to treat acute or chronic HCV. In many embodiments, the N83 inhibitor compound is administered over a period of from about 1 to about 7 days, or from about 1 to about 2 weeks, or from about 2 to about 3 weeks, or from about 3 to about 4 weeks, or from about 1 to about 2 months, or from about 2 to about 3 months, or from about 4 to about 6 months, or from about 6 to about 8 months, or from about 8 to about 12 months, or at least for 1 year and can be entered in longer the first time interval. The N83 inhibitor compound can be administered 5 times a day, 4 times a day, 3 times a day, 2 times a day, every day, every other day, 2 times a week, 3 times a week, 1 once a week, every other week, 3 Once a month or once a month. In other embodiments, the N83 inhibitor compound is administered by continuous infusion.

In many embodiments, the N83 inhibitor compound of the invention is administered orally.

In connection with the administration methods described above for treating a HS virus infection in a patient, the N83 inhibitor compound of the invention can be administered to a patient at a dosage of from 0.01 to about 100 mg / kg of patient weight per day divided from 1 to 5 doses per day. In some embodiments, the N83 inhibitor compound is administered at a dosage of from about 0.5 to about 75 mg / kg of human body weight per day, divided from 1 to 5 doses per day.

The amount of active ingredient that can be combined with a carrier to formulate a dosage form may vary depending on the patient to whom the treatment is prescribed and the particular route of administration. The usual pharmaceutical form contains from about 5 to about 95% of the active ingredient (by weight). In other embodiments, the pharmaceutical form may contain from about 20 to about 80% of the active ingredient.

One of skill in the art can easily determine that the dose concentration may vary as a function of the specific compound of the N83 inhibitor, the severity of the symptoms, the patient's susceptibility to side effects. Preferred dosages for a given N83 inhibitor compound are readily determined by a person skilled in the art using a variety of means. Preferred agents are those that determine the biological activity of a given interferon receptor agonist.

In many embodiments, multiple doses of the N83 inhibitor compound are administered. For example, the N83 inhibitor compound is administered once a month, 2 times a month, 3 times a month, a week later, 1 time a week, 2 times a week, 3 times a week, 4 times a week, 5 times a week, 6 time

- 71 012389 per week, every other day, 2 times a day, for a period of time ranging from 1 day to 1 week, or from 2 to about 4 weeks, or from 1 to about 2 months, or from 2 to about 4 months, or from 4 to about 6 months, or from 6 to about 8 months, or from 8 to about 12 months, or from 1 year to 2 years, or from 2 years to 4 years, or more.

Combination therapy with ribavirin.

In some embodiments, the methods provide combination therapy comprising administering an N83 inhibitor compound as described above and an effective amount of ribavirin. Ribavirin can be administered in doses of approximately 400 mg, 800 mg, 1000 mg or 1200 mg / day.

In one embodiment, the invention provides any of the methods described above that are modified to include co-administering to a patient a therapeutically effective amount of ribavirin during a desired course of treatment of an N83 inhibitor compound.

In another embodiment, the invention provides any of the methods described above that are modified to include co-administration of 800 mg to about 1200 mg of ribavirin orally per day for a patient for a desired course of treatment with a N83 inhibitor compound.

In another embodiment, the invention provides any of the methods described above that are modified to include co-administering to a patient (a) 1000 mg of ribavirin orally administered per day if the patient has a body weight of less than 75 kg, or;

(B) 1200 mg of ribavirin orally per day if the patient's body weight is greater than or equal to 75 kg, where the daily dose of ribavirin can be divided into two doses during the desired course of treatment with the N83 inhibitor compound.

Combination therapy with levovirin.

In some embodiments, the methods disclose combination therapy comprising administering an N83 inhibitor compound as described above and an effective amount of levovirin. Levovirin can be administered in doses of about 30 to 60 mg, 60 to 125 mg, 125 to 200 mg, 200 to 300 mg, 300 to 400 mg, 400 to 1200 mg, 600 to 1000 mg, 700 to 900 mg per day or about 10 mg / kg of body weight per day. In some embodiments, levovirin can be administered in doses of about 400 mg, about 800 mg, about 1000 mg, or about 1200 mg / kg per day during the desired course of treatment with the N83 inhibitor compound.

Combination therapy with viramidine.

In some embodiments, the methods disclose combination therapy comprising administering an N83 inhibitor compound as described above and an effective amount of viramidine. Viramidine can be administered in doses of about 30 to 60 mg, 60 to 125 mg, 125 to 200 mg, 200 to 300 mg, 300 to 400 mg, 400 to 1200 mg, 600 to 1000 mg, 700 to 900 mg per day or about 10 mg / kg of body weight per day. In some embodiments, viramidine can be administered at doses of about 800 mg, about 1000 mg, or about 1200 mg / kg per day during the desired course of treatment with the N83 inhibitor compound.

Combination therapy with thymosin-α.

In some embodiments, the methods provide combination therapy comprising administering an N83 inhibitor compound as described above and an effective amount of thymosin-α. Thymosin-α (Ζηάηχίη ™) is usually given by subcutaneous injection. Thymosin-α can be administered 3 times a day, 2 times a day, every day, every other day, 2 times a week, 3 times a week, 1 time a week, every other week, 3 times a month or 1 time a month, continuously continuously or continuously during the desired course of treatment with the compound of the N83 inhibitor. In many embodiments, thymosin-α is administered 2 times per week during the desired course of treatment with the N83 inhibitor compound.

Effective dosages of thymosin-α range from 0.5 to about 5 mg, for example, from about 0.5 to 1.0 mg, from 1.0 to 1.5 mg, from 1.5 to 2.0 mg, 2.0 to 2.5 mg, 2.5 to 3.0 mg, 3.0 to 3.5 mg, 3.5 to 4.0 mg, 4.0 to 4.5 mg, or 4.5 to about 5.0 mg. In specific embodiments, thymosin-α is administered in dosages containing an amount of 1.0 or 1.6 mg.

Thymosin-α is administered over a period of time ranging from 1 day to 1 week, or from 2 to about 4 weeks, or from about 1 to about 2 months, or from about 2 to about 4 months, or from about 4 to about 6 months, or from about 6 to about 8 months, or from about 8 to about 12 months, or from 1 year to 2 years, or from 2 to 4 years, or more. In one embodiment, thymosin-α is administered over the entire course of treatment desired with the N83 inhibitor compound.

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Combination therapy with interferon (interferons).

In many embodiments of the invention, the methods provide combination therapy comprising administering an # 83 inhibitor compound as described above and an effective amount of an interferon receptor agonist. In some embodiments, a compound of formula I and type I or III interferon receptor agonists are co-administered in the treatment methods of the invention. Type I interferon receptor agonists suitable for use herein include any interferon alpha (IFN-α). In some embodiments, interferonalfa is interferon-alpha conjugated to PEG. In some embodiments, interferon-alpha is a consensus interferon, such as INΕΕKSΕN® interferon-a-kosh. In still some other embodiments, interferon-alpha is a mono-PEGylated (linear 30 kDa) consensus interferon.

Effective doses of IFN-a range from about 3 to 27 micrograms, from 4 to 10 IU, from about 90 to 180 micrograms, or from about 18 to about 90 micrograms. Effective dosages of INΕΕKSΕN® consensus IFN-α include approximately 3 μg, approximately 6 μg, approximately 9 μg, approximately 12 μg, approximately 15 μg, approximately 18 μg, approximately 21 μg, approximately 24 μg, approximately 27 μg, approximately 30 μg of drug per dose. Effective dosages of IFN-a-2a and IFN-a-2b vary from 3 to 10 ppm (IU) dose. Effective dosages of ΡΕCA8Υ8® IFN-a-2a conjugated to PEG contain the drug in an amount of about 90 to 270 μg, or about 180 μg per dose. Effective dosages of PEG-STKON® IFN-a-2b conjugated to PEG contain from about 0.5 to 3.0 μg of drug / kg body weight per dose. Effective dosages of PEGylated Consensus Interferon (PEG-CIFN) contain from about 18 to 90 μg, or from 27 to 60 μg, or about 45 μg of CIFN amino acids / kg body weight per dose of PEG-CIFN. Effective dosages of mono-PEGylated (30 kDa, linear) CIFN contain an amount of from about 45 to about 270 μg, or from about 60 to 180 μg, or from about 90 to 120 μg, or from 90 to 120 μg of the drug per dose. IFN-α can be administered daily, every other day, 1 time per week, 3 times a week, every other week, 3 times a month, 1 time per month, mainly continuously or continuously.

In many embodiments, type I or type III and / or type II interferon receptor agonists are administered over a period of from about 1 to about 7 days, or from about 1 to about 2 weeks, or from about 2 to about 3 weeks, or about 3 weeks to about 4 weeks, or from about 1 month to about 2 months, or from about 2 months to about 3 months, from about 4 months to about 6 months, or from about 6 months to about 8 months, or from about 8 months to about12 months or at least 1 year and can be administered over a longer period of time. Dosage regimens may include administration 3 times a day, 2 times a day, daily, every other day, 2 times a week, 3 times a week, 1 time a week, every other week, 3 times a month or 1 time a month. In some embodiments, the invention discloses any of the above methods in which a desired amount of IFN-α is administered subcutaneously to a patient by bolus injection daily, every other day, 2 times a week, 3 times a week, 1 time per week, every other week, 3 times month or 1 time per month or is administered to the patient subcutaneously per day with optional continuous or continuous delivery during the desired treatment. In other embodiments, the invention discloses any of the methods described above in which the desired amount of PEGylated IFN-α (PEG IFN-α) is administered subcutaneously to a patient by bolus delivery once a week, every other week, 3 times a month or 1 time per month for desired treatment.

In other embodiments, the compound # 83 inhibitor and the type II interferon receptor agonist are co-administered in the treatment methods of the invention. A type II interferon receptor agonist suitable for use herein also includes interferon-γ (IFN-γ).

Effective dosages of IFN-γ can vary from about 0.5 to 500 μg / m ² , usually from 1.5 μg / m ² to 200 pg / m ² , depending on the size of the patient. This activity is based on 10 ⁶ international units (IU) per 50 μg of protein. IFN-γ can be administered daily, every other day, 3 times a week, or mainly continuously or continuously.

In specific embodiments of interest, IFN-γ is administered to a patient in unit dosage form from about 25 to about 500 μg, from about 50 to 400 μg, or from 100 to 300 μg. In specific embodiments of the invention of interest, the dose is 200 μg IFN-γ. In many embodiments of interest, IFN - ',' - 1b is administered.

Where the dosage is 200 μg per dose, the amount of IFN-γ per body weight (if the body weight is from 45 to 135 kg) is in the range from 4.4 μg IFN-γ per 1 kg of body weight to about 1.48 μg IFN- γ per 1 kg of body weight.

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The body surface of the patients in question usually varies from 1.33 m ² to about 2.50 m ² . thus. in many embodiments, the dosage of IFN-γ varies from 150 to about 20 μg / m ² .

For example. the dosage of IFN-γ varies from approximately 20 to 30 μg / m ² . from 30 to 40 μg / m ² . from 40 to 50 μg / m ² . from 50 to b0 mcg / m ² . from b0 to 70 μg / m ² . from 70 to 80 μg / m ² . from 80 to 90 μg / m ² . from 90 to 100 μg / m ² . from 100 to 110 μg / m ² . from 110 to 120 μg / m ² . from 120 to 130 μg / m ² . from 130 to 140 μg / m ² . from 140 to 150 μg / m ² . In some embodiments, the dosage group ranges from 25 to about 100 μg / m ² . In other embodiments, the dosage group ranges from 25 to about 50 μg / m ² .

In some embodiments, a Type I or Type III interferon receptor agonist is administered in a first dosing regimen. followed by a second dosage regimen. A first dosing regimen for administering an interferon receptor type I or type III agonist (also referred to as an “administration regimen”) typically involves administering a higher dose of an interferon receptor agonist type II or type III. For example. in the case of 1pGegdep® consensus IFN-α (CIFN). the first dosing regimen involves the introduction of a CIFN of approximately 9. 15. 18. 18. 27 mcg. The first dosing regimen may include one dosed event or at least two or more dosed events. The first dosing regimen for the administration of type I or type III interferon receptor agonists can be carried out daily. in one day. 3 times a week. in a week. 3 times a month. Once a month, mostly continuously or continuously.

The first dosing regimen is the administration of type I or type III interferon receptor agonists during the first time period. where the time period can last 4 weeks. at least 8 weeks or at least about 12 weeks.

A second dosage regimen for administering an interferon receptor type II or type III agonist (also referred to as a “maintenance regimen”) typically involves administering a lower dose of an interferon receptor agonist type II or type III. For example. in the case of KIFN. a second dosing regimen involves administering a CIFN of at least about 3. 9. 15. 15. 18 μg. The second dosing regimen may include one dosed event or at least two or more dosed events.

A second dosing regimen for administration of type I or type III interferon receptor agonists can be administered daily. in one day. 3 times a week. in a week. 3 times a month. 1 time per month. mostly continuously or continuously.

In some embodiments of the invention. where the mode of "introduction / maintenance" of the agonists of interferon receptors type I or type III. An “initiating” dose of type II interferon receptor agonists (eg, IFN-γ) is included. In these embodiments, IFN-γ is administered over a period of from 1 to 14 days, or from about 2 to 10 days, or from 3 to 7 days before treatment with type I or type III interferon receptor agonists. This time period is referred to as the “initiating phase”.

In some of these embodiments, treatment with type II interferon receptor agonists continues throughout the course of treatment with type I or type III interferon receptor agonists. In other embodiments, the treatment of type II interferon receptor agonists is terminated before the end of the treatment of type I or type III interferon receptor agonists. In these embodiments, the total treatment time for type II interferon receptor agonists (including the “initiation phase”) is from about 2 days to 30 days. from 8 days to 20 days. from 10 days to 18 days or from 12 days to 1b days. In still other embodiments, treatment with type II interferon receptor agonists is discontinued. as soon as treatment with interferon type I or type III receptor agonists begins.

In other embodiments, type I or type III interferon receptor agonists are administered in an individual dosage regimen. For example. in the case of KIFN. The dose of CIFN usually varies from about 3 to 15 mcg. from about 9 to 15. 18 mcg. A dose of type I or type III interferon receptor agonists is usually administered daily. in one day. 3 times a week. in a week. 3 times a month. 1 time per month. mostly continuously or continuously. A dose of type I or type III interferon receptor agonists is usually administered over a period of time. where the time period may be. eg. at least about 24 to 48 weeks or longer.

In some embodiments of the invention. where an individual administration regimen for type I or type III interferon receptor agonists is administered. An “initiating dose” of a Type II interferon receptor agonist (eg, IFN-γ) is usually administered. In these embodiments, IFN-γ is administered over a period of from 1 to 14 days, or from about 2 to 10 days, or from 3 to 7 days before treatment with type I or type III interferon receptor agonists. This time period is referred to as the “initiating phase”. In some of these embodiments, treatment with type II interferon receptor agonists continues throughout the course of treatment with type I or type III interferon receptor agonists. In other embodiments, the treatment of type II interferon receptor agonists is discontinued before the end of treatment

- 74 012389 agonists of interferon receptors type Ι or type ΙΙΙ. In these embodiments, the total treatment time for type ΙΙ interferon receptor agonists (including the “initiation phase”) is from about 2 days to 30 days, from 8 days to 20 days, from 10 days to 18 days, or from 12 days to 16 days. In still other embodiments, the treatment with type ΙΙ interferon receptor agonists is discontinued as soon as treatment with type Ι or type интер interferon receptor agonists begins.

In further embodiments, a compound of inhibitor # 83, type типа or type он interferon receptor agonists, type типа interferon receptor agonist, are co-administered during the desired treatment time in accordance with the methods of the invention. In some embodiments of the invention, the Ν83 inhibitor compound, interferon-alpha, and some interferon-γ are administered together during the desired treatment time in accordance with the methods of the invention.

In some embodiments, the invention discloses methods using an amount of type Ι or type интер interferon receptor agonists, type ΙΙ interferon receptor agonists, and compound Ν83 inhibitor compounds effective in treating a HS virus infection in a patient. In some embodiments, the invention discloses methods using an effective amount of IFN-α, IFN-γ, and compound # 83 inhibitor for the treatment of HS virus infection in a patient. In one embodiment, the invention discloses a method using an effective amount of a consensus IFN-α, IFN-γ and a Ν83 inhibitor compound for treating a HS virus infection in a patient.

Typically, an effective amount of consensus interferon (CIFN) and IFN-γ suitable for use in the methods of the invention is provided by using a ratio of 1 μg CIFN: 10 μg IFN-γ, where both CIFN and IFN-γ are not conjugated to PEG and non-glycosylated species .

In one embodiment, the invention discloses any of the methods described above that are modified to use an effective amount of ΙΝΕΕΒΌΕΝ® consensus IFN-α and IFN-γ in the treatment of a viral infection of HS in a patient, comprising administering to the patient a dose of INΡΕJACΕN® containing from 1 to 30 μg of the drug доз® dose, subcutaneously daily, every other day, 3 times a week, every other week, 3 times a month, 1 time a month, mainly continuously or continuously in combination with a dose of IFN-γ containing an amount of from about 10 to 300 microns g of medicine per dose of IFN-γ, subcutaneously daily, every other day, 3 times a week, every other week, 3 times a month, 1 time per month, mainly continuously or continuously for the desired period of treatment with compound Ν83 inhibitor.

In another embodiment, the invention discloses any of the methods described above that are modified to use an effective amount of ΙΝΕΕΒΌΕΝ® consensus IFN-α and IFN-γ in treating a viral infection in a patient, comprising administering to the patient a dose of ΙΝΕΕΒΌΕΝ® containing from 1 to 9 μg of the drug per ΙΝΕΕΒΌΕΝ® dose, subcutaneously daily, every other day, 3 times a week, every other week, 3 times a month, 1 time per month or per day, mainly continuously or continuously in combination with a dose of IFN-γ containing an amount of approximately about 10 to 100 ug of drug per IFN-γ dose, subcutaneously daily, every other day, three times a week, a week, three times per month, one time per month, substantially continuously or continuously, for the desired duration of treatment with an inhibitor Ν83 compound.

In another embodiment, the invention discloses any of the methods described above that are modified to use an effective amount of INNYaSN® consensus IFN-α and IFN-γ in the treatment of a viral infection in a patient, comprising administering to the patient a dose of INNYaSN® containing 1 μg of the drug per dose of INYaSN®, daily, every other day, 3 times a week, every other week, 3 times a month, 1 time per month or per day, mainly continuously or continuously in combination with a dose of IFN-γ containing an amount of from about 10 to 50 μg of the drug per the dose of IFNγ, subcutaneously daily, every other day, 3 times a week, every other week, 3 times a month, 1 time per month, mostly continuously or continuously for the desired treatment period with compound Ν83 inhibitor.

In another embodiment, the invention discloses any of the methods described above that are modified to use an effective amount of INNYaCN® consensus IFN-α and IFN-γ in the treatment of a viral infection in a patient, comprising administering to the patient a dose of INJACN® containing approximately 9 μg of the drug per dose of INJACN ®, subcutaneously daily, every other day, 3 times a week, every other week, 3 times a month, 1 time per month or per day, mainly continuously or continuously in combination with a dose of IFN-γ containing an amount of approximately 90 to 100 mcg of the drug per dose of IFN-γ, subcutaneously daily, every other day, 3 times a week, every other week, 3 times a month, 1 time per month, mostly continuously or continuously for the desired treatment period with compound Ν83 inhibitor.

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In another embodiment, the invention discloses any of the methods described above that are modified to use an effective amount of INΕΕΚCΕN® consensus IFN-α and IFN-γ in the treatment of a viral infection in a patient, comprising administering to the patient a dose of INΕΕΚCΕN® containing about 30 μg of the drug per dose of INΕΕΚCΕN ®, subcutaneously daily, every other day, 3 times a week, every other week, 3 times a month, 1 time per month or per day, mainly continuously or continuously in combination with a dose of IFN-γ containing an amount of approximately 200 to 300 μg of the drug per dose of IFN-γ, subcutaneously daily, every other day, 3 times a week, every other week, 3 times a month, 1 time per month, mainly continuously or continuously for the desired period of treatment with the N83 inhibitor compound.

In another embodiment, the invention discloses any of the methods described above that are modified to use an effective amount of consensus IFN-α conjugated to PEG and IFN-γ in the treatment of a viral infection in a patient, comprising administering to the patient a dose of consensus IFN-α conjugated to PEG (PEG -KIFN), containing from 4 to 60 μg KIFN of amino acid weight per dose of PEG-KIFN subcutaneously every week, every other week, 3 times a month, 1 time per month or per day, mainly continuously or continuously in combination with a weekly dose of IFN-γ, containing an amount of from about 30 to 1000 μg of the drug per week divided by the doses administered subcutaneously daily, every other day, 3 times a week, every other week, 3 times a month, 1 time per month, mostly continuously or continuously for a desired period of treatment with a N83 inhibitor compound.

In another embodiment, the invention discloses any of the methods described above that are modified to use an effective amount of a consensus IFN-α conjugated to PEG and IFN-γ in the treatment of a viral infection in a patient, comprising administering to a patient a dose of a consensus IFN-α conjugated to PEG (PEG -KIFN), containing in the amount of 18 to 24 μg of the weight of the amino acid KIFN per dose of PEG-KIFN subcutaneously every week, every other week, 3 times a month, 1 time per month or per day, mainly continuously or continuously in combination with total the weekly dose of IFN-γ, containing the amount from about 100 to 300 μg of the drug per week, divided by the doses administered subcutaneously daily, every other day, 3 times a week, every other week, 3 times a month, 1 time per month, mainly continuously or continuously during the desired period of treatment with the compound of the N83 inhibitor.

Typically, an effective amount of IFN-α-2a, or 2b, or 2c, and IFN-γ, suitable for use in the methods of the invention, is provided using a dose ratio of 1 millionth unit (ME) of IFN - «- 2a. or 2b or 2c: 30 μg IFN-γ, which are not pegylated or glycosylated species.

In another embodiment, the invention discloses any of the methods described above that are modified to use an effective amount of IFN ^ -2a, or 2b or 2c and IFN-γ in the treatment of a viral infection in a patient, comprising administering to the patient a dose of IFN ^ -2a, or, 2b or 2c, containing in an amount of about 1 to 20 IU medications per dose of IFN-α-2a, or 2b, or 2c subcutaneously daily, every other day, 2 times a week, 3 times a week or per day, mainly continuously or continuously in combination with a dose of IFN-γ containing an amount of from approximately 30 to 600 μg of the drug per dose of IFN-γ, subcutaneously daily, every other day, 3 times a week, every other week, 3 times a month, 1 time per month, mostly continuously or continuously for the desired period of treatment with the N83 inhibitor compound.

In another embodiment, the invention discloses any of the above methods, modified to use an effective amount of IFN ^ -2a, or 2b, or 2c, and IFN-γ in treating a viral infection in a patient, comprising administering to the patient a dose of IFN ^ -2a, or 2b, or 2c, containing in the amount of approximately 3 IU of the drug per dose of IFN ^ -2a, or 2b, or 2c subcutaneously daily, every other day, 2 times a week, 3 times a week or per day, mainly continuously or continuously in combination with a dose of IFN- γ containing approximately 100 μg of Lek CTBA in IFN-γ dose, subcutaneously daily, every other day, three times a week, a week, three times per month, one time per month, substantially continuously or continuously, for the desired duration of treatment with an inhibitor compound N83.

In another embodiment, the invention discloses any of the above methods, modified to use an effective amount of IFN ^ -2a, or 2b, or 2c, and IFN-γ in treating a viral infection in a patient, comprising administering to the patient a dose of IFN ^ -2a, or 2b, or 2c, containing in an amount of approximately 10 IU of the drug per dose of IFN ^ -2a, or 2b, or 2c subcutaneously daily, every other day, 2 times a week, 3 times a week or per day, mainly continuously or continuously in combination with a dose of IFN- γ containing approximately 300 mcg of Lek per dose of IFN-γ, subcutaneously daily, every other day, 3 times a week, every other week, 3 times a month, 1 time per month, mostly continuously or continuously for the desired period of treatment with the N83 inhibitor compound.

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In another embodiment, the invention discloses any of the methods described above that are modified to use an effective amount of ΡΕ6Λ8Υ8® IFN-a-2a conjugated to PEG and IFN-γ in the treatment of a viral infection in a patient, comprising administering to the patient a dose of RESAST8® containing approximately from 90 to 360 μg of the drug per dose of RESAST8® subcutaneously once a week, every other week, 3 times a month or monthly in combination with the total weekly dose of IFN-γ, containing an amount from about 30 to 1000 μg of the drug per Yeh-lii divided by the dose administered subcutaneously daily, every other day, 2 times a week, three times a week administered substantially continuously or continuously, for the desired duration of treatment with an inhibitor compound N83.

In another embodiment, the invention discloses any of the methods described above that are modified to use an effective amount of PECA8-8 IFN-a-2a conjugated with PEG and IFN-γ in the treatment of a viral infection in a patient, comprising administering to the patient a dose of RESA8-88 containing approximately 180 μg of the drug per dose of PECA8Υ8® subcutaneously once a week, every other week, 3 times a month or monthly in combination with a total weekly dose of IFN-γ containing an amount of about 100 to 300 μg of the drug per week under dosed on a dose administered subcutaneously daily, every other day, 2 times a week, 3 times a week, administered mainly continuously or continuously for a desired period of treatment with a compound of the N83 inhibitor.

In another embodiment, the invention discloses any of the methods described above that are modified to use an effective amount of PEG INNKΘN® IFN-a-2b conjugated to PEG and IFN-γ in treating a viral infection in a patient, comprising administering to the patient a dose of PEC INΤKΘN® containing from about 0.75 to 3.0 μg of the drug per 1 kg of body weight per dose of PEC INΘK®N® subcutaneously once a week, every other week, 3 times a month or monthly in combination with a total weekly dose of IFN-γ containing an amount of from approximately 30 d 1000 mcg drug per week in divided doses administered subcutaneously daily, every other day, 2 times a week, three times a week administered substantially continuously or continuously, for the desired treatment duration Ν83 inhibitor compound.

In another embodiment, the invention discloses any of the methods described above that are modified to use an effective amount of PEG INNKΘN® IFN-a-2b conjugated to PEG and IFN-γ in treating a viral infection in a patient, comprising administering to the patient a dose of PEC INΤKΘN® containing the amount of approximately 1.5 μg of the drug per 1 kg of body weight per dose of RES INΘK подкN® subcutaneously once a week, after a week, 3 times a month or monthly in combination with a total weekly dose of IFN-γ containing an amount of from about 100 to 300 μg l Drugs per week divided by doses administered subcutaneously daily, every other day, 2 times a week, 3 times a week, administered mainly continuously or continuously during the desired treatment period with compound Ν83 inhibitor.

In one embodiment, the present invention discloses any of the above methods, which comprises administering to a patient with a HS viral infection an effective amount of an N83 inhibitor; and some regimen of 9 μg INΕEXEN® consensus IFN-α, administered subcutaneously daily or 2 times a week, and ribivirin, administered orally daily, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for patients weighing less than 75 kg, and 1200 mg for patients weighing 75 kg or more.

In one embodiment, the present invention discloses any of the above methods, which comprises administering to a patient with a HS viral infection an effective amount of an N83 inhibitor; and some mode of 9 mcg INΕEXEN® consensus IFN-α, administered subcutaneously daily or 2 times a week; 50 μg of Acettipe® human IFN - ',' - 1b. administered subcutaneously 2 times a week; and ribivirin, administered orally daily, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for patients weighing less than 75 kg, and 1200 mg for patients weighing 75 kg or more.

In one embodiment, the present invention discloses any of the above methods, which comprises administering to a patient with a HS viral infection an effective amount of an N83 inhibitor; and a regimen of 9 μg INΕEXEN® consensus IFN-α administered subcutaneously daily or 2 times a week; 100 μg of Acettipe® human IFN - ',' - 1b. administered subcutaneously 2 times a week; and ribivirin, administered orally daily, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for patients weighing less than 75 kg, and 1200 mg for patients weighing 75 kg or more.

In one embodiment, the present invention discloses any of the above methods, which comprises administering to a patient with a HS viral infection an effective amount of an N83 inhibitor; and a regimen of 9 μg INΕEXEN® consensus IFN-α administered subcutaneously daily or 2 times a week; and 50 μg of Acettipe® human IFN - ',' - 1b. administered subcutaneously 2 times a week - 77 012389 li; where the duration of therapy is 48 weeks.

In one embodiment, the present invention discloses any of the methods described above, which comprises administering to a patient with a HS viral infection an effective amount of a Ν83 inhibitor; and a regimen of 9 μg INΕEΚCEN® consensus IFN-α, administered subcutaneously daily or 2 times a week; and 100 μg AcDttype® human IFN-γ-Φ, administered subcutaneously 2 times a week; where the duration of therapy is 48 weeks.

In one embodiment, the present invention discloses any of the methods described above, which comprises administering to a patient with a HS viral infection an effective amount of a Ν83 inhibitor; and some regimen of 9 μg I \ ΡЕΡСОN® consensus IFN-α, administered subcutaneously daily or 2 times a week; 25 μg AcNttype® human IFN-γ-Φ, administered subcutaneously 2 times a week; and ribivirin, administered orally daily, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for patients weighing less than 75 kg, and 1200 mg for patients weighing 75 kg or more.

In one embodiment, the present invention discloses any of the methods described above, which comprises administering to a patient with a HS viral infection an effective amount of a Ν83 inhibitor; and some regimen of 9 μg I \ ΡЕΡСОN® consensus IFN-α, administered subcutaneously daily or 2 times a week; 200 μg Asyttipe® human IFN-γ-Φ, administered subcutaneously 2 times a week; and ribivirin, administered orally daily, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for patients weighing less than 75 kg, and 1200 mg for patients weighing 75 kg or more.

In one embodiment, the present invention discloses any of the methods described above, which comprises administering to a patient with a HS viral infection an effective amount of a Ν83 inhibitor; and some regimen of 9 μg I \ ΡЕΡСОN® consensus IFN-α, administered subcutaneously daily or 2 times a week; and 25 μg Asyttipe® human IFN-γ-Φ, administered subcutaneously 2 times a week; where the duration of therapy is 48 weeks.

In one embodiment, the present invention discloses any of the methods described above, which comprises administering to a patient with a HS viral infection an effective amount of a Ν83 inhibitor; and some regimen of 9 μg I \ ΡЕΡСОN® consensus IFN-α, administered subcutaneously daily or 2 times a week; and 200 μg AcDttype® human IFN-γ-Φ, administered subcutaneously 2 times a week; where the duration of therapy is 48 weeks.

In one embodiment, the present invention discloses any of the methods described above, which comprises administering to a patient with a HS viral infection an effective amount of a Ν83 inhibitor; and some mode of 100 μg of mono-PEGylated (30 kDa, linear) consensus IFN-α, administered subcutaneously every ten days or 1 time per week; and ribivirin, administered orally daily, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for patients weighing less than 75 kg, and 1200 mg for patients weighing 75 kg or more.

In one embodiment, the present invention discloses any of the methods described above, which comprises administering to a patient with a HS viral infection an effective amount of a Ν83 inhibitor; and a regimen of 100 μg of mono-PEGylated (30 kDa, linear) consensus IFN-α administered subcutaneously every ten days or 1 time per week; and 50 μg AsNtipe® human IFN-γ-Φ, administered subcutaneously 2 times a week; and ribivirin, administered orally daily, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for patients weighing less than 75 kg, and 1200 mg for patients weighing 75 kg or more.

In one embodiment, the present invention discloses any of the methods described above, which comprises administering to a patient with a HS viral infection an effective amount of a Ν83 inhibitor; and a regimen of 100 μg of mono-PEGylated (30 kDa, linear) consensus IFN-α administered subcutaneously every ten days or 1 time per week; and 100 μg Asyttipe® human IFN-γ-Φ, administered subcutaneously 2 times a week; and ribivirin, administered orally daily, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for patients weighing less than 75 kg, and 1200 mg for patients weighing 75 kg or more.

In one embodiment, the present invention discloses any of the methods described above, which comprises administering to a patient with a HS viral infection an effective amount of a Ν83 inhibitor; and some mode of 100 μg of mono-PEGylated (30 kDa, linear) consensus IFN-α, administered subcutaneously every 10 days or 1 time per week; and 50 μg AcDttype® human IFN-γ-Φ, administered subcutaneously 2 times a week; where the duration of therapy is 48 weeks.

In one embodiment, the present invention discloses any of the methods described above, which comprises administering to a patient with a HS viral infection an effective amount of a Ν83 inhibitor; and a regimen of 100 μg of mono-PEGylated (30 kDa, linear) consensus IFN-α administered subcutaneously every ten days or 1 time per week; and 100 mcg Asyttipe® human

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IFN-y-1b, administered subcutaneously 2 times a week; where the duration of therapy is 48 weeks.

In one embodiment, the present invention discloses any of the methods described above, which comprises administering to a patient with a HS viral infection an effective amount of a Ν83 inhibitor; and a regimen of 150 μg of mono-PEGylated (30 kDa, linear) consensus IFN-α administered subcutaneously every ten days or 1 time per week; and ribivirin, administered orally daily, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for patients weighing less than 75 kg, and 1200 mg for patients weighing 75 kg or more.

In one embodiment, the present invention discloses any of the methods described above, which comprises administering to a patient with a HS viral infection an effective amount of a Ν83 inhibitor; and a regimen of 150 μg of mono-PEGylated (30 kDa, linear) consensus IFN-α administered subcutaneously every ten days or 1 time per week; and 50 μg Asyttie® human IFN-y-1b, administered subcutaneously 2 times a week; and ribivirin, administered orally daily, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for patients weighing less than 75 kg, and 1200 mg for patients weighing 75 kg or more.

In one embodiment, the present invention discloses any of the methods described above, which comprises administering to a patient with a HS viral infection an effective amount of a Ν83 inhibitor; and a regimen of 150 μg of mono-PEGylated (30 kDa, linear) consensus IFN-α administered subcutaneously every ten days or 1 time per week; and 100 μg Asyttie® human IFN-y-1b, administered subcutaneously 2 times a week; and ribivirin, administered orally daily, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for patients weighing less than 75 kg, and 1200 mg for patients weighing 75 kg or more.

In one embodiment, the present invention discloses any of the methods described above, which comprises administering to a patient with a HS viral infection an effective amount of a Ν83 inhibitor; and a regimen of 150 μg of mono-PEGylated (30 kDa, linear) consensus IFN-α administered subcutaneously every ten days or 1 time per week; and 50 μg Asyttie® human IFN-y-1b, administered subcutaneously 2 times a week; where the duration of therapy is 48 weeks.

In one embodiment, the present invention discloses any of the methods described above, which comprises administering to a patient with a HS viral infection an effective amount of a Ν83 inhibitor; and 150 μg of mono-PEGylated (30 kDa, linear) consensus IFN-α, administered subcutaneously every ten days or 1 time per week; and 100 μg Asyttie® human IFN-y-1b, administered subcutaneously 2 times a week; where the duration of therapy is 48 weeks.

In one embodiment, the present invention discloses any of the methods described above, which comprises administering to a patient with a HS viral infection an effective amount of a Ν83 inhibitor; and a regimen of 200 μg of mono-PEGylated (30 kDa, linear) consensus IFN-α administered subcutaneously every ten days or 1 time per week; and ribivirin, administered orally daily, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for patients weighing less than 75 kg, and 1200 mg for patients weighing 75 kg or more.

In one embodiment, the present invention discloses any of the methods described above, which comprises administering to a patient with a HS viral infection an effective amount of a Ν83 inhibitor; and 200 μg of mono-PEGylated (30 kDa, linear) consensus IFN-α, administered subcutaneously every ten days or 1 time per week; and 50 μg Asyttie® human IFN-y-1b, administered subcutaneously 2 times a week; and ribivirin, administered orally daily, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for patients weighing less than 75 kg, and 1200 mg for patients weighing 75 kg or more.

In one embodiment, the present invention discloses any of the methods described above, which comprises administering to a patient with a HS viral infection an effective amount of a Ν83 inhibitor; and a regimen of 200 μg of mono-PEGylated (30 kDa, linear) consensus IFN-α administered subcutaneously every ten days or 1 time per week; and 100 μg Asyttie® human IFN-y-1b, administered subcutaneously 2 times a week; and ribivirin, administered orally daily, where the duration of therapy is 48 weeks. In this embodiment, ribavirin is administered in an amount of 1000 mg for patients weighing less than 75 kg, and 1200 mg for patients weighing 75 kg or more.

In one embodiment, the present invention discloses any of the methods described above, which comprises administering to a patient with a HS viral infection an effective amount of a Ν83 inhibitor; and a regimen of 200 μg of mono-PEGylated (30 kDa, linear) consensus IFN-α administered subcutaneously every ten days or 1 time per week; and 50 μg Asyttie® human IFN-y-1b, administered subcutaneously 2 times a week; where the duration of therapy is 48 weeks.

In one embodiment, the present invention discloses any of the methods described above, which comprises administering to a patient with a HS viral infection an effective amount of a Ν83 inhibitor; and a regimen of 200 μg of mono-PEGylated (30 kDa, linear) consensus IFN-α administered subcutaneously every ten days or 1 time per week; and 100 mcg Asyttie® human

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IFN-y-1b, administered subcutaneously 2 times a week; where the duration of therapy is 48 weeks.

Any of the methods described above involves administering an N83 inhibitor, a type I interferon receptor agonist (e.g., IFN-α) and a type II interferon receptor agonist (e.g., some IFN-γ), and can be enhanced by the administration of an effective amount of an TNF-α antagonist α (for example, some TNF-α antagonist that is different from pirphenidone and its analogues). For a non-limiting example, TNF-α antagonists that are suitable for use in such combination therapies include ΕΝΒΒΕΕ®, WEMGSABE® and NYMJA ™.

In one embodiment, the present invention discloses a method of using an effective amount of E \ BBB; effective amount of IFN-α; effective amount of IFN-γ; and an effective amount of an N83 inhibitor for treating a viral HS infection in a patient, comprising administering to the patient a dose of E / BB® containing from about 0.1 μg to 23 mg per dose, from about 0.1 to 1 μg, from about 1 to 10 μg, approximately 10 to 100 μg, approximately 100 μg to 1 mg, approximately 1 to 5 mg, approximately 5 to 10 mg, approximately 10 to 15 mg, approximately 15 to 20 mg, or approximately 20 to 23 mg ВЕВВЬ®, subcutaneous daily, every other day, 2 times a week, 3 times a week, 1 time a week, every week Liu, three times per month 1 month or once every month, or per day substantially continuously or continuously, for the desired treatment period.

In one embodiment, the present invention discloses a method of using an effective amount of WEMGSABE®; effective amount of IFN-α; an effective amount of IFN-γ and an effective amount of an N83 inhibitor for treating a viral HS infection in a patient, comprising administering to the patient a dose of WEMGSABE® containing an amount of about 0.1 to 4.5 mg / kg, about 0.1 to 0.5 mg / kg, from about 0.5 to 1.0 mg / kg, from about 1.0 to 1.5 mg / kg, from about 1.5 to 2.0 mg / kg, from about 2.0 to 2, 5 mg / kg, approximately 2.5 to 3.0 mg / kg, approximately 3.0 to 3.5 mg / kg, approximately 3.5 to 4.0 mg / kg, approximately 4.0 to 4.5 mg / kg per dose of VEMGSABE®, intravenously daily, cher Every day, 2 times a week, 3 times a week, 1 time a week, every week, 3 times a month 1 time a month or every month or day, mostly continuously or continuously during the desired period of treatment.

In one embodiment, the present invention discloses a method of using an effective amount of NIMJA ™; effective amount of IFN-α; effective amount of IFN-γ; and an effective amount of an N83 inhibitor for treating a HS virus infection in a patient, comprising administering to the patient a dose of NIMJA ™ containing from about 0.1 μg to 35 mg per dose, from about 0.1 to 1 μg, from about 1 to 10 μg, approximately 10 to 100 μg, approximately 100 μg to 1 mg, approximately 1 to 5 mg, approximately 5 to 10 mg, approximately 10 to 15 mg, approximately 15 to 20 mg, or approximately 20 to 25 mg , approximately 25 to 30 mg, approximately 30 to 35 mg per dose of NIMJA ™, subcutaneous daily, black h day, 2 times per week, 3 times per week, one time per week, every week, three times per month, 1 month, or once every month, or per day, substantially continuously or continuously, for the desired treatment period.

Combination therapy with pirfenidone.

In many embodiments, the methods disclose combination therapy comprising administering an N83 inhibitor compound as described above and an effective amount of pirfenidone or an analogue thereof. In some embodiments, a N83 inhibitor compound, one or more interferon receptor agonists, and pirfenidone or analogs thereof are co-administered in the treatment methods of the invention. In some embodiments, the compound is an N83 inhibitor, some type I interferon receptor agonist, and pirfenidone (or some other) analogue thereof are co-administered. In other embodiments, the compound is an N83 inhibitor, some type I interferon receptor agonist, some type II interferon receptor agonist, and pirfenidone (or its analogs) are administered together. Type I interferon receptor agonists suitable for use herein include IFN-α, such as interferon ^^ a, interferon ^^ b, interferon-α-con ₁ , and IFN-α conjugated to PEG, such as PEG interferon ^^ a, PEG interferon - - - 2b and consensus interferons conjugated to PEG, such as mono-PEGylated (30 kDa, linear) consensus interferon. Type II interferon receptor agonists suitable for use herein include interferon-γ.

Pirfenidone or some analogue thereof can be administered once a month, 2 times a month, 1 time per week, 2 times a week, 3 times a week, 4 times a week, 5 times a week, 6 times a week or divided into daily doses, which are taken from one to 5 times a day for a period of time ranging from about 1 day to 1 week, or from 2 to about 4 weeks, or from about 1 to about 2 months, or from about 2 to about 4 months, or from about 4 to about 6 months, or from about 6 to about 8 months, or from about 8 to approx. but 12 months or 1 year to 2 years, or from 2 years to 4 years or more.

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Effective dosages of pirfenidone or specific analogues of pirfenidone include a patient-dependent dose ranging from about 5 to 125 mg / kg / day, or a fixed dose from 400 to 3600 mg / day, or about 1800 mg per day, or from about 1200 to 1600 mg / day, administered orally, divided from one to five doses per day. Other dosages and forms of pirfenidone and specific analogues of pirfenidone suitable for use in the treatment of fibrotic diseases are described in US Pat. Nos. 5,310,562; 5,518,729; 5716632 and 6090822.

In one embodiment, the present invention discloses any of the methods described above, which comprises co-administering to a patient a therapeutically effective amount of pirfenidone or its analogs during a desired course of treatment with a N83 inhibitor compound.

Combination therapy with TNF-α antagonists.

In many embodiments of the invention, the methods disclose combination therapy comprising administering an N83 inhibitor compound as described above and an effective amount of TNF-α antagonists in combination therapy for treating HS viral infection.

Effective doses of TNF-α antagonists vary from 0.1 μg to 40 mg per dose, eg about from 0.1 before 0.5 mcg on dose about from 0.5 before 1,0 mcg on dose about from 1,0 before 5,0 mcg on dose about from 5,0 before 10 mcg on dose about from 10 before twenty mcg on dose about from twenty before thirty mcg on dose about from thirty before 40 mcg on dose about from 40 before fifty mcg on dose about from fifty before 60 mcg on dose about from 60 before 70 mcg on dose about from 70 before 80 mcg on dose about from 80 before 90 mcg on dose about from 90 before one hundred mcg on dose about from one hundred before 150 mcg on dose about from 150 before 200 mcg on dose about from 200 before 250 mcg on dose about from 250 before 300 mcg on dose about from 300 before 400 mcg on dose about from 400 before 500 mcg on dose about from 500 before 600 mcg on dose about from 600 before 700 mcg on dose about from 700 before 800 mcg on dose about from 800 before 900 mcg on dose about from 900 before 1000 mcg on dose about from one before 10 mg on dose about from 10 before fifteen mg on dose about from fifteen before twenty mg on dose about from twenty before 25 mg on dose about from 25 before thirty mg on dose about from thirty before 35 mg on dose

approximately 35 to 40 mg per dose.

In some embodiments, effective dosages of TNF-α antagonists are expressed as mg / kg body weight. In these embodiments, effective dosages of TNF-α antagonists vary from about 0.1 to 10 mg / kg body weight, for example from about 0.1 to 0.5 mg / kg body weight, from about 0.5 to 1.0 mg / kg body weight, approximately from

1.0 to 2.5 mg / kg body weight, approximately 2.5 to 5.0 mg / kg body weight, approximately

5.0 to 7.5 mg / kg body weight, from about 7.5 to 10 mg / kg body weight.

In many embodiments, the TNF-α antagonist is administered over a period of from 1 day to 1 week, or from 2 to about 3 weeks, from 3 to about 4 weeks, from about 1 to about 2 months, from about 2 to about 3 months from about 3 to about 4 months, from about 4 to about 6 months, or from about 6 to about 8 months, or from about 8 to about 12 months, or at least 1 year and can be administered over a longer time interval. The TNF-α antagonist can be administered 3 times a day, 2 times a day, every day, every other day, 2 times a week, 3 times a week, 1 time a week, every week, 3 times a month, 1 time a month, mostly continuously or continuously during the desired treatment period.

In many embodiments, multiple doses of TNF-α antagonists are administered. For example, an TNF-α antagonist is administered once a month, 2 times a month, 3 times a month, every week, 1 time per week, 2 times a week, 3 times a week, 4 times a week, 5 times a week, 6 times a week, every other day, 2 times a day, 3 times a day mostly continuously or continuously for a period of time varying from about 1 day to 1 week, or from 2 to about 4 weeks, from about 1 to about 2 months or from about 2 to about 4 months, from about 4 to about 6 months, or from about 6 to about 8 months, or from about 8 to p about 12 months, or from 1 year to 2 years, or from 2 years to 4 years or more.

TNF-α antagonist and compound inhibitor No. 3A are usually administered in separate dosage forms. The TNF-α antagonist and compound # 3A inhibitor can be administered mainly simultaneously, or after about 30 minutes, 1, 2, 4, 8, 16, 24, 36, 72 hours, 4 days, 7 days, or about 2 weeks.

In one embodiment, the invention discloses a method using an effective amount of an TNF-α antagonist, an effective amount of an N83 inhibitor compound, for treating a HS virus infection in a patient, comprising administering to the patient a dose of TNF-α antagonist containing from about 0.1 μg to 40 mg per dose TNF-α antagonist subcutaneously daily, every other day,

- 81 012389 times a week, 3 times a week or per day, mainly continuously or continuously during the desired period of treatment with a compound of the N83 inhibitor.

In one embodiment, the present invention discloses a method of using an effective amount of ΕNBKΕ ^ ® and an effective amount of an N83 inhibitor for treating a HS virus infection in a patient, comprising administering a dose of ΕNBK.Ε ^ ® to the patient. containing an amount of from about 0.1 μg to 23 mg per dose, from about 0.1 to 1 μg, from about 1 to 10 μg, from about 10 to 100 μg, from about 100 μg to 1 mg, from about 1 to 5 mg, from about 5 to 10 mg, from about 10 to 15 mg, from about 15 to 20 mg, or from about 20 to 23 mg of NBC.Ε ^ ®. subcutaneously daily, every other day, 2 times a week, 3 times a week, 1 time a week, every week, 3 times a month 1 time a month or every month or day, mostly continuously or continuously for the desired period of treatment with the N83 inhibitor compound .

In one embodiment, the present invention discloses a method of using an effective amount of ΒΕΜ ^ ΛΌΕ® and an effective amount of an N83 inhibitor for treating a HS virus infection in a patient, comprising administering to the patient a dose of ΒΕΜ ^ ΛΌΕ® containing from about 0.1 to 4.5 mg / kg, approximately 0.1 to 0.5 mg / kg, approximately 0.5 to 1.0 mg / kg, approximately 1.0 to 1.5 mg / kg, approximately 1.5 to 2.0 mg / kg, approximately 2.0 to 2.5 mg / kg, approximately 2.5 to 3.0 mg / kg, approximately 3.0 to 3.5 mg / kg, approximately 3.5 to 4.0 mg / kg, approximately 4.0 to 4.5 mg / kg per dose of KEMESLEE®, intravenously daily, every other day, 2 times a week, 3 times a week, 1 time per week, each weekly, 3 times a month, 1 time a month, or every month or day, substantially continuously or continuously for the desired treatment period with the N83 inhibitor compound.

In one embodiment, the present invention discloses a method of using an effective amount of NiMGEL ™ and an effective amount of an N83 inhibitor to treat HS virus infection in a patient, comprising administering to the patient a dose of NiM ^ KA ™ containing from about 0.1 μg to 35 mg per dose, approximately 0.1 to 1 μg, approximately 1 to 10 μg, approximately 10 to 100 μg, approximately 100 μg to 1 mg, approximately 1 to 5 mg, approximately 5 to 10 mg, approximately 10 to 15 mg from about 15 to 20 mg or p approximately 20 to 25 mg, approximately 25 to 30 mg, approximately 30 to 35 mg per dose of NiM ^ KA ™, subcutaneous daily, every other day, 2 times a week, 3 times a week, 1 time per week, every week , once a month, 1 time a month, or every month or day, generally continuously or continuously during the desired treatment period with the N83 inhibitor compound.

Combination therapy with thymosin-α.

In many embodiments, the methods disclose combination therapies comprising administering an effective amount of an N8 inhibitor compound as described above and an effective amount of thymosin-α in combination therapy for treating HS viral infection.

Effective dosages of thymosin-α vary from about 0.5 to 5 mg, for example, from about 0.5 to 1.0 mg, from about 1.0 to 1.5 mg, from about 1.5 to 2.0 mg, from about 2.0 to 2.5 mg, or from about 2.5 to 3.0 mg, from about 3.0 to 3.5 mg, from about 3.5 to 4.0 mg, from about 4.0 to 4.5 mg, approximately 4.5 to 5 mg. In specific embodiments, thymosin-α is administered in doses containing 1.0 or 1.6 mg of the substance.

In one embodiment, the invention discloses a method using an effective amount of ΖA ^ AXIN ™ thymosin-α and an effective amount of an N83 inhibitor compound for treating a HS virus infection in a patient, comprising administering to the patient a dose of ΖΑΠΑΧ! ^ ™ containing from about 1.0 to 1 , 6 mg per dose, subcutaneously 2 times a week for the desired treatment period with the N83 inhibitor compound.

Combination therapy with TNF-α antagonists and interferon.

In some embodiments, the present invention discloses a method for treating a viral infection of a HS in a patient with a viral injection of HS, the method comprising administering an effective amount of an N83 inhibitor, an effective amount of TNF-α antagonists, and an effective amount of one or more interferons.

In one embodiment, the present invention discloses any of the methods described above that are modified to use an effective amount of IFN-γ and an effective amount of TNF-α antagonist in treating a viral infection of HS in a patient, which comprises administering to the patient a dose of IFN-γ containing from about 10 to 300 μg of the drug per dose of IFN-γ administered subcutaneously daily, every other day, 2 times a week, 3 times a week, every week, every other week, 3 times a month, 1 time per month or per day intermittently or continuously, in combination with a dose of TNF-α antagonist containing an amount of about 0.1 μg to 40 mg of TNF-α antagonist per dose administered subcutaneously daily, every other day, 2 times a week, or 3 times a week or per day mostly continuously or continuously for the desired ne

- 82 012389 of the treatment period with the compound of the Ν83 inhibitor.

In one embodiment, the present invention discloses any of the methods described above that are modified to use an effective amount of IFN-γ and an effective amount of TNF-α antagonist in treating a viral infection of HS in a patient, which comprises administering to the patient a dose of IFN-γ containing from about 10 to 100 μg of the drug per dose of IFN-γ administered subcutaneously daily, every other day, 2 times a week, 3 times a week, every week, every other week, 3 times a month, 1 time per month or per day intermittently or continuously, in combination with a dose of TNF-α antagonist containing an amount of about 0.1 μg to 40 mg of TNF-α antagonist per dose administered subcutaneously daily, every other day, 2 times a week, or 3 times a week or per day mostly continuously or continuously during the desired treatment period with a compound of inhibitor Ν83.

In another embodiment, the present invention discloses any of the methods described above that are modified to use an effective amount of IFN-γ and an effective amount of TNF-α antagonist in treating a viral infection of HS in a patient, which comprises administering to the patient a total weekly dose of IFN-γ containing an amount from about 30 to 1000 mcg of the drug per week divided into doses administered subcutaneously daily, every other day, 2 times a week, 3 times a week or administered mainly continuously or continuously in combination with a dose of TNF-α antagonist containing an amount of approximately 0.1 μg to 40 mg of TNF-α antagonist per dose administered subcutaneously daily, every other day, 2 times a week or 3 times a week or per day, mainly continuously or continuously during the desired treatment period with a compound of inhibitor Ν83.

In another embodiment, the present invention discloses any of the methods described above that are modified to use an effective amount of IFN-γ and an effective amount of TNF-α antagonist in treating a viral infection of HS in a patient, which comprises administering to the patient a total weekly dose of IFN-γ containing an amount from about 100 to 300 mcg of the drug per week divided into doses administered subcutaneously daily, every other day, 2 times a week, 3 times a week or administered mainly continuously or continuously in combination with a dose of TNF-α antagonist containing an amount of approximately 0.1 μg to 40 mg of TNF-α antagonist per dose administered subcutaneously daily, every other day, 2 times a week or 3 times a week or per day, mainly continuously or continuously during the desired treatment period with a compound of inhibitor Ν83.

In one embodiment, the invention discloses any of the methods described above that are modified to use an effective amount of INΕΕKSΕN® consensus IFN-α and an TNF-α antagonist in the treatment of HS virus infection in a patient, which comprises administering to the patient a dose of INΕΕKSΕN® containing in an amount of from about 1 to 30 mcg of the drug per dose INΕΕKSΕN®, subcutaneously daily, every other day, 2 times a week, 3 times a week, weekly, every other week, 3 times a month, 1 time per month or per day, mainly continuously or continuously in a complex doses with a dose of TNF-α antagonist containing from about 0.1 μg to 40 mg of TNF-α antagonist per dose, subcutaneously daily, every other day, 2 times a week, 3 times a week or per day, mostly continuously or continuously for the desired treatment period with a compound of inhibitor Ν83.

In one embodiment, the invention discloses any of the methods described above that are modified to use an effective amount of INΕΕKSΕN® consensus IFN-α and an TNF-α antagonist in the treatment of HS virus infection in a patient, which comprises administering to the patient a dose of INΕΕKSΕN® containing from about 1 to 9 mcg of the drug per dose INΕΕKSΕN®, subcutaneously daily, every other day, 2 times a week, 3 times a week, weekly, every other week, 3 times a month, 1 time per month or per day, mainly continuously or continuously in combination with a dose a TNF-α antagonist containing from about 0.1 μg to 40 mg of a TNF-α antagonist per dose, subcutaneously daily, every other day, 2 times a week, 3 times a week or per day, mostly continuously or continuously for a desired period treatment with a compound of inhibitor Ν83.

In another embodiment, the present invention discloses any of the methods described above that are modified to use an effective amount of a PEGylated consensus IFN-α and an TNF-α antagonist in the treatment of a viral infection in a patient, which comprises administering to the patient a dose of PEGylated consensus IFN-α (PEG KIFN), containing from about 4 to 60 μg KIFN of amino acid weight per dose of PEG-KIFN, subcutaneously weekly, every other week, 3 times a month, 1 time per month; in combination with a dose of TNF-α antagonist containing approximately 0.1 μg to 40 mg of TNF-α antagonist per dose, subcutaneously daily, every other day, 2 times a week, 3 times a week or per day, mostly continuously or continuously during the desired treatment period with compound # 83.

- 83 012389

In another embodiment, the present invention discloses any of the methods described above that are modified to use an effective amount of a pegylated consensus IFN-α and an TNF-α antagonist in the treatment of a viral infection in a patient, which comprises administering to the patient a dose of a pegylated consensus IFN-α (PEG KIFN) containing approximately 18 to 24 micrograms of CIFF amino acid weight per dose of PEG-CIFN, subcutaneously weekly, every other week, 3 times a month, 1 time per month; in combination with a dose of TNF-α antagonist containing approximately 0.1 μg to 40 mg of TNF-α antagonist per dose, subcutaneously daily, every other day, 2 times a week, 3 times a week or per day, mostly continuously or continuously during the desired treatment period with compound # 83.

In another embodiment, the invention discloses any of the above methods, modified to use an effective amount of IFN - "- 2a. or 2b or 2c and an effective amount of a TNF-α antagonist in treating a viral infection in a patient, comprising administering to a patient a dose of IFN ^ -2a, or 2b, or 2c, containing from about 1 to 20 IU of the drug per dose of IFN ^ -2a, or 2b, or 2c, subcutaneously daily, every other day, 2 times a week, 3 times a week or per day, mainly continuously or continuously in combination with a dose of a TNF-α antagonist containing from about 0.1 μg to 40 mg of a TNF-α antagonist α per dose, subcutaneous daily, every other day, 2 times a week, 3 times a week or per day, mostly continuously whether continuously for the desired treatment duration Ν83 inhibitor compound.

In another embodiment, the invention discloses any of the methods described above that are modified to use an effective amount of IFN ^ -2a, or 2b, or 2c and an effective amount of TNF-α antagonist in treating a viral infection in a patient, comprising administering to the patient a dose of IFN ^ -2a, or 2b, or 2c, containing approximately 3 IU of the drug per dose of IFN ^ -2a, or 2b, or 2c subcutaneously daily, every other day, 2 times a week, 3 times a week or per day, mainly continuously or continuously; in combination with a dose of TNF-α antagonist, containing from about 0.1 μg to 40 mg of TNF-α antagonist per dose, subcutaneously daily, every other day, 2 times a week, 3 times a week or per day, mostly continuously or continuously for the desired treatment period with a compound of inhibitor Ν83.

In another embodiment, the invention discloses any of the methods described above that are modified to use an effective amount of IFN ^ -2a, or, 2b, or 2c, and an effective amount of an TNF-α antagonist in treating a viral infection in a patient, comprising administering to the patient a dose of IFN ^ -2a, or 2b, or 2c, containing from about 10 IU of the drug per dose of IFN ^ -2a, or 2b, or 2c subcutaneously daily, every other day, 2 times a week, 3 times a week or per day, mostly continuously or continuously; in combination with a dose of TNF-α antagonist containing approximately 0.1 μg to 40 mg of TNF-α antagonist per dose, subcutaneously daily, every other day, 2 times a week, 3 times a week or per day, mostly continuously or continuously during the desired treatment period with compound # 83.

In another embodiment, the invention discloses any of the methods described above that are modified to use an effective amount of PECA8U8® IFN ^ -2a conjugated to PEG and an effective amount of a TNF-α antagonist in treating a viral infection in a patient, comprising administering to the patient a dose of REOA8U8® containing in an amount approximately 90 to 360 μg of the drug per dose of REOA8U8® subcutaneously once a week, every other week, 3 times a month or monthly in combination with a dose of TNF-α antagonist containing approximately from 0.1 μg to 40 mg of TNF-α antagonist per dose, subcutaneously daily, every other day, 2 times a week, 3 times a week or per day, mostly continuously or continuously during the desired treatment period with compound Ν83 inhibitor.

In another embodiment, the invention discloses any of the methods described above modified to use an effective amount of REOA8U8® IFN ^ -2a conjugated to PEG and an effective amount of a TNF-α antagonist in treating a viral infection in a patient, comprising administering to the patient a dose of REOA8U8® containing approximately 180 μg of the drug per dose of REOA8U8® subcutaneously once a week, every other week, 3 times a month or monthly in combination with a dose of TNF-α antagonist containing from about 0.1 μg to 40 mg ant TNF-α gonista per dose, subcutaneously daily, every other day, 2 times a week, three times a week or a day substantially continuously or continuously, for the desired duration of treatment with compound inhibitor Ν83.

In another embodiment, the invention discloses any of the methods described above that are modified to use an effective amount of REO GLTCOK® IFN ^ -2b conjugated to PEG and an effective amount of a TNF-α antagonist in treating a viral infection in a patient, comprising administering to the patient a dose of REO! No. HA. OK®, containing approximately 0.75 to 3.0 μg of the drug per 1 kg of body weight per dose of REO INTKΟN® subcutaneously once a week, every other week, 3 times a

- 84 012389 month or monthly in combination with a dose of TNF-α antagonist. containing in an amount of from about 0.1 μg to 40 mg of TNF-α antagonist per dose. subcutaneously daily. in one day. 2 times per week. 3 times a week or per day. substantially continuously or continuously during the desired treatment period with the K83 inhibitor compound.

In another embodiment, the invention discloses any of the above methods. modified to use an effective amount of RES 1KTVOK® IFN ^^ b. conjugated to PEG and an effective amount of an TNF-α antagonist in the treatment of a viral infection in a patient. comprising administering to the patient a dose of RES 1KTVOK®. containing approximately 1.5 μg of the drug per 1 kg of body weight per dose of RES 1KTVOK® subcutaneously once a week. in a week. 3 times a month or monthly in combination with a dose of TNF-α antagonist. containing in an amount of from about 0.1 μg to 40 mg of TNF-α antagonist per dose. subcutaneously daily. in one day. 2 times per week. 3 times a week or per day. substantially continuously or continuously during the desired treatment period with the K83 inhibitor compound.

Combination therapy with other antiviral agents.

Other agents. such as K83 HCV inhibitors. they are also attractive drugs for combination therapy and are considered for use in combination therapies. described here. Ribozymes. such as Hep1ahute ™. and phosphorothioates of oligonucleotides. which are complementary to HCV protein sequences and which inhibit the expression of viral capsid proteins. also suitable for use in combination therapies. described here.

In some embodiments, additional antiviral agents are administered during the full course of treatment with the K83 inhibitor compound of the invention. and the beginning and end of treatment periods coincide. In other embodiments, an additional antiviral agent is administered over a period of time. which overlaps with the treatment of K83 with inhibitory compounds. for example, treatment with an additional antiviral agent may begin before treatment with K83 inhibitor compounds begins and end before treatment with K83 inhibitor compounds; treatment with an additional antiviral agent can begin after the start of treatment with K83 inhibitor compounds and end after treatment with K83 inhibitor compounds; treatment with an additional antiviral agent can begin after treatment with K83 inhibitor compounds has commenced and end before treatment with K83 inhibitor compounds or treatment with an additional antiviral agent can begin before treatment with K83 inhibitor compounds ends after treatment with K83 inhibitor compounds.

The K83 inhibitor compound can be administered together with (i.e., simultaneously in separate dosage forms; simultaneously in the same dosage form; simultaneously in separate forms and after about 48. 3b. 24. 1b. 12. 8. 4. 2 1 hour after 30.15 minutes or less) of one or more additional anti-virus agents.

As an example. not limiting the scope of claims. any of the above methods. characterized by IFN-α mode. can be modified by replacing the IFN-α mode with the mono-PEGylated (30 kDa linear) consensus IFN-α mode. comprising administering a dose of mono-PEGylated (30 kDa. linear) consensus IFN-α. containing 100 μg of the drug per dose. subcutaneously once a week. 1 time every eight days or 1 time every ten days during the desired treatment period with the K83 inhibitor compound.

As an example. not limiting the scope of claims. any of the above methods. characterized by IFN-α mode. can be modified by replacing the IFN-α mode with the mono-PEGylated (30 kDa linear) consensus IFN-α mode. including the introduction of a dose of monoPEGylated (30 kDa. linear). consensus IFN-α. containing 150 mcg of drug per dose. subcutaneously once a week. 1 time every eight days or 1 time every ten days during the desired treatment period with the K83 inhibitor compound.

As an example. not limiting the scope of claims. any of the above methods. characterized by IFN-α mode. can be modified by replacing the IFN-α mode with the mono-PEGylated (30 kDa linear) consensus IFN-α mode. including the introduction of a dose of mono-PEGylated (30 kDa. linear). consensus IFN-α. containing 200 mcg of drug per dose. subcutaneously once a week. 1 time every eight days or 1 time every ten days during the desired treatment period with the K83 inhibitor compound.

As an example. not limiting the scope of claims. any of the above methods. characterized by IFN-α mode. can be modified by replacing IFN-α mode with 1KEEVSEK® interferon-alpha-con ₁ mode. including the introduction of a dose of YUTEVSEC® interferon-alpha-con ₁ . containing 9 mcg of drug per dose. subcutaneously 1 time per day or 3 times a week for the desired treatment period with the compound of the K83 inhibitor.

- 85 012389

As an example, not limiting the scope of claims, any of the methods described above characterized by the IFN-α mode can be modified by replacing the IFN-α mode with the GYREKSEM® interferon-alpha-con ₁ regimen, including the administration of a dose of UTEXSE® interferon-alfacon ₁ containing 15 μg of the drug per dose, subcutaneously 1 time per day or 3 times a week for the desired treatment period with compound # 83 inhibitor.

As an example, not limiting the scope of claims, any of the methods described above, characterized by the IFN-α mode, can be modified by replacing the IFN-α mode with the ^ REXEC® interferon-alpha-con ₁ mode, including the administration of a dose of UTEXEN® interferon-alpha-con ₁ 25 μg of the drug per dose, subcutaneously 1 time per day or 3 times per week for the desired treatment period with compound Ν83 inhibitor.

As an example, not limiting the scope of claims, any of the methods described above that differ in the IFN-γ regimen may be modified by replacing the IFN-γ regimen with the IFN-γ regimen, including the administration of a dose of IFN-γ containing 50 μg of the drug per dose, subcutaneously 3 times a week for the desired treatment period with compound # 83 inhibitor.

As an example, not limiting the scope of claims, any of the methods described above that differ in the IFN-γ regimen may be modified by replacing the IFN-γ regimen with the IFN-γ regimen, including the administration of a dose of IFN-γ containing 100 μg of the drug per dose, subcutaneously 3 times a week for the desired treatment period with compound # 83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ, can be modified by replacing the combined IFN-α and IFN-γ according to the invention with IFN-α and IFN-γ combined mode, including:

(a) administering a dose of mono-PEGylated (30 kDa, linear) consensus IFN-α containing 100 μg of the drug per dose, subcutaneously once a week, once every eight days, or once every ten days;

(b) administering a dose of IFN-γ, containing 50 μg of the drug per dose, subcutaneously 3 times during the desired treatment period with compound # 83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods that differ in the mode of TNF antagonist can be modified by replacing the TNF antagonist mode with a TNF antagonist mode, including the introduction of a dose of TNF antagonist selected from the group:

(a) etanercept in an amount of 25 mg of the drug per dose subcutaneously 2 times a week;

(b) infliximab in the amount of 3 mg of the drug per 1 kg of body weight per dose intravenously at 0, 2 and 6 weeks and then every 8th week; or (c) adalimumab in the amount of 40 mg of the drug per dose subcutaneously 1 time to the introducer or once every 2 weeks during the desired period of treatment with a compound of inhibitor Ν83.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ, can be modified by replacing the combined IFN-α and IFN-γ according to the invention with IFN-α and IFN-γ combined mode, including:

(a) administering a dose of mono-PEGylated (30 kDa, linear) consensus IFN-α containing 100 μg of the drug per dose, subcutaneously once a week, once every eight days, or once every ten days;

(b) administering a dose of IFN-γ containing 100 μg of the drug per dose, subcutaneously 3 times during the desired treatment period with compound # 83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ, can be modified by replacing the combined IFN-α and IFN-γ according to the invention with IFN-α and IFN-γ combined mode, including:

(a) administering a dose of mono-PEGylated (30 kDa, linear) consensus IFN-α containing 150 μg of the drug per dose, subcutaneously once a week, once every eight days, or once every ten days;

(b) administering a dose of IFN-γ containing 50 μg of the drug per dose subcutaneously 3 times during the desired treatment period with compound # 83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ, can be modified by replacing the combined IFN-α and IFN-γ according to the invention with IFN-α and IFN-γ combined mode, including:

(a) administering a dose of mono-PEGylated (30 kDa, linear) consensus IFN-α containing 150 μg of the drug per dose, subcutaneously once a week, once every eight days, or once every ten days;

(b) administering a dose of IFN-γ containing 100 μg of the drug per dose, subcutaneously 3 times during the desired treatment period with compound ингиб83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ, can be modified by replacing the combined

- 86 012389 IFN-α and IFN-γ modes according to the invention for IFN-α and IFN-γ combined mode, including:

(a) administering a dose of mono-PEGylated (30 kDa, linear) consensus IFN-α containing 200 μg of the drug per dose, subcutaneously once a week, once every eight days, or once every ten days;

(b) administering a dose of IFN-γ containing 50 μg of the drug per dose subcutaneously 3 times during the desired treatment period with compound # 83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ, can be modified by replacing the combined IFN-α and IFN-γ according to the invention with IFN-α and IFN-γ combined mode, including:

(a) administering a dose of mono-PEGylated (30 kDa, linear) consensus IFN-α containing 200 μg of the drug per dose, subcutaneously once a week, once every eight days, or once every ten days;

(b) administering a dose of IFN-γ containing 100 μg of the drug per dose, subcutaneously 3 times during the desired treatment period with compound ингиб83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ, can be modified by replacing the combined IFN-α and IFN-γ according to the invention with IFN-α and IFN-γ combined mode, including:

(a) dosing INΡΕJACΕN® interferon-alpha-con ₁ containing 9 μg of the drug per dose, subcutaneously 3 times a week;

(b) administering a dose of IFN-γ containing 25 μg of the drug per dose, subcutaneously 3 times during the desired treatment period with compound ит83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ, can be modified by replacing the combined IFN-α and IFN-γ according to the invention with IFN-α and IFN-γ combined mode, including:

(a) dosing INΡΕJACΕN® interferon-alpha-con ₁ containing 9 μg of the drug per dose, subcutaneously 3 times a week;

(b) administering a dose of IFN-γ containing 50 μg of the drug per dose subcutaneously 3 times during the desired treatment period with compound # 83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ, can be modified by replacing the combined IFN-α and IFN-γ according to the invention with IFN-α and IFN-γ combined mode, including:

(a) dosing INΡΕJACΕN® interferon-alpha-con ₁ containing 9 μg of the drug per dose, subcutaneously 3 times a week;

(b) administering a dose of IFN-γ containing 100 μg of the drug per dose, subcutaneously 3 times during the desired treatment period with compound # 83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ, can be modified by replacing the combined IFN-α and IFN-γ according to the invention with IFN-α and IFN-γ combined mode, including:

(a) dosing INΡΕJACΕN® interferon-alpha-con ₁ , containing 9 μg of the drug per dose, subcutaneously 1 time daily;

(b) administering a dose of IFN-γ containing 25 μg of the drug per dose, subcutaneously 3 times during the desired treatment period with compound ит83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ, can be modified by replacing the combined IFN-α and IFN-γ according to the invention with IFN-α and IFN-γ combined mode, including:

(a) dosing INΡΕJACΕN® interferon-alpha-con ₁ , containing 9 μg of the drug per dose, subcutaneously 1 time daily;

(b) administering a dose of IFN-γ, containing 50 μg of the drug per dose, subcutaneously 3 times during the desired treatment period with compound # 83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ, can be modified by replacing the combined IFN-α and IFN-γ according to the invention with IFN-α and IFN-γ combined mode, including:

(a) dosing INΡΕJACΕN® interferon-alpha-con ₁ , containing 9 μg of the drug per dose, subcutaneously 1 time daily;

(b) administering a dose of IFN-γ containing 100 μg of the drug per dose, subcutaneously 3 times during the desired treatment period with compound ингиб83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ, can be modified by replacing the combined IFN-α and IFN-γ according to the invention with IFN-α and IFN-γ combined mode, including:

- 87 012389 (a) administering a dosage INΕΕΚSΕN® interferon-alpha _con-s containing 15 ug of drug per dose, subcutaneously three times per week;

(b) administering a dose of IFN-γ containing 25 μg of the drug per dose subcutaneously 3 times during the desired treatment period with the N83 inhibitor compound.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ, can be modified by replacing the combined IFN-α and IFN-γ according to the invention with IFN-α and IFN-γ combined mode, including:

(a) administering a dosage INΕΕΚSΕN® interferon-alpha _con-s containing 15 ug of drug per dose, subcutaneously three times per week;

(b) administering a dose of IFN-γ containing 50 μg of the drug per dose, subcutaneously 3 times during the desired treatment period with the compound N83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ, can be modified by replacing the combined IFN-α and IFN-γ according to the invention with IFN-α and IFN-γ combined mode, including:

(a) administering a dosage INΕΕΚSΕN® interferon-alpha _con-s containing 15 ug of drug per dose, subcutaneously three times per week;

(b) administering a dose of IFN-γ containing 100 μg of the drug per dose subcutaneously 3 times during the desired treatment period with the compound N83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ, can be modified by replacing the combined IFN-α and IFN-γ according to the invention with IFN-α and IFN-γ combined mode, including:

(a) administering a dosage INΕΕΚSΕN® interferon-alpha _con-s containing 15 ug of drug per dose, subcutaneously once daily 1;

(b) administering a dose of IFN-γ containing 25 μg of the drug per dose subcutaneously 3 times during the desired treatment period with the N83 inhibitor compound.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ, can be modified by replacing the combined IFN-α and IFN-γ according to the invention with IFN-α and IFN-γ combined mode, including:

(a) administering a dose of INΕΕΚCΕN® interferon-alpha-koshch, containing 15 μg of the drug per dose, subcutaneously 1 time daily;

(b) administering a dose of IFN-γ containing 50 drugs per dose, subcutaneously 3 times during the desired treatment period with the N83 inhibitor compound.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ, can be modified by replacing the combined IFN-α and IFN-γ according to the invention with IFN-α and IFN-γ combined mode, including:

(a) administering a dose of INΕΕΚCΕN® interferon-alpha-koshch, containing 15 μg of the drug per dose, subcutaneously 1 time daily;

(b) administering a dose of IFN-γ containing 100 μg of the drug per dose subcutaneously 3 times during the desired treatment period with the compound N83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ and an TNF antagonist, can be modified by replacing the described IFN-α and IFN-γ mode and TNF antagonist with IFN-α and IFN-γ and TNF antagonist, including:

(a) administering a dose of mono-PEGylated (30 kDa, linear) consensus IFN-α containing 100 μg of the drug per dose, subcutaneously once a week, once every eight days, or once every ten days;

(b) administering a dose of IFN-γ containing 100 μg of the drug per dose, subcutaneously 3 times a week; and (c) administering a dose of a TNF antagonist selected from the group (ί) etanercept in an amount of 25 mg subcutaneously 2 times a week, (ίί) infliximab in an amount of 3 mg of drug per 1 kg of body weight intravenously at 0-, 2- and 6- weeks and then every 8th week or (ίίί) adalimumab in an amount of 40 mg subcutaneously once a week or once every 2 weeks for the desired period of treatment with a compound of the N83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ and an TNF antagonist, can be modified by replacing the described IFN-α and IFN-γ mode and TNF antagonist with IFN-α and IFN-γ and TNF antagonist, including:

(a) administering a dose of mono-PEGylated (30 kDa, linear) consensus IFN-α containing 100 μg of the drug per dose, subcutaneously once a week, once every eight days, or once every ten days;

- 88 012389 (b) the introduction of a dose of IFN-γ containing 50 μg of the drug per dose, subcutaneously 3 times a week; and (c) administering a dose of TNF antagonist selected from the group (ί) etanercept in an amount of 25 mg subcutaneously 2 times a week, (ίί) infliximab in an amount of 3 mg of drug per 1 kg of body weight intravenously at 0, 2 and 6 weeks and then every 8th week or (ίίί) adalimumab in an amount of 40 mg subcutaneously once a week or once every 2 weeks for a desired period of treatment with a compound of the N83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ and an TNF antagonist, can be modified by replacing the described IFN-α and IFN-γ mode and TNF antagonist with IFN-α and IFN-γ and TNF antagonist, including:

(a) administering a dose of mono-PEGylated (30 kDa, linear) consensus IFN-α containing 150 μg of the drug per dose, subcutaneously once a week, once every eight days, or once every ten days;

(b) administering a dose of IFN-γ containing 50 μg of the drug per dose, subcutaneously 3 times a week; and (c) administering a dose of TNF antagonist selected from the group (ί) etanercept in an amount of 25 mg subcutaneously 2 times a week, (ίί) infliximab in an amount of 3 mg of drug per 1 kg of body weight intravenously at 0, 2 and 6 weeks and then every 8th week or (ίίί) adalimumab in an amount of 40 mg subcutaneously once a week or once every 2 weeks for a desired period of treatment with a compound of the N83 inhibitor.

As an example, not limiting the scope of claims, any of the methods described above that differ in the combination mode of IFN-α and IFN-γ and an TNF antagonist can be modified by replacing the described IFN-α and IFN-γ mode and an TNF antagonist with IFN-α and IFN-γ and TNF antagonist, including:

(a) administering a dose system of mono-PEGylated (30 kDa, linear) consensus IFN-α containing 150 μg of the drug per dose, subcutaneously once a week, once every eight days, or once every ten days;

(b) the introduction of a system of doses of IFN-γ, containing in an amount of 100 μg of the drug per dose, subcutaneously 3 times a week; and (c) administration of a dose system of a TNF antagonist selected from the group (ί) etanercept in an amount of 25 mg subcutaneously 2 times a week, (ίί) infliximab in an amount of 3 mg of drug per 1 kg of body weight intravenously at the 0, 2 and 6th a week and then every 8th week or (ίίί) adalimumab in an amount of 40 mg subcutaneously once a week or once every 2 weeks for the desired period of treatment with a compound of the N83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ and an TNF antagonist, can be modified by replacing the described IFN-α and IFN-γ mode and TNF antagonist with IFN-α and IFN-γ and TNF antagonist, including:

(a) administering a dose system of mono-PEGylated (30 kDa, linear) consensus IFN-α containing 200 μg of the drug per dose, subcutaneously once a week, once every eight days or once every ten days;

(b) the introduction of a system of doses of IFN-γ containing 50 μg of the drug per dose, subcutaneously 3 times a week; and (c) administration of a dose system of a TNF antagonist selected from the group (ί) etanercept in an amount of 25 mg subcutaneously 2 times a week, (ίί) infliximab in an amount of 3 mg of drug per 1 kg of body weight intravenously at 0-, 2- and 6 weeks and then every 8th week or (ίίί) adalimumab in an amount of 40 mg subcutaneously 1 time per week or 1 time in 2 weeks during the desired period of treatment with a compound of the N83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ and an TNF antagonist, can be modified by replacing the described IFN-α and IFN-γ mode and TNF antagonist with IFN-α and IFN-γ and TNF antagonist, including:

(a) administering a dose system of mono-PEGylated (30 kDa, linear) consensus IFN-α containing 200 μg of the drug per dose, subcutaneously once a week, once every eight days, or once every ten days;

(b) the introduction of a system of doses of IFN-γ containing 100 μg of the drug per dose, subcutaneously 3 times a week; and (c) administering a dose system of a TNF antagonist selected from the group (ί) etanercept in an amount of 25 mg subcutaneously 2 times a week, (ίί) infliximab in an amount of 3 mg of drug per 1 kg of body weight intravenously at 0-, 2- and 6 weeks and then every 8th week or (ίίί) adalimumab in an amount of 40 mg subcutaneously 1 time per week or 1 time in 2 weeks during the desired period of treatment with a compound of the N83 inhibitor.

- 89 012389

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ and an TNF antagonist, can be modified by replacing the described IFN-α and IFN-γ mode and TNF antagonist with IFN-α and IFN-γ and TNF antagonist, including:

(a) the introduction of a system of doses of GNEYACEN® interferon-alpha-con ₁ containing 9 μg of the drug per dose, subcutaneously 3 times a week;

(b) the introduction of a system of doses of IFN-γ containing 25 μg of the drug per dose, subcutaneously 3 times a week; and (c) administration of a dose system of a TNF antagonist selected from the group (ί) etanercept in an amount of 25 mg subcutaneously 2 times a week, (and) infliximab in an amount of 3 mg of drug per 1 kg of body weight intravenously at 0-, 2- and 6 weeks and then every 8th week or (ίίί) adalimumab in an amount of 40 mg subcutaneously 1 time per week or 1 time in 2 weeks during the desired period of treatment with a compound of the N83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ and an TNF antagonist, can be modified by replacing the described IFN-α and IFN-γ mode and TNF antagonist with IFN-α and IFN-γ and TNF antagonist, including:

(a) the introduction of a system of doses of GNEYACEN® interferon-alpha-con ₁ containing 9 μg of the drug per dose, subcutaneously 3 times a week;

(b) the introduction of a system of doses of IFN-γ containing 50 μg of the drug per dose, subcutaneously 3 times a week; and (c) administration of a dose system of a TNF antagonist selected from the group (ί) etanercept in an amount of 25 mg subcutaneously 2 times a week, (ίί) infliximab in an amount of 3 mg of drug per 1 kg of body weight intravenously at 0-, 2- and 6 weeks and then every 8th week or (ίίί) adalimumab in an amount of 40 mg subcutaneously 1 time per week or 1 time in 2 weeks during the desired period of treatment with a compound of the N83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ and an TNF antagonist, can be modified by replacing the described IFN-α and IFN-γ mode and TNF antagonist with IFN-α and IFN-γ and TNF antagonist, including:

(a) the introduction of a system of doses of GNEYACEN® interferon-alpha-con ₁ containing 9 μg of the drug per dose, subcutaneously 3 times a week;

(b) the introduction of a system of doses of IFN-γ containing 100 μg of the drug per dose, subcutaneously 3 times a week; and (c) administration of a dose system of a TNF antagonist selected from the group (ί) etanercept in an amount of 25 mg subcutaneously 2 times a week, (ίί) infliximab in an amount of 3 mg of drug per 1 kg of body weight intravenously at 0-, 2- and 6 weeks and then every 8th week or (ίίί) adalimumab in an amount of 40 mg subcutaneously 1 time per week or 1 time in 2 weeks during the desired period of treatment with a compound of the N83 inhibitor.

As an example, not limiting the scope of claims, any of the methods described above that differ in the combination mode of IFN-α and IFN-γ and an TNF antagonist can be modified by replacing the described IFN-α and IFN-γ mode and an TNF antagonist with IFN-α and IFN-γ and TNF antagonist, including:

(a) the introduction of a system of doses of GNEYACEN® interferon-alpha-con ₁ containing 9 μg of the drug per dose, subcutaneously 1 time daily;

(b) the introduction of a system of doses of IFN-γ containing 25 μg of the drug per dose, subcutaneously 3 times a week; and (c) administration of a dose system of a TNF antagonist selected from the group (ί) etanercept in an amount of 25 mg subcutaneously 2 times a week, (ίί) infliximab in an amount of 3 mg of drug per 1 kg of body weight intravenously at 0-, 2- and 6 weeks and then every 8th week or (ίίί) adalimumab in an amount of 40 mg subcutaneously 1 time per week or 1 time in 2 weeks during the desired period of treatment with a compound of the N83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ and an TNF antagonist, can be modified by replacing the described IFN-α and IFN-γ mode and TNF antagonist with IFN-α and IFN-γ and TNF antagonist, including:

(a) administering a dose system of GNJACEN® interferon-alpha-con ₁ containing 9 μg of the drug per dose subcutaneously 1 time daily;

(b) the introduction of a system of doses of IFN-γ containing 50 μg of the drug per dose, subcutaneously 3 times a week; and

- 90 012389 (c) introduction of a dose system of a TNF antagonist selected from the group (ί) etanercept in an amount of 25 mg subcutaneously 2 times a week, (ίί) infliximab in an amount of 3 mg of drug per 1 kg of body weight intravenously at 0-, 2- and 6 weeks and then every 8th week or (ίίί) adalimumab in an amount of 40 mg subcutaneously 1 time per week or 1 time in 2 weeks during the desired period of treatment with a compound of the N83 inhibitor.

As an example, not limiting the scope of claims, any of the methods described above that differ in the combination mode of IFN-α and IFN-γ and an TNF antagonist can be modified by replacing the described IFN-α and IFN-γ mode and an TNF antagonist with IFN-α and IFN-γ and TNF antagonist, including:

(a) the administration of a dose system of INΕEXCEN® interferon-alpha-kosh containing 9 μg of the drug per dose, subcutaneously 1 time daily;

(b) the introduction of a system of doses of IFN-γ containing 100 μg of the drug per dose, subcutaneously 3 times a week; and (c) administration of a dose system of a TNF antagonist selected from the group (ί) etanercept in an amount of 25 mg subcutaneously 2 times a week, (ίί) infliximab in an amount of 3 mg of drug per 1 kg of body weight intravenously at 0-, 2- and 6 weeks and then every 8th week or (ίίί) adalimumab in an amount of 40 mg subcutaneously 1 time per week or 1 time in 2 weeks during the desired period of treatment with a compound of the N83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ and an TNF antagonist, can be modified by replacing the described IFN-α and IFN-γ mode and TNF antagonist with IFN-α and IFN-γ and TNF antagonist, including:

(a) administering a dose system of INΕEXCEN® interferon-alpha-kosh, containing 15 μg of the drug per dose, subcutaneously 3 times a week;

(b) the introduction of a system of doses of IFN-γ containing 25 μg of the drug per dose, subcutaneously 3 times a week; and (c) administration of a dose system of a TNF antagonist selected from the group (ί) etanercept in an amount of 25 mg subcutaneously 2 times a week, (ίί) infliximab in an amount of 3 mg of drug per 1 kg of body weight intravenously at 0-, 2- and 6 weeks and then every 8th week or (ίίί) adalimumab 40 mg subcutaneously once a week or once every 2 weeks for the desired period of treatment with a compound of the N83 inhibitor.

As an example, not limiting the scope of claims, any of the methods described above that differ in the combination mode of IFN-α and IFN-γ and an TNF antagonist can be modified by replacing the described IFN-α and IFN-γ mode and an TNF antagonist with IFN-α and IFN-γ and TNF antagonist, including:

(a) administering a dose system of INΕEXCEN® interferon-alpha-kosh, containing 15 μg of the drug per dose, subcutaneously 3 times a week;

(b) the introduction of a system of doses of IFN-γ containing 50 μg of the drug per dose, subcutaneously 3 times a week; and (c) administration of a dose system of a TNF antagonist selected from the group (ί) etanercept in an amount of 25 mg subcutaneously 2 times a week, (ίί) infliximab in an amount of 3 mg of drug per 1 kg of body weight intravenously at 0-, 2- and 6 weeks and then every 8 weeks or (ίίί) adalimumab in an amount of 40 mg subcutaneously once a week or once every 2 weeks for the desired period of treatment with a compound of the N83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ and an TNF antagonist, can be modified by replacing the described IFN-α and IFN-γ mode and TNF antagonist with IFN-α and IFN-γ and TNF antagonist, including:

(a) administering a dose system of INΕEXCEN® interferon-alpha-kosh, containing 15 μg of the drug per dose, subcutaneously 3 times a week;

(b) the introduction of a system of doses of IFN-γ containing 100 μg of the drug per dose, subcutaneously 3 times a week; and (c) administration of a dose system of a TNF antagonist selected from the group (ί) etanercept in an amount of 25 mg subcutaneously 2 times a week, (ίί) infliximab in an amount of 3 mg of drug per 1 kg of body weight intravenously at 0-, 2- and 6 weeks and then every 8th week or (ίίί) adalimumab in an amount of 40 mg subcutaneously 1 time per week or 1 time in 2 weeks during the desired period of treatment with a compound of the N83 inhibitor.

As an example, not limiting the scope of claims, any of the methods described above that differ in the combination mode of IFN-α and IFN-γ and an TNF antagonist can be modified by replacing the described IFN-α and IFN-γ mode and an TNF antagonist with IFN-α and IFN-γ and TNF antagonist, including:

- 91 012389 (a) the administration of a dose system of INEΕK6ΕN® interferon-alpha-kosh, containing 15 μg of the drug per dose, subcutaneously 1 time per day;

(b) the introduction of a system of doses of IFN-γ containing 25 μg of the drug per dose, subcutaneously 3 times a week; and (c) administration of a dose system of a TNF antagonist selected from the group (ί) etanercept in an amount of 25 mg subcutaneously 2 times a week, (ίί) infliximab in an amount of 3 mg of drug per 1 kg of body weight intravenously at 0-, 2- and 6 weeks and then every 8th week or (ίίί) adalimumab in an amount of 40 mg subcutaneously 1 time per week or 1 time in 2 weeks during the desired treatment period with compound ингиб83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ and an TNF antagonist, can be modified by replacing the described IFN-α and IFN-γ mode and TNF antagonist with IFN-α and IFN-γ and TNF antagonist, including:

(a) administering an INEΈK6ΕN® interferon-alpha-clot dose system containing 15 μg of the drug per dose subcutaneously once a day;

(b) the introduction of a system of doses of IFN-γ containing 50 μg of the drug per dose, subcutaneously 3 times a week; and (c) administration of a dose system of a TNF antagonist selected from the group (ί) etanercept in an amount of 25 mg subcutaneously 2 times a week, (ίί) infliximab in an amount of 3 mg of drug per 1 kg of body weight intravenously at 0-, 2- and 6 weeks and then every 8th week or (ίίί) adalimumab in an amount of 40 mg subcutaneously 1 time per week or 1 time in 2 weeks during the desired treatment period with compound ингиб83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, characterized by a combination of IFN-α and IFN-γ and an TNF antagonist, can be modified by replacing the described IFN-α and IFN-γ mode and TNF antagonist with IFN-α and IFN-γ and TNF antagonist, including:

(a) administering an INEΈK6ΕN® interferon-alpha-clot dose system containing 15 μg of the drug per dose subcutaneously once a day;

(b) the introduction of a system of doses of IFN-γ, containing in an amount of 100 μg of the drug per dose, subcutaneously 3 times a week; and (c) administration of a dose system of a TNF antagonist selected from the group (ί) etanercept in an amount of 25 mg subcutaneously 2 times a week, (ίί) infliximab in an amount of 3 mg of drug per 1 kg of body weight intravenously at 0-, 2- and 6 weeks and then every 8th week or (ίίί) adalimumab in an amount of 40 mg subcutaneously 1 time per week or 1 time in 2 weeks during the desired treatment period with compound ингиб83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods that differ in the combination mode of IFN-α and TNF antagonist can be modified by replacing the described regime of IFN-α and TNF antagonist with IFN-α and TNF antagonist, including:

(a) administering a dose system of mono-PEGylated (30 kDa, linear) consensus IFN-α containing 100 μg of the drug per dose, subcutaneously once a week, once every eight days or once every ten days;

(b) administration of a dose system of a TNF antagonist selected from the group (ί) etanercept in an amount of 25 mg subcutaneously 2 times a week, (ίί) infliximab in an amount of 3 mg of drug per 1 kg of body weight intravenously at 0-, 2- and 6- weeks and then every 8th week or (ίίί) adalimumab in an amount of 40 mg subcutaneously once a week or once every 2 weeks during the desired treatment period with compound Ν83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods that differ in the combination mode of IFN-α and TNF antagonist can be modified by replacing the described regime of IFN-α and TNF antagonist with IFN-α and TNF antagonist, including:

(a) administering a dose system of mono-PEGylated (30 kDa, linear) consensus IFN-α containing 150 μg of the drug per dose, subcutaneously once a week, once every eight days or once every ten days;

(b) administration of a dose system of a TNF antagonist selected from the group (ί) etanercept in an amount of 25 mg subcutaneously 2 times a week, (ίί) infliximab in an amount of 3 mg of drug per 1 kg of body weight intravenously at 0-, 2- and 6- weeks and then every 8th week or (ίίί) adalimumab in an amount of 40 mg subcutaneously once a week or once every 2 weeks during the desired treatment period with compound Ν83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods that differ in the combination mode of IFN-α and TNF antagonist can be modified by replacing the described regime of IFN-α and TNF antagonist with IFN-α and TNF antagonist, including:

- 92 012389 (a) the administration of a system of doses of mono-PEGylated (30 kDa, linear) consensus IFN-α containing 200 μg of the drug per dose, subcutaneously once a week, once every eight days or once every ten days;

(b) administration of a dose system of a TNF antagonist selected from the group (ί) etanercept in an amount of 25 mg subcutaneously 2 times a week, (ίί) infliximab in an amount of 3 mg of drug per 1 kg of body weight intravenously at 0-, 2- and 6- weeks and then every 8th week or (ίίί) adalimumab in an amount of 40 mg subcutaneously once a week or once every 2 weeks during the desired treatment period with compound Ν83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods that differ in the combination mode of IFN-α and TNF antagonist can be modified by replacing the described regime of IFN-α and TNF antagonist with IFN-α and TNF antagonist, including:

(a) administering a dose system of INΕEΚCEN® interferon-alpha-con ₁ containing 9 μg of the drug per dose, subcutaneously once a day or 3 times a week;

(b) administration of a dose system of a TNF antagonist selected from the group (ί) etanercept 25 mg subcutaneously 2 times a week, (ίί) infliximab in the amount of 3 mg of the drug per 1 kg of body weight intravenously at 0-, 2- and 6th weeks and then every 8th week or (ίίί) adalimumab in an amount of 40 mg subcutaneously 1 time per week or 1 time in 2 weeks during the desired treatment period with compound Ν83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods that differ in the combination mode of IFN-α and TNF antagonist can be modified by replacing the described regime of IFN-α and TNF antagonist with IFN-α and TNF antagonist, including:

(a) the introduction of a dose system I \ ΡЕΡСОN® interferon-alpha-con ₁ , containing 15 μg of the drug per dose, subcutaneously 1 time per day or 3 times a week;

(b) administration of a dose system of a TNF antagonist selected from the group (ί) etanercept in an amount of 25 mg subcutaneously 2 times a week, (ίί) infliximab in an amount of 3 mg of drug per 1 kg of body weight intravenously at 0-, 2- and 6- weeks and then every 8th week or (ίίί) adalimumab in an amount of 40 mg subcutaneously once a week or once every 2 weeks during the desired treatment period with compound Ν83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods that differ in the combination mode of IFN-γ and TNF antagonist can be modified by replacing the described regime of IFN-γ and TNF antagonist with the IFN-γ mode and TNF antagonist, including:

(a) the introduction of a system of doses of IFN-γ containing 25 μg of the drug per dose, subcutaneously 3 times a week; and (c) administration of a dose system of a TNF antagonist selected from the group (ί) etanercept in an amount of 25 mg subcutaneously 2 times a week, (ίί) infliximab in an amount of 3 mg of drug per 1 kg of body weight intravenously at 0-, 2- and 6 weeks and then every 8th week or (ίίί) adalimumab in an amount of 40 mg subcutaneously 1 time per week or 1 time in 2 weeks during the desired treatment period with compound ингиб83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods that differ in the combination mode of IFN-γ and TNF antagonist can be modified by replacing the described regime of IFN-γ and TNF antagonist with the IFN-γ mode and TNF antagonist, including:

(a) the introduction of a dose system of IFN-γ containing 50 μg of the drug per dose, subcutaneously 3 times a week; and (c) administration of a dose system of a TNF antagonist selected from the group (ί) etanercept in an amount of 25 mg subcutaneously 2 times a week, (ίί) infliximab in an amount of 3 mg of drug per 1 kg of body weight intravenously at 0-, 2- and 6 weeks and then every 8th week or (ίίί) adalimumab in an amount of 40 mg subcutaneously 1 time per week or 1 time in 2 weeks during the desired treatment period with compound ингиб83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods that differ in the combination mode of IFN-γ and TNF antagonist can be modified by replacing the described regime of IFN-γ and TNF antagonist with the IFN-γ mode and TNF antagonist, including:

(a) the introduction of a system of doses of IFN-γ containing 100 μg of the drug per dose, subcutaneously 3 times a week; and (c) administration of a dose system of a TNF antagonist selected from the group (ί) etanercept in an amount of 25 mg subcutaneously 2 times a week, (ίί) infliximab in an amount of 3 mg of drug per 1 kg of body weight intravenously at 0-, 2- and 6 weeks and then every 8th week or (ίίί) adalimumab in an amount of 40 mg subcutaneously 1 time per week or 1 time in 2 weeks during the desired treatment period with compound ингиб83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods, which includes a mono-PEGylated (30 kDa, linear) consensus IFN-α mode, can be modified by replacing the described mono-PEGylated (30 kDa, linear) consensus mode

- 93 012389 soy-IFN-α to the PEG regimen of interferon-alpha-2a, including the introduction of a system of doses of PEG interferon-alpha-2a, containing 180 μg of the drug per dose, subcutaneously 1 time per week during the desired treatment period with the compound of inhibitor Ν83 .

As an example, not limiting the scope of claims, any of the above methods, which includes a mono-PEGylated (30 kDa linear) consensus IFN-α mode, can be modified by replacing the described mono-PEGylated (30 kDa linear) consensus IFN-α mode with a PEG interferon mode alpha-2b, including the introduction of a system of doses of PEG interferon-alpha-2b, containing from 1.0 to 1.5 μg of the drug per 1 kg of body per dose, subcutaneously 1 time per week for the desired treatment period with compound Ν83 inhibitor.

As an example, not limiting the scope of claims, any of the methods described above can be modified by the additional administration of a dose of ribivirin containing 400, 800, 1000 or 1200 mg of the drug orally per day, in two or more doses per day, for a desired period treatment with a compound of inhibitor Ν83.

As an example, not limiting the scope of claims, any of the methods described above can be modified by the additional administration of a dose of ribivirin containing (ί) 1000 mg of the drug orally per day for patients weighing less than 75 kg or (ίί) in the amount of 1200 mg of the drug orally per day for patients weighing more than or equal to 75 kg, in two or more doses per day, during the desired treatment period with compound Ν83 inhibitor.

As an example, not limiting the scope of claims, any of the above methods can be modified by replacing the described mode of the inhibitor Ν83 with the mode of the inhibitor Ν83, which includes the introduction of a system of doses from 0.01 to 0.1 mg of the drug per 1 kg of body weight orally daily, in two or more daily doses during the desired treatment period with a соедин83 inhibitor compound.

As an example, not limiting the scope of claims, any of the above methods can be modified by replacing the described mode of the inhibitor Ν83 with the mode of the inhibitor Ν83, which includes the introduction of a system of doses from 0.1 to 1 mg of the drug per 1 kg of body weight orally daily, in two or more receptions per day during the desired period of treatment with a compound of inhibitor Ν83.

As an example, not limiting the scope of claims, any of the methods described above can be modified by replacing the described mode of the inhibitor Ν83 with the regime of the inhibitor Ν83, which includes the introduction of a system of doses from 1 to 10 mg of the drug per 1 kg of weight orally daily, in two or more doses in day, during the desired treatment period with a compound of inhibitor # 83.

As an example, not limiting the scope of claims, any of the above methods can be modified by replacing the described mode of the inhibitor Ν83 with the mode of the inhibitor Ν83, which includes the introduction of a system of doses from 10 to 100 mg of the drug per 1 kg of body weight orally daily, in two or more doses in day, during the desired treatment period with a compound of inhibitor # 83.

As an example, not limiting the scope of claims, any of the methods described above characterized by the Ν85Β inhibitor mode can be modified by replacing the described Ν85Β inhibitor mode with the Ν85Β inhibitor mode, which includes introducing a system of doses from 0.01 to 0.1 mg of the drug per 1 kg of weight orally daily, in two or more doses per day, for the desired treatment period with a compound of inhibitor Ν83.

As an example, not limiting the scope of claims, any of the methods described above characterized by the Ν85Β inhibitor regimen can be modified by replacing the described Ν85Β inhibitor regimen with the Ν85Β inhibitor regimen, including the administration of a system of doses from 0.1 to 1 mg of the drug per 1 kg of body weight per day , in two or more doses per day, during the desired treatment period with compound # 83.

As an example, not limiting the scope of claims, any of the methods described above characterized by the Ν85Β inhibitor regimen can be modified by replacing the described Ν85Β inhibitor regimen with the Ν85Β inhibitor regimen, which includes introducing a system of doses from 1 to 10 mg of the drug per 1 kg of body weight orally daily, two or more daily doses during the desired treatment period with a compound of inhibitor ит83.

As an example, not limiting the scope of claims, any of the methods described above characterized by the Ν85Β inhibitor regimen can be modified by replacing the described Ν85Β inhibitor regimen with the Ν85Β inhibitor regimen, including the administration of a system of doses of 10 to 100 mg of the drug per 1 kg of body weight orally daily, in two or more daily doses during the desired treatment period with a соедин83 inhibitor compound.

Patient identification.

In some embodiments, the specific drug regimen used to treat patients with HS virus infection is selected according to certain parameters of the disease that appear in the patient, such as the initial viral load, the genotype of the patient’s HS virus infection, histology of the liver and / or stage of liver fibrosis in a patient.

- 94 012389

Thus. in some embodiments, the present invention discloses any of the methods described above for treating hepatitis C virus infection, wherein the method is modified to treat a patient with an adverse treatment outcome within 48 weeks.

In other embodiments, the invention discloses any of the above methods for treating a viral infection of HS. wherein the described method is modified to treat a patient. with a lack of therapeutic effect. where the patient undergoes a 48-week course of therapy.

In other embodiments, the invention discloses any of the above methods for treating a viral infection of HS. in which the described method is modified to treat a patient with a relapse of the disease. where the patient undergoes a 48-week course of therapy.

In other embodiments, the invention discloses any of the above methods for treating a viral infection of HS. wherein the described method is modified to treat a patient. HCV-infected genotype 1. where the patient undergoes a 48-week course of therapy.

In other embodiments, the invention discloses any of the above methods for treating a viral infection of HS. wherein the described method is modified to treat a patient. HCV-infected genotype 4. where the patient undergoes a 48-week course of therapy.

In other embodiments, the invention discloses any of the above methods for treating a viral infection of HS. wherein the described method is modified to treat a patient. HCV-infected genotype 1. where the patient has a high viral load (BBH). where “BBH” refers to the viral load of HCV more than 2x10 ^b HCV genomic copies per 1 ml of serum and where the patient undergoes a 48-week course of therapy.

In one embodiment of the invention, the invention discloses any of the above methods for treating a viral infection of HS. in which the described method is modified to include the stages:

(1) patient identification. having a progressive or severe stage of liver fibrosis. evaluated by the Knodell system (Kpoye11) with an index of 3 or 4. and then (2) the patient undergoes drug therapy according to the described method for a period of time from about 24 to b0 weeks. or from 30 weeks to 1 year. or from 3b to 50 weeks. or from 40 to 48 weeks. or at least 24 weeks. or at least 30 weeks. or at least 3b weeks. or at least 40 weeks. or at least 48 weeks. or at least b0 weeks.

In another embodiment, the invention discloses any of the methods described above for treating a viral infection of HS. in which the described method is modified to include the stages:

(1) patient identification. having a progressive or severe stage of liver fibrosis. evaluated using the Knodell system (Kpoye11) with an index of 3 or 4. and then

2) conducting the patient drug therapy according to the described method for a period of time from about 40 to 50 weeks or about 48 weeks.

In another embodiment, the invention discloses any of the methods described above for treating a viral infection of HS. in which the described method is modified to include the stages:

(1) patient identification. having a viral infection of HS genotype 1. and an initial viral load of more than 2 million viral genomic copies per 1 ml of patient serum. and then (2) administering drug therapy to the patient according to the described method for a period of time from about 24 to b0 weeks. or from 30 weeks to 1 year. or from 3b to 50 weeks. or from 40 to 48 weeks. or at least 24 weeks. or at least 30 weeks. or at least 3b weeks. or at least 40 weeks. or at least 48 weeks. or at least b0 weeks.

In another embodiment, the invention discloses any of the methods described above for treating a viral infection of HS. in which the described method is modified to include the stages:

(1) patient identification. having a viral infection of HS genotype 1 and an initial viral load of more than 2 million viral genomic copies per 1 ml of patient serum. and then (2) administering drug therapy to the patient according to the described method for a period of time from about 40 to 50 weeks or about 48 weeks.

In another embodiment, the invention discloses any of the methods described above for treating a viral infection of HS. in which the described method is modified to include the stages:

(1) patient identification. having a viral infection of HS genotype 1 and an initial viral load of more than 2 million viral genomic copies per 1 ml of patient serum or early stage liver fibrosis. estimated by the Knodell system (Kpoye11). with an index of 0. 1 or 2. and then

- 95 012389 (2) administering drug therapy to a patient according to the described method for a period of time from about 24 to 60 weeks, or from 30 weeks to 1 year, or from 36 to 50 weeks, or from 40 to 48 weeks, or at least 24 weeks, or at least 30 weeks, or at least 36 weeks, or at least 40 weeks, or at least 48 weeks, or at least 60 weeks.

In another embodiment of the invention, the invention discloses any of the methods described above for treating a viral infection of HS, wherein the described method is modified to include the steps of:

(1) identification of a patient having a viral infection of HS genotype 1 and an initial viral load of more than 2 million viral genomic copies per 1 ml of patient serum or early stage liver fibrosis, evaluated by the Knodell system (Kio4e11), with an index of 0, 1 or 2, and then (2) administering drug therapy to the patient according to the described method for a period of time from about 40 to 50 weeks or about 48 weeks.

In another embodiment of the invention, the invention discloses any of the methods described above for treating a viral infection of HS, wherein the described method is modified to include the steps of:

(1) identifying a patient having a viral infection of HS genotype 1 and an initial viral load of more than 2 million viral genomic copies per 1 ml of patient serum, and then (2) administering drug therapy to the patient according to the described method for a period of time from about 20 to 50 weeks, or from 24 to 48 weeks, or from 30 to 40 weeks, or up to about 20 weeks, or up to 24 weeks, or up to 30 weeks, or up to 36 weeks, or up to 48 weeks.

In another embodiment of the invention, the invention discloses any of the methods described above for treating a viral infection of HS, wherein the described method is modified to include the steps of:

(1) identifying a patient having a viral infection of HS genotype 1 and an initial viral load of more than 2 million viral genomic copies per 1 ml of patient serum, and then (2) administering drug therapy to the patient according to the described method for a period of time from about 20 to 24 weeks.

In another embodiment of the invention, the invention discloses any of the methods described above for treating a viral infection of HS, wherein the described method is modified to include the steps of:

(1) identifying a patient having a viral infection of HS genotype 1 and an initial viral load of more than 2 million viral genomic copies per 1 ml of patient serum, and then (2) administering drug therapy to the patient according to the described method for a period of time from about 24 to 48 weeks.

In another embodiment of the invention, the invention discloses any of the methods described above for treating a viral infection of HS, wherein the described method is modified to include the steps of:

(1) identifying a patient having a viral infection with HS genotype 2 or 3, and then (2) administering drug therapy to the patient according to the described method for a period of time from about 24 to 60 weeks, or from 30 weeks to 1 year, or from 36 to 50 weeks, or from 40 to 48 weeks, or at least 24 weeks, or at least 30 weeks, or at least 36 weeks, or at least 40 weeks, or at least 48 weeks, or at least 60 weeks.

In another embodiment of the invention, the invention discloses any of the methods described above for treating a viral infection of HS, wherein the described method is modified to include the steps of:

(1) identifying a patient having a viral infection with HS genotype 2 or 3, and then (2) administering drug therapy to the patient according to the described method for a period of time from about 20 to 50 weeks, or from 24 to 48 weeks, or from 30 to 40 weeks, or up to about 20 weeks, or up to 24 weeks, or up to 30 weeks, or up to 36 weeks, or up to 48 weeks.

In another embodiment of the invention, the invention discloses any of the methods described above for treating a viral infection of HS, wherein the described method is modified to include the steps of:

(1) identifying a patient having a viral infection of HS genotype 2 or 3, and then (2) administering drug therapy to the patient according to the described method for a period of time from about 20 to 24 weeks.

In another embodiment of the invention, the invention discloses any of the methods described above for treating a viral infection of HS, wherein the described method is modified to include the steps of:

(1) identifying a patient having a viral infection of HS genotype 2 or 3, and then (2) administering drug therapy to the patient according to the described method for a period of at least 24 weeks.

- 96 012389

In another embodiment of the invention, the invention discloses any of the methods described above for treating a viral infection of HS, wherein the described method is modified to include the steps of:

(1) identifying a patient having a viral infection with HS genotype 1 or 4, and then (2) administering drug therapy to the patient according to the described method for a period of time from about 24 to 60 weeks, or from 30 weeks to 1 year, or from 36 to 50 weeks, or from 40 to 48 weeks, or at least 24 weeks, or at least 30 weeks, or at least 36 weeks, or at least 40 weeks, or at least 48 weeks, or at least 60 weeks.

In another embodiment of the invention, the invention discloses any of the methods described above for treating a viral infection of HS, wherein the described method is modified to include the steps of:

(1) identifying a patient having a HS virus infection that is different from any of the HCV genotypes 5, 6, 7, 8 and 9, and then (2) administering drug therapy to the patient according to the described method for a period of time from about 20 to 50 weeks.

In another embodiment of the invention, the invention discloses any of the methods described above for treating a viral infection of HS, wherein the described method is modified to include the steps of:

(1) identifying a patient having a viral infection of HS characterized by any of the HCV genotypes 5, 6, 7, 8 and 9, and then (2) administering drug therapy to the patient according to the described method for a period of time of at least about 24 weeks and up to 48 weeks.

Objects suitable for treatment.

Any of the above treatment regimens can be carried out on patients who are diagnosed with HS viral infection. Any of the above regimes can be applied to patients in whom the previous treatment of a viral infection of the HS did not have a therapeutic effect ("patients whose treatment failed", including patients with no therapeutic effect and patients with relapse of the disease).

Patients who have been clinically diagnosed with a viral infection of HS are of particular interest in many embodiments of the invention. Patients who have been diagnosed with hepatitis C under clinical conditions are considered to have HCV RNA in the blood and / or serum anti-HCV antibodies. Such patients include anti-HCV EH8 positive patients and patients with positive recombinant immunoblot assay (CDVA). Such patients may, but not necessarily, also have elevated serum ALT levels.

Patients who are clinically diagnosed with a viral infection of HS include patients who have not been exposed to any effect (for example, patients who have not previously been treated for a viral infection of HS, namely those who have not previously been treated with IFN-α-based therapy) and / or ribavirin) and patients in whom the preliminary treatment of a viral infection of the HS did not have an effect ("patients whose treatment failed"). Patients whose treatment failed, include patients with no therapeutic effect (i.e., patients whose HCV titer did not decrease significantly or not enough with pre-treatment for HCV, for example, IFN-α pre-monotherapy and IFN-α and ribavirin combination therapy or preliminary combination therapy with IFN-α conjugated to PEG and ribavirin); and patients with relapse of the disease (i.e., patients who have been pretreated with HCV, for example, patients who have previously received IFN-α monotherapy, preliminary combination therapy with IFN-α and ribavirin, or preliminary combination therapy with IFN-α conjugated with PEG, and ribavirin, and the HCV titer first decreased and then increased).

In particular embodiments of interest, patients have an HCV titer of at least 10 ⁵ , at least about 5x10 ⁵ , or at least about 10 ⁶ , or at least about 2x10 ⁶ genomic copies of HCV / ml serum. The patient can be infected with any HCV genotype (genotype 1, including 1a and 1b, 2, 3, 4, 6, etc. and subtypes (e.g. 2a, 2b, 3a, etc.)), especially complex for treatment with genotypes such as HCV genotype 1 and specific subtypes of HCV and quasivids.

- 97 012389

HCV-positive patients (as described above) who have severe fibrosis or early cirrhosis (not decompensated, Child-Pugh class A or less), or more advanced cirrhosis (decompensated, Child-Pugh class B or C) are also of interest. due to the chronic form of a viral infection of HS and in which the virus is present in the blood, despite preliminary antiviral IFN-α therapy, or who cannot tolerate IFN-α therapy, or who have contraindications to such therapies. In specific embodiments of the invention, HCV-positive patients with stage 3 or 4 liver fibrosis according to the METAUSC gradation system are suitable for treatment by the methods of the present invention. In other embodiments, patients suitable for treatment by the methods of the present invention are patients with decompensated cirrhosis with clinical manifestations, including patients with severely advanced cirrhosis, including those awaiting a liver transplant. In still other embodiments, patients suitable for treatment with the methods of the present invention include patients with weaker degrees of fibrosis, including patients with early fibrosis (stages 1 and 2 according to the METAU ^ K, LiyDd and 8sieyeeg gradation system or stages 1, 2 or 3 according to the Ibac system).

Obtaining viral inhibitors of section A.

Compounds of general formula I can be synthesized in the same manner as described below for compounds of general formulas P-Xxx. The synthesis of various specific compounds of the general formula I is described in the examples below. The person skilled in the art will determine the variations in the sequence and then determine the changes in the respective reaction conditions by analogy with the reactions given here or otherwise known, which can be suitably used in the processes described below to obtain compounds of formula I.

The reaction products described herein can be isolated by conventional methods, such as extraction, distillation, chromatography, and the like.

Salts of compounds of the formulas described above are prepared by reacting the corresponding bases or acids with a stoichiometric equivalent of a compound of formula I.

Obtaining viral inhibitors of section B.

The meaning of the terms and structural names used in this section is the same as the names and conditions of section B above. Any reference in this section to any number or designation should be considered in the context of the corresponding numbering or designation of symbols used in this section or section B above, in contrast to the context, a similar or identical numbering or designation of symbols used here elsewhere is possible if not specified otherwise.

Compounds of formulas PX can be synthesized in accordance with the methods described below. Methodology

Obtaining compounds of General formula I.

Two methods were used to prepare compounds of general formula I. In both methods, intermediate compounds 1 and 4 were obtained in accordance with the procedures described in international application PCT / CA00 / 00353 (publication number \ UO 00/59929). Intermediate 4 was also acquired by K8P Atsho Ac1J8.

- 98 012389

Example 1-1 Synthesis of compound 101 (compound AB00220042) by method A

R

Connection 101 (Connection AK00220042)

Method A

Stage 1. Synthesis of 28- (1-Ethoxycarbonyl-2-vinylcyclopropylcarbamoyl) -4B-hydroxypyrrolidine-1-carboxylic acid tert-butyl ether (3)

IT

2 3

1: 1 (1H, 25)! (18, 2H)

Into a flask with ethyl- (1B, 28) / (18.2V) -1-amino-2-vinylcyclopropylcarboxylate (1, 1.0 g, 5.2 mmol), trans - \ - (tert-butoxycarbonyl) -4- hydroxy-B-proline (2, 1.3 g, 1.1 eq.), and O- (7-azabenzotriazol-1yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (NATI) (2.7 g, 1.1 equiv.) Was added 30 ml of DMF to obtain a solution. The solution was then cooled to 0 ° C in an ice bath, after which a solution of Ν, Ν-diisopropylethylamine (ΌΠΛ) (4.4 ml, 4 equiv.) In DMF (15 ml) was slowly added with stirring. The reaction mixture was allowed to warm to room temperature and was stirred overnight.

The reaction was completed after 16 hours based on control by high performance liquid chromatography (HPLC). The mixture was diluted with EluAc ethyl acetate (100 ml), washed with water (3x40 ml), saturated ANCO ₃ solution (2x40 ml) and brine (2x40 ml), then dried over ₂ 8O ₄ and concentrated to give a dark red oil . The mixture was purified on silica gel (eluent: acetone / hexane 3: 7) to give pure substance 3 as a tan powder (770 mg, 32%).

Stage 2. Synthesis of 3,4-dihydro-1H-isoquinoline-2-carboxylic acid 1-tert-butoxycarbonyl-5 (1B-ethoxycarbonyl-28-vinylcyclopropylcarbamoyl) pyrrolidin-3B-yl ether (5) and 3,4-dihydro- 1Nisoquinoline-2-carboxylic acid 1-tert-butoxycarbonyl-5- (18-ethoxycarbonyl-2B-vinylcyclopropylcarbamoyl) pyrrolidin-3B-yl ester (6)

- 99 012389

5 (1 / = ?, 25) 6 (13.2 ")

Dipeptide 3 (300 mg, 0.81 mmol) was dissolved in dichloromethane (ESM) (8 ml), after which carbodiimide (SEG) (163 mg, 1.2 equiv.) Was added in one portion. The reaction was stirred overnight at room temperature. After 15 hours, the reaction was completed based on control by thin layer chromatography (TLC) (ESM / MeOH 9: 1). 1,2,3,4-Tetrahydroisoquinoline (0.32 ml, 3 equiv.) Was added dropwise to the reaction mixture and the reaction was stirred at room temperature overnight.

After 22 hours, the reaction was completed based on TLC. The reaction mixture was diluted with dichloromethane (15 ml), washed with 1N. aqueous HC1 (15 ml), brine (15 ml), dried over No. ₂ 8O ₄ and concentrated. The product was purified on silica gel (eluent: ESM / E1 ₂ O / acetone 30: 10: 1). The highlighted top spot (TLC) (5) was a white powder (169 mg, 40%), and the bottom spot (6) was a white solid precipitate (156 mg, 38%).

MS (mass spectrum) t / e 550 (M '+ No.).

Step 3. Synthesis of 3,4-dihydro-1H-isoquinoline-2-carboxylic acid 1- (28-tert-butoxycarbonylamino-non-8-enoyl) -5- (1H-ethoxycarbonyl-28-vinylcyclopropylcarbamoyl) pyrrolidin-3H-yl ether (7)

Upper isomer 5 (118 mg, 0.22 mmol) was dissolved in 4N. HC1 (dioxane, 8 ml) and left at room temperature for 90 minutes to remove Boc (tert-butyloxycarbonyl) protecting groups. The solution was concentrated, then dissolved in acetonitrile, then again concentrated twice. Compound 4 (66.8 mg, 1.1 equiv.) And NATi (93.5 mg, 1.1 equiv.) Were added to the light brown precipitate, after which 2 ml of DMF in the nitrogen atomosphere was added. The reaction was cooled in an ice bath for 15 minutes, after which 0.5 ml of a solution in DMF EHEA (0.13 ml, 4 equiv.) Was added to the reaction mixture dropwise with stirring. The ice bath was removed to slowly increase the temperature to room temperature and the reaction mixture was stirred overnight.

After 24 hours, the reaction mixture turned dark brown. A TLC test indicated completion of the reaction. The reaction mixture was diluted with ethyl acetate (EJAc) (30 ml) and washed with water (3x15 ml), saturated NaΗCO3 solution (2x15 ml), brine (15 ml), dried (No. ₂ 8О ₄ ) and concentrated to give 7 as an orange oily precipitate (156 mg). The compound was used in the next step without further purification.

MS m / e 703 (\ E- \ a).

- 100 012389

Step 4. Synthesis of (18.4K, 68.148.18K) -14-tert-butoxycarbonylamino-18- (3,4-dihydro-1Η-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diazatricyclo [ 14.3.0.0 ^4.6 ] nonadec-7-en-4-carbocyclic acid ethyl ester (8)

Product 7 (135 mg, 0.2 mmol) was dissolved in 20 ml of dichloroethane Og18o1ue, after which Nolan catalyst (5 mg, 0.3 equiv.) Was added at room temperature under a nitrogen atmosphere. The solution became crimson. The reaction mixture was placed in an oil bath (50 ° C.) and stirred overnight.

After 10 hours, the reaction mixture turned dark brown. The TLC chromatogram (ESM / ESAc 1: 1) showed the appearance of a new spot with a lower K _T value. The reaction mixture was concentrated and purified on silica gel (eluent: OSM / E1OAc, gradient from 5: 1 to 2: 1) to give product 8 as a yellow-brown powder (75 mg, 58%).

MS t / e 653.1 (M ⁺ +1).

Stage 5. Synthesis of (18.4K, 68.148.18K) -14-tert-butoxycarbonylamino-18- (3,4-dihydro-1Nisoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diazatricyclo [14.3. 0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound 101)

Compound 101

Macrocyclic ether 8 (60 mg, 0.092 mmol) was dissolved in 0.9 ml of a solvent mixture (THF / MeOH / H ₂ O 2: 1: 1), after which ^^ ОΗ-Н ₂ О (23 mg, 6 equiv. ) The mixture was stirred at room temperature overnight. After 18 h, TCX (OSM / MeOCH 9: 1) showed the appearance of a new clean spot with a smaller K _T. The reaction mixture was concentrated almost to dryness and partitioned between 1N. aqueous 11Cl (15 ml) and dichloromethane OSM (20 ml). The aqueous layer was extracted again with OSM (2x10 ml). The organic layers were combined, dried over Xa ₂ 8 O ₄ and concentrated to give compound 101 as a light brown powder (50 mg, 87%).

¹ Η NMR (СО ₃ ОО, 400 MHz) δ 1.20-1.67 (m, 21Η), 1.70-1.83 (m, 1Η), 1.88-2.10 (m, 1Η) , 2.12-2.58 (m, 4Η), 2.82 (m, 2Η), 3.60-3.80 (m, 2Η), 3.86 (m, 1Η), 4.20 (m , 1Η), 4.35 (m, 1Η), 4.54 (s, 7Η), 4.58 (m, 3Η), 5.295.41 (m, 2Η), 5.57 (m, 1Η), 7 , 0-7.24 (m, 4Η).

MS t / e 625.1 (M ⁺ +1).

Example 1-1a

Connection AK00220122

- 101 012389 (18.48.6H, 148.18H) -14-tert-Butoxycarbonylamino-18- (3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound

AY00220122) was obtained in accordance with the procedures described in example 1-1, replacing compound 5 with 6 in stage 3.

MS t / e 625 (M ⁺ +1).

Example 1-2. The synthesis of compound 101 (compound AY00220042) according to method B.

Method B

Compound 101 was obtained in accordance with the above procedure. The synthesis of macrocyclic intermediate 10 described herein is similar to that described in PCT / CA00 / 00353 (Publication Number AO 00/59929).

Stage 1. Synthesis of (28-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl) -4H-hydroxypyrrolidine-1carboxylic acid tert-butyl ether (3)

Into a flask with ethyl (1H, 28) / (18.2H) -1-amino-2-vinylcyclopropylcarboxylate (1, 1.0 g, 5.2 mmol), trans-Y- (tert-butoxycarbonyl) -4-hydroxy L-proline (2, 1.3 g, 1.1 eq.) And O- (7-azabenzotriazol-1-yl) -

1,1,3,3-tetramethyluronium hexafluorophosphate (NATI) (2.7 g, 1.1 eq.) Was added 30 ml of DMF to obtain a solution. The solution was then cooled to 0 ° C in an ice bath, after which a solution of Ν, Ν-diisopropylethylamine (ΌΙΕΛ) (4.4 ml, 4 equiv.) In DMF (15 ml) was slowly added with stirring. The reaction mixture was allowed to warm to room temperature and was stirred overnight.

After 16 hours, the reaction was completed, as demonstrated by high performance liquid chromatography (HPLC). The mixture was diluted with ethyl acetate-Ac (100 ml), washed with water (3x40 ml), saturated NaHCΟ ₃ solution (2x40 ml) and brine (2x40 ml), then dried over No. 8O ₄ and concentrated to give a dark red oil. The mixture was purified on silica gel (eluent: acetone / hexane 3: 7) to give pure substance 3 as a tan powder (770 mg,

32%).

- 102 012389

Stage 2. Synthesis of 1K - {[1- (28-tert-butoxycarbonylamino-non-8-enoyl) -4K-hydroxypyrrolidine25-carbonyl] amino} -28-vinylcyclopropanecarboxylic acid ethyl ester (9)

Compound 3 (2.85 g, 7.7 mmol) was dissolved in 10 ml of 4N. HC1 (dioxane) was left at room temperature for 90 minutes to remove the Boc-protecting groups. The solution was concentrated, then extracted with acetonitrile, then again concentrated twice. Compound 4 (2.2 g, 8.1 mmol) and NATI (3.2 g, 8.5 mmol) were added to the resulting light brown precipitate, after which 80 ml of DMF in the nitrogen atomosphere was added. The reaction was cooled in an ice bath for 15 minutes, after which 5 ml of a solution of EHEA (5.4 ml, 30.9 mmol) in DMF were added to the reaction mixture dropwise with stirring. The ice bath was removed to slowly raise the temperature to room temperature, and the reaction mixture was stirred overnight.

After 18 h, TLC showed completion of the reaction. The reaction mixture was diluted with EuAc (300 ml) and washed with water (3x150 ml), saturated Na растворомCΟz solution (2x150 ml), brine (150 ml), dried (No. ₂ 8О ₄ ) and the solvent removed. The product was purified on silica gel by flash chromatography on B1O1ad 40M (eluent = 3 to 5% MeOH in an ESM) to give 9 as a brown solid (3.5 g, 87%).

Stage 3. Synthesis of (18.4K, 68.148.18K) -14-tert-butoxycarbonylamino-18-hydroxy-2.15-dioxo-3,16 diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4-carbon ethyl ester acids (10)

Compound 9 (2.6 g, 5.0 mmol) was dissolved in 500 ml of dichloroethane Ep8O1ue in a 1 L round bottom flask to give a solution. The solution was degassed by bubbling nitrogen for 1 h. Then, the Hoveida catalyst (0.25 equiv.) Was added at room temperature under a nitrogen atmosphere. The reaction mixture was placed in a preheated oil bath (50 ° C.) and stirred overnight. After 16 hours, the reaction mixture turned dark brown. TLC (ESM / EJAc 1: 1) showed complete conversion and the appearance of a new spot with a lower value of K. The reaction mixture was concentrated and purified on silica gel (Vu1ade 40 M, eluent = ESM / EJAc gradient from 1: 1 to 1: 2) to obtain product 10 as a tan powder (0.64 g, 52%).

¹ H NMR (SES13, 400 MHz) δ 1.21 (t, 1 = 7.0 Hz, 3H), 1.43 (s, 9H), 1.20-1.50 (m, 6H), 1, 53-1.68 (m, 2H), 1.83-1.96 (m, 2H), 1.98-2.28 (m, 4H), 2.60 (m, 1H), 3.13 ( broad s, 1H), 3.68 (m, 1H), 3.94 (m, 1H), 4.01-4.19 (m, 2H), 4.48 (m, 1H), 4.56 (br.s, 1H), 4.79 (m, 1H), 5.26 (t, 1 = 9.4 Hz, 1H), 5.36 (d, 1 = 7.8 Hz, 1H), 5 53 (m, 1H); 7.19 (br s, 1H).

MS t / e 494.0 (M ⁺ +1).

- 103 012389

Stage 4. Synthesis of (18.4K, 68.148.18K) -14-tert-butoxycarbonylamino-18- (3,4-dihydro-1Nisoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diazatricyclo [14.3. 0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid ethyl ester (11)

Macrocyclic intermediate 10 (110 mg, 0.22 mmol) was dissolved in dichloromethane (OCM) (2.2 ml), after which carbodiimide (CO!) (45 mg, 0.27 mmol) was added in one portion. The reaction mixture was stirred at room temperature overnight. After 15 hours, the reaction was completed, as shown by ΤСX ЩСМ / МеОН 9: 1). 1,2,3,4-Tetrahydroisoquinoline (0.14 ml, 1.1 mmol) was added dropwise to the reaction mixture, and the reaction mixture was stirred at room temperature overnight. After 22 hours, ΤCX showed completion of the reaction. The reaction mixture was diluted with dichloromethane (6 ml) and washed with 1N. aqueous HC1 (2x2 ml), saturated N1111CO ₃ solution (2 ml), brine (2 ml), dried (No. ₂ 8O ₄ ) and concentrated. The product was purified on silica gel (Vyuade 40 M, eluent: 2 to 4% MeOH in dichloromethane) to give 11 as a pale yellow powder (131 mg, 90%).

Step 5. The compound was hydrolyzed in the same manner as described in step 5 of Example 1-1 to give compound 101.

The following compounds were also prepared according to method B described above, with the substitution of 1,2,3,4-tetrahydroisoquinoline for various other secondary amines. Most amines were purchased commercially or are compounds known in the literature and were obtained using the procedures described in 81okkeg, O.E. Te1gayebgop Bay. 1996, 37 (31), 5453-5456; Syap, K \. Vuogdats & Mei1sta1 Sjet1e1gu, 2000, 8, 2085-2094; Vessyesh, V. et al., I. May. Siet. 1991, 34, 2624-2633. The preparation of starting compounds for amines that were not directly synthesized in accordance with the procedures described in the literature, or specific starting compounds that were not described in the literature earlier, is given in each example based on our knowledge.

Example 1-3

Compound AK00226824 (18.4K, 68.148.18K) -14-tert-Butoxycarbonylamino-18- (6,7-dimethoxy-3,4-dihydro-1H-isoquinoline2-carbonyloxy) -2.15-dioxo-3.16- diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4-carboxylic acid (compound AK00226824) was synthesized according to method B, only 6,7-dimethoxy-1,2,3,4tetrahydroisoquinoline was used in stage 4 .

MS t / e 585.2 (M ⁺ + 1-100).

- 104 012389

Example 1-4

Compound AK00226825 (18.4B, 68.148.18B) -14-tert-Butoxycarbonylamino-2.15-dioxo-18- (1,3,4,9-tetrahydro-L-carboline 2-carbonyloxy) -3,16-diazatricyclo [ 14.3.0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound

AB00226825) was synthesized according to Method B, only 2,3,4,9-tetrahydro-1H-Lcarboline was used in step 4.

MS t / e 564.2 (M ⁺ + 1-100).

Example 1-5

R

Compound AK00291871 (18.4V, 68.148.18V) -14-tert-Butoxycarbonylamino-18- (1,3-dihydroisoindole-2-carbonyloxy) 2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound AB00291871) was synthesized according to method B, only 2,3-dihydro-1H-isoindole was used in step 4.

¹ H NMR (CBC1 ₃ , 500 MHz) δ 1.21-1.44 (m, 8H), 1.32 (s, 9H), 1.54-1.62 (m, 2H), 1.78- 1.88 (m, 2H), 2.042.13 (m, 1H), 2.16-2.23 (m, 1H), 2.24-2.36 (m, 2H), 2.66-2, 74 (m, 1H), 3.87-3.90 (m, 1H), 4.15 (d, 1 = 11.0 Hz, 1H), 4.37-4.43 (m, 1H), 4 61-4.77 (m, 5H), 5.18 (t, 1 = 10.3 Hz, 1H), 5.24-5.31 (m, 1n), 5.40-5.45 (m , 1H), 5.585.66 (m, 1H), 7.11-7.30 (m, 4H).

MS t / e 611.0 (M ⁺ +1).

Example 1-6

R

Compound AK00291875 (18.4V, 68.148.18V) -14-tert-butoxycarbonylamino-18- (2,3-dihydroindole-1-carbonyloxy) -2.15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4,6 ] -7-en-4-carboxylic acid (compound AB00291875) was synthesized according to method B, only 2,3-dihydro-1H-indole was used in step 4.

MS t / e 610.9 (M ⁺ +1).

- 105 012389

Example 1-7

Compound AK00294382 (18.4K, 68.148.18K) -14-tert-Butoxycarbonylamino-2.15-dioxo-18- (8-trifluoromethyl-3,4-dihydro1H-isoquinoline-2-carbonyloxy) -3,16-diazatricyclo [ 14.3.0.0 ^{4 '6]} nonadeca-7-ene-4-carboxylic acid (compound AK00294382) was synthesized according to method B, except 8-trifluoromethyl-

1,2,3,4-tetrahydroisoquinoline was used in step 4.

MS t / e 693.0 (M ⁺ )

Example 1-8

Compound AK00294383 (18.4K, 68.148.18K) -14-tert-Butoxycarbonylamino-2.15-dioxo-18- (6-trifluoromethyl-3,4-dihydro1H-isoquinoline-2-carbonyloxy) -3,16-diazatricyclo [ 14.3.0.0 ^{4 '6]} nonadeca-7-ene-4-carboxylic acid (compound AK00294383) was synthesized according to method B, except 6-trifluoromethyl-

1,2,3,4-tetrahydroisoquinoline was used in step 4.

¹ H NMR (500 MHz, ATP1 ₃ ) δ 7.46-7.38 (m, 2H), 7.26-7.18 (m, 1H), 6.98 (s, 1H), 5.62 ( q, 1H), 5.42 (s, 1H), 5.21-5.15 (m, 2H), 4.78-4.60 (m, 3H), 4.40 (s, 1H), 4 , 16-4.00 (m, 1H), 3.92-3.81 (m, 1H), 3.80-3.60 (m, 2H), 3.00-2.85 (m, 2H) 2.72-2.64 (br s, 1H); 2.40-1.18 (m, 20H).

MS t / e 693.0 (M ⁺ ).

Example 1-9

Compound AK00294384 (18.4K, 68.148.18K) -14-tert-Butoxycarbonylamino-18- (5-fluoro-3,4-dihydro-1H-isoquinoline-2carbonyloxy) -2,15-dioxo-3,16-diazatricyclo [ 14.3.0.0 ^{4 '6]} nonadeca-7-ene-4-carboxylic acid (compound AK00294384) was synthesized according to method B, except 5-fluoromethyl-1,2,3,4tetragidroizohinolin was used in step 4.

^{1 H NMR} (500 MHz, SES 13) δ 7.19-7.11 (m, 1H), 7.05 (m, 1H), 6.91 (t, 2H), 5.62 (q, 1H), 5 40 (s, 1H), 5.24 (d, 1H), 5.20 (t, 1H), 4.78 (s, 1H), 4.64-4.56 (m, 2H), 4, 42 (s, 1H), 4.12-4. 02 (m, 1H), 3.92-3.81 (m, 1H), 3.783.61 (m, 2H), 2.84-2.80 (m, 2H), 2.74-2.64 ( m, 1H), 2.36-2.18 (m, 2H), 1.91-1.81 (m, 2H), 1.64-1.54 (m, 2H), 1.48-1, 10 (m, 15H).

MS t / e 643.0 (M ⁺ ).

- 106 012389

Example 1-10

Compound AK00301745 (18.4K, 68.148.18K) -18- (5-amino-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -14-tert-butyloxycarbonylamino-2.15-dioxo-3.16- diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound AK00301745) was synthesized according to method B, only 5-amino-1,2,3,4tetrahydroisoquinoline was used in step 4.

MS t / e 640.1 (Μ +)

Example 1-11

R

Compound AK00301749 (18.4K, 68.148.18K) -18- (7-amino-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -14-tert-butoxycarbonylamino-2.15-dioxo-3.16- diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4-carboxylic acid (compound AK00301749) was synthesized according to method B, only 7-amino-1,2,3,4tetrahydroisoquinoline was used in step 4.

MS m / s 640.1 (Μ +), 641.1 (M ⁺ +1)

Example 1-12

Compound AK00304000 (18.4K, 68.148.18K) -14-tert-Butoxycarbonylamino-2.15-dioxo-18- (2-phenylamino-6,7-dihydro-4Nthiazolo [5,4-c] pyridin-5-carbonyloxy ) -3,16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4-carboxylic acid (compound AK00304000) was synthesized according to method B, only phenyl (4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) amine was used in step 4.

MS t / e 721.2 (Μ-1).

- 107 012389

Example 1-13

(18.4K, 68.148.18K) -14-tert-Butoxycarbonylamino-18- (7-chloro-3,4-dihydro-1H-isoquinoline-2carbonyloxy) -2,15-dioxo-3,16-diazatricyclo [14.3. 0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound No. 00304062) was synthesized according to method B, only 7-chloro-1,2,3,4-tetrahydroisoquinoline was used in step 4.

MS t / e 659.0 (M ⁺ ), 661.0 (M ⁺ +2).

Example 1-14

(18.4K, 68.148.18K) -14-tert-Butoxycarbonylamino-18- (6-fluoro-3,4-dihydro-1H-isoquinoline-2carbonyloxy) -2,15-dioxo-3,16-diazatricyclo [14.3. 0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound No. 00304063) was synthesized according to method B, only 6-fluoro-1,2,3,4tetrahydroisoquinoline was used in step 4.

MS m / v 643.0 (M), 644.0 (M ⁺ +1).

Example 1-15

(18.4K, 68.148.18K) -14-tert-Butoxycarbonylamino-18- (4,4-spirocyclobutyl-3,4-dihydro-1-Nizoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diazatricyclo [ 14.3.0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound No. 00304065) was synthesized according to method B, only

4,4-spirocyclobutyl-1,2,3,4-tetrahydroisoquinoline was used in step 4.

'Η NMR (400 MHz, 06-acetone) δ 7.99 (d, 1Η), 7.57-7.66 (m, 1Η), 7.27 (t, 1Η), 7.09-7.22 (m, 2Η), 5.99 (broad s, 1Η), 5.56 (dd, 1Η), 5.42 (broad s, 1Η), 5.19-5.30 (m, 1Η), 4.52-4.70 (m, 1Η), 4.27-4.42 (m, 1Η), 4.17-4.27 (m, 1Η), 3.91 (dd, 1Η), 3, 63-3.82 (m, 2Η), 2.22-2.51 (m, 6Η), 1.93-2.20 (m, 3Η), 1.79-1.91 (m, 1Η), 1.52-1.66 (m, 1Η), 1.16-1.50 (m, 19Η).

MS t / ζ 665.1 (M + 1).

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Example 1-15a. Preparation of 4.4-spirocyclobutyl-1.2.3.4-tetrahydroisoquinoline

A. To a solution of 1-phenyl-1-cyclopropane carbonitrile (2.00 g, 12.7 mmol) in 100 ml of THF was added a 1.0 M solution of L1A1H ₄ (19.1 ml. 19.1 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature for 15 hours. Then it was slowly neutralized at 0 ° С with 10 ml of Н ₂ О and then 10 ml of 1.0N. KaOH and stirred at room temperature for 15 hours. The solution was filtered and THF was removed on a rotary evaporator. The aqueous solution was extracted with EJAc and the organic extract was washed with H ₂ O and brine. dried over Ka ₂ 8O ₄ and concentrated to give 0.70 g (34%) of pure oil. which was used in the next step without further purification.

B. To a solution of C- (1-phenylcyclobutyl) methylamine (0.70 g. 4.34 mmol) and triethanolamine TEA (0. 6 ml. 4.78 mmol) in 40 ml of THF at 0 ° C was added dropwise methyl chloroformate. The reaction mixture was stirred at room temperature for 15 hours. The next day, water and E! OAc were added and the organic layer was separated and washed with 1N. HC1 and saline. dried over Ka28O4. concentrated to an oil and used in the next step without further purification.

C. A mixture of (1-phenylcyclobutylmethyl) carbamic acid methyl ester (0.95 g, 4.34 mmol) and 2-amino-1-phenylpropan-1-ol (PPA) (20 ml) was placed in a sand bath. preheated to 150 ° C. After 30 minutes, the reaction mixture was cooled to room temperature. After cooling, water was added dropwise and the solution was extracted twice with ESM dichloromethane. The organic extracts were washed with brine. dried over Ka ₂ 8O ₄ . concentrated to a pure oil. which was used directly in the next step without further purification.

Ό. To a solution of 3.4-dihydro-2H-isoquinolin-1-one (0.40 b, 2.17 mmol) in 20 ml of THF at 0 ° C was added dropwise a 1.0 M solution of L1L1H ₄ (3.2 b ml, 3.2 b mmol). The reaction mixture was warmed to room temperature and stirred for 15 hours. Then, 5 ml of H2O and then 5 ml of 1.0N were slowly neutralized at 0 ° С. KaOH and stirred at room temperature for 1.5 h. The solution was filtered and THF was removed on a rotary evaporator. The aqueous solution was extracted with E! OAc and the organic extract was washed with H2O and brine. dried over Ka28O4 and concentrated to give 0.21 g (5b%) of pure oil. which was used in the next step without further purification.

Example 1-1b

Compound AK00304066 (18.4B.b8.148.18B) -14-tert-Butoxycarbonylamino-18- (4.4-dimethyl-3.4-dihydro-1H-isoquinoline-2carbonyloxy) -2.15-dioxo-3.1b-diazatricyclo [14.3.0.0 ⁴ . ^b ] nonadec-7-en-4-carboxylic acid (compound AB003040bb) was synthesized according to method B. only 4.4-dimethyl-1.2.3.4 tetrahydroisoquinoline was used in step 4.

¹ H NMR (400 MHz. Th _b- acetone) δ 7.98 (d. 1H). 7.39 (broad s. 1H). 7.09-7.24 (m. 3H). 5.99 (broad s. 1H). 5.57 (dd. 1H). 5.37-5.4b (broad s. 1H). 5.24 (dd. 1H). 4.55-4.b9 (m. 1H). 4.2b-4.3b (m. 1H). 4.1b-4.2b (m. 1H). 3.90 (dd. 1H). 3.40-3.49 (m, 1H). 2.28-2.50 (m. 4H). 1.98-2.09 (2H). 1.79-1.92 (m, 1H). 1.52-1.b5 (m. 3H). 1.1b-1.51 (m. 22H).

MS t / ζ b53.0 (M ⁺ +1).

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Example 1-16a

4,4-Dimethyl-1,2,3,4-tetrahydroisoquinoline was obtained following the experimental steps A to Ό in Example 1-15a, 2-methyl-2-phenylpropionitrile (obtained according to Sagop, 8 .; Vaζ ^ Isζ, E .; Ao | c1k, 1.M, I. At. Sket. 8os. 2000, 122, 712-713) was converted to the title compound.

Example 1-17

(18.4K, 68.148.18K) -14-tert-Butoxycarbonylamino-18- (4-methyl-3,4-dihydro-1 H-isoquinoline-2carbonyloxy) -2,15-dioxo-3,16-diazatricyclo [14.3 .0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound AK00304067) was synthesized according to method B, only 4-methyl-1,2,3,4tetrahydroisoquinoline was used in step 4.

¹ H NMR (400 MHz, 06-acetone) δ 7.93-8.03 (m, 1H), 7.04-7.28 (m, 4H), 6.02 (br s, 1H), 5 56 (dd, 1H), 5.40 (m, 1H), 5.23 (dd, 1H), 4.66-4.85 (m, 1H), 4.54-4.64 (m, 1H) ), 4.34-4.54 (m, 1H), 4.17-4.34 (m, 1H), 3.91 (dd, 1H), 3.57-3.78 (m, 1H), 3.42-3.57 (m, 1H), 2.26-2.52 (m, 4H), 1.96-2.09 (m, 2.0), 1.77-1.92 (m 1.0), 1.501.64 (m, 3.0), 1.13-1.50 (m, 17H).

MS t / ζ 639.0 (M + 1).

Example 1-17a

4-Methyl-1,2,3,4-tetrahydroisoquinoline was obtained from 2-phenylpropylamine in accordance with Hypea ai, Ο.Κ; 8a11, Ό.Ι .; Mopp, 1.A. I. Honey. Sket. 1988, 31, 433-444.

Example 1-18

Compound AK00304103 (18.4K, 68.148.18K) -14-tert-Butoxycarbonylamino-18- (2-tert-butylamino-6,7-dihydro-4Nthiazolo [5,4-c] pyridin-5-carbonyloxy) -2, 15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4-carboxylic acid (compound AK00304103) was synthesized according to method B, only tert-butyl (4,5,6,7- tetrahydrothiazolo [5,4-c] pyridin-2-yl) amine was used in step 4.

MS t / e 731.2 (M + 1).

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Example 1-19

Compound AK00304154 (18.4K, 68.148.18K) -18- (2-amino-6,7-dihydro-4H-thiazolo [5,4-c] pyridine-5-carbonyloxy) -14-tert-butoxycarbonylamino-2.15- dioxo-3,16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4-carboxylic acid (compound AK00304154) was synthesized according to method B, only 4,5,6,7tetrahydrothiazolo [5,4- c] pyridin-2-ylamine was used in step 4.

MS t / e 675.1 (M ⁺ +1).

Example 1-20

Compound AK00304158 (18.4K, 68.148.18K) -14-tert-Butoxycarbonylamino-18- (2-methyl-6,7-dihydro-4H-thiazolo [5,4c] pyridin-5-carbonyloxy) -2,15- dioxo-3,16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4-carboxylic acid (compound AK00304158) was synthesized according to method B, only 2-methyl4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridine was used in step 4.

MS t / e 546.2 (M ⁺ + 1-100).

Example 1-21

Compound AB.00304183 (18.4K, 68.148.18K) -14-tert-Butoxycarbonylamino-18- (7,8-dihydro-5H-pyrido [4,3 -4] pyrimidine-6carbonyloxy) -2,15-dioxo 3,16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4-carboxylic acid (compound AK00304183) was synthesized according to method B, only 5,6,7,8tetrahydropyrido [4,3-4] pyrimidine was used in stage 4.

MS t / e 625.2 (M-1).

- 111 012389

Example 1-22

Compound AK00312023 (18.4K, 68.148.18K) -14-tert-Butoxycarbonylamino-18- (3,4-dihydro-1H-isoquinoline-2carbonyloxy) -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^{4 , 6} ] nonadecane-4-carboxylic acid (compound AK00312023) was synthesized according to method B, only the cyclization product 10 in step 3 was subsequently reduced with H ₂ / Ky-A1 ₂ O ₃ before the next step of the compound (\\ 'O 0059929, pp. 76-77).

MS t / e 625.3 (M-1).

Example 1-23

(18.4K, 68.148.18K) -18- (6-amino-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -14-tert-butoxycarbonylamino-2.15-dioxo-3.16-diazatricyclo [14.3. 0.0 ^4.6 ] nonadec-7-en-4-carboxylic (compound AK00314578) was synthesized according to method B, only tetrahydroisoquinolin-6-ylamine was used in step 4.

MS (pol. ES) t / ζ 540.2 [initial, (M ⁺ +1) -100 (Boc group)].

Example 1-24 Acid

1,2,3,4-

(18.4K, 68.148.18K) -18- (2-Acetylamino-6,7-dihydro-4H-thiazolo [5,4-c] pyridin-5-carbonyloxy) -14-tert-butoxycarbonylamino-2,15-dioxo 3,16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4-carboxylic acid (compound AK00314685) was synthesized according to method B, only No. (4,5,6,7tetrahydrothiazolo [5,4- c] pyridin-2-yl) acetamide was used in step 4.

MS t / e 589.2 (M ⁺ + 1-100).

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Example 1-25

Compound AK00315997 (18.4K, 68.148.18K) -14-tert-Butoxycarbonylamino-18- (5-dimethylamino-3,4-dihydro-1 Nizoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound AK00315997) was synthesized according to method B, only dimethyl (1,2,3,4-tetrahydroisoquinolin-5-yl) amine (example 1-25a) was used in stage 4.

MS t / e 668.0 (M ⁺ ).

Example 1-25a

The synthesis of dimethyl (1,2,3,4-tetrahydroisoquinolin-5-yl) amine is described in the following scheme:

To a solution of 5-aminotetrahydroisoquinoline (3.68 g, 24.8 mmol) in 1,4-dioxane (100 ml) was added 3N. HaO11 (8.27 ml, 24.8 mmol). After cooling to 0 ° C, phos) ₂ O (5.42 g, 24.8 mmol) in 1,4-dioxane (10 ml) was added dropwise and stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate EJAc (2x). The combined organic layers were washed with saturated aqueous NaΗCΟ ₃ , water, brine, then dried and concentrated. The precipitate was purified on silica gel by column chromatography to obtain 5.44 g (88%) of the desired 0C-protected product as a white precipitate.

To a solution of the product obtained in the previous step described above (0.2 g, 0.81 mmol) in THF (5 ml) was added NaΗ at 0 ° C. After 15 minutes, SNC was added and stirred overnight at room temperature. After completion, the reaction mixture was cooled with ice water, extracted with EAAc (25 ml), dried (Ν α ₂ 8 Ο ₄ ) and concentrated. Voc groups were removed using a mixture of 60% trifluoroacetic acid-dichloromethane ESM (2 ml) at 0 ° C to obtain 110 mg (77.5%) of the final product as a light green solid.

MS 177.1 (MH ⁺ ).

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Example 1-26

Compound AB00315998 (18.4B, 68.148.18B) -14-tert-Butoxycarbonylamino-18- (5-chloro-1,3-dihydroisoindole-2carbonyloxy) -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^{4 , 6} ] nonadec-7-en-4-carboxylic acid (compound AB00315998) was synthesized according to method B, only 5-chloro-2,3-dihydro-1Nisoindole was used in step 4.

¹ H NMR (400 MHz, SES1e) δ 7.24-7.02 (m, 3H), 6.82 (s, 1H), 5.68-5.51 (m, 1H), 5.36 (s , 1H), 5.11-4.96 (m, 2H), 4.67-4.44 (m, 5H), 4.29-4.20 (m, 1H), 4.20-4.11 (m, 1H), 3.82-3.74 (m, 1H), 2.69-2.55 (m, 1H), 2,312.15 (m, 1H), 2.14-2.06 (m , 1H), 2.03 (s, 1H), 2.01-1.86 (m, 1H), 1.86-1.24 (m, 11H), 1.22 (s, 9H).

MS m / v 644.9 (M ⁺ ), 646.9 (M ⁺ +2).

Example 1-27

(18.4V, 68.148.18B) -14-tert-Butoxycarbonylamino-18- (5,6-dichloro-1,3-dihydroisoindole-2carbonyloxy) -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^{4 , 6} ] nonadec-7-en-4-carboxylic acid (compound AB00315999) was synthesized according to method B, only 5,6-dichloro-2,3-dihydro-1Nisoindole was used in step 4.

¹ H NMR (400 MHz, SES 1 e) δ 7.29 (s, 1H), 7.22 (s, 1H), 7.06 (s, 1H), 5.57-5.50 (m, 1H), 5.33 (s, 1H), 5.23-5.09 (m, 2H), 4.73-4.65 (m, 1H), 4.64-4.48 (m, 5H), 4, 33-4.29 (m, 1H), 4.11-4.02 (m, 1H), 3.82-3.74 (m,

1H), 2.73-2.61 (m, 1H), 2.29-2.08 (m, 3H), 2.01 (s, 1H), 1.83-1.65 (m, 2H) 1.63-1.46 (m, 2H); 1.40-1.12 (m,

15H).

MS t / e 678.9 (M ⁺ ), 681 (M ⁺ +2).

Example 1-28

(18,4B, 68,148,18B) -14-tert-Butoxycarbonylamino-18- (4B-methyl-3,4-dihydro-1H-isoquinoline-2carbonyloxy) -2,15-dioxo-3,16-diazatricyclo [14.3. 0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound AB00320122) was synthesized according to method B, only 4B-methyl-1,2,3,4-tetrahydroisoquinoline was used in step 4.

- 114 012389 ¹ H NMR (400 MHz, C1) :()!)) Δ 7.02-7.24 (m, 3H), 5.59 (dd, 1H), 5.30-5.44 (m , 2H), 4.66-4.81 (m, 1H), 4.14-4.64 (m, 3H), 3.83-3.92 (m, 1H), 3.58-3.81 (m, 1H), 3.44-3.56 (m, 1H), 2.86-3.86 (m, 1H), 2.23-2.58 (m, 4H), 1.87-2 13 (m, 2H), 1.70-1.87 (m, 1H), 1.50-1.70 (m, 3H), 1.07-1.51 (m, 19H), 0.80 -0.96 (m, 2H).

MS t / ζ 639.0 (M + 1).

Example 1-29

(18.4J, 68.148.18J) -14-tert-butoxycarbonylamino-18- (48-methyl-3,4-dihydro-1 H-isoquinoline-2carbonyloxy) -2,15-dioxo-3,16-diazatricyclo [14.3 .0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound AY00320123) was synthesized according to method B, only 48-methyl-1,2,3,4tetrahydroisoquinoline was used in step 4.

¹ H NMR (400 MHz, NE OM ₃₎ δ 7,01-7,23 (m, 3H), 5.58 (dd, 1H), 5,32-5,45 (m, 2H), 4.66 -4.82 (m, 1H), 4.12-4.64 (m, 3H), 3.86-3.94 (m, 1H), 3.52-3.74 (m, 1H), 3 , 43-3.56 (m, 1H), 2.88-3.85 (m, 1H), 2.24-2.60 (m, 4H), 1.87-2.15 (m, 2H) 1.71-1.87 (m, 1H), 1.52-1.70 (m, 3H), 1.07-1.52 (m, 19H), 0.80-0.96 (m, 2H).

MS t / ζ 639.0 (M + 1).

Example 1-30

(18,4J, 68,148,18J) -14-tert-butoxycarbonylamino-18- [4- (2-methoxyphenyl) piperidin-1carbonyloxy] -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound AY00320576) was synthesized according to method B, only

4- (2-methoxyphenyl) piperidine was used in step 4.

MS: t / e583.3 (M + 1-100).

Example 1-31

Compound AK00320577 (18.4J, 68.148.18J) -14-tert-Butoxycarbonylamino-18- (6-methoxy-1,3,4,9-tetrahydro-L-carboline-2carbonyloxy) -2,15-dioxo-3, 16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4-carboxylic acid (compound AY00320577) was synthesized according to method B, only 6-methoxy-2,3,4,9tetrahydro-1 H-b β-carboline was used in stage 4.

MS t / e 594.2 (M + 1-100).

- 115 012389

Example 1-32

Compound AK00301383 (18.4J.68.148.18J) -14-tert-Butoxycarbonylamino-2.15-dioxo-18- (1-piperidin-1-ylmethyl-3.4-dihydro-1 H-isoquinoline-2-carbonyloxy) -3.16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound AY00301383) was synthesized according to method B, only 1-piperidin-1-ylmethyl-1.2.3.4-tetrahydroisoquinoline was used in step 4.

¹ H NMR (500 MHz, CB ₃ OH) δ 7.33-7.24 (m, 4H), 7.20 (br.s, 1H), 6.61 (br.s, 1H), 5.75 -5.52 (m, 2H), 5.50-5.33 (m, 2H), 4.63-4.43 (m, 2H), 4.42-4.07 (m, 4H), 3 96 (br.s, 1H), 3.67-3.11 (m, 5H), 3.06-2.88 (m, 2H), 2.86-2.74 (m, 2H), 2 56-2.35 (m, 3H), 2.23 (q, 1H), 2.04-1.90 (m, 2H), 1.89-1.52 (m, 10H), 1.51 -1.32 (m, 12H).

MS (pol. ARP) t / ζ 722.3 (M ⁺ +1).

Example 1-33

Compound AK00333842 (18.4J.68.148.18J) -14-tert-Butoxycarbonylamino-18- (6-methoxy-1-methoxymethyl-3.4-dihydro-1Nisoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound AY00333842) was synthesized in accordance with the procedures described in example 1-2, only 6-methoxy-1-methoxymethyl-1.2.3.4-tetrahydroisoquinolinium chloride was used to replace 1,2,3,4-tetrahydroisoquinoline in step 4.

MS (ARCE) t / ζ 697.2 (M-1).

Example 1-34

Compound AK00365349 (18.4J.68.148.18J) -14-tert-Butoxycarbonylamino-18- (5-fluoro-1-methoxymethyl-3,4-dihydro-1 Nizoquinoline-2-carbonyloxy) -2.15-dioxo-3, 16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4-carboxylic acid (compound AY00365349) was synthesized in accordance with the procedures described in example 1-2, only 5-fluoro-1-methoxymethyl-1, 2,3,4-tetrahydroisoquinolinium chloride was used to replace 1,2,3,4-tetrahydroisoquinoline in stage 4.

MS (ARST-) t / ζ 685.3 (M-1).

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Example 1-35

Compound AK00333224 (18.4K, 68.148.18K) -14-tert-Butoxycarbonylamino-18- (1-dimethylaminomethyl-3,4-dihydro-1 Nizoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound AK00333224) was synthesized in accordance with the procedures described in example 1-2, only dimethyl (1,2,3,4-tetrahydroisoquinolin-1 -methyl) amine (synthesized according to Example 1-35a) was used to replace 1,2,3,4-tetrahydroisoquinoline in step 4.

MS (ARSN) t / ζ 582.3 (MH ⁺ -Boc).

Example 1-35a

Dimethyl (1,2,3,4-tetrahydroisoquinolin-1-ylmethyl) amine was synthesized in a similar manner as shown in Example 3-76a, only in step 1, phenethylamine was used to replace 2- (3-methoxyphenyl) ethylamine in the first part of step 3, dimethylamine was used to replace sodium methoxide as the nucleophile. The crude product was used in the next reaction of the compound without further purification.

Example 1-36

Compound AK00333225 (18.4K, 68.148.18K) -14-tert-Butoxycarbonylamino-18- (1-morpholin-4-ylmethyl-3,4-dihydro-1Nisoquinoline-2-carbonyloxy) -2.15-dioxo-3, 16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4-carboxylic acid (compound AK00333225) was synthesized in accordance with the procedures described in example 1-2, only 1-morpholin-4-ylmethyl-1, 2,3,4-tetrahydroisoquinoline (synthesized according to Example 1-36a) was used to replace the 1,2,3,4-tetrahydroisoquinoline in step 4.

MS (APCI) t / ζ 722.3 (M-1).

- 117 012389

Example 1-36a

1-Morpholin-4-ylmethyl-1,2,3,4-tetrahydroisoquinoline was synthesized in a similar manner as shown in Example 3-76a, only in step 1, phenethylamine was used to replace 2- (3-methoxyphenyl) ethylamine and In the first part of stage 3, dimethylamine was used to replace sodium methoxide as the nucleophile. The crude product was used in the further reaction of the compound without purification.

Example 1-37

Compound AK00333248 (18.4K, 68.148.18K) -14-tert-Butoxycarbonylamino-18- (6-methoxy-1-piperidin-1-ylmethyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2.15- dioxo-3,16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4 carboxylic acid (compound AK00333248) was synthesized in accordance with the procedures described in example 1-2, only 6-methoxy-1-piperidine 1-ylmethyl-1,2,3,4-tetrahydroisoquinoline (synthesized according to Example 1-37a) was used to replace

1,2,3,4-tetrahydroisoquinoline in step 4.

MS (ΛRSΖ-) t / ζ 750.4 (M-1).

Example 1-37a

6-Methoxy-1-piperidin-1-ylmethyl-1,2,3,4-tetrahydroisoquinoline was synthesized in a similar manner, as shown in Example 3-76a, only in the first part of stage 3, piperidine was used to replace sodium methoxide as nucleophile. The crude product was used in the next reaction of the compound without further purification.

Example 1-38

Compound AK00333276 (18.4K, 68.148.18K) -14-tert-Butoxycarbonylamino-18- (6-methoxy-1-morpholin-4-ylmethyl-3,4-dihydro-1 Η-isoquinoline-2-carbonyloxy) -2.15 - dioxo-3,16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4 carboxylic acid (compound AK00333276) was synthesized in accordance with the procedures described in example 1-2, only 6-methoxy-1-morpholine -4-ylmethyl-1,2,3,4-tetrahydroisoquinoline (synthesized according to Example 1-38a) was used to replace

1,2,3,4-tetrahydroisoquinoline in step 4.

- 118 012389

MS (APC1-) t / ζ 750.3 (M-1).

Example 1-38a

6-Methoxy-1-morpholin-4-ylmethyl-1,2,3,4-tetrahydroisoquinoline was synthesized in a similar manner, as shown in Example 3-76a, only in the first part of stage 3, morpholine was used to replace sodium methoxide as nucleophile. The crude product was used in the next reaction of the compound without further purification.

Example 1-39

Compound AK00333277 (18.4B, 68.148.18B) -14-tert-Butoxycarbonylamino-18- (1-dimethylaminomethyl-6-methoxy-3,4-dihydro-1 H-isoquinoline-2-carbonyloxy) -2,15-dioxo-3 , 16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4 carboxylic acid (compound AB00333277) was synthesized according to the procedures described in example 1-2, only (6-methoxy-1,2,3, 4-tetrahydroisoquinolin-1-ylmethyl) dimethylamine (synthesized according to Example 1-39a) was used to replace

1,2,3,4-tetrahydroisoquinoline in step 4.

MS (APC1 +) t / ζ 712.3 (MH ⁺ ).

Example 1-39a

(6-Methoxy-1,2,3,4-tetrahydroisoquinolin-1-ylmethyl) dimethylamine was synthesized in a similar manner as shown in example 3-76a, only in the first part of stage 3, dimethylamine was used to replace sodium methoxide as nucleophile . The crude product was used directly in the reaction of the compound without further purification.

Example 1-40

(18.4B, 68.148.18B) -14-tert-Butoxycarbonylamino-18- (4-fluoro-1,3-dihydroisoindole-2carbonyloxy) -2.15-dioxo-3.16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound AB00365369) was synthesized in accordance with the procedures described in example 1-2, only 4-fluoro-2,3-dihydro-1H-isoindole was used to replace 1,2 , 3,4-tetrahydroisoquinoline in step 4.

¹ H NMR (500 MHz, OMSO) δ 12.21 (br.s, 1H), 8.66 (br.s, 1H), 7.35 (q, 1H), 7.19 (d, 1H), 7.11 (q, 2H), 7.03 (br.s, 1H), 5.51 (q, 1H), 5.33-5.21 (m, 2H), 4.66 (s, 4H) 4.22 (q, 1H), 4.24 (t, 1H), 3.99-3.89 (m, 1H), 3.73-3.64 (m, 1H), 2.65-2 55 (m, 1H), 2.28-2.08 (m, 3H), 1.77-1.61 (m, 2H), 1.54-1.42 (m, 1H), 1.42 -1.03 (m, 16H).

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MS (ARSP) t / ζ 627.3 (Μ-1).

Example 1-41

(18.4K, 68.148.18K) -14-tert-Butoxycarbonylamino-18- [5- (2-morpholin-4-ylmethoxy) -1,3-dihydroisoindole-2-carbonyloxy] -2,15-dioxo-3,16- diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4 carboxylic acid (compound AK00371946) was synthesized in accordance with the procedures described in example 1-2, only 5- (2-morpholin-4-ylethoxy) -2, 3-dihydro-1H-isoindole (obtained in accordance with the procedures described in 3. Heb. Sb. 2002, Vo1. 45, No. 26, 5771, method for producing S, and in Vyuogd. Heb. Sb. Bey. 11 (2001 ), 685-688. For Вос-Boc-protected amines, the starting compound was ¹ H NMR (500 MHz, CBC1 ₃ ) δ 7.13 (dd, 1Η), 6.85-6.74 (m, 2Η), 4, 61 (t, 4Η ), 4.10 (t, 2Η), 3.73 (t, 4Η), 2.81 (t, 2Η), 2.61-2.54 (m, 4Η), 1.51 (s, 9Η) , MS (ARSA +) t / ζ 349.1 (M + 1)) was used to replace 1,2,3,4tetrahydroisoquinoline in step 4.

MS (ARSN) t / ζ 640.3 [(M + 1) -Boc].

Example 1-42

(18.4K, 68.148.18K) -14-tert-Butoxycarbonylamino-18- [5- (2-dimethylaminoethoxy) -1,3-dihydroisoindole-2-carbonyloxy] -2,15-dioxo-3,16-diazatricyclo [14.3. 0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound AK00371947) was synthesized according to the procedures described in Example 1-2, only [2- (2,3-dihydro-1H-isoindol-5-yloxy) ethyl] dimethylamine (obtained in accordance with the procedures described in 3. Eb. Sb. 2002, Vo1. 45, No. 26, 5771, preparation method Ό, and in Vyuogd. Sb. Sb. 1, e11. 11 (2001) 685 -688. For Вос-Boc-protected amines, the starting compound was ¹ H NMR (500 MHz, CBC1 ₃ ) δ 7.14 (dd, 1Η), 6.88-6.76 (m, 2Η), 4.61 (t, 4Η), 4.04 (t, 2Η), 2.72 (t, 2Η), 2.34 (s, 6H), 1.50 (s, 9H), MS (ARSA +) t / ζ 307.1 (Μ + 1)) was used to replace 1,2,3,4tetrahydroisoquinoline in stage 4.

MS (ARSN) t / ζ 698.2 (M + 1).

- 120 012389

Example 1-43

(18.4K, 68.148.18K) -14-tert-Butoxycarbonylamino-18- [5- (2-isopropylaminoethoxy) -1,3-dihydroisoindole-2-carbonyloxy] -2,15-dioxo-3,16-diazatricyclo [14.3. 0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound AK00371948) was synthesized according to the procedures described in Example 1-2, only [2- (2,3-dihydro-1H-isoindol-5-yloxy) ethyl] isopropylamine (obtained in accordance with the procedures described in 1. May. SN. 2002, νο1. 45, No. 26, 5771, method for producing Ό, and in Βϊοογ§. May. SN. 1, e11. 11 (2001) 685-688. For N-Boc-protected amines, the starting compound was ¹ H NMR (500 MHz, REDD 7.13 (dd, 1H), 6.86-6.75 (m , 2H), 4.62 (t, 4H), 4.06 (t, 2H), 2.99 (t, 2H), 2.88 (septuplet, 1H), 1.62 (br.s, 1H) 1.51 (s, 9H), 1.10 (d, 6H), MS (ARSN) t / ζ 321.2 (M + 1)), was used to replace 1,2,3,4-tetrahydroisoquinoline in stage 4.

Compounds with the general structural formula II were prepared according to the general scheme described below. Compounds of structural formula Y were first subjected to removal of the Boc-protecting group, followed by a nucleophilic attack of an amino group on an electrophile, with the formation of carbamate, amide or urea.

- 121 012389

Example 2-1

Connection AK00247310

Stage 1. Preparation of (18.4K, 68.148.18K) -14-amino-18- (3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2.15-dioxo-3,16-diazatricyclo [14.3. 0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid ethyl ester

The N-Βο-protected starting compound (102 mg, 0.16 mmol) was dissolved in 6 ml of 4N IS1 (dioxane) and left at room temperature for 90 minutes. High pressure liquid chromatography demonstrated the complete removal of Βοс-protecting groups. The reaction mixture was concentrated, extracted with acetonitrile and again twice concentrated. The resulting light brown powder was used in the next step.

Stage 2. Obtaining (18.4K, 68.148.18K) -14-Cyclopentyloxycarbonylamino-18- (3,4-dihydro-1Nisoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^{4 , 6} ] non-adec-7-en-4-carboxylic acid ethyl ester

A solution of phosgene toluene (0.42 ml, 1.9 M, 0.80 mmol) was added dropwise to a solution of cyclopentinol (42 mg, 0.48 mmol) in THF (16 ml). The mixture was stirred at room temperature for 2 hours to form cyclopentyl chloroformate reagent. The reaction mixture was concentrated to half its volume. Then 1) CM was diluted to the original volume and re-concentrated to half the volume in order to completely remove the excess phosgene. The solution of the resulting cyclopentyl chloroformate was then diluted with THF (16 ml), cooled to 0 ° C and added to the solid precipitate (0.16 mmol) from step 1 at 0 ° C. ΤΕΑ (0.11 ml, 0.81 mmol) was then added to the reaction mixture and the mixture was stirred at 0 ° C for 2 hours. As shown by HPLC, the reaction was completed. The reaction mixture was concentrated, extracted with ΕΐΟΑc (15 ml) and then washed with water, saturated sodium bicarbonate and brine (10 ml each), dried over Νο ₂ 8Ο ₄ and concentrated again. The resulting viscous yellow oil was purified by flash chromatography on Βω ^^ 408 (eluent = hexane / ΕΐΟΑc 1: 1) to obtain the desired product as a white crisp powder (65.2 mg, 63%). MS (ΜΗ ⁺ 665.2).

- 122 012389

Stage 3. Preparation of (18.4K, 68.148.18K) -14-cyclopentyloxycarbonylamino-18- (3,4-dihydro-1Nisoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^{4 , 6} ] non-adec-7-en-4-carboxylic acid (compound AK00247310)

Then follow the same hydrolysis procedures as described in step 5 of Example 1-1.

The following compounds were also prepared using the same procedures as described above in Example 2-1, replacing cyclopentyl chloroformate with other electrophiles and / or

P ₂ -tetrahydroisoquinoline with other starting amines, as illustrated in step 4 of method B of Example 1-2.

Example 2-2

Compound AK00294376 (18.4K, 68.148.18K) -18- (3,4-Dihydro-1 H-isoquinoline-2-carbonyloxy) - 14-methoxycarbonylamino 2.15-dioxo-3.16-diazatricyclo [14.3.0.0 ^{4, 6} ] nonadec-7-en-4-carboxylic acid (compound AK00294376) was synthesized in accordance with the procedures described in example 2-1, only methyl chloroformate was used in stage 2.

Example 2-3

Compound AK00304074 (18.4K, 68.148.18K) -14-Cyclopentyloxycarbonylamino-18- (5-fluoro-3,4-dihydro-1 H-isoquinoline-2carbonyloxy) -2.15-dioxo-3.16-diazatricyclo [14.3 .0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound AK00304074) was synthesized in accordance with the procedures described in examples 1-2 and 2-1, only 5-fluoro-1,2,3,4 β-tetrahydroisoquinoline was used in step 4 of Example 1-2.

MS t / e 583.2 (m ⁺ +1).

- 123 012389

Example 2-4

Compound AK00304075 (18.4K, 68.148.18K) -14-Cyclopentyloxycarbonylamino-2.15-dioxo-18- (8-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -3,16-diazatricyclo [14.3. 0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound AK00304075) was synthesized in accordance with the procedures described in examples 1-2 and 2-1, only 8-trifluoromethyl-1,2,3,4- tetrahydroisoquinoline was used in stage 4 of example 1-2.

MS t / e 705.1 (M ⁺ +1).

Example 2-5

Compound AK00304076 (18.4K, 68.148.18K) -14-Cyclopentylcarbonylamino-18- (1,3-dihydroisoindole-2-carbonyloxy) 2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4,6 ] non-in- 7-en-4-carboxylic acid (compound AK00304076) was synthesized according to the procedures described in examples 1-2 and 2-1, only 2,3-dihydro-1H-isoindole was used in stage 4 of example 1-2.

MS t / e 623.2 (M +1).

Example 2-6

Compound AK00304125 (18.4K, 68.148.18K) -18- (3,4-Dihydro-1H-isoquinoline-2-carbonyloxy) -14- (2-fluoroethoxycarbonylamino) -2.15-dioxo-3,16-diazatricyclo [ 14.3.0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound

AK00304125) was synthesized in accordance with the procedures described in example 2-1, only

2-fluoroethanol was used to form the chloroformate reagent in step 2 instead of cyclopentanol.

MS t / e 615.1 (M ⁺ +1).

- 124 012389

Example 2-7

° 5

Compound AK00304126 (18.4K, 68.148.18K) -18- (3,4-Dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-14 (tetrahydrofuran-38-yloxycarbonylamino) -3,16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound AK00304126) was synthesized in accordance with the procedures described in examples 2-1, only tetrahydrofuran-38-ol was used to form the chloroformate reagent in the step 2 instead of cyclopentanol.

MS t / e 639.2 (M ⁺ +1).

Example 2-8

(18.4K, 68.148.18K) -18- (3,4-Dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-14 (tetrahydrofuran-3K-yloxycarbonylamino) -3,16-diazatricyclo [14.3 .0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound AK00304127) was synthesized in accordance with the procedures described in examples 2-1, only tetrahydrofuran-3K-ol was used to form the chloroformate reagent in stage 2 instead cyclopentanol.

MS t / e 639.2 (M ⁺ +1).

Example 2-9

(18.4K, 68.148.18K) -18- (3,4-Dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-14 (tetrahydropyran-4-yloxycarbonylamino) -3,16-diazatricyclo [14.3 .0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound AK00320002) was synthesized in accordance with the procedures described in examples 2-1, only tetrahydropyran-4-ol was used to form the chloroformate reagent in stage 2 instead cyclopentanol.

MS t / e 653.2 (M ⁺ +1).

- 125 012389

Example 2-10

(18.4K, 68.148.18K) -18- (1,3-Dihydroisoindole-2-carbonyloxy) -2,15-dioxo-14- (tetrahydrofuran3K-yloxycarbonylamino) -3,16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound AK00320074) was synthesized in accordance with the procedures described in examples 1-2 and 2-1, only 2,3-dihydro-1H-isoindole was used in step 4 of example 1 -2 and tetrahydrofuran-3K-ol was used to form the chloroformate reagent in step 2 instead of cyclopentanol.

MS t / e 625.2 (M ⁺ +1).

Example 2-11

Compound AK00320075 (18.4K, 68.148.18K) -18- (1,3-Dihydroisoindole-2-carbonyloxy) -2,15-dioxo-14- (terahydrofuran38-yloxycarbonylamino) -3,16-diazatricyclo [14.3.0.0 ^{4 , 6} ] nonadec-7-en-4-carboxylic acid (compound AK00320074) was synthesized in accordance with the procedures described in examples 1-2 and 2-1, only 2,3-dihydro-1H-isoindole was used in stage 4 Example 1-2 and tetrahydrofuran-38-ol was used to form the chloroformate reagent in step 2 instead of cyclopentanol.

MS t / e 625.2 (M ⁺ +1).

Example 2-12

Compound АЯ00320076 (18,4К, 68,148,18К) -18- (1,3-Dihydroisoindole-2-carbonyloxy) -2,15-dioxo-14- (tetrahydrofuran38-yloxycarbonylamino) -3,16-diazatricyclo [14.3.0.0 ^{4 , 6} ] nonadec-7-en-4-carboxylic acid (compound AK00320076) was synthesized in accordance with the procedures described in examples 1-2 and 2-1, only 2,3-dihydro-1H-isoindole was used in stage 4 in example 1-2 and 2-fluoroethanol was used to form the chloroformate agent in step 2 in example 2-1 instead of cyclopentanol.

MS t / e 601.1 (M ⁺ +1).

- 126 012389

Example 2-13

(18.4K, 68.148.18K) -18- (1,3-Dihydroisoindole-2-carbonyloxy) -2,15-dioxo-14- (tetrahydropyran-4yloxycarbonylamino) -3,16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound AK00320076) was synthesized in accordance with the procedures described in examples 1-2 and 2-1, only 2,3-dihydro-1H-isoindole was used in stage 4 in the example 1-2 and tetrahydropyran-4-ol was used to form the chloroformate agent in step 2 in Example 2-1 instead of cyclopentanol.

MS t / e 601.1 (M ⁺ +1).

Example 2-14

Compound AK00320445 (18.4K, 68.148.18K) -18- (5,6-Dichloro-1,3-dihydroisoindole-2-carbonyloxy) -2,15-dioxo-14 (tetrahydrofuran-3K-yloxycarbonylamino) -3.16 -diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4-carboxylic acid (compound AK00320445) was synthesized in accordance with the procedures described in examples 1-2 and 2-1, only 5,6-dichloro-2 , 3-Dihydro-1H-isoindole was used in step 4 in Example 1-2 and tetrahydrofuran-3K-ol was used to form the chloroformate agent in Step 2 in Example 2-1 instead of cyclopentanol.

MS t / e 693.0 (M ⁺ ), 695.1 (M ⁺ +2).

Example 2-15

Compound AK.00320448 (18.4K, 68.148.18K) -18- (5,6-Dichloro-1,3-dihydroisoindole-2-carbonyloxy) -2,15-dioxo-14 (tetrahydrofuran-3K-yloxycarbonylamino) -3 , 16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4-carboxylic acid (compound AK00320445) was synthesized in accordance with the procedures described in examples 1-2 and 2-1, only 5-chloro-2 , 3-dihydro-1H-isoindole was used in step 4 in Example 1-2 and tetrahydrofuran-3K-ol was used to form the chloroformate agent in step 2 in Example 2-1 instead of cyclopentanol.

¹ H NMR (500 MHz, SBAB) δ 7.38 (s, 1H), 7.32-7.28 (m, 2H), 7.22 (d, 1H), 7.10 (br.s, 1H ), 5.56-5.50 (q, 1H), 5.42-5.38 (t, 1H), 5.35 (br.s, 1H), 4.80-4.48 (m, 6H) ), 4.44 (m, 1H), 4.16 (d, 1H), 3.84 (dd, 1H), 3.78-3.69 (m, 1H), 3.68-3.60 ( m, 1H), 3.50 (t, 1H), 2.55-2.36 (m, 3H), 2.21-2.12 (m, 1H), 1.98-1.85 (m, 1H), 1.72-1.62 (m, 2H), 1.61-1.51 (m, 2H), 1.50-1.20 (m, 9H).

MS t / e 659.1 (M ⁺ ), 661.1 (M ⁺ +2).

- 127 012389

Example 2-1b

AK00248689

Synthesis of (18.4B.b8.148.18B) -14- (Cyclopentanecarbonylamino) -18- (3.4-dihydro-1 H-isoquinoline-2carbonyloxy) -2.15-dioxo-3.1b-diazatricyclo [14.3.0.0 ⁴ . ^b ] nonadec-7-en-4-carboxylic acid (compound AB248b89).

Cyclopentyl carboxylic acid was first added to the P8-TPP resin (4-hydroxy-2.3.5.tetrafluorobenzamidomethyl polystyrene) (purchased from Agdopai! Tespo1od1ek) to form an active ester. The activated ether on resin (2b mg. 1.1b mmol / g. 0.03 mmol) was left to swell in 0.5 ml of chloroform first. followed by the addition of an MP-carbonate resin (coarse-grained resin-triethylammonium methyl polystyrene carbonate) (purchased from Agdopa: Tesipo1od1ec. 300 mg. 2.5 mmol / g. 0.75 mmol). To the mixture of these resins was then added a 0.5 M solution in chloroform of a macrocyclic compound (15 mg. 0.02 mmol) and the reaction mixture was stirred overnight at room temperature. As shown by the HPLC. the reaction was completed after 1b hours. The reaction mixture was filtered and then concentrated to obtain pure K-acylated product. which was then hydrolyzed. following hydrolysis procedures. as described in step 5 of Example 1-1 to obtain the desired product AB248b89 as a white solid. (12.5 mg. 88%).

MS (APC1 +) t / ζ b21.3 (MH ⁺ ).

Example 2-17

ABOUT

Compound AK00248687 (18.4B.b8.148.18B) -18- (3.4-Dihydro-1 H-isoquinoline-2-carbonyloxy) - 14- (2.2-dimethylpropionylamino) -2.15-dioxo-3.1b-diazatricyclo [14.3.0.0 ⁴ . ^b ] nonadec-7-en-4-carboxylic acid (compound

AB00248b87) was synthesized in accordance with the procedures. as described in example 2-1 b. only tert-butyl carboxylic acid was first added to the P8-TPP resin.

MS (APC1 ⁺ ) t / ζ b09.3 (MH ⁺ ).

- 128 012389

Example 2-18

ρ

Compound AK00248688 (18.4K, 68.148.18K) -18- (3,4-Dihydro-1 H-isoquinoline-2-carbonyloxy) - 14- (isobutyrylamino) -2.15-dioxo-3.16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4-carboxylic acid (compound AK00248688) was synthesized according to the procedures as described in Example 2-16, only isopropyl carboxylic acid was first added to the P8-TPP resin.

MS (ΛRSΖ ⁺ ) t / ζ 595.3 (WE ⁺ ).

Example 2-19

o = (

Connection AK00298989

Synthesis of (18.4K, 68.148.18K) -14- (2-tert-butoxycarbonylamino-3-methylbutyrylamino) -18- (3,4-dihydro-1 P-isoquinoline-2-carbonyloxy) -2,15-dioxo-3, 16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-4carboxylic acid (compound AK298989)

14-amino-18- (3,4-dihydro-1 P-isoquinoline-2-carbonyloxy) -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4- carboxylic acid ethyl ether (120 mg, 217 μmol) and N-α-t-Boc- valine N-hydroxysuccinamide ether (96 mg, 300 μmol) were mixed together in 1.1 ml of dichlomethane for 14 hours. The solvent was removed. under vacuum and ethyl acetate was added. The phases were separated and the aqueous layer was washed twice with 500 μl of ethyl acetate. The combined organic phases were dried over MgSO ₄ and the solvents were removed in vacuo to give the desired compound as a white solid (132 mg, 81%).

MS t / ζ 752.2 (MS).

- 129 012389

Example 2-20

Compound AK00301338 (18.4K, 68.148.18K) -18- (3,4-Dihydro-1H-isoquinoline-2-carbonyloxy) -14- {3-methyl-2 - [(pyrazine-2carbonyl) amino] butyrylamino} - 2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4-carboxylic acid (compound AK00301338) was synthesized in accordance with the same procedures as described in example 2-19, only 3-methyl-2 - [(pyrazin-2-carbonyl) amino] butanoic acid 2,5dioxopyrrolidin-1-yl ester was used to replace the hydroxysuccinamide ester.

MS t / e 730.3 (M ⁺ +1).

Example 2-21

Ν— ⁷

0 = ^

Ν-α-t-Boc-b-valine Ν-

Compound AY00304072 (18.4K, 68.148.18K) -18- (3,4-Dihydro-1H-isoquinoline-2-carbonyloxy) -14- {2 - [(6-dimethylaminopyridin-3-carbonyl) amino] -3- methylbutyrylamino} -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4,6 ] inadequate 7-en-4-carboxylic acid (compound AK00304072) was synthesized in accordance with the procedures as described in example 2-19, only 2 - [(6-Dimethylaminopyridin-3-carbonyl) amino] -3-methylbutanoic acid 2,5-dioxopyrrolidin-1-yl ester was used to replace Ν-α-t-Boc-Ь-valine Ν-hydroxysuccinamide ester.

¹ H NMR (SPeOP, 500 MHz) δ 8.69 (s, 1H), 8.46 (s, 1H), 8.37-8.39 (m, 1H), 8.14-8.21 (m , 2H), 7.07-7.18 (m, 5H), 5.63 (q, 1H), 5.36-5.42 (m, 2H), 4.49-4.56 (m, 3 H), 4.42-4.45 (m, 1H), 4.31-4.32 (m, 1H), 3.92-3.95 (m, 1H), 3.65-3.72 ( m, 2H), 2.85-2.91 (m, 2H), 2.33-2.55 (m, 4H), 1.93-2.03 (m, 3H), 1.61-1, 68 (m, 3H), 1.27-1.52 (m, 12H), 0.86-0.96 (m, 8 N).

MS t / e 770.4 (M-1).

Example 2-22

Compound AK.00304073 (18.4K, 68.148.18K) -18- (3,4-Dihydro-1H-isoquinoline-2-carbonyloxy) -14- {3-methyl-2 - [(pyridin-3carbonyl) amino] butyrylamino } -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4-carboxylic

- 130 012389 acid (compound AY003 04073) was synthesized according to the procedures as described in Example 2-19, only 2,5-dioxopyrrolidin-1-yl ester of succinamide ester.

MS t / e 729.2 (M ⁺ +1).

Example 2-23

3-methyl-2 - [(pyridin-3-carbonyl) amino] butanoic acid was used to replace \ -c / -t-Boc-E-valine \ -hydroxy-

Compound AK00298990 (18.4J, 68.148.18J) -14- (2-amino-3-methylbutyrylamino) -18- (3,4-dihydro-1H-isoquinoline-2carbonyloxy) -2.15-dioxo-3.16- diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound 298990) was obtained in accordance with the same procedures as described in Step 1 of Example 2-1.

MS t / e 624.2 (M ⁺ +1).

Example 2-24

Connection AK00294378

Synthesis of (18.4J, 68.148.18J) -14- (3-Cyclopentylureido) -18- (3,4-dihydro-1H-isoquinoline-2carbonyloxy) -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound AY294378)

14-amino-2,15-dioxo-18- (8-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -3,16-diazatricyclo [14.3.0.0 ^4,6 ] non-7-hydrochloride hydrochloride en-4-carboxylic acid ethyl ether (49 mg, 74 μmol), diisopropylethylamine (29 mg, 222 μmol) and cyclopentyl isocyanate (25 mg, 222 μmol) were dissolved in 375 μl of dichloromethane and stirred at 19 ° C for 1 h The reaction mixture was transferred to a C18 evaporation column and eluted with water / acetonitrile (10 to 100%) containing 0.1% TPA to obtain the title product as a white solid (42 mg, 77%).

MS t / ζ 732.2 (MH ⁺ ).

- 131 012389

Example 2-25

Compound AK00294377 (18.4B, 68.148.18B) -14- (3-tert-Butylureido) -18- (3,4-dihydro-1H-isoquinoline-2-carbonyloxy) -2.15-dioxo-3.16-diazatricyclo [ 14.3.0.0 ^4,6 ] nonadec-7-en-4-carboxylic acid (compound AB00294377) was synthesized in accordance with the procedures described in examples 1-2 and 2-24, only tert-butyl isocyanate was used instead of cyclopentyl isocyanate in the procedure of example 2 -24.

MS t / e 624.1 (M ⁺ +1).

Example 2-26

Compound AK00304077 (18.4V, 68.148.18V) -14- (3-Cyclopentylureido) -18- (5-fluoro-3,4-dihydro-1H-isoquinoline-2carbonyloxy) -2.15-dioxo-3.16- diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4-carboxylic acid (compound AB00304077) was synthesized in accordance with the procedures described in examples 1-2 and 2-24, only 5-fluoro-1,2, 3,4-tetrahydroisoquinoline was used to replace 1,2,3,4tetrahydroisoquinoline in step 4 of Example 1-2.

MS t / e 654.2 (M ⁺ +1).

Example 2-27

Compound AK00304078 (18.4V, 68.148.18V) -14- (3-Cyclopentylureido) -2.15-dioxo-18- (8-trifluoromethyl-3,4-dihydro-1Nisoquinoline-2-carbonyloxy) -3.16- diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4-carboxylic acid (compound AB00304078) was synthesized in accordance with the procedures described in examples 1-2 and 224, only 8-trifluoromethyl-1,2,3, 4-tetrahydroisoquinoline was used to replace 1,2,3,4tetrahydroisoquinoline in step 4 of Example 1-2.

MS t / e 704.1 (M ⁺ +1).

- 132 012389

Example 2-28

Compound AK00304079 (18.4Κ, 68.148.18B) -14- (3-Cyclopentylureido) -18- (1,3-dihydroisoindole-2-carbonyloxy) -2.15-dioxo-3.16-diazatricyclo [14.3.0.0 ^4.6 ] non-adec-7-en-4-carboxylic acid (compound AB00304079) was synthesized according to the procedures described in examples 1-2 and 2-24, only 2,3-dihydro1H-isoindole was used to replace 1,2,3 , 4-tetrahydroisoquinoline in step 4 of Example 1-2.

MS t / e 622.2 (M ⁺ +1).

Example 2-29

Compound AK00320078 (18.4Κ, 68.148.18B) -14- (3-tert-Butylureido) -18- (1,3-dihydroisoindole-2-carbonyloxy) -2.15-dioxo-3.16-diazatricyclo [14.3.0.0 ^{4 , 6} ] nonadec-7-en-4-carboxylic acid (compound AB00320078) was synthesized in accordance with the procedures described in examples 1-2 and 2-24, only 2,3-dihydro1H-isoindole was used to replace 1,2 The 3,4-tetrahydroisoquinoline in Step 4 of Example 1-2 and the tert-butyl isocyanate were used to replace the cyclopentyl isociant in the procedures of Example 2-24.

MS t / e 610.1 (M ⁺ +1).

Example 2-30

Compound AK00320221 (18.4Κ, 68.148.18B) -18- (3,4-Dihydro-1H-isoquinoline-2-carbonyloxy) -2,15-dioxo-14- [3 (tetrahydrofuran-3-yl) ureido] - 3,16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4-carboxylic acid (compound AB00320221) was synthesized in accordance with the procedures described in examples 1-2 and 2-24, only 3-isocyanatotetrahydrofuran was used to replace cyclopentyl isocyanate in the procedure of example 2-24.

MS t / e 638.2 (M ⁺ +1).

- 133 012389

Example 2-31

Compound AK00320449 (18.4K, 68.148.18K) -14- (3-tert-Butylureido) -18- (5-chloro-1,3-dihydroisoindole-2-carbonyloxy) 2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound AK00320449) was synthesized according to the procedures described in examples 1-2 and 2-24, only 5-chloro 2,3-dihydro-1H β-isoindole was used to replace 1,2,3,4-tetrahydroisoquinoline in step 4 of Example 1-2 and tert-butyl isocyanate was used to replace cyclopentyl isociant in the procedures of Example 2-24.

² H NMR (500 MHz, SEZOE) δ 7.34 (s, 1H), 7.28-7.25 (m, 2H), 7.24 (s, 1H), 7.20 (s, 1H), 5.51 (m, 2H), 5.40 (s, 1H), 4.73-4.60 (m, 3H), 4.53 (t, 1H), 4.38 (d, 1H), 4 28 (d, 1H), 3.98 (dd, 1H), 2.43 (m, 2H), 2.38-2.30 (m, 1H), 2.12-2.00 (m, 2H) ), 1.81-1.70 (m, 1H), 1.64-1.56 (m, 3H), 1.48-1.20 (m, 8H), 1.18 (s, 9H). MS m / v 644.0 (M ⁺ ), 645.9 (M ⁺ +2)

Example 2-32

Compound ΑΚ0032045Θ (18.4K, 68.148.18K) -14- (3-tert-Butylureido) -18- (5,6-dichloro-1,3-dihydroisoindole-2-carbonyloxy) 2.15-dioxo-3.16 -diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4-carboxylic acid (compound AK00320450) was synthesized in accordance with the procedures described in examples 1-2 and 2-24, only 5,6-dichloro-2 , 3-dihydro-1H-isoindole was used to replace the 1,2,3,4-tetrahydroisoquinoline in step 4 of Example 1-2 and tert-butyl isocyanate was used to replace the cyclopentyl isociant in the procedures of Example 2-24.

² H NMR (500 MHz, CO 3 OH) δ 7.50 (s, 1H), 7.38 (s, 1H), 5.56 (q, 1H), 5.42-5.38 (m, 2H), 4.72-4.61 (m, 4H), 4.55 (t, 1H), 4.34 (dd, 1H), 4.28 (d, 1H), 3.92 (dd, 1H), 2 45-2.32 (m, 2H), 2.32-2.18 (m, 1H), 2.08-2.00 (m, 1H), 1.75-1.68 (m, 1H) 1.63-1.54 (m, 3H); 1.50-1.22 (m, 8H); 1.18 (s, 9H).

MS t / e 678.0 (M ⁺ ), 680.0 (M ⁺ +2).

Example 2-33

SAO

Compound AK00365381 (18.4K, 68.148.18K) -14-Cyclopentyloxycarbonylamino-18- (5-fluoro-1-methoxymethyl-3,4-dihydro1H-isoquinoline-2-carbonyloxy) -2.15-dioxo-3.16- diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4-carboxylic acid (compound AK00365381) was synthesized in accordance with the procedures described in

- 134 012389 examples 1-2 and 2-1, only 5-fluoro-1-methoxymethyl-1,2,3,4-tetrahydroisoquinolinium chloride was used to replace the 1,2,3,4-tetrahydroisoquinoline in step 4 of example 1- 2.

MS (ARSB) t / ζ 697.4 (M-1).

Obtaining compounds with General structural formula IV

Compounds with the general structural formula IV were obtained in accordance with the scheme given above (Kyap e! A1., Vuogd. & May. C11et. Bey., 1997, 7 (23), 3017-3022; International application PCT / i802 / 39926 , \\ Ό 03/053349).

Example 3-1

Connection AK00261408

Synthesis of (18.4K, 68.148.18K) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonaminocarbonyl-2.15-dioxo-3.16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-18-yl ether (AK00261408)

Macrocyclic acid (compound 101), 7 mg, 0.011 mmol, was dissolved in 0.1 ml of DMF, followed by the addition of SET (1.8 mg, 0.011 mmol). The mixture was stirred at 40 ° C. in an oil bath for 1 hour. Then cyclopropylsulfonamide (2.0 mg, 0.017 mmol) was added to the reaction mixture, followed by the addition of 1) WB (1.7 mg, 0.011 mmol). The reaction mixture was stirred at 40 ° C. overnight. After 14 hours, the completion of the reaction was demonstrated by a combination of liquid chromatography and mass spectrometry.

The reaction mixture was cooled to room temperature, partitioned between 2 ml of EA and 2 ml of 5% HC1 (aq). The organic layer was washed with water, sodium bicarbonate (2 ml), then dried (No. ₂ 8 O ₄ ). The resulting product was purified on Vu1ade 12M (eluent = OSM: MeOH 20: 1) to give AK00261408 (4.2 mg, 52%).

¹ H NMR (SES13, 500 MHz) δ 0.80-2.10 (m, 25H), 2.20-2.27 (m, 1H), 2.37-2.59 (m, 3H), 2 84 (m, 1H), 3.60-3.70 (m, 1H), 3.82-3.90 (m, 1H), 4.20-4.30 (m, 2H), 4.45 -4.70 (m, 5H), 4.95-5.05 (m, 2H), 5.30-5.48 (m, 2H), 5.74 (m, 1H), 6.74 (m , 1H). 7.0-7.23 (m, 4H).

MS t / e 728.0 (M ⁺ H).

- 135 012389

Example 3-2

Compound AK00261407 (18.4J, 68.148.18J) -3,4-Dihydro-1 H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-2,15-dioxo-4- (propane-2-sulfonylaminocarbonyl) -3 , 16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en18-yl ether (compound АЯ00261407) was synthesized in accordance with the procedures described in example 3-1, only isopropylsulfonamide was used to replace cyclopropylsulfonamide in the addition step. MS t / e 728.4 (M-1). Example 3-3

(18.4J, 68.148.18J) -3,4-Dihydro-1 H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-methanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18yl ether (compound AY00254906) was synthesized according to the procedures described in Example 3-1, only methylsulfonamide was used to replace cyclopropylsulfonamide in the coupling step.

¹ H NMR (SPS1 ₃ , 500 MHz) δ 1.20-1.52 (m, 16H), 1.54-1.98 (m, 5H), 2.20-2.30 (m, 1H), 2.38-2.46 (m, 1H), 2.47-2.59 (m, 3H), 2.84 (m, 1H), 3.18 (s, 3H), 3.56-3, 70 (m, 1H), 3.82-3.90 (m, 1H), 4.22-4.33 (m, 2H), 4.47-4.69 (m, 4H), 4.90- 5.10 (m, 2H), 5.47 (br.s, 1H), 5.74 (m, 1H), 6.74 (m, 1H), 7.03-7.23 (m, 4H) .

MS t / e 701.9 (M ⁺ ), 602.2 (related, MH ⁺ Boc group).

Example 3-4

Compound AK00261409 (18.4J, 68.148.18J) -3,4-Dihydro-1 H-isoquinoline-2-carboxylic acid 4- (butane-1-sulfonylaminocarbonyl) -14-tert-butoxycarbonylamino-2.15-dioxo-3 , 16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7en-18-yl ester (compound АЯ00261409) was synthesized according to the procedures described in example 3-1, only n-butylsulfonamide was used to replace cyclopropylsulfonamide in the step joining.

- 136 012389 ¹ H NMR (SPS1 ₃ , 500 MHz) δ 0.80-1.03 (m, 7H), 1.20-2.10 (m, 22H), 2.20-2.60 (m, 4H), 2.84 (m, 1H), 3.20 (m, 1H), 3.44 (m, 1H), 3.65 (m, 1H), 3.80-3.95 (m, 1i) ), 4.20-4.34 (m, 2H), 4.50-4.65 (m, 4H), 4.95-5.05 (m, 1H), 5.30-5.39 (m , 1H), 5.44-5.49 (m, 1H), 5.74 (m, 1i), 6.74 (m, 1H), 7.0-7.23 (m, 4H).

MS t / e 743.3 (Μ ⁺ , ARSG).

Example 3-5

Compound AK00282131 (18.4K, 68.148.18K) -3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 14-cyclopentyloxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3.16-diazatricyclo [14.3.0.0 ^{4 , 6} ] non-adec-7-en-18-yl ester (compound AK00282131) was synthesized in accordance with the procedures described in examples 2-1 and 3-1.

MS t / e 738.4 (Μ-1).

Example 3-6

Compound AK00294381 (18.4K, 68.148.18K) -1.3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3.16-diazatricyclo [14.3.0.0 ^4.6 ] non-relative -7-en-18-ethyl ester (compound AK00294381) was synthesized in accordance with the procedures described in examples 1-5 and 3-1.

¹ H NMR (SPS1 ₃ , 500 MHz) δ 0.89-2.08 (m, 25H), 2.21-2.28 (m, 1H), 2.41-2.49 (m, 1H), 2.51-2.61 (m, 2H), 2.91 (m, 1H), 3.83 (m, 1H), 4.21 (m, 1H), 4.40 (d, 1 = 11, 7 Hz, 1H), 4.53-4.80 (m, 5H), 4.95-5.04 (m, 2H), 5.47 (br.s, 1H), 5.72 (m, 1H) ), 6.77 (m, 1H), 7.16 (m, 1H), 7.23-7.31 (m, 3H).

MS t / e 712.3 (ARSG, Μ-Η).

Example 3-7

Compound AK00298996 (18.4K, 68.148.18K) -5-Fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3.16- diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound AK00298996) was synthesized in accordance with the procedures described in examples 1-2 and 3-1, only 5-fluoro-1,2, 3,4-tetrahydroisoquinoline was used to

- 137 012389 replacement of 1,2,3,4-tetrahydroisoquinoline in stage 4 of example 1-2.

¹ Η NMR (400 MHz, ATP1 ₃ ) δ 10.05 (s, 1Η), 8.12 (s, 1Η), 7.04 (s, 1Η), 6.84-6.73 (m, 2Η) , 6.70 (s, 1Η), 5.65 (s, 1Η), 5.40 (s, 1Η), 4.59 (m, 2Η), 4.54-4.40 (m, 3Η), 4.30-4.10 (m, 2n), 3.82-3.74 (m, 1H), 3.72-3.51 (m, 2Η), 2.92-2.68 (m, 3Η ), 2.55-2.30 (m, 3Η), 2.21-2.15 (m, 1Η), 2.00-1.60 (m, 3H), 1.40-0.75 (m , 18Η).

MS t / e 746.0 (M ⁺ ).

Example 3-8

(18.4K, 68.148.18K) -8-Trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3.16-diazatricyclo [14.3. 0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound AK00298997) was synthesized in accordance with the procedures described in examples 1-2 and 3-1, only 5-fluoro-1,2,3,4- tetrahydroisoquinoline was used to replace 1,2,3,4-tetrahydroisoquinoline in step 4 of Example 1-2.

¹ H NMR (500 MHz, C1XOO) δ 7.55 (dd, 1Η), 7.42 (dd, 1Η), 7.35 (t, 1Η), 5.71-5.61 (m, 1Η), 5.40 (m, 1Η), 4.60 (s, 1H), 4.52 (m, 1H), 4.42 (m, 1H), 4.15 (m, 1H), 3.91 (m , 1H), 3.78-3.62 (m, 2H), 3.00-2.82 (m, 3H), 2.582.52 (m, 3H), 2.51-2.32 (m, 2H) ), 1.86-1.56 (m, 3H), 1.41 (m, 2H), 1.32-1.21 (m, 5H), 1.04-0.98 (m, 14H).

MS t / e 795.9 (M ⁺ ).

Example 3-9

ABOUT

Compound AK00301746 (18.4K, 68.148.18K) -7-Chloro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3.16- diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound AK00301746) was synthesized in accordance with the procedures described in examples 1-2 and 3-1, only 7-chloro-1,2, 3,4-tetrahydroisoquinoline was used to replace 1,2,3,4-tetrahydroisoquinoline in step 4 of Example 1-2.

¹ H NMR (400 MHz, ATP1 ₃ ) δ 10.10 (s, 1H), 7.08 (d, 1H), 7.02-6.96 (m, 2H), 6.60 (d, 1H) 5.64 (q, 1H), 5.40 (s, 1H), 4.92-4.41 (m, 2H), 4.55-4.40 (m, 3H), 4.28-4 12 (m, 2H), 3.82-3.75 (m, 1H), 3.65-3.46 (m, 3n), 2.88-2.80 (m, 1H), 2.78 -2.56 (m, 2H), 2.52-2.42 (m, 1H), 2.38-2.30 (m, 1H), 2.21-2.12 (q, 1H), 1 82-1.74 (m, 2H), 1.45-1.12 (m, 16H), 1.10-0.98 (m, 2H), 0.90-0.75 (m, 2H) .

MS t / e 761.9 (M ⁺ ).

- 138 012389

Example 3-10

Compound AK00301747 (18.4K, 68.148.18K) -6-Trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3,16-diazatricyclo [ 14.3.0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound AK00301747) was synthesized in accordance with the procedures described in examples 1-2 and 3-1, only 6-trifluoromethyl-1,2,3, 4-tetrahydroisoquinoline was used to replace 1,2,3,4-tetrahydroisoquinoline in step 4 in Example 1-2.

¹ H NMR (500 MHz, SOYUO) δ 7.44 (m, 2H), 7.38-7.30 (m, 1H), 7.28-7.24 (m, 1H), 5.65 (q , 1H), 5.40 (m, 1H), 5.08 (m, 1H), 4.56 (br s, 2H), 4.60-4.50 (m, 1H), 4.48 ( m, 1H), 4.15 (d, 1H), 3.88 (d, 1H), 3.75-3.67 (m, 2H), 2.93-2.82 (m, 3H), 2 66-2.54 (m, 1H), 2.52-2.44 (m, 1H), 2.42-2.40 (m, 2H), 1.91-1.76 (m, 2H) 1.74-1.70 (dd, 1H), 1.64-1.58 (m, 1H), 1.54-1.36 (m, 4H), 1.34-1.25 (m, 12H), 1.50-1.20 (m, 2H), 1.00-0.70 (m, 1H), 0.520.34 (m, 1H).

MS t / e 795.9 (M ⁺ ).

Example 3-11

Compound AK00301751 (18.4K, 68.148.18K) -6-Fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16 diazatricyclo [14.3. 0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound AK00301751) was synthesized in accordance with the procedures described in examples 1-2 and 3-1, only 6-fluoro-1,2,3,4 tetrahydroisoquinoline was used to replace 1,2,3,4-tetrahydroisoquinoline in step 4 in Example 1-2.

¹ H NMR (500 MHz, SEZOE) δ 7.21-7.02 (m, 1H), 6.92 (m, 2H), 6.92 (m, 2H), 5.68 (q, 1H), 5.40 (m, 1H), 5.08 (t, 1H), 4.58 (m, 2H), 4.45 (m, 1H), 4.12 (d, 1H), 3.88 (d , 1H), 3.78-3.60 (m, 3H), 2.86-2.72 (m, 3H), 2.712.61 (m, 1H), 2.52-2.42 (m, 1H ), 2.41-2.34 (m, 1H), 1.88-1.76 (m, 2H), 1.74-1.70 (m, 1H), 1.64-1.58 (m , 1H), 1.56-1.38 (m, 2H), 1.37-1.24 (m, 14H), 1.13-1.04 (m, 2H), 1.02-0.89 (m, 1H), 0.88-0.82 (m, 1H).

MS t / e 746.0 (zero),

MS t / e 757.2 (m ⁺ +1).

- 139 012389

Example 3-12

Compound AK00304080 (18.4K, 68.148.18K) -5-Fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14- (3-cyclopentyl ureido) -4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3 , 16-diazatricyclo [14.3.0.0 ^{4, b} ] nonadec-7en-18-yl ester (compound AK00304080) was synthesized according to the procedures described in examples 1-2, 2-24 and 3-1, only 5-fluoro- 1,2,3,4-tetrahydroisoquinoline was used to replace 1,2,3,4-tetrahydroisoquinoline in step 4 of Example 1-2.

Example 3-13

R

Compound ACH303081 (18.4K, 68.148.18K) -8-Trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14- (3cyclopentylureido) -4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3.16- diazatricyclo [14.3.0.0 ^4.6 ] non-adec-7-en-18-yl ester (compound AK00304081) was synthesized in accordance with the procedures described in examples 1-2, 2-24 and 3-1, only 8-trifluoromethyl- 1,2,3,4 tetrahydroisoquinoline was used to replace 1,2,3,4-tetrahydroisoquinoline in step 4 of Example 1-2.

MS t / e 807.2 (M ⁺ +1).

Example 3-14

Compound AK00304082 (18.4K, 68.148.18K) -1,3-Dihydroisoindole-2-carboxylic acid 14- (3-cyclopentylureido) -4cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3.16-diazatricyclo [14.3.0.0 ^4.6 ] non-adec-7-ene-18-ethyl ester (compound AK00304082) was synthesized according to the procedures described in examples 1-2, 2-24 and 3-1, only 2,3-dihydroisoindole was used to replace 1,2,3, 4 tetrahydroisoquinoline in step 4 of Example 1-2.

MS t / e 725.2 (M ⁺ +1).

- 140 012389

Example 3-15

Compound AK00304161 (18.4K, 68.148.18K) -3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-14- (2-fluoroethoxycarbonylamino) -2,15-dioxo-3,16-diazatricyclo [ 14.3.0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound ΑΕ00304161) was synthesized in accordance with the procedures described in examples 1-2, 2-1 and 3-1, only 2-fluoroethanol was used for the formation of the chloroformate reagent in step 2 in Example 2-1 instead of cyclopentanol.

MS t / e 718.1 (M ⁺ +1).

Example 3-16 ° = <

R

Compound AY00304162 (18.4K, 68.148.18K) -3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14- (tetrahydrofuran-38-yloxycarbonylamino) -3,16- diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound ΑΕ00304162) was synthesized in accordance with the procedures described in examples 1-2, 2-1 and 3-1, only tetrahydrofuran-38- ol was used to form the chloroformate reagent in step 2 in Example 2-1 instead of cyclopentanol.

MS t / e 742.1 (M ⁺ +1).

Example 3-17

Compound AK.00304163 (18.4K, 68.148.18K) -3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14- (tetrahydrofuran-3K-yloxycarbonylamino) -3, 16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester (compound ΑΕ00304163) was synthesized in accordance with the procedures described in examples 1-2, 2-1 and 3-1, only tetrahydrofuran- 3K-ol was used to form the chloroformate reagent in step 2 in Example 2-1 instead of cyclopentanol.

¹ H NMR (b ^6- Benzene, 500 MHz) δ 10.53 (s, 1Η), 6.78-6.96 (m, 4Η), 5.83-5.90 (m, 1Η), 5, 66 (q, 1Η), 5.185.21 (m, 1Η), 5.13 (br.s, 1Η), 5.04 (br., 1Η), 4.41-4.87 (m, 3Η) 3.85-4.05 (m, 4Η), 3.67-3.74 (m, 1n), 3.463.53 (m, 3Η), 3.23-3.34 (m, 1Η), 2 , 80-2.85 (m, 1Η), 2.34-2.59 (m, 4Η), 1.84-1.99 (m, 4Η), 0.98-1.60 (m, 14Η) , 0.42-0.47 (m, 1Η), 0.27-0.32 (m, 1Η).

MS t / e 741.2 (M-1).

- 141 012389

Example 3-18

Compound AK00311814 (18.4K, 68.148.18K) -2-Phenylamino-6,7-dihydro-4H-thiazolo [5,4-c] pyridine-5-carboxylic acid

14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4,6 ] non-7-ene-18-yl ester (compound AK00311814) was synthesized in accordance with the procedures described in examples 1-2 and 3-1, only phenyl (4,5,6,7-tetrahydrothiazolo [5,4c] pyridin-2-yl) amine was used to replace 1,2,3,4-tetrahydroisoquinoline in the step 4 in example 1-2.

MS t / e 826.2 (M ⁺ +1).

Example 3-19

Compound AK00311815 (18.4K, 68.148.18K) -1-piperidin-1-ylmethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3, 16 diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester (compound AK00311815) was synthesized in accordance with the procedures described in examples 1-2 and 3-1, only 1-piperidin-1-ylmethyl- 1,2,3,4 tetrahydroisoquinoline was used to replace 1,2,3,4-tetrahydroisoquinoline in step 4 of Example 1-2.

¹ H NMR (500 MHz, SCDS) δ 8.94 (d, 1H), 7.59 (s, 1H), 7.31-7.23 (m, 3H), 7.22-7.15 (m , 2H), 5.74-5.64 (m, 2H), 5.47 (br.s. 1H), 5.06 (t, 1H), 4.54 (dt, 1H), 4.40- 4.17 (m, 4H), 4.11-4.04 (m, 1H), 3.96-3.88 (m, 1H), 3.75-3.40 (m, 5H), 3, 14-2.32 (m, 7H), 2.05 (dd, 1H), 1.99-1.68 (m, 5H), 1.65-0.95 (m, 24H).

MS (PO8 Ξ8Ι) t / ζ 825.4 (M ⁺ ).

Example 3-20

Compound AK00312024 (18.4K, 68.148.18K) -4,4-Spirocyclobutyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid

14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4,6 ] non-7-ene-18-yl ester (compound AK00312024) was synthesized in accordance with the procedures described in examples 1-2 and 3-1, only 4,4-spirocyclobutyl-1,2,3,4tetrahydroisoquinoline was used instead of 1,2,3,4-tetrahydroisoquinoline in step 4 in example 1-2.

- 142 012389 ¹ H NMR (400 MHz, C1) _: ()!)) Δ 7.54-7.60 (m, 1H), 7.26 (dd, 1H), 6.97-7.21 (m , 1H), 5.66 (dd, 1H), 5.375.48 (m, 1H), 5.11 (dd, 1H), 4. 58 (s, 2H), 4.39 (t, 3H), 4 11-4.26 (m, 1H), 3.77-3.96 (m, 1H), 3.87 (ΐ, 3H), 3.603.70 (m, 1H), 2.83-2.93 (m, 1H), 2.23-2.68 (m, 6H), 1.70-2.23 (m, 7H), 1.18-1.69 (m, 18H), 0.81-1 12 (m, 3H).

MS t / ζ 767.9 (M ⁺ +1)

Example 3-21

Compound AK00312025 (18.4K, 68.148.18K) -4,4-Dimethyl-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3.16 -diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester (compound AK00312025) was synthesized in accordance with the procedures described in examples 1-2 and 3-1, only 4,4-dimethyl-1 , 2,3,4-tetrahydroisoquinoline was used to replace 1,2,3,4-tetrahydroisoquinoline in step 4 of Example 1-2.

¹ H NMR (400 MHz, ΟΌ3ΟΌ) δ 7.31-7.40 (m, 1H), 6.97-7.23 (m, 3H), 5.67 (dd, 1H), 5.34-5 49 (m, 1H), 5.09 (dd, 1H), 4.64 (s, 1H), 4.50-4.61 (m, 1H), 4.33-4.44 (m, 3H) ), 4.11-4.24 (m, 1.0), 3.82-3.95 (m, 3H), 3.363.55 (m, 2H), 2.84-2.94 (m, 1H ), 2.25-2.69 (m, 4H), 1.68-2.24 (m, 4H), 1.15-1.68 (m, 23H), 0.81-1.15 (m , 3H).

MS t / ζ 756.0 (M + 1).

Example 3-22

(18.4K, 68.148.18K) -4-Methyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3,16-diazatricyclo [ 14.3.0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound AK00312026) was synthesized in accordance with the procedures described in examples 1-2 and 3-1, only 4-methyl-1,2,3, 4-tetrahydroisoquinoline was used to replace 1,2,3,4-tetrahydroisoquinoline in step 4 of Example 1-2.

¹ H NMR (400 MHz, ΟΌ3ΟΌ) δ 7.76 (s, 1H), 6.98-7.24 (m, 3H), 5.67 (dd, 1H), 5.2-5.51 (m , 1H), 5.04-5.15 (dd, 1H), 4.28-4.63 (m, 5H), 4.10-4.24 (m, 1H), 3.81-3.96 (m, 3H), 3.37-3.78 (m, 2H), 2.83-3.06 (m, 2H), 2.542.71 (m, 1H), 2.25-2.54 (m , 3H), 1.69-1.94 (m, 3H), 1.16-1.69 (m, 20n), 0.81-1.15 (3H).

MS t / ζ 742.0 (M ⁺ +1).

Example 3-23

(18.4K, 68.148.18K) -4,4-Spirocyclobutyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4

- 143 012389 cyclopropanesulfonylaminocarbonyl-2.15-dioxo-14- (tetrahydrofuran-3-yloxycarbonylamino) -3.1-diazatricyclo [14.3.0.0 ⁴ . ^b ] non-adec-7-en-18-yl ether (compound AB00314b35) was synthesized in accordance with the procedures. described in examples 1-2. 2-1 and 3-1. only 4.4-spirocyclobutyl-1.2.3.4 tetrahydroisoquinoline was used to replace the 1.2.3.4-tetrahydroisoquinoline in step 4 of Example 1-2 and tetrahydrofuran-3B-ol was used to replace the cyclopentanol in step 2 of Example 2-1 to form chloroformate reagents.

¹ H NMR (500 MHz. C1) ₂ C1 ₂ ) δ 10.24-10.29 (s. 1H). 7.49-7.55 (m, 1H). 7.24 (dd. 1H). 7.14 (dd. 1H). 7.04 (dd. 1H). b.81 (d. 1H). 5.71 (dd. 1H). 4.95 (dd. 1H). 4.90 (br.s. 1H). 4.48-4.59 (m, 3H). 4.17-4.30 (m, 2H). 3.513.74 (m, 3H). 3.51-3.72 (bN). 2.80-2.8b (m, 1H). 2.3b-2.54 (m. 3H). 2.10-2.33 (m. 4H). 1.80-2.10 (m.BN). 1.241.80 (m. 7H). 0.b5-1.24 (m. 10H).

MS t / ζ 741.2 (M ⁺ +1).

Example 3-24

Compound AK00314654 (18.4B.b8.148.18B) -4.4-Dimethyl-3.4-dihydro-1H-isoquinoline-2-carboxylic acid 4cyclopropanesulfonylaminocarbonyl-2.15-dioxo-14- (tetrahydrofuran-3 8-yloxycarbonylamino) 3.1b-diazate .0.0 ⁴ . ^b ] non-adec-7-en-18-yl ether (compound AB00314b54) was synthesized in accordance with the procedures. described in examples 1-2. 2-1 and 3-1. only 4.4-dimethyl-1.2.3.4 tetrahydroisoquinoline was used to replace 1.2.3.4-tetrahydroisoquinoline in step 4 of Example 1-2 and tetrahydrofuran-38-ol was used to replace cyclopentanol in step 2 in Example 2-1 to form chloroformate reagents.

¹ H NMR (500 MHz. C1) ₂ C1 ₂ ) δ 8.51-8.b4 (br.s. 1H). 7.2b-7.3b (m. 1H). 7.09-7.19 (m. 2H). b. 98-7.08 (m. 1H). 5.70 (dd. 1H). 4.95 (dd. 1H). 4.83 (d. 1H). 4.44-4.72 (m, 3H). 4.17-4.30 (m, 2H). 3.25-3.91 (m. 9H). 2.802.8b (m, 1H). 2.35-2.55 (m, 4H). 2.13-2.34 (m. 4H). 1.91-2.07 (m, 2H). 1.80-1.90 (m, 2H). 1.bb-1.80 (m. 2H). 1.51-1.03 (m, 2H). 1.30-1.51 (m 2n). 0.9b-1.15 (m, 3H). 0.b5-0.95 (m. 9H).

MS t / ζ 770.1. (M ⁺ +1).

Example 3-25

(18.4B.b8.148.18B) -4-Methyl-3.4-dihydro-1H-isoquinoline-2-carboxylic acid 14- (3-tert-butylureido) -4-cyclopropanesulfonidaminocarbonyl-2.15-dioxo-3.1-diazatricyclo [14.3.0.0 ⁴ . ^b ] non-adec-7-en-18-yl ether (compound AB00314b5b) was synthesized in accordance with the procedures. described in examples 1-2. 2-24 and 3-1. only 4-methyl-1.2.3.4 tetrahydroisoquinoline was used to replace 1.2.3.4-tetrahydroisoquinoline in step 4 of Example 1-2, and tert-butyl isocyanate was used to replace cyclopentyl isocyanate in Example 2-24.

¹ H NMR (500 MHz. C1) ₂ C1 ₂ ) δ 7.b0-7.72 (m, 1H). 7.0b-7.48 (m, 4H). 5.73 (dd. 1H). 5.39-5.48 (m, 1H). 5.18-5.27 (br.s 1H). 4.98 (dd. 1H). 4.79-4.90 (br.s. 1H). 4.30-4.72 (m. 4H). 3.40-3.77 (m, 5H). 2.97 (d. 1n). 2.83-2.90 (m, 1H). 2.37-2.58 (m, 3H). 2.17-2.30 (dt. 1H). 2.22-2.35 (dt. 1n). 1.97-2.07 (m 1n). 1.82-1.95 (m, 2H). 1.08-1.79 (m, 1H). 1.55-1.bb (m. 2H). 1.05-1.55 (m, 15H). 0.83-0.98 (m, 3H).

MS t / ζ 741.2 (M ⁺ +1).

- 144 012389

Example 3-26

Compound AK00314719 (18.4B, 68.148.18B) -3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo [14.3. 0.0 ^4.6 ] nonadec-7en-18-yl ester (compound AB00314719) was synthesized in accordance with the procedures described in examples 1-22 and 3-1. MS t / e 630.2 (M ⁺ + 1-100). Example 3-27

Compound AK00320001 (18.4V, 68.148.18B) -3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 14- (3-tert-butylureido) -4cyclopropanesulfonidaminocarbonyl-2.15-dioxo-3.16-diazatricyclo [ 14.3.0.0 ^4,6 ] nonadec-7-en-18yl ether (compound AB00320001) was synthesized in accordance with the procedures described in examples 1-2, 2-24 and 3-1, only tert-butylisocyanate was used to replace cyclopentyl isocyanate in example 2-24.

MS t / e 725.7 (M-1).

Example 3-28

Compound AB00320073 (18.4B, 68.148.18B) -1,3-Diidro-isoindole-2-carboxylic acid 4-cyclopropanesulfonidaminocarbonyl-14- (2-fluoroethoxycarbonylamino) -2.15-dioxo-3,16-diazatricyclo [14.3. 0.0 ^4.6 ] nonadec-7en-18-yl ester (compound AB00320073) was synthesized in accordance with the procedures described in examples 1-2, 2-1 and 3-1, only 2,3-dihydro-1H-isoindole was used to replace 1,2,3,4tetrahydroisoquinoline in step 4 in Example 1-2, and 2-fluoroethanol was used to replace cyclopentanol in step 2 in Example 2-1 to form chloroformate reagents.

MS t / e 704.0 (M ⁺ +1).

- 145 012389

Example 3-29

Compound AK00320079 (18.4H, 68.148.18H) -1,3-dihydroisoindole-2-carboxylic acid 4-cyclopropanesulfonidaminocarbonyl-14- (tetrahydrofuran-3H-yloxycarbonylamino) -2.15-dioxo-3.16-diazatricyclo [14.3. 0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound АЯ00320079) was synthesized in accordance with the procedures described in examples 1-2, 2-1 and 3-1, only 2,3-dihydro-1Н- isoindole was used to replace 1,2,3,4-tetrahydroisoquinoline in step 4 of Example 1-2 and tetrahydrofuran-3H-ol was used to replace cyclopentanol in step 2 of Example 2-1 to form a chloroformate reagent.

MS t / e 728.1 (M + 1).

Example 3-30 o = 4

Compound AK00320080 (18.4J, 68.148.18J) -1,3-dihydroisoindole-2-carboxylic acid 4-cyclopropanesulfonidaminocarbonyl-14- (tetrahydrofuran-38-yloxycarbonylamino) -2.15-dioxo-3.16-diazatricyclo [14.3. 0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound АЯ00320080) was synthesized in accordance with the procedures described in examples 1-2, 2-1 and 3-1, only 2,3-dihydro-1Н- isoindole was used to replace 1,2,3,4-tetrahydroisoquinoline in step 4 of Example 1-2 and tetrahydrofuran-38-ol was used to replace cyclopentanol in step 2 of Example 2-1 to form a chloroformate reagent.

MS t / e 728.1 (M ⁺ +1).

Example 3-31

Compound AY00320081 (18.4J, 68.148.18J) -1,3-dihydroisoindole-2-carboxylic acid 4-cyclopropanesulfonidaminocarbonyl-2,15-dioxo-14- (tetrahydropyran-4-yloxycarbonylamino) -3,16-diazatricyclo [14.3. 0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound АЯ00320081) was synthesized in accordance with the procedures described in examples 1-2, 2-1 and 3-1, only 2,3-dihydro-1Н- isoindole was used to replace 1,2,3,4-tetrahydroisoquinoline in step 4 of example 1-2 and tetrahydropyran-4-ol was used to replace cyclopentanol in step 2 of example 2-1 to form a chloroformate reagent.

MS t / e 742.1 (M ⁺ +1).

- 146 012389

Example 3-32

oA

Compound АЯ00320082 (18,4В, 68,148,18В) -3,4-Dihydro-1Н-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonidaminocarbonyl-2.15 - dioxo-14- (tetrahydropyran-4-yloxycarbonylamino) -3,16- diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester (compound AB00320082) was synthesized in accordance with the procedures described in examples 1-2, 2-1 and 3-1, only tetrahydropyran-4- ol was used to replace cyclopentanol in step 2 of example 2-1 to form a chloroformate reagent.

MS t / e 756.1 (M ⁺ +1).

Example 3-33

Compound AK00320119 (18.4B, 68.148.18B) -5-Chloro-1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo [14.3. 0.0 ^4.6 ] nonadec-7en-18-yl ester (compound AB00320119) was synthesized in accordance with the procedures described in examples 1-2 and 3-1, only 5-chloro-2,3-dihydro-1H-isoindole was used to replace 1,2,3,4tetrahydroisoquinoline in stage 4 of example 1-2.

¹ H NMR (500 MHz, CBAOV) δ 7.36 (s, 1H), 7.30 (s, 1H), 7.28 (s, 1H), 7.22 (s, 1H), 7.12- 7.20 (m, 1H), 6.64 (br s, 1H), 5.72-5.64 (m, 1H), 5.41 (s, 1H), 5.14-5.04 ( m, 1H), 4.80-4.62 (m, 2H), 4.61-4.56 (t, 1H), 4.544.48 (m, 1H), 4.10 (d, 1H), 3 85 (d, 1H), 2.90 (m, 1H), 2.65 (br.s, 1H), 2.54-2.48 (m, 1H), 2.46-2.32 (m , 2H), 1.91-1.72 (m, 2H), 1.64-1.56 (m, 2H), 1.56-1.21 (m, 8n), 1.18 (s, 9H ), 1.12-1.05 (m, 1H) 1.00 (m, 1H), 0.94-0.82 (m, 2H).

MS t / e 747.9 (M ⁺ )

Example 3-34 '' 'Ν'

R

Compound AK00320120 (18.4B, 68.148.18B) -5-Dimethylamino-3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo [ 14.3.0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound AB00320120) was synthesized in accordance with the procedures described in examples 1-2 and 3-1, only dimethyl (1,2,3,4- tetrahydroisoquinolin-5yl) amine (Example 1-25a) was used to replace 1,2,3,4-tetrahydroisoquinoline in Step 4 of Example

1-2.

- 147 012389 ¹ H NMR (400 MHz, SPS1 ₃ ) δ 10.08 (s, 1H), 7.13-7.05 (m, 1H), 6.88-6.81 (d, 1H), 6 77 (d, 1H), 6.68 (d, 1H), 6.61-6.53 (s, 1H), 5.71-5.60 (q, 1H), 5.40 (s, 1H) ), 5.00-4.88 (m, 2H), 4.55-4.38 (m, 3n), 4.24-4.16 (m, 2H), 3.88-3.77 (d , 1H), 3.64-3.41 (m, 3H), 2.91-2.69 (m, 3H), 2.61 (s, 6H), 2.53-2.41 (m, 2H) ), 2.40-2.39 (m, 1H), 2.22-

2.11 (m, 1H), 1.89-1.72 (m, 1H), 1.61-1.22 (m, 10H), 1.18 (s, 9H), 1.09-0, 97 (m, 2H), 0.91-0.76 (m, 2H).

MS: 771.1 (M ⁺ ), 772.1 (M ⁺ +1), 773.1 (M ⁺ +2).

Example 3-35

R

Compound AK00320121 (18.4K, 68.148.18K) -5,6-Dichloro-1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3,16-diazatricyclo [ 14.3.0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound AK00320121) was synthesized in accordance with the procedures described in examples 1-2 and 3-1, only 5,6-dichloro-2,3- dihydro-1H-isoindole was used to replace 1,2,3,4-tetrahydroisoquinoline in step 4 of Example 1-2.

¹ H NMR (500 MHz, C1GOO) δ 7.52 (s, 1H), 7.38 (s, 1H), 6.61 (br.s, 1H), 5.72-5.65 (q, 1H ), 5.40 (s, 1H),

5.08 (t, 1H), 4.78-4.62 (m, 3H), 4.63-4.57 (t, 1H), 4.50 (d, 1H), 4.20 (d, 1H), 3.65 (d, 1H), 2.90 (m, 1H), 2.55 (m, 1H), 2.52-2.45 (m, 1H), 2.46-2.31 (m, 2H), 1.91-1.75 (m, 3H), 1.67-1.60 (m, 1H), 1.58-1.25 (m, 8H), 1.18 (s 9H), 1.12-1.05 (m, 2H), 1.04-0.81 (m, 2H).

MS t / e 781.9 (M ⁺ ).

Example 3-36

Compound AK00320220 (18.4K, 68.148.18K) -1,3-dihydroisoindole-2-carboxylic acid 14- (3-tert-butylureido) -4cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3,16-diazatricyclo [14.3.0.0 ^{4 , 6} ] non-adec-7-en-18yl ether (compound AK00320220) was synthesized in accordance with the procedures described in examples 1-2, 2-24 and 3-1, only 2,3-dihydro-1H-isoindole was used for substitutions of 1,2,3,4tetrahydroisoquinoline in step 4 of Example 1-2 and t-butyl isocyanate was used to replace cyclopentyl isocyanate in Example 2-24.

MS t / e 713.1 (M ⁺ +1).

- 148 012389

Example 3-37

Compound AK00320222 (18.4K, 68.148.18K) -3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylminocarbonyl-2,15-dioxo-14- [3- (tetrahydrofuran-3-yl) ureido] -3,16-diazatricyclo [14.3.0.0 ^4,6 ] non-inadequate 7-en-18-yl ether (compound AK00320222) was synthesized in accordance with the procedures described in examples 1-2, 2-24 and 3-1, only 3 β-isocyanatotetrahydrofuran was used to replace cyclopentyl isocyanate in Example 2-24. MS t / e 740.8 (M ⁺ +1).

Example 3-38

(18.4K, 68.148.18K) -3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 14- (3-cyclopentylureido) 4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3.16-diazatricyclo [14.3.0.0 ^4,6 ] non-adec-7-en-18yl ether (compound AK00320403) was synthesized in accordance with the procedures described in examples 1-2, 2-24 and 3-1. MS t / e 739.2 (M ⁺ +1). Example 3-39

Compound AK00320446 (18.4K, 68.148.18K) -5-Chloro-1,3-Dihydroisoindole-2-carboxylic acid 14- (3-tert-butylureido) -4cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo [ 14.3.0.0 ^4,6 ] nonadec-7-en-18yl ether (compound AK00320446) was synthesized in accordance with the procedures described in examples 1-2, 2-24 and 3-1, only 5-chloro-2,3- dihydro-1H-isoindole was used to replace 1,2,3,4tetrahydroisoquinoline in step 4 of Example 1-2 and tert-butyl isocyanate was used to replace cyclopentyl isocyanate in Example 2-24.

¹ H NMR (500 MHz, DP ₃ OD) δ 7.35 (s, 1H), 7.28 (s, 1H), 7.26 (s, 1H), 7.02 (s, 1H), 7, 18 (s, 1H), 5.655.72 (q, 1H), 5.45 (s, 1H), 5.06 (t, 1H), 4.74-4.60 (m, 4H), 4.56 (t, 1H), 4.46 (m, 1H), 4.22 (d, 1H), 3.87-3.91 (dd, 1H), 2.86-2.94 (m, 1H), 2.65-2.54 (m, 1H), 2.52-2.45 (m, 1H), 2.42-2.34 (m, 2H), 1.92-1.83 (m, 1H) ), 1.781.70 (m, 2H), 1.62-1.56 (m, 1H), 1.54-3.92 (m, 4H), 1.39-1.23 (m, 7H), 1.12 (s, 9H), 1.02-0.98 (m, 1H), 0.94-0.86 (m, 1H).

MS t / e 747.1 (M ⁺ ), 749.1 (M ⁺ +2)

- 149 012389

Example 3-40

(18,4K, 68,148,18K) -5,6-Dichloro-1,3-dihydroisoindole-2-carboxylic acid 14- (3-tert-butylureido) -4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo [ 14.3.0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound AK00320447) was synthesized according to the procedures described in examples 1-2, 2-24 and 3-1, only 5,6-dichloro- 2,3-dihydro-1H-isoindole was used to replace 1,2,3,4-tetrahydroisoquinoline in step 4 of Example 1-2, and t-butyl isocyanate was used to replace cyclopentyl isocyanate in Examples 2-24.

MS t / e 781.1 (M ⁺ ), 783.1 (M ⁺ +2).

Example 3-41

Compound AK00320506 (18.4K, 68.148.18K) -1-piperidin-1-methylmethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-cyclopentyloxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3.16- diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound AK00320506) was synthesized in accordance with the procedures described in examples 1-2, 2-1 and 3-1, only 1-piperidine 1-ylmethyl-1,2,3,4tetrahydroisoquinoline was used to replace 1,2,3,4-tetrahydroisoquinoline in step 4 of Example 1-2.

MS (PO8 E8C t / ζ 837.4 (M ⁺ ).

Example 3-42

(18.4K, 68.148.18K) -3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 4-benzenesulfonylaminocarbonyl-14-tert-butoxycarbonylamino-2.15-dioxo-3.16-diazatricyclo [14.3.0.0 ^{4 , 6} ] nonadec-7en-18-yl ester (compound AK00320547) was synthesized in accordance with the procedures described in examples 1-2 and 3-1, only benzenesulfonamide was used to replace cyclopropylsulfonamide in example 3-1.

MS t / e 762.3 (M-1).

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Example 3-43

Compound AK00320548 (18.4K, 68.148.18K) -3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (4-methoxybenzenesulfonylaminocarbonyl) -2.15-dioxo-3.16 diazatricyclo [ 14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester (compound AK00320548) was synthesized in accordance with the procedures described in examples 1-2 and 3-1, only 4-methoxybenzenesulfonamide was used to replace cyclopropylsulfonamide in the example 3-1.

MS t / e 792.3 (M-1).

Example 3-44

Compound AK00320549 (18.4K, 68.148.18K) -3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-2.15-dioxo-4- (toluene-4-sulfonylaminocarbonyl) -3, 16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en18-yl ester (compound AK00320549) was synthesized according to the procedures described in examples 1-2 and 3-1, only 4-methylbenzenesulfonamide was used to replace cyclopropylsulfonamide at the stage of joining in example 3-1.

MS t / e 776.3 (M ⁺ +1).

Example 3-45

Compound AK00320556 (18.4K, 68.148.18K) -1-Piperidin-1K-ylmethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-cyclopentyloxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3, 16 diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound AK00320556) was synthesized in accordance with the procedures described in examples 1-2, 2-1 and 3-1, only 1-piperidine 1K-ylmethyl1,2,3,4-tetrahydroisoquinoline was used to replace 1,2,3,4-tetrahydroisoquinoline in step 4 of Example 1-2.

¹ H NMR (500 MHz, SP3OP) δ 8.99 (br.s, 1H), 7.34-7.13 (m, 6H), 5.75-5.65 (m, 2H), 5.44 (broad s, 1H), 5.06 (t, 1H), 4.60 (t, 1H), 4.51 (d, 1H), 4.44-4.16 (m, 2H), 4, 12-3.97 (m, 2H), 3.86 (d, 1H), 3.75-3.38 (m, 2H), 3.07 (t, 2H), 2.96-2.86 ( m, 1H), 2.78 (d, 1H), 2.66 (br.s, 1H), 2.56-2.26 (m, 3H), 2.06 (d, 1H), 1.99 -1.66 (m, 10H), 1.65-1.21 (m, 18H), 1.15-0.95 (m, 3H).

MS (PO8 E81) t / ζ 837.4 (M ⁺ ).

- 151 012389

Example 3-46

Compound AK00320557 (18.4K, 68.148.18K) -1-piperidin-15-ylmethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid

14-cyclopentyloxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16 diazatricyclo [14.3.0.0 ^4,6 ] non-7-ene-18-yl ester (compound AK00320557) was synthesized in accordance with the procedures described in examples 1 -2, 2-1 and 3-1, only 1-piperidin-18-ylmethyl1,2,3,4-tetrahydroisoquinoline was used to replace the 1,2,3,4-tetrahydroisoquinoline in step 4 of Example 1-2.

¹ H NMR (500 MHz, C1M) 1 ”δ 7.32-7.14 (m, 6H), 6.87 (br.s, 1H), 5.72-5.60 (m, 2H), 5 47-5.39 (m, 1H),

5.11 (br.s, 1H), 4.58 (t, 1H) 4.53-3.86 (m, 8H), 3.67-3.40 (m, 2H), 3.08-2 85 (m, 1H), 2.78 (d, 1H), 2.65-2.24 (m, 4H), 2.10-1.22 (m, 27H), 1.19 (dt, 1H) ), 1.10-1.02 (m, 2H), 1.01-0.93 (m, 1H), 0.89 (q, 1H).

MS (PO8 E8C t / ζ 837.4 (M ⁺ ).

Example 3-47

Compound AY00320574 (18.4K, 68.148.18K) -5-Chloro-1,3-dihydroisoindole-2-carboxylic acid 14- (3-cyclopentylureido) 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo [14.3 .0.0 ^4.6 ] nonadec-7-en-18yl ether (compound AK00320574) was synthesized in accordance with the procedures described in examples 1-2, 2-24 and 3-1, only 5-chloro-2,3-dihydro -1H-isoindole was used to replace 1,2,3,4tetrahydroisoquinoline in step 4 of Example 1-2.

MS t / e 759.1 (M ⁺ ), 761.1 (M ⁺ +2).

Example 3-48

R

Compound ΑΒ00320575 (18.4K, 68.148.18K) -5,6-Dichloro-1,3-dihydroisoindole-2-carboxylic acid 14- (3-cyclopentylureido) -4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3.16- diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7en-18-yl ester (compound AK00320575) was synthesized in accordance with the procedures described in examples 1-2, 2-24 and 3-1, only 5,6-dichloro- 2,3-dihydro-1H-isoindole was used to replace 1,2,3,4-tetrahydroisoquinoline in step 4 of Example 1-2.

MS t / e 793.1 (M ⁺ ).

- 152 012389

Example 3-49

(BUT

O y ° n / \ 7

Compound AK00320578 (18.4E, 68.148.18H) -3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-14- (2,2,2-trifluoroethoxycarbonylamino) -3, 16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester (compound АЯ00320578) was synthesized in accordance with the procedures described in examples 1-2, 2-24 and 3-1, only 2, 2,2-trifluoroethanol was used to replace cyclopentanol in step 2 of Example 2-1 to form a chloroformate reagent.

MS t / e 754.0 (M ⁺ +1).

Example 3-50 p

Compound AK00320579 (18.4E, 68.148.18H) -3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-14- (2,2-difluoroethoxycarbonylamino) -2.15-dioxo-3.16- diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound AY00320578) was synthesized in accordance with the procedures described in examples 1-2, 2-24 and 3-1, only 2.2- difluoroethanol was used to replace cyclopentanol in step 2 of Example 2-1 to form a chloroformate reagent.

MS t / e 736.0 (M ⁺ +1).

Example 3-51

Ν '

Compound AK00320580 (18.4E, 68.148.18H) -3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-14- (2-fluoro-1-fluoromethylethoxycarbonylamino) -2.15-dioxo-3, 16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester (compound АЯ00320580) was synthesized in accordance with the procedures described in examples 1-2, 2-24 and 3-1, only 1, 3-difluoropropan-2-ol was used to replace cyclopentanol in step 2 of Example 2-1 to form a chloroformate reagent.

MS t / e 750.1 (M ⁺ +1).

- 153 012389

Example 3-52

^OD about

Compound AK00320581 (18.4B, 68.148.18B) -3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-14- (2,2,2-trifluoro-1-methylethoxycarbonylamino) -2.15- dioxo-3,16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester (compound AB00320581) was synthesized in accordance with the procedures described in examples 1-2, 2-1 and 3-1 , only 1,1,1-trifluoropropan-2-ol was used to replace cyclopentanol in step 2 of Example 2-1 to form a chloroformate reagent.

MS t / e 768.1 (M ⁺ +1).

Example 3-53

oA

Compound AK00320582 (18.4B, 68.148.18B) -3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-14- (2,2,2-trifluoro-1,1 -dimethylethoxycarbonylamino) -3,16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester (compound AB00320582) was synthesized in accordance with the procedures described in examples 1-2, 2-1 and 3 -1, only 1,1,1-trifluoro-2-methylpropan-2-ol was used to replace cyclopentanol in step 2 of Example 2-1 to form a chloroformate reagent.

MS t / e 782.1 (M ⁺ +1).

Example 3-54

Compound AK00324375 (18.4B, 68.148.18B) -3,4-Dihydro-1H-isoquinoline-2-carboxylic acid 14-cyclopentyloxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3.16-diazatricyclo [14.3.0.0 ^{4 , 6} ] non-adec-7-en-18-yl ester (compound AB00324375) was synthesized in accordance with the procedures described in examples 1-2, 2-1 and 3-1.

MS t / e 740.5 (M ⁺ +1).

- 154 012389

Example 3-55

SAO

Compound AK00334191 (18.4K, 68.148.18K) -4-Fluoro-1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo [14.3. 0.0 ^4.6 ] nonadec-7en-18-yl ester (compound AK00334191) was synthesized according to the procedures described in Example 1-2, 4-fluoro-2,3-dihydro-1H-isoindole was used instead of 1,2 , 3.4 tetrahydroisoquinoline.

¹ H NMR (500 MHz, _6th Acetone) b 10.70 (br s, 1H), 8.34 (d, 1H), 7.39-7.33 (m, 1H), 7.20 ( d, 1H), 7.107.02 (m, 2H), 6.13 (d, 1H), 5.70 (q, 1H), 5.44 (br.s, 1n), 4.99 (t, 1H) ), 4.78-4.59 (m, 5H), 4.18-4.08 (m, 1H), 3.88-3.81 (m, 1H), 2.86-2.78 (m , 3H), 2.71-2.60 (m, 1H), 2.52-2.35 (m, 3H), 1.92-1.81 (m, 2H), 1.75 (t, 1H), 1.61-1.14 (m, 17H), 1.04-0.95 (m, 2H).

APC1 MS t / ζ 730.4 (M-1).

Example 3-55a. The 4-fluoro-2,3-dihydro-1H-isoindole used in Example 3-55 was prepared in the following two steps.

Stage 1

Best results are obtained when the starting material is dissolved in a 0.5 M ratio in formamide and heated to 125 ° C. for 1 to 5 hours, depending on volume. The starting material is insoluble in formamide until the temperature exceeds> 60 ° C. After completion of the reaction, as was observed using a combination of liquid chromatography and mass spectrometry (chromatography-mass spectrometry) (arsted), the heat was removed and a 3-fold volume of water with respect to the reaction volume was added to the reaction. Then the reaction mass cools to room temperature and mixes until a pale yellow precipitate forms. The yellow solid product was filtered and washed with water before drying overnight, the product is obtained in a yield between 7077%.

Stage 2

ABOUT

To the starting compound in a round bottom flask was added 4 equiv. 1 M BH ₃ -THF dropwise using an additional funnel to form a golden solution, which when heated and stirred becomes copper. The reaction mass was then heated at the boil for 18 hours.

The reaction mass was then cooled to room temperature and then to 0 ° C in an ice bath. 4 eq. MeOH was added dropwise and the ice bath was removed, so the cooled reaction mass was warmed to room temperature. The reaction mass turned dark during this heating procedure. Then 6n. HCl was added dropwise at room temperature until the pH of the paper showed an acidic reaction of the mixture, and the reaction was boiling (63 ° C) for 1 h. The reaction mass was cooled to room temperature. At this point, the reaction mass was concentrated and washed with Εΐ ₂ Ο (2x) and an ESM (2x). The aqueous layer was then adjusted to pH 11 with ΝαΟΗ granules. More water was added and the aqueous layer was extracted with ether (4x). The combined extracts were dried over Να ₂ 8Ο ₄ and concentrated to give a tan oil product that was used directly. The return mass is always slightly higher than the theoretical one, but the material was used in its raw form to obtain a yield> 80% in the next stage. Example 3-56

o ^ o

Compound AK00333833 (18.4J, 68.148.18J) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4.6 ] non-relative -7-en-18-ethyl ester (compound АЯ00333833) was synthesized according to examples 1-2 and 3-1, only in stages 1-2 similar to example, 2,3-dihydro-1H-isoindole was used in stage 4, product 10 of the exchange reaction from step 3 of Example 1-2 was then reduced with H2 / YAN-A12O3 before the next compound step in accordance with the procedures described in the literature (MO 0059929, pp. 76-77).

¹ H NMR (400 MHz, SPe8OSP3) δ 11.11 (s, 1H), 8.89 (s, 1H), 7.16-7.29 (m, 4H), 6.95 (d, 1H), 5.25 (br.s, 1H), 4.50-4.60 (br.s, 4H), 4.40 (dd, 1H), 4.23 (d, 1H), 3.93 (m, 1H), 3.68 (d, 1H), 2.92 (m, 1H), 2.32 (dd, 1H),

2.11 (m, 1H), 1.40-1.68 (m, 2H), 0.92-1.40 (m, 19H).

MS t / ζ 717.0 (M ⁺ 1).

Example 3-57

(18,4J, 68,148,18J) -5-amino-1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3,16-diazatricyclo [14.3.0.0 ^{4 , 6} ] non-adec-7-en-18-yl ester (compound AY00334286) was synthesized in accordance with the procedures shown in the following scheme:

- 156 012389

Step 1. Synthesis of (18.4K, 68.148.18K) -14-tert-Butoxycarbonylamino-2.15-dioxo-18triisopropylsilanyloxy-3.16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-4-carbon acid ethyl ester.

Imidazole (827 mg, 1.2 eq.) And PR8C1 (2.15) were added to a solution of the free hydroxymacrocyclic intermediate (compound 10 of Example 1-2, 5.0 g, 10.1 mmol) in Ep8O1ue ΩΓΜ (30 ml). g, 1.1 equiv.). The reaction mixture was stirred at room temperature for 18 hours. TLC (5% HeΜ- ^ CΜ) showed that a significant amount of the starting compound still remained. More imidazole (410 mg), PR8C1 (1 g) and ESAR (121 mg) were added to this reaction mixture. After stirring overnight, a small amount of the starting compound remained in the reaction mixture. The reaction mixture was washed with water (2x25 ml). The combined aqueous layers were again washed with ΩΓΜ (25 ml). The combined organic layers were dried and concentrated to give a pale yellow oil. The crude product was used in the next step without preliminary purification.

Step 2. Synthesis of (18.4K, 68.148.18K) -14-tert-butoxycarbonylamino-2.15-dioxo-18triisopropylsilanyloxy-3.16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-4-carbon acids.

The ester from step 1 was dissolved in a mixture of THF (20 ml) and HeΜ (20 ml). To this mixture was then added HOH-NgO (2.1 g, 50 mmol) in water (10 ml) and stirred for 12 hours at room temperature. Chromatography-mass spectrometry showed complete completion of the reaction. The reaction mixture was concentrated almost to dryness. The solid precipitate was then dissolved in 50 ml of water, acidified with 2N. HC1, and extracted with E! OAc (2x50 ml). The combined organic layers were dried over anhydrous No. ₂ 8O ₄ and concentrated. The crude material was used in the next step without further purification.

Step 3. Synthesis of (18.4K, 68.148.18K) - (4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-18triisopropylsilanyloxy-3.16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-14-yl) carbamic acid tert-butyl ether.

The acid from step 2 was first dissolved in 25 ml of Ep8O1ue1, 2-dichloroethane. SE was added to this solution! (2.2 g, 13.8 mmol) in one portion and the reaction mixture was stirred at 50 ° C for 3 hours. Then cyclopropylsulfonamide (3.3 g, 27.5 mmol) was added to the reaction mixture, followed by the addition of EVi (4.2 g, 27.5 mm: ol), and the reaction was stirred at 50 ° C. for 4 hours. HPLC indicated complete reaction. For processing, the reaction mixture was washed with water (2x50 ml), and the organic layer was dried (anhydrous No. ₂ 8Ο ₄ ) and concentrated. The crude material was used in the next step without further purification.

- 157 012389

Step 4. Synthesis of (18.4K, 68.148.18K) - (4-cyclopropanesulfonylaminocarbonyl-18-hydroxy-2.15 dioxo-3.16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-14-yl) carbamic acid tert-butyl ether.

The crude product from step 3 was first dissolved in THF (40 ml). TBAP (3.6 g, 13.7 mmol, 1.5 eq.) Was then added to the solution and stirred at room temperature for 2 hours. TLC indicated completion of the reaction. The reaction mixture was then concentrated to dryness, redissolved in ESAc and washed with water. The organic layer was dried (anhydrous Na ₂ 8 O ₄ ) and concentrated. For purification, the crude product was dissolved in BSM (50 ml) and washed with a 3N solution. NaOΗ. The aqueous layer was neutralized 2n. HC1 and extracted with BSM (2x25 ml). The combined organic layers were dried (Xa ₂ 8O ₄ ) and concentrated to give a white precipitate (2.4 g, 46%).

MS t / ζ (ΛRSΖ +) 469.1 (MH ⁺ -Boc).

Stage 5. Synthesis of (18.4K, 68.148.18K) -5-amino-1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3,16-diazatricyclo [14.3. 0.0 ^4.6 ] non-adec-7-en-18-yl ester (compound AK00334286).

To a solution of the BSE product from step 4 (19 mg, 33 μmol) was added C ^ Ζ (7 mg, 1.3 equiv.) And the reaction mixture was stirred at room temperature overnight. HPLC showed a complete completion of the reaction. Then 2,3-dihydro-1H-isoindol-5-ylamine (18 mg, 4 equiv.) Was added. After 4 hours of reaction at room temperature, the HPLC showed complete completion of the reaction. The reaction mixture was transferred directly onto silica gel and eluted from 1 to 5% methanol / BSM. The pure product was isolated as a white solid.

MS t / ζ (ΛRSΖ +) 629.2 (MH ⁺ -Boc).

Example 3-58

Connection AK00334385

Synthesis of (18.4K, 68.148.18K) -4-amino-1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3,16-diazatricyclo [14.3.0.0 ^{4, 6} ] nonadec-7-en-18-yl ester (compound AK00334385) was synthesized in a similar manner as described in Example 3-57, replacing 2,3-dihydro-1H-isoindol-5-ylamine in step 5 with 2.3 dihydro-1H-isoindol-5-ylamine. Also, the final product was purified back by phase column chromatography (eluent = 5 to 100% acetonitrile in water) to obtain the final product as a beige solid.

MS t / ζ (APCb) 728.2 (M ⁺ ).

Example 3-59

Synthesis of (18.4K, 68.148.18K) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-2.15-dioxo-4-trifluoromethanesulfonylaminocarbonyl-3.16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7 en-18-yl ester (compound AK00340479) was used in accordance with the procedures described in Example 3-6, only trifluoromethanesulfonamide was used to replace cyclopropanesulfonamide.

- 158 012389 ¹ Η NMR (400 MHz, b ₆ -acetone) δ 7.98 (br.s, 1Η), 7.23-7.35 (m, 4Η), 6.13 (br.s., 1Η) , 5.70 (q, 1Η), 5.44 (broad s, 1Η), 4.98-5.02 (m, 1Η), 4.61-4.72 (m, 5Η), 4.49 (d, 1Η), 4.16-4.18 (m, 1Η), 3.87-3.90 (m, 1Η), 2.57-2.59 (m, 2Η), 2.38-2 51 (m, 2Η), 1.82-1.92 (m, 2Η), 1.72-1.79 (m, 2Η), 1.21-1.59 (m, 8n), 1.21 (s, 9Η).

MS t / ζ (APC1-) 741.1 (M ⁺ ).

Example 3-60

ABOUT

Compound AK00365387 (18.4K, 68.148.18K) -1,3-Dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (4-carboxybenzenesulfonylaminocarbonyl) -2.15-dioxo-3.16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en18-yl ester (compound AK00365387) was synthesized according to the procedures described in Example 3-6, only 4-sulfamoylbenzoic acid was used to replace cyclopropanesulfonamide.

MS t / ζ (APC1-) 792.3 (M-1).

Example 3-61

(18.4K, 68.148.18K) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (5-carboxy-2-chlorobenzenesulfonylaminocarbonyl) -2.15-dioxo-3,16-diazatricyclo [14.3 .0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound AK00365388) was synthesized according to the procedures described in Example 3-6, only 4-chloro-3-sulfamoylbenzoic acid was used to replace cyclopropanesulfonamide.

MS t / ζ (APC1-) 826.2 (M-2).

Example 3-62

Compound AK00365425 (18.4K, 68.148.18K) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (3-carboxy-4-methoxybenzenesulfonylaminocarbonyl) -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester (compound AK00365425) was synthesized according to the procedures described in example 3-6, only 2-methoxy-5-sulfamoylbenzoic acid was used to replace cyclopropanesulfonamide .

MS t / ζ (APC1-) 822.3 (M-1).

- 159 012389

Example 3-63

Compound AK00365426 (18.4K, 68.148.18K) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (5-carboxy-4-chloro-2-fluorobenzenesulfonylaminocarbonyl) -2.15-dioxo-3 , 16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound AK00365426) was synthesized according to the procedures described in example 3-6, only 2-chloro-4-fluoro-5 Sulfamoylbenzoic acid has been used to replace cyclopropanesulfonamide.

MS t / ζ (APCS) 844.2 (M-2).

Example 3-64

Compound AK00365572 (18.4K, 68.148.18K) -1,3-Dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (4-dimethylaminobenzenesulfonylaminocarbonyl) -2.15-dioxo-3.16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec7-en-18-yl ester (compound AK00365572) was synthesized according to the procedures described in Example 3-6, only 4-dimethylaminobenzoic acid was used to replace cyclopropanesulfonamide.

MS t / ζ (ARPC) 791.3 (M-1).

Example 3-65

Compound AK.00333801 (18.4K, 68.148.18K) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino2,15-dioxo-4- (propane-2-sulfonylaminocarbonyl) -3,16-diazatricyclo [ 14.3.0.0 ^4,6 ] nonadec-7-en-18yl ether (compound AK.00333801) was synthesized in accordance with the procedures described in Example 3-6, only propane-2-sulfonic acid was used to replace cyclopropanesulfonamide.

MS t / ζ (APCS) 714.4 (M-1).

- 160 012389

Example 3-66

(18,4B, 68,148,18B) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-benzenesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4,6 ] non-in-7 en-18-yl ester (compound AB00333802) was synthesized in accordance with the procedures described in example 3-6, only benzenesulfonamide was used to replace cyclopropanesulfonamide.

MS t / ζ (APC1-) 748.3 (M-1).

Example 3-67

Compound AK00333803 (18.4B, 68.148.18B) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4methanesulfonylaminocarbonyl-2.15-dioxo-3.16-diazatricyclo [14.3.0.0 ^4.6 ] non-relative -7-en-18-yl ester (compound AB00333803) was synthesized in accordance with the procedures described in example 3-6, only methanesulfonamide was used to replace cyclopropanesulfonamide.

MS t / ζ (APC1-) 686.4 (M-1).

Example 3-68

Compound AK00334188 (18.4B, 68.148.18B) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (5-chloro-thiophen-2-sulfonylaminocarbonyl) -2.15-dioxo-3.16 β-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en18-yl ester (compound AB00334188) was synthesized in accordance with the procedures described in example 3-6, only 5-chloro-thiophen-2-sulfonic acid was used for replacement cyclopropanesulfonamide.

MS t / ζ (APC1-) 788.3 (M-2).

- 161 012389

Example 3-69

About 9;

Compound AK00334247 (18.4K, 68.148.18K) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (5-acetylamino [1,3,4] thiadiazole-2-sulfonylaminocarbonyl) -2, 15-dioxo-3,16 diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester (compound AK00334247) was synthesized according to the procedures described in example 3-6, only N- (5-sulfamoyl - [1,3,4] thiadiazole-2yl) acetamide was used to replace cyclopropanesulfonamide.

¹ H NMR (400 MHz, d ₆ -acetone) δ 7.24-7.31 (m, 4H), 5.96 (br.s.d, 1H), 5.42 (br.s, 1H), 5, 28 (m, 1H), 5.15 (m, 1H), 4.68 (m, 6H), 4.49 (m, 1H), 4.14 (m, 2H), 2.60 (m, 1H ), 2.25-2.36 (m, 5H), 1.70-2.19 (m, 8H), 1.19-1.48 (m, 4 N), 1.30 (s, 9 N )

MS t / ζ (LRS) 813.3 (M-1).

Example 3-70

(18.4K, 68.148.18K) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (4-cyanobenzenesulfonylaminocarbonyl) -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^{4, 6} ] nonadec-7-en-18-ethyl ester (compound AK00334248) was synthesized according to the procedures described in Example 3-6, only 4-cyanobenzenesulfonamide was used to replace cyclopropanesulfone mid.

¹ H NMR (400 MHz, d ₆ -acetone) δ 11.32 (br s, 1H), 8.36 (br s, 1H), 8.04-8.15 (m, 4H), 7, 22-7.35 (m, 4H), 6.12 (br.s, 1H), 5.47 (br.s, 1H), 5.28 (q, 1H), 4.60-4.72 ( m, 5H), 4.48-4.54 (m, 2H), 4.14-4.17 (m, 1H), 3.863.90 (m, 1H), 2.37-2.52 (m, 4H), 1.72-1.85 (m, 2H), 1.59-1.62 (m, 1H), 1.20-1.55 (m, 8H), 1.20 (s, 9H) .

MS t / ζ (LRS) 773.3 (M-1).

Example 3-71

(18.4K, 68.148.18K) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (4-nitrobenzenesulfonylaminocarbonyl) -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^{4, 6} ] non-adec-7-en-18yl ether (compound AK00334249) was synthesized according to the procedures described in Example 3-6, only 4-nitrobenzenesulfonamide was used to replace cyclopropanesulfone 162 012389 mid.

¹ H NMR (400 MHz. Yb-acetone) δ 11.39 (br s, 1H). 8.4b (d. 2H). 8.35 (br.s. 1H). 8.23 (d. 2H). 7.23-7.3b

Example 3-72 p

C1

Compound AK00334250 (18.4B.b8.148.18B) -1.3-Dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (4-chlorobenzenesulfonylaminocarbonyl) -2.15-dioxo-3.1b-diazatricyclo [14.3.0.0 ⁴ . ^b ] non-adec-7-en-18yl ether (compound AB00334250) was synthesized in accordance with the procedures. described in example 3-b. only 4-chlorobenzenesulfonamide was used to replace cyclopropanesulfonamide.

¹ H NMR (400 MHz. Yb-acetone) δ 11.1b (br.s. 1H). 8.34 (br.s. 1H). 7.9b (d. 2H). 7.b5 (d. 2H). 7.22-7.3b

MS t / ζ (APC1-) 782.3 (M-2).

Example 3-73

Compound AK00334341 (18.4B.b8.148.18B) -1.3-Dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (4-methoxybenzenesulfonylaminocarbonyl) -2.15-dioxo-3.1b-diazatricyclo [14.3.0.0 ⁴ . ^b ] non-adec-7-en-18yl ether (compound AB00334341) was synthesized in accordance with the procedures. described in example 3-b. only 4-methoxybenzenesulfonamide was used to replace cyclopropanesulfonamide.

¹ H NMR (400 MHz. Yb-acetone) δ 8.2b (br.s. 1H). 7.84 (d. 2H). 7.19-7.32 (m. 4H). 7.05 (d. 2H). b.08 (brd. 1H). 5.43 (broad s, 1H). 5.25 (q. 1H). 4.55-4.b7 (m. 5H). 4.48 (q, 2H). 4.10-4.14 (m. 1H). 3.87 (p. 3H). 3.823.87 (m, 1H). 2.29-2.47 (m, 4H). 1.74-1.84 (m, 2H). 1.51-1.55 (m, 1H). 1.37-1.47 (m. 4H). 1.20-1.32 (m. 5H). 1.17 (p. 9H).

MS t / ζ (APC1-) 779.1 (M-1). Example 3-74 'OH

Connection AK00364266

- 1b3 012389 (18.4K, 68.148.18K) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (5-carboxy-1-methyl-1H-pyrrole-2-sulfonylaminocarbonyl) -2, 15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester (compound AK00364266) was synthesized according to the procedures described in example 3-6, only 1-methyl- 5-sulfamoyl-1H-pyrrole-2-carboxylic acid was used to replace cyclopropanesulfonamide.

¹ H NMR (400 MHz, 06-acetone) δ 10.84 (br s, 1H), 8.27 (br s, 1H), 7.59 (d, 1H), 7.24-7.35 (m, 4H), 7.18 (d, 1H), 6.10 (br.s.d, 1H), 5.50 (br.s.d, 1H), 5.46 (m, 1H), 5.36 ( q, 1H), 4.59-4.71 (m, 6H), 4.48 (d, 1H), 4.13-4.17 (m, 1H), 4.00 (s, 3H), 3 85-3.89 (m, 1H), 2.35-2.59 (m, 4H), 1.71-1.90 (m, 2H), 1.62-1.65 (m, 1H) 1.20-1.51 (m, 8H); 1.20 (s, 9H).

MS t / ζ (APCS) 795.4 (M-1).

Example 3-75

Compound AK00365427 (18.4K, 68.148.18K) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (thiophene-2-sulfonylaminocarbonyl) -2.15-dioxo-3,16-diazatricyclo [14.3 .0.0 ^4.6 ] nonadec-7-en-18-ethyl ester (compound AK00365427) was synthesized in accordance with the procedures described in Example 3-6, only thiophene-2-sulfonic acid was used to replace cyclopropanesulfonamide.

MS t / ζ (ARPC) 754.4 (M-1).

Example 3-76

BUT)

Compound AK00334339 (18.4K, 68.148.18K) -6-Methoxy-1-methoxymethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo 3,16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester (compound AK00334339) was synthesized according to the procedures described in example 3-6, only 6-methoxy-1-methoxymethyl- 1,2,3,4 tetrahydroisoquinoline (for synthesis see Example 3-76a) was used instead of 2,3-dihydro-1Nisoindole.

MS t / ζ (ARPC) 800.5 (M-1).

- 164 012389

Example 3-76a

The synthesis of 6-methoxy-1-methoxymethyl-1,2,3,4-tetrahydroisoquinolinium chloride is depicted in the following scheme:

Stage 1. Synthesis of 2-chloro - \ - [2- (3-methoxyphenyl) ethyl] acetamide.

The amine, 2- (3-methoxyphenyl) ethylamine, was taken as a 0.6 M solution in BSM, followed by the addition of TEM (2 equiv.). The mixture was cooled in an isopropanol / dry ice bath. When the temperature of the reaction mixture reaches -60 ° C, a solution of chloroacetyl chloride in BSM (2.6 M) will be added dropwise so as to keep the temperature below -60 ° C. After complete addition, the reaction mixture was stirred at -60 ° C for 1 h. Then the reaction mixture was heated to -20 ° C and filtered through CP filter paper to remove some of the TEA-HC1 salts. The filtrate was warmed to room temperature and transferred to a separation funnel, where it was washed with 1N. HC1 (2x) and saline. The organic layer was dried over MgSO ₄ and concentrated to give a dark red solid. This crude product was directly used in the next step without further purification.

Stage 2. Synthesis of 1-chloromethyl-6-methoxy-3,4-dihydroisoquinolinium chloride.

eq. P ₂ O ₅ (12.9 g) was boiled in xylene (180 ml) to form a 0.25 M solution. The crude product from step 1 was also boiled in xylene (45 ml) to form a 0.5 M solution and then was added dropwise through a dropping funnel to the P2O5 solution. The mixture was stirred and heated at the boil for 1 hour. Then the reaction mixture was cooled to room temperature, and xylene was decanted at this stage. Then the flask was placed in an ice bath and stirred until, with careful addition of ice, water, ethyl acetate and 4 M \ aOH, the pH was> 12. The reaction mixture was kept at a temperature of <25 ° C until a pH of 12 was reached. The reaction mixture was extracted with ethyl acetate (3x). The combined organic extracts were dried over MgSO ₄ and concentrated to give a dark solution. It was cooled in an ice bath until 400 ml of cold HbO was added, followed by the addition of 100 ml of cold HCl / E1 ₂ O. A precipitate formed, which was filtered and washed with E1 ₂ O. A solid precipitate was immediately transferred under high vacuum for 2 hours to obtain the desired product as a colored solid. This crude product was directly used in the next step without further purification.

Stage 3. Synthesis of 6-methoxy-1-methoxymethyl-1,2,3,4-tetrahydroisoquinolinium chloride.

The crude product from step 2 was added to one part of TEA (5 equiv.) And NaI (0.1 equiv.) In MeOH at 0 ° C. Then 2.2 equiv. \ aOMe was added and the homogeneous reaction mass became cloudy. The reaction mass was then stirred at 0 ° C for 1 h. Chromatography-mass spectrometry showed that imine is in the form of a free base.

The reaction mass was then cooled to 0 ° C in an ice bath and \ ABH ₄ (1.5 equiv.) Was carefully added. Then the reaction was again warmed to room temperature and stirred for 2 hours. After complete completion of the reaction, as shown by chromatography-mass spectrometry, the solution was concentrated, treated with 1N. \ aO11 and extracted ESAA. The organic layer was dried over Md8O ₄ and concentrated. The resulting residue was dissolved in MeOH and cooled in an ice bath. HC1 gas was bubbled through the solution for 10 minutes. The reaction mixture was concentrated and redissolved in MeOH. After re-concentration, the reaction mixture was placed under high vacuum overnight. The crude material was triturated with EJAc (3x) to form the product in the form of a brown solid when placed overnight under high vacuum. This crude product was directly used in the next step without further purification.

MS t / ζ (PO8EM) 208.1 (MH ⁺ ).

- 165 012389

Example 3-77

Compound AK00365193 (18.4J, 68.148.18J) -5-Fluoro-1-methoxymethyl-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3 , 16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester (compound АЯ00365193) was synthesized in accordance with the procedures described in example 3-76, only 5-fluoro-1-methoxymethyl-1 , 2,3,4-tetrahydroisoquinolinium chloride (for synthesis see Example 3-77a) was used to replace 6-methoxy-1-methoxymethyl-1,2,3,4-tetrahydroisoquinolinium chloride.

¹ H NMR (500 MHz, DP ₃ OD) δ 8.99-8.91 (m, 1H), 7.23-7.15 (m, 1H), 7.13-6.99 (m, 2H) 6.99-6.90 (m, 1H), 5.68 (q, 1H), 5.41 (br s, 1H), 5.35-5.21 (m, 1H), 5.06 (t, 1H), 4.60-4.31 (m, 3H), 4.30-4.05 (m, 3H), 3.96-3.81 (m, 1H), 3.80-3 56 (m, 3H), 3.35 (d, 3H), 2.98-2.30 (m, 9H), 1.91-1.68 (m, 4H), 1.64-0.95 (m, 16H).

MS (ARSG-) t / ζ 788.3 (M-1).

Example 3-77a

The synthesis of 5-fluoro-1-methoxymethyl-1,2,3,4-tetrahydroisoquinolinium chloride was carried out in a similar manner as illustrated in Example 3-76a, except that in step 1, instead of 2- (3-methoxyphenyl) ethylamine used 2- (2-fluoro-phenyl) ethylamine.

Example 3-78

(18,4J, 68,148,18J) -4-Fluoro-1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (4-carboxybenzenesulfonylaminocarbonyl) -2.15-dioxo-3,16-diazatricyclo [ 14.3.0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound AY00365438) was synthesized according to the procedures described in Example 3-55, except that 4-sulfamoylbenzoic acid was used to replace cyclopropanesulfonamide.

¹ H-NMR (500 MHz, DP ₃ OD) δ 8.92 (d, 1H), 8.25-8.19 (m, 1H), 8.15 (d, 2H), 8.04 (d, 2H), 7.36-7.27 (m, 1H), 7.14 (d, 1H), 7.05-6.95 (m, 2H), 5.42 (br s, 1H), 5 26 (q, 1H), 4.82-4.50 (m, 8H), 4.10-4.00 (m, 1H), 3.85 (d, 1H), 3.75-3.69 (m, 1H), 2.60-2.39 (m, 4H), 2.26 (s, 2H), 1.89-1.84 (m, 1H), 1.81-1.05 (m , 15H).

MS (ARSG-) t / ζ 810.2 (M-1).

- 166 012389

Example 3-79

Connection AK00340303

Synthesis of (18.4K, 68.148.18K) -4-fluoro-1,3-dihydroisoindole-2-carboxylic acid 14- {2-cyclohexyl2 - [(pyrazine-2-carbonyl) amino] acetylamino} -4-cyclopropanesulfonylaminocarbonyl-2 , 15-dioxo-3,16 diazatricyclo [14.3.0.0 ^4.6 ] non-adec-7-en-18-yl ester (compound AK00340303)

The starting material (AK00334191, example 3-55, 10 mg, 13.7 μl) was dissolved in 1 ml of 50% trifluoroacetic acid TPA (1) CM) and stirred at room temperature for 1 h. The reaction mixture was concentrated to dryness, extracted with acetonitrile and concentrated again. Repeat the above process 1 more time to remove excess trifluoroacetic acid. The resulting solid precipitate was then dissolved in OCE (137 μl), cooled to 0 ° C in an ice bath, after which amino acid, cyclohexyl [(pyrazine-2-carbonyl) amino] acetic acid (1.05 equiv.), NATi ( 10 mg) and [)! EA (4 drops). The mixture was slowly warmed to room temperature and stirred overnight. Finally, the reaction mixture was transferred directly to a C-18 column and purified by reverse phase column chromatography to give the desired compound as a white precipitate.

MS (ARP) t / ζ 876.1 (M-1).

Example 3-80

0 ^ 0

Compound AK00340122 (18.4K, 68.148.18K) -4-Fluoro-1,3-dihydroisoindole-2-carboxylic acid 14- (2-acetylamino-2cyclohexylacetylamino) -4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3.16- diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester (compound AK00340122) was synthesized according to the procedures described in Example 3-79, except that acetylaminocyclohexylacetic acid was used to replace cyclohexyl [ (pyrazine-2-carbonyl) amino] acetic acid.

MS (APCI) t / z 811.3 (M-1).

- 167 012389

Example 3-81

Connection AK00340156

Synthesis of (18.4K, 68.148.18K) -4-fluoro-1,3-dihydroisoindole-2-carboxylic acid 14- [2- (4methoxyphenyl) acetylamino] -4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3.16- diazatricyclo [14.3.0.0 ^4.6 ] non-adec-7-en-18-yl ester (compound AK00340156).

ml 50% trif. The starting compound (AK00334191, example 3-55, 10 mg, 13.7 pmol) was dissolved in 1 toroacetic acid (ISM) and stirred at room temperature for 1 h. The reaction mixture was concentrated to dryness, extracted with acetonitrile and concentrated again. Repeat the above process 1 more time to remove excess trifluoroacetic acid. The resulting solid precipitate was then dissolved in ISE (137 μl), after which (4-methoxyphenyl) acetic acid chloride (2 drops) was added, 1) P: L (4 drops). The mixture was stirred overnight. Finally, the reaction mixture was transferred directly to a C-18 column and purified by reverse phase column chromatography. The compound was then purified by normal phase silica gel chromatography (eluent = 40% EJAe / hexane with 1% formic acid) to give the desired compound as a white precipitate.

¹ H NMR (500 MHz, SP3OP) δ 7.33 (p, 1H), 7.15 (d, 1H), 7.05-6.92 (m, 3H), 6.65 (dd, 2H), 5.68 (q, 1H), 5.40 (br s, 1H), 5.09 (t, 1H), 4.78-4.46 (m, 7H), 4.43-4.24 ( m, 2H), 3.89-3.80 (m, 1H), 3.68 (d, 3H), 3.21 (d, 1H), 2.69-2.57 (m, 1H), 2 52-2.30 (m, 5H); 2.06-0.80 (m, 15H).

MS (ARCE) t / ζ 778.3 (M-1).

Example 3-82

(18.4K, 68.148.18K) -4-Fluoro-1,3-dihydroisoindole-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-14- [2- (3-methoxyphenyl) acetylamino] -2.15-dioxo-3.16 β-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester (compound AK00340178) was synthesized according to the procedures described in example 3-81, except that (3-methoxyphenyl) acetyl chloride was used to replace (4-methoxyphenyl) acetyl chloride.

¹ H NMR (500 MHz, SP3OP) δ 7.32 (br s, 1H), 7.14 (d, 1H), 7.05-6.92 (m, 3H), 6.76-6.58 (m, 2H), 5.68 (q, 1H), 5.41 (br s, 1H), 5.09 (t, 1H), 4.76-4.46 (m, 7H), 4, 43-4.26 (m, 2H), 3.91-3.82 (m, 1H), 3.69 (d, 3H), 2.94-2.85 (m, 1H), 2.70- 2.57 (m, 1H), 2.52-2.30 (m, 5H), 2.06-0.80 (m, 15H).

MS (ARCE) t / ζ 778.3 (M-1).

- 168 012389

Example 3-83

(18.4J, 68.148.18J) -4-Fluoro-1,3-dihydroisoindole-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-14-phenylacetylamino-3.16-diazatricyclo [14.3.0.0 ^4.6 ] non-adec-7-en-18yl ether (compound AY00340188) was synthesized according to the procedures described in Example 3-81, except that phenylacetyl chloride was used to replace (4-methoxyphenyl) chloride.

MS (ARCE) t / ζ 748.4 (M-1).

Example 3-84

Compound AK00334314 (18.4J, 68.148.18J) -5-Methoxy-1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo [14.3. 0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound AY00334314) was synthesized in accordance with the procedures described in example 3-6, except that 5-methoxy-2,3-dihydro-1H- isoindole (obtained by the method as described: US, Volume 53, No. 22, 1988, S. 5381-5383) was used to replace

2,3-dihydro-1H-isoindole.

MS t / ζ (APST-) 742.3 (M-1).

Example 3-85

Compound AK00334399 (18.4J, 68.148.18J) -4,7-Difluoro-1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo [ 14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ether (compound АЯ00334399) was synthesized in accordance with the procedures described in example 3-6, except that 4,7-difluoro-2,3- dihydro-1H-isoindole (obtained by the method as described in US, vol. 53, No. 22, 1988, p. 5381-5383) was used instead

2,3-dihydro-1 H-isoindole.

- 169 012389 ¹ H NMR (500 MHz, CO ₃ OO) δ 8.97 (s, 1H), 6.99-6.85 (m, 2H), 5.69 (q, 1H), 5.42 ( broad s, 1H), 5.07 (t, 1H), 4.83-4.57 (m, 6H), 4.51 (d, 1H), 4.13-4.02 (m, 1H) 3.85 (t, 1H), 2.94-2.86 (m, 1H), 2.73-2.59 (m, 1H), 2.552.28 (m, 4H), 1.89-1 70 (m, 3H); 1.65-1.22 (m, 10H); 1.18-0.96 (m, 10H).

MS t / ζ (ARSG) 746.1 (M-1).

Example 3-86

oae

Compound ΑΒ00338066 (18.4K, 68.148.18K) -4-Fluoro-1,3-dihydroisoindole-2-carboxylic acid 14- (3-tert-butylureido) -4cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo [ 14.3.0.0 ⁴ . ^b ] nonadec-7-en-18-ethyl ester (compound AK00338066) was synthesized according to the procedures described in Example 3-36, except that 4-fluoro-2,3-dihydro-1H-isoindole was used to replace

2,3-dihydro-1H-isoindole.

¹ H NMR (500 MHz, CO ₃ O) δ 7.38-7.28 (m, 1H), 7.13 (d, 1H), 7.01 (p, 1H), 5.69 (q, 1H) ), 5.45 (br s, 1H), 5.07 (t, 1H), 4.83-4.66 (m, 4H), 4.59 (q, 1H), 4.49 (d, 1H), 4.37-4.17 (m, 2H), 3.94-3.84 (m, 1H), 3.72 (t, 1H), 2.95-2.87 (m, 1H) 2.68-2.29 (m, 5H); 2.09-1.22 (m, 11H); 1.12-0.95 (m, 12H).

MS (APC-) t / ζ 729.3 (M-1).

Example 3-87

Compound AK00338070 (18.4K, 68.148.18K) -4-Fluoro-1,3-dihydroisoindole-2-carboxylic acid 14- (3,3-dimethylbutyrylamino) -4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16- diazatricyclo [14.3.0.0 ⁴ . ^b ] nonadec-7en-18-yl ester (compound AK00338070) was synthesized according to the procedures described in examples 3-81, except that 3,3-dimethylbutyryl chloride was used to replace (4-methoxyphenyl) acetyl chloride .

MS (ARSG) t / ζ 728.3 (M-1).

Example 3-88

- 170 012389 (18.4K, 68.148.18K) -4-Fluoro-1,3-dihydroisoindole-2-carboxylic acid 14- (4,4,4-trifluorobutyrylamino) -4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3 , 16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7 en-18-yl ester (compound AK00338071) was synthesized in accordance with the procedures described in example 3-81, except that 4,4,4- trifluorobutyryl chloride was used to replace (4-methoxyphenyl) acetyl chloride.

MS (APCI) t / ζ 754.3 (M-1).

Example 3-89

(18.4K, 68.148.18K) -5-Isopropylamino-1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3.16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound AK00341649) was synthesized according to the procedures, except that (2,3-dihydro-1H-isoindol-5-yl) isopropylamine (obtained by the method as described in Ogd Leyegs, 2003, Volume 5, No. 6, pp. 793-796) was used instead of 2,3-dihydro1 H-isoindole.

¹ H NMR (500 MHz, (ΊΜ) Ο) δ 8.94 (br.sd., 1H), 7.52 (s, 1H), 7.48 (d, 1H), 7.41-7.32 ( m, 2H), 7.32-7.24 (m, 2H), 5.69 (q, 1H), 5.41 (br s, 1H), 5.07 (t, 1H), 4.82 -4.66 (m, 3H), 4.60 (t, 1H), 4.52 (t, 1H), 4.08 (d, 1H), 3.85 (d, 1H), 3.80- 3.68 (m, 1H), 2.94-2.87 (m, 1H), 2.71-2.59 (m, 1H), 2.55-2.45 (m, 1H), 2, 45-2.30 (m, 3H), 1.88-1.69 (m, 3H), 1.61 (t, 1H), 1.58-0.94 (m, 25H).

MS (APCI) t / ζ 770.1 (M-1).

Example 3-90

(18.4K, 68.148.18K) -5-Hydroxy-1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3,16-diazatricyclo [14.3.0.0 ^{4 , 6} ] non-inadequate 7-en-18-yl ester (compound AK00364936) was synthesized in accordance with the procedures described in example 3-6, except that 2,3-dihydro-1H-isoindol-5-ol (obtained by the method as described in US Volume 53, No. 22, 1988, pp. 5381-5383) was used to replace 2,3-dihydro-1 Nisindole.

MS t / ζ (APCB) 728.2 (M-1).

- 171 012389

Example 3-91

(18.4B, 68.148.18B) -1,3-dihydroisoindole-2,5-dicarboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4.6 ] 5-methyl ether nonadec-7en-18-yl ester (compound AB00365083) was synthesized according to the procedures described in Example 3-57, except that 2,3-dihydro-1Nisoindole-5-carboxylic acid methyl ester (obtained as shown in example 3-91a) was used instead

2,3-dihydro-1H-isoindol-5-ylamine in step 5.

MS t / ζ (APC1 +) 672.2 (MH ⁺ -Boc).

Example 3-91 a

MeOGs

2,3-Dihydro-1H-isoindole-5-carboxylic acid methyl ester was synthesized according to the following scheme:

Pc1 (0Ac) ₂ , ϋΡΡΡ, TEM

СО, ΜεΟΗΌΜδΟ (1: 1)

TEM C CM (1: 1)

MeO ₂ C

A mixture of 5-bromo-1,3-dihydroisoindole-2-carboxylic acid tert-butyl ester (200 mg, 0.67 mmol), Pb (OAc) ₂ (30 mg, 0.2 eq.), E) PPP (55 mg, 0.2 eq.), TEA (0.93 ml, 10 eq.) and MeOH: RMSO (1: 1.4 ml) was stirred for 16 h in an atmosphere of CO (balloon) at 80 ° C. Chromatography-mass spectrometry and TLC (20% EJAc-Hexane) showed completion of the reaction. The reaction mixture was concentrated to remove MeOH, diluted with EuAc (10 ml) and washed with water (2x25 ml). The organic layer was dried (No. ₂ 8 O ₄ ), concentrated and purified by silica gel column chromatography (eluent = 20% EJAc-hexane) to obtain pure 1,3-dihydroisoindole-2,5-dicarboxylic acid 2-tert-butyl ether 5- methyl ether (150 mg, 81%).

MS (APC1 +) t / ζ 178.1 (MH ⁺ -Boc).

The product mentioned above was exempted from the protective groups by treatment with 50% TEA (TFA) -OSM for 1 h at 0 ° С - room temperature. The reaction mixture was concentrated to dryness, redissolved in 1) C \ -1 and neutralized with a saturated solution of MP 1CO ₃ . The organic layer was separated, dried and concentrated to give a free base, which was used directly in the next compound step without further purification.

Example 3-92

R

Compound AK00333831 (18.4V, 68.148.18B) -1,3-dihydroisoindole-2-carboxylic acid 14-cyclopentyloxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3.16-diazatricyclo [14.3.0.0 ^4.6 ] non- -7en-18-yl ester (compound AB00333831) was synthesized according to the procedures described in Example 3-5, except that 2,3-dihydro-1H-isoindole was used instead

- 172 012389

1,2,3,4-tetrahydroisoquinoline.

¹ H NMR (400 MHz, NE OM ₃₎ δ 7,36-7,22 (m, 3H), 7.21-7.16 (m, 1H), 5,74-5,60 (m, 1H) 5.40 (s, 1H), 5.205.03 (m, 1H), 4.80-4.54 (m, 6H), 4.38-4.28 (m, 1H), 4.18 (m , 1H), 3.90-3.80 (m, 1H), 2.96-2.85 (m, 1n), 2.70-2.31 (m, 4H), 1.92-0.98 (m, 24P).

MS t / ζ (APC1-) 724.4 (M-1).

Example 3-93

Compound AK00340494 (18.4K, 68.148.18K) -5-Morpholin-4-yl-1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfoylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo [ 14.3.0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound AK00340494) was synthesized in accordance with the procedures described in example 3-6, except that 5-morpholin-4-yl-2, 3-dihydro-1Nisoindole (obtained by the method as described in 3. Ex. CHN. 2000, 65, 1144-1157) was used instead of 2,3-dihydro-1H-isoindole.

¹ H NMR (400 MHz, VMSO- ₆ ) δ 7.80-7.22 (m, 1H), 7.22-7.15 (m, 1H), 7.00-6.81 (m, 2H ), 5.45 (m, 1H), 5.26 (m, 1H), 4.62-4.50 (m, 4H), 4.42 (m, 1H), 4.28-4.10 ( m, 2H), 3.98 (m, 1H), 3.76 (m, 4H), 3.12 (m, 4H), 2.712.60 (m, 1H), 2.40-1.45 (m , 3H), 1.40-1.21 (m, 10H), 0.98-0.61 (m, 4H).

MS t / ζ (APC1 +) 699.2 (MH ⁺ -Boc).

Example 3-94

(18.4K, 68.148.18K) -5-Cyano-1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^{4 , 6} ] non-adec-7en-18-yl ester (compound AK00365082) was synthesized according to the procedures described in Example 3-6, except that 2,3-dihydro-1H-isoindole-5-carbonitrile (obtained by the method described in 3. OGN. Net. 1998, 63, 8224-8228) was used to replace 2,3-dihydro-1H isoindole.

MS t / ζ (APC1 +) 639.1 (MH ⁺ -Boc).

Example 3-95

Connection AK00365252

- 173 012389 (18.4K, 68.148.18K) -5-Ethylcarbamoyl-1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo [14.3 .0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound AK00365252) was synthesized in accordance with the procedures described in the following scheme:

Compound AK00365083 (70 mg, 91 pmol), the synthesis of which was described earlier in this document, was dissolved in a mixture of THF: MeOH (2: 1.3 ml), after which 1 ml of an aqueous solution of L1OH-H ₂ O was added. The reaction mixture was stirred for 1 h at room temperature. Chromatography-mass spectrometry showed complete hydrolysis, the reaction mixture was stirred for another 30 min, before it was concentrated, neutralized with 0.1 N. HC1 and extracted with 5 ml of E1OAc. The organic layer was dried (Νο ₂ 8Ο ₄ ), concentrated and purified by silica gel column chromatography (eluent = 5-7% MeOH-OSM) to obtain the hydrolysis product as a white precipitate.

MS (APC1 +) t / ζ 658.1 (MH ⁺ -Boc).

The product from the step described above (23 mg, 30 μmol) was dissolved in anhydrous DMF (2 ml), after which ethylamine (3 equivalents), 1-hydroxy-7-azabenzotriazole BUT AT (3 equivalents) and

O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium NATI hexafluorophosphate (3 eq.) And at the end of Ν, Ν-diisopropylethylamine EHEA (6 eq.) Was added dropwise. The reaction mixture was stirred at room temperature overnight. Chromatography-mass spectrometry showed complete completion of the reaction. The reaction mixture was diluted with E1OAc (5 ml) and washed with water (2x10 ml). The organic layer was dried, concentrated and the crude product was purified by preparative TLC.

MS (APC1 +) 685.2 (MH ⁺ -BoC).

Example 3-96

Compound AK00334218 (18.4K, 68.148.18K) -5-Chloro-1,3-dihydroisoindole-2-carboxylic acid 14-cyclopentyloxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3.16-diazatricyclo [14.3.0.0 ^{4 , 6} ] non-adec-7-en-18-yl ester (compound AK00334218) was synthesized according to the procedures described in Example 3-5, except that 5-chloro-2,3-dihydro-1H-isoindole was used instead of 1,2,3,4-tetrahydroisoquinoline.

¹ H NMR (400 MHz, CO; C 1) δ 7.55 (br s, 1H), 7.19-7.33 (m, 3H), 5.63-5.73 (m, 2H), 5.27-5.34 (m, 1H), 4.98 (t, 1H), 4.52-4.72 (m, 5H), 4.48 (t, 1H), 4.34-4, 44 (m, 1H), 4.06-4.15 (m, 1H), 2.77-2.90 (m, 2H), 2.54 (br s, 1H), 2.24-2, 44 (m, 3H), 1.64-1.75 (m, 2H), 1.13-1.57 (m, 18H), 0.91-1.09 (m, 4H).

MS t / ζ 759.9 (M + 1).

- 174 012389

Example 3-97

Compound AK.00334220 (18.4K, 68.148.18K) -5-Chloro-1,3-dihydroisoindole-2-carboxylic acid 14- (tetrahydrofuran-3yloxycarbonylamino) -4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3.16- diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester (compound AK00334220) was synthesized in accordance with the procedures described in example 3-16, except that 5-chloro-2,3- dihydro-1H-isoindole was used instead of 1,2,3,4-tetrahydroisoquinoline.

¹ H NMR (400 MHz, SP ₃ SP) δ 7.57 (br s, 1H), 7.20-7.34 (m, 3H), 5.87-5.93 (m, 1H), 5 65 (q, 1H), 5.31 (br s, 1H), 5.23-5.29 (m, 1H), 4.98 (t, 1H), 4.44-4.71 (m 5H), 4.29-4.39 (m, 1H), 4.07-4.18 (m, 1H), 3.70-3.87 (m, 4H), 3.61-3.70 (m, 1H), 3.44-3.55 (m, 2H), 3.30-3.42 (m, 1H), 2.76-2.89 (m, 2H), 2.54 (broad s, 1H), 2.36-2.46 (m, 1H), 2.24-2.36 (m, 2H), 1.69-1.76 (m, 1H), 1.59-1 69 (m, 1H), 1.13-1.56 (m, 8H), 0.90-1.10 (m, 4H).

MS t / ζ 762.0 (M + 1).

Example 3-98

(18,4K, 68,148,18K) -5-Chloro-1,3-dihydroisoindole-2-carboxylic acid 14- (2-fluoroethoxycarbonylamino) -4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo [14.3. 0.0 ^4.6 ] nonadec-7en-18-yl ester (compound AK00334222) was synthesized according to the procedures described in Example 3-28, except that 5-chloro-2,3-dihydro-1H-isoindole was used instead of 2,3-dihydro-1H-isoindole.

¹ H NMR (400 MHz, SP ₃ NW δ 7.53 (br s, 1H), 7.20-7.33 (m, 3H), 5.93 (d, 1H), 5.67 (q, 1H), 5.32 (br.s, 1H), 4.93-5.05 (m, 1H), 4.52-4.72 (m, 5H), 4.47 (t, 1H), 4 39 (t, 1H), 4.25-4.36 (m, 2H), 4.12-4.25 (m, 2H), 3.653.96 (m, 2H), 2.76-2.89 (m, 2H), 2.54 (br s, 1H), 2.22-2.44 (m, 3H), 1.67-1.76 (m, 1H), 1.13-1.60 (m, 10H); 0.91-1.13 (m, 4H).

MS t / ζ 737.9 (M + 1).

Example 3-99

(18,4K, 68,148,18K) -5-Chloro-1,3-dihydroisoindole-2-carboxylic acid 14- (3,3-dimethylbutyrylamino) -4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo [ 14.3.0.0 ^4.6 ] nonadec-7en-18-yl ester (compound AK00334225) was synthesized in accordance with the procedures described

- 175 012389 in Example 3-81, except that 3,3-dimethylbutyryl chloride was used instead of (4-methoxyphenyl) acetyl chloride and 5-chloro-2,3-dihydro-1H-isoindole was used instead of 4- fluoro-2,3-dihydro-1 H-isoindole.

¹ H NMR (400 MHz, SBSK) δ 7.60 (br.s, 1H), 7.15-7.33 (m, 3H), 6.54-6.65 (m, 1H), 5.63 -5.73 (m, 1H), 5.33 (br s, 1H), 4.93-5.02 (m, 1H), 4.53-4.65 (m, 3H), 4.39 -4.48 (m, 2H), 4.28-4.38 (m, 1H), 3.74-3.83 (m, 2n), 2.77-2.89 (m, 1H), 2 54 (br s, 1H), 2.23-2.44 (m, 3H), 1.68-1.91 (m, 4H), 1.12-1.54 (m, 11H), 0 91-1.11 (m, 4H); 0.76-0.90 (m, 9H).

MS t / ζ 746.2 (M + 1).

Example 3-100

(18,4K, 68,148,18K) -5-Chloro-1,3-dihydroisoindole-2-carboxylic acid 14- (2-cyclopentylacetylamino) -4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo [14.3. 0.0 ^4.6 ] nonadec-7en-18-yl ester (compound AK00334226) was synthesized according to the procedures described in Example 3-81, except that cyclopentylacetyl chloride was used instead of (4-methoxyphenyl) acetyl chloride and 5 -chloro-2,3-dihydro-1H-isoindole was used instead of 4-fluoro-2,3-dihydro-1 H-isoindole.

¹ H NMR (400 MHz, ATP1 ₃ ) δ 10.85 (br s, 1H), 6.95-7.30 (m, 3H), 5.87-6.02 (m, 1H), 5, 63-5.79 (m, 1H), 5.43-5.52 (m, 1H), 4.93-5.08 (m, 1H), 4.52-4.85 (m, 5n), 4.31-4.52 (m, 1H), 3.79-3.95 (m, 1H), 3.60-3.75 (m, 2H), 3.14 (q, 1H), 2, 90 (br.s, 1H), 2.37-2.63 (m, 3H), 2.14-2.29 (m, 1H), 1.73-2.12 (m, 6H), 1, 16-1.74 (m, 13H), 0.96-1.16 (m, 4H), 0.68-0.96 (m, 9H).

MS t / ζ 758.2 (M + 1).

Example 3-101

Compound AK00340173 (18.4K, 68.148.18K) -5-Chloro-1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (5-chloro-thiophen-2-sulfonylaminocarbonyl) -2.15- dioxo-3,16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester (compound AK00340173) was synthesized in accordance with the procedures described in examples 3-6, except that the amide 5 β-chlorothiophen-2-sulfonic acid was used instead of cyclopropanesulfonamide and 5-chloro-2,3-dihydro-1H-isoindole was used instead of 2,3-dihydro-1H-isoindole.

¹ H NMR (400 MHz, HSS) δ 8.07 (d, 1H), 7.50 (d, 1H), 7.16-7.32 (m, 3H), 6.98 (d, 1H), 5.86 (broad s,

1H), 5.27-5.39 (m, 2H), 4.81-4.92 (m, 1H), 4.58-4.64 (m, 2n), 4.51-4.58 ( m, 2H), 4.44 (t, 1H), 4.33 (d, 1H), 4.104.20 (m, 1H), 3.73-3.81 (m, 1H), 2.47 (br s, 1H), 2.16-2.41 (m, 3H), 1.63-1.77 (m, 2H), 1.47-1.57 (m, 2n), 1.071.47 (m , 17H).

MS t / ζ 724.1 (M + 1-Boc).

- 176 012389

Example 3-102

Compound AK00340526 (18.4K, 68.148.18K) -5-Bromo-1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo [14.3. 0.0 ^4.6 ] non-adec-7en-18-yl ester (compound AK00340526) was synthesized according to the procedures described in Example 3-6, except that 5-bromo-2,3-dihydro-1H-isoindole was used instead of 2,3-dihydro-1 H-isoindole.

¹ H NMR (400 MHz, ATP1 ₃ ) δ 10.31 (br s, 1H), 7.36-7.44 (m, 1H), 6.99-7.32 (m, 3H), 5, 70 (q, 1H), 5.425.49 (m, 1H), 5.06-5.13 (m, 1H), 4.99 (t, 1H), 4.52-4.78 (m, 5H) 4.32-4.44 (m, 1H), 4.16-4.27 (m, 1i), 3.78-3.89 (m, 1H), 3.33-3.42 (m, 1H), 2.85-2.94 (m, 1H), 2.40-2.64 (m, 3H), 2.20-2.32 (m, 1H), 1.68-1.97 ( m, 4H), 1,171.67 (m, 16H), 1.01-1.17 (m, 3H), 0.80-0.98 (m, 2H).

MS t / ζ 694.0 (M + 1-Boc).

Example 3-103

Compound AK00333462 (18.4K, 68.148.18K) -4K-Methyl-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3.16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound AK00333462) was synthesized in accordance with the procedures described in example 3-1, except that 4K-methyl-1,2,3 , 4-tetrahydroisoquinoline (prepared according to the procedures described in Example 1-17a, except that an enantiomerically pure starting material was used instead of the racemic mixture) linked instead of 1,2,3,4-tetrahydroisoquinoline.

MS t / ζ 642.2 (M + 1-Boc).

Example 3-104

(18.4K, 68.148.18K) -48-Methyl-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3,16-diazatricyclo [14.3 .0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound AK00333463) was synthesized according to the procedures described in example 3-1, except that 48-methyl-1,2,3,4 - 177 012389 tetrahydroisoquinoline (obtained in accordance with the procedures described in Example 1-17a. Except that instead of the racemic mixture an enantiomerically pure starting material was used) was used instead of 1 .2.3.4-tetrahydroisoquinoline.

MS t / ζ b42.2 (M + 1-Boc).

Example 3-105

Compound АЯ00345032 (18.4В.b8.148.18В) -5- [2- (morpholine-4-carbonyloxy) ethoxy] -1.3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3.1 diazatricyclo [14.3.0.0 ⁴ . ^b ] non-adec-7-en-18-yl ether (compound AB00345032) was synthesized in accordance with the procedures. described in example 3-b. except for that. that 2- (2.3-dihydro-1Nisoindol-5-yloxy) morpholine-4-carboxylic acid ethyl ester (obtained in accordance with the procedures described in 3. May. SN. 2002. vol. 45. No. 2b. 5771. method for producing I ) and in Vuogd. May. Oh. 1.e.I. 11 (2001) b85-b88) was used instead of 2.3-dihydro-1H-isoindole.

MS (APC1-) t / ζ 885.4 (M-1).

Example 3-10b

Compound АЯ00345075 (18.4В.b8.148.18В) -5- (3-Morpholin-4-ylpropoxy) - 1.3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3.1b-diazatri .0.0 ⁴ . ^b ] non-adec-7-en-18-yl ether (compound AB00345075) was synthesized in accordance with the procedures. described in example 3-b. except for that. that 5- (3-Morpholin-4-ylpropoxy) -2.3 dihydro-1H-isoindole (obtained in accordance with the procedures described in 3. Mei. SN. 2002. vol. 45. No. 2b. 5771. method of obtaining I). and in Vuogd. May. Oh. Yeah. 11 (2001) b85-b88) was used instead of 2.3-dihydro-1H-isoindole.

MS (APC1-) t / ζ 855.b (M-1).

- 178 012389

Example 3-107

(18.4K, 68.148.18K) -5- (2-Morpholin-4-yl-ethoxy) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16- diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester (compound AK00345090) was synthesized in accordance with the procedures described in example 3-6, except that 5- (2-morpholin-4 -ylethoxy) -2,3-dihydro-1H-isoindole (obtained in accordance with the procedures described in I. Furniture. C11et. 2002, vol. 45, No. 26, 5771, production method O, and in Wuogd. Furniture. Siesche Ley. 11 (2001), 685-688) was used instead of 2,3-dihydro-1H-isoindole.

MS (APCI) t / z 841.5 (M-1).

Example 3-108

Compound AK00345094 (18.4K, 68.148.18K) -5- (2-Isopropylaminoethoxy) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3,16-diazatricyclo [ 14.3.0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound AK00345094) was synthesized in accordance with the procedures described in Example 3-6, except that [2- (2,3-dihydro- 1H-isoindole-5yloxy) ethyl] isopropylamine (tormented in accordance with the procedures described in I. Furniture. C11 Sep. 2002, Volume 45, No. 26, 5771, Method for Preparation of O, and in Wuogd. Furniture. Sket. Ea. 11 (2001) 685-688) was used in place 2,3-dihydro-1H-isoindole.

MS (APCI) t / ζ 813.5 (M-1).

- 179 012389

Example 3-109

Compound AK00345095 (18.4K, 68.148.18K) -5- (2-Dimethylaminoethoxy) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3,16-diazatricyclo [ 14.3.0.0 ^4.6 ] nonadec-7-en-18-yl ester (compound AK00345095) was synthesized according to the procedures described in Example 3-6, except that [2- (2,3-dihydro- 1H-isoindole-5yloxy) ethyl] dimethylamine (obtained in accordance with the procedures described in I. Honey. Bet. 2002, volume 45, No. 26, 5771, method of obtaining I), and in Vuogd. Honey. Cbt. Trouble. 11 (2001) 685-688) was used instead of 2,3-dihydro-1H-isoindole.

MS (APCI) t / ζ 799.5 (M-1).

Example 3-110

(18,4K, 68,148,18K) -5- (2-Imidazole-1-ethoxy)-1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16- diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester (compound AK00345096) was synthesized in accordance with the procedures described in example 3-6, except that 5- (2-imidazol-1 -ylethoxy) -2,3-dihydro-1H-isoindole (obtained in accordance with the procedures described in I. Honey. Bet. 2002, volume 45, No. 26, 5771, method of obtaining I), and Vyuogd. Honey. Cbt. Trouble. 11 (2001) 685-688) was used instead of 2,3-dihydro-1H-isoindole.

MS (APCI) t / ζ 822.5 (M-1).

- 180 012389

Example 3-111

(18,4J, 68,148,18J) -5- (2-Pyrazol-1-yl-ethoxy) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16- diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester (compound AY00364924) was synthesized in accordance with the procedures described in example 3-6, except that 5- (2-pyrazol-1 -ylethoxy) -2,3-dihydro-1H-isoindole (obtained in accordance with the procedures described in I. May. Sket. 2002, vol. 45, No. 26, 5771, method for producing O, and in Βϊοογ§. May. Sket. . 11 (2001) 685-688) was used instead of 2,3-dihydro-1H-isoindole.

MS (ARSP) t / ζ 742.1 [(M-100) +18].

Example 3-112

Compound AK00340495 (18.4J, 68.148.18J) -5- (4-Methylpiperazin-1-yl) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3, 16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester (compound AY00340495) was synthesized by the method as described in example 3-57, replacing 2,3-dihydro-1H-isoindol-5- ylamine in step 5 on 5- (4-methylpiperazin1-yl) -2,3-dihydro-1H-isoindole (obtained in accordance with the method described in I. Ogd. Sket. 2000, 65, 1144-1157).

¹ H-NMR (400 MHz, (OMSO- ₆ ) 7.72-7.40 (m, 1H), 7.22-7.05 (m, 1H), 6.95-6.70 (m, 2H), 5.55-5.45 (m, 1H), 5.35-5.22 (m, 2H), 4.62-4.50 (m, 4H), 4.40 (m, 1H) , 4.30-4.08 (m, 2H), 4.0-3.89 (m, 1H), 3.10 (m, 3H), 2.65 (m, 1H), 2.42 (m , 3H), 2.33-2.20 (m, 6H), 1.85-1.50 (m, 5H), 1.42-1.0 (m, 14H), 0.82-0.55 (m, 4H).

MS (ARSN) 712.3 (MH ⁺ -Boc).

Example 3-113

Compound AK00365084 (18.4J, 68.148.18J) -1,3-dihydroisoindole-2,5-dicarboxylic acid 2- (14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo [14.3 .0.0 ^4.6 ] non-ade-7- 181 012389 en-18-yl) ether (compound AK00365084) was synthesized according to procedures similar to those described in example 3-91, except that the product AK00365083 from this example was then hydrolyzed with L1OH in a mixture of THF-MeOH-H ₂ O to give AK00365084.

MS: 658 (M-Βοο). Example 3-114

Compound AK00364989 (18.4K, 68.148.18K) -5- (2-Methylthiazol-4-yl) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3, 16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester (compound AK00364989) was synthesized by the method as described in example 3-57, replacing 2,3-dihydro-1H-isoindol-5- ylamine in step 5 to 5- (2-methylthiazol-4yl) -2,3-dihydro-1H-isoindole.

¹ H NMR (400 MHz, SP3COSP3) δ 10.69 (br.s, 1H) 8.32 (br.s, 1H), 7.94 (d, 1H), 7.88 (d, 1H), 7 70 (d, 1H), 7.34 (dd, 1H), 6.08-6.16 (m, 1H), 5.69 (q, 1H), 5.45 (br s, 1H), 5.00 (t, 1H), 4.58-4.81 (m, 5H), 4.44-4.53 (m, 1H), 4.12-4.21 (m, 1H), 3, 83-3.91 (m, 1H), 2.86-2.97 (m, 1H), 2.57-2.71 (m, 1H), 2.33-2.54 (m, 3H), 1.811.96 (m, 2H), 1.75 (dd, 1H), 1.17-1.63 (m, 20H), 1.06-1.17 (m, 1H), 0.94-1, 06 (m, 2H).

MS t / ζ 711.2 (M + 1-100). Example 3-114a

The synthesis of 5- (2-methylthiazol-4-yl) -2,3-dihydro-1H-isoindole was carried out in accordance with the experiments of steps AP of Example 3-115a, only using thioacetamide in step E.

Example 3-115

ΗΝ-

Compound AK00365019 (18.4K, 68.148.18K) -5- (2-Isopropylaminothiazol-4-yl) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo 3,16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester (compound AK00365019) was synthesized by the method as described in example 3-57, replacing 2,3-dihydro-1H-isoindole-5 -ylamine in step 5 on [4- (2,3-dihydro1H-isoindol-5-yl) thiazol-2-yl] isopropylamine.

H NMR (400 MHz, SP3COSP3) δ 10.69 (br s, 1H), 8.27-8.36 (m, 1H), 7.28-7.50 (m, 2H) 7.01-7 , 20 (m,

MS t / ζ 754.2 (M + 1-100).

- 182 012389

Example 3-115a

The synthesis of [4- (2,3-dihydro-1H-isoindol-5-yl) thiazol-2-yl] isopropylamine is illustrated in the following scheme:

A. To a solution of 1 ml of ethyl vinyl ether in 4 ml of THF at -78 ° C was added dropwise tert-VI (0.79 ml, 1.34 mmol). The solution was warmed to room temperature and stirred for 30 minutes. A 0.5 M solution of Ζη (Ί ₃ in THF (3.02 ml, 1.51 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 30 minutes. This mixture was used without further purification.

B. To a solution of aryl bromide (0.200 g, 0.67 mmol) and P0 (PP ₃ ) ₄ (39 mg, 0.33 mmol) dissolved in THF, in a atmosphere of Ν ₂ , the crude derivative of vinyl zinc from stage A was introduced. Reaction mixture heated at 50 ° C for 36 h, then filtered through an Al ₂ O ₃ layer with EuAc and concentrated to an oil, which was then used without further purification.

C. The crude oil from stage B was dissolved in THF (2 ml) and 1N. HCl (2 ml) and stirred for 1 h. The reaction mixture was extracted with EULAc and separated, and the organic layer was washed with a saturated solution of ΝπΙ 1CO ₃ and brine, and dried over No. ₂ 8O ₄ , and concentrated to obtain an orange oil. This oil was purified by chromatography (5: 1 hexane: EuAc) to give a white solid. (95 mg, 54%).

one). To a solution of 1.0 M (dimethyltrimethylsilylaminosilyl) methyl lithium 1.111 11) 8 (4.0 ml, 4.0 mmol) in an atmosphere of Ν ₂ at -78 ° C was added dropwise trimethylsilyl chloride TM8C1 (3.38 ml, 26.6 mmol). The ketone from step C in 3 ml of THF was added to the resulting mixture. The reaction mixture was stirred at -78 ° C for 30 minutes and heated to 0 ° C. FTTB (shown in the diagram) (1.10 g, 2.93 mmol) was added and the reaction mixture was stirred for 30 min at 0 ° C, concentrated to a solid and extracted with ethyl acetate and water. The organic layer was washed with water and brine, dried over Na ₂ 8 O ₄ and concentrated, and the resulting oil was purified by chromatography (5: 1 hexane: EuAc) to give a yellow precipitate (0.64 g, 71%).

E. A suspension of bromketone (75 mg, 0.22 mmol), Na ₂ CO ₃ (37 mg, 0.44 mmol) and 1-isopropyl thiourea (26 mg, 22 mmol) in a CJN were heated at the boil for 30 minutes. The reaction mixture was extracted with EJAc and separated, and the organic layer was washed with a saturated solution of Νπ раствором 1CO ₃ and brine, dried over а a ₃ 8О ₃ and concentrated to give a yellow oil. Oil was

- 183 012389 purified by chromatography (3: 1 hexane: 2-methoxy-2-methylpropane) to give a pure oil. (77 mg, 97%).

R. Boc amine from step E was stirred in 4n. HCl / dioxane (2.0 ml) for 1 h and concentrated to a white solid. This residue was extracted with 0.1 N. HC1 and washed with ESM. The aqueous layer was alkalinized 1.0N. \ aON and extracted with ESM, dried, concentrated and used without further purification.

4. Obtaining macrocyclic aminoproline intermediates.

Example 4-1. Synthesis of ethyl ester (18.4B, 68.148.18B) -18-amino-14-tert-butoxycarbonylamino 2.15-dioxo-3.16-diazatricyclo [14.3.0.0 ⁴ . ^b ] nonadec-7-en-4-carboxylic acid

A. To a solution of (28.4B) -4-amino-1- [benzyloxycarbonyl] pyrrolidine-2-methylcarboxylate hydrochloride (2.00 g, 2.34 mmol) in methylene chloride (25 ml) was added 2- (trimethylsilyl) ethyl pnitrophenyl carbonate (1.98 g, 6.99 mmol) and triethylamine (1.81 ml, 13.34 mmol). The reaction mixture was stirred for 3 days, applied to silica gel and eluted with 40% EJAc / hexane to give a colorless oil. The oil was dissolved in methanol (20 ml) and mixed with 10% palladium-carbon in a hydrogen atmosphere from a balloon. After stirring for 4 hours, the reaction mixture was filtered and concentrated. The resulting solid residue was dissolved in 1N. aqueous HC1 (75 ml) and was extracted with methylene chloride (75 ml). The aqueous layer was adjusted to basic pH by the addition of sodium hydroxide and again extracted with methylene chloride (100 ml). Both organic extracts were combined, concentrated and the resulting residue was purified by silica gel chromatography eluting with 10% methanol / methylene chloride to give a brown solid (1.29 g, 70%).

Chromatography-mass spectrum = 289 (H ⁺ ).

B. A solution of 4 (B) - (2-trimethylsilylethylcarbonylamino) pyrrolidine 2 (8) carboxylic acid methyl ester (1.29 g, 4.50 mmol), 2 (8) -tert-butoxycarbonylamino-non-8-enol acid (1 , 22 g, 4.51 mmol), NATI (2.06 g, 5.41 mmol) and diisopropylethylamine (1.18 ml, 6.76 mmol) in dimethylformamide (10 ml) were stirred overnight. The reaction mixture was diluted with ethyl acetate (150 ml), washed with 1N. aqueous HC1 (2x100 ml), dried over magnesium sulfate and concentrated. Chromatography on silica gel gave an oil which was stirred with lithium hydroxide (0.28 g, 6.76 mmol) in methanol (5 ml) for 2 hours. The reaction mixture was diluted with methylene chloride, washed with 1N. aqueous HC1, dried over magnesium sulfate and concentrated to give 1.2 d (49%) of the product.

C. To 1 (B) -tert-butoxycarbonylamino-2 (8) -vinylcyclopropanecarboxylic acid ethyl ester (0.70 g, 2.75 mmol) was added 4N. HC1 / dioxane solution (2.87 ml, 11.46 mmol). After stirring for 2 hours, the reaction mixture was concentrated to give a solid residue. To this solid residue was added 1- (2 (O-tert-butoxycarbonylamino-non-8-enoyl) -4 (B) - (2-trimethylsilylethylcarbonylamino) pyrrolidin-2 (8) -carboxylic acid (1.21 g, 2, 29 mmol), NATI (1.05 g, 2.75 mmol), diisopropylethylamine (1.60 ml, 9.17 mmol) and methylene chloride (10 ml) and the reaction mixture was stirred for 18 hours at room temperature. was transferred onto silica gel and eluted with a solution of 50% ethyl acetate / hexane to give the product as a colorless oil (1.27 g, 83%). 665 (H ⁺ ).

Ώ. Ethyl ester solution 1 - {[1- (2 (8) -tert-butoxycarbonylamino-non-8-enoyl) -4 (B) - (2trimethylsilylethylcarbonylamino) pyrrolidine-2 (8) -carbonyl] amino} -2 (8) -vinylcyclopropane-1- (B) carboxylic acid (1.27 g, 1.91 mmol) in methylene chloride (195 ml) was degassed for 1 h by bubbling K through a solution. Ruthenium dichloro (o-isopropoxyphenylmethylene) (trichlorohexylphosphine) (11) (0.057 g. 0.09 b mmol) was added to the reaction mixture and the mixture was stirred at 40 ° C. for 1 b. The reaction mixture was concentrated. applied to silica gel and eluted with 50% ethyl acetate / hexane. The resulting oil was treated with TWAG (1.0 M in THF. 2.87 ml) and heated to 50 ° C for 4 hours. The reaction mixture was applied to silica gel and eluted with 20% methanol / methylene chloride to give a tan solid (0.b5 g .b9%).

¹ H NMR (SPS1 _3. 400 MHz) δ 1.0b-1.bb (m. 17H). 1.85-1.95 (m, 2H). 2.0-2.1 (m, 1H). 2.1-2.2 (m. 1H). 2.2-

Hz 1H). 5.20 (t. 1 = 8.1 Hz. 1H). 5.34 (d. 1 = 8.1 Hz. 1H). 5.47 (dt. 1 = 4.5. 10.8 Hz. 1H). 7.08 (p. 1H). 493 (H ⁺ ).

5. Obtaining compounds with the General structural formula V νη ₂

2.1UN about

V

Example 5-1

ΌΗ

Connection AK00287262

Synthesis of (18.4B.b8.148.18B) -14-tert-butoxycarbonylamino-18 - [(3.4-dihydro-1H-isoquinoline-2carbonyl) amino] -2.15 -dioxo-3.1b-diazatricyclo [14.3.0.0 ^{4 / |} ] non-adec-7-ene-4-carboxylic acid (compound AB002872b2)

A solution of 3.4-dihydro-1H-isoquinoline-2-carbonyl chloride (0.030 g. 0.152 mmol). ethyl ester (18.4B.b8.148.18B) -18-amino-14-tert-butoxycarbonylamino-2.15-dioxo-3.1b-diazatricyclo [14.3.0.0 ⁴ . ^b ] nonadec-7-en-4-carboxylic acid (0.025 g. 0.050 mmol). EGEA (0.027 ml. 0.153 mmol) and a catalytic amount of EMAP were stirred in methylene chloride (0.3 ml) for 18 hours. The reaction mixture was transferred to silica gel. the product was eluted with 40% acetone / hexane and isolated as a white solid. The substance was dissolved in methanol and treated with lithium hydroxide (0.011 g, 0.254 mmol) and 1 drop of water. After stirring for 5 hours, the reaction mixture was diluted with methylene chloride (30 ml). washed with 1n. aqueous HC1 (30 ml). saline solution (30 ml). dried over magnesium sulfate and concentrated to afford the title compound as a white solid.

Chromatography-mass spectroscopy LMSC = b24 (MH ⁺ ).

The following compound was also obtained. using the method. described in example 5-1. replacing

1.3-dihydroisoindole-2-carbonyl chloride to 3.4-dihydro-1H-isoquinoline-2-carbonyl chloride.

Chromatography-mass spectroscopy LMSC = b10 (H ⁺ ).

- 185 012389

Example 5-2

Compound AK00298980 (18.4K, 68.148.18K) -14-tert-Butoxycarbonylamino-18 - [(1,3-dihydroisoindole-2-carbonyl) amino] 2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^{4 , 6} ] nonadec-7-en-4-carboxylic acid (compound AK00298980) was prepared according to the procedures described in Example 5-1, replacing 3,4-dihydro-1Nisoquinoline-2 carbonyl chloride with 1,3-dihydroisoindole-2 carbonyl chloride.

MS t / e 608.2 (M-1).

Example 5-3

Compound AK00304160 (18.4K, 68.148.18K) -14-tert-Butoxycarbonylamino-18 - [(3,4-dihydro-2H-isoquinoline-1-carbonyl) amino] -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound

AK00304160) was prepared according to the procedures described in Example 5-1, replacing 3,4-dihydro-1H-isoquinoline-2-carbonyl chloride with 3,4-dihydro-2H-quinoline-1-carbonyl chloride.

MS t / e 524.3 (M ⁺ + 1-100).

6. Obtaining compounds with the General structural formula ΥΙ

Example 6-1

Compound AK00304010 (18.4K, 68.148.18K) -14-tert-Butoxycarbonylamino-18 - [(3,4-dihydro-1H-isoquinoline-2carbothioyl) amino] -2.15-dioxo-3.16-diazatricyclo [14.3 .0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid (compound AK00304010) was obtained using the same procedure as described in step 4 of Example 1-2, only carbonyldiimidazole was replaced with thiocarbonyldiimidazole.

Chromatography-mass spectrometry LMSC = 640 (H ⁺ ).

MS m / v 640.1 (M ⁺ +1).

- 186 012389

7. Obtaining compounds with General structural formula VII

Example 7-1

ABOUT

Connection AB.00287266

Synthesis of (18.4K, 68.148.18K) - {4-Cyclopropanesulfonylaminocarbonyl-18 - [(3,4-dihydro-1Nisoquinoline-2-carbonyl) amino] -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-14yl} carbamic acid tert-butyl ether (compound LC00287266) was obtained in accordance with the procedures described in example 3-1, based on the acid obtained by the procedures described in example 5-2 .

MS t / e 727.0 (M ⁺ +1).

Example 7-2

Compound AY00304008 (18.4K, 68.148.18K) - {4-Cyclopropanesulfonylaminocarbonyl-18 - [(1,3-dihydroisoindole-2carbonyl) amino] -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-14-yl} carbamic acid tert-butyl ether (compound LC00304008) was obtained in accordance with the procedures described in example 3-1, based on the acid obtained by the procedures described in example 5-2.

MS t / e 613.2 (M + 1-100).

Example 7-3 o

Compound AK00304014 (18.4K, 68.148.18K) -1,3-dihydroisoindole-2-carboxylic acid [14- (3-cyclopentylureido) -4cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3,16-diazatricyclo [14.3.0.0 ^{4, 6} ] nonadec-7-en-18yl] amide (compound LC00304014) was obtained in accordance with the procedures described in example 2-24, starting from acylsulfonamide obtained in accordance with the procedures described in example 7-4.

MS t / e 724.2 (M ⁺ +1).

- 187 012389

Example 7-4 h

Compound АЯ00304012 (18.4Κ, 68.148.18Κ) - {4-Cyclopropanesulfonylaminocarbonyl-18 - [(3.4-dihydroisoquinoline-2carbothoyl) amino] -2.15-dioxo-3.16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-ene-7 14-yl} carbamic acid tert-butyl ether (compound AK00304012) was obtained in accordance with the procedures described in example 3-1, based on the acid obtained by the procedures described in example 6-1.

MS t / e 743.0 (M ⁺ +1).

Example 7-5

(18.4 ^ 68.148.18K) -5-Fluoro-1-methoxymegyl-3,4-dihydro-1 N-isoquinoline-2-carboxylic acid 14 amino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3.16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7en-18-yl ether, HCl salt (compound AK00424775) was synthesized by dissolving the compound AK00335293 (84 mg) in 0.5 ml of 4 M HC1 / dioxane and stirring the mixture at room temperature for 16 hours. The reaction mass was concentrated, extracted with acetonitrile and concentrated again. The hydrochloride was dried overnight under high vacuum to give the product as a white solid (80 mg) + ARSG

MS w / ζ 690.1 (M + 1).

Example 7-6

Compound AK00424874 (18.4 ^ 68.148.18K) -4-Fluoro-1-methoxymethyl-1,3-dihydro-1 H-isoindole-2-carboxylic acid 14amino-4-cyclopropanesulfonylaminocarbonyl-2.15-dioxo-3.16-diazatricyclo [14.3 .0.0 ^4.6 ] nonadec-7en-18-yl ester, HC1 salt (compound AK00424874) was synthesized by dissolving the compound

AK00334191 (98 mg) in 0.5 ml of 4 M HC1 / dioxane, and the mixture was stirred at room temperature for 16 hours. The reaction mass was concentrated, extracted with acetonitrile and concentrated again. The hydrochloride was dried overnight under high vacuum to give the product as a white solid (89 mg) + APC1.

MS t / ζ 632.1 (M + 1).

Example 8. N83-N84A protease analysis.

Formation of complex Ν83 with Ν84Ά-2.

Ν83 full length recombinant protein obtained with E. soi or Baculovirus was diluted to 3.33 μM with analytical buffer, the material was transferred to an Eppendorf tube and placed in a water bath at 4 ° C in a refrigerator. An appropriate amount of No. 4A-2 diluted to 8.3 mM with assay buffer was added to an equivalent volume of Ν83 in step 2.1.1 (conversion factor 3.8 mg / 272 µl of assay buffer). The material was transferred to an Eppendorf tube and placed in a water bath at 4 ° C in a refrigerator.

After cooling the system to 4 ° C, equal volumes of solutions Ν83 and No. 4A-2 were mixed in an Eppendorf tube and carefully mixed using a manual pipetting device, the mixture was incubated for 15 min in a water bath at 4 ° C. The final concentration in the mixture was 1.67 μM Ν83, 4.15 mM Zh4A-2 (2485-fold molar excess of N84A-2).

After 15 minutes at 4 ° C, the Eppendorf tube with N83 / \ 84A-2 was removed from the refrigerator and placed at room temperature in a water bath for 10 minutes. Material N83 / N84A-2 was separated without residue into the corresponding volumes and stored at -80 ° C (E.co11 Ν83 acts at 2 nM in the analysis, aliquot of 25 μl. Baculovirus Ν83 acts at 3 nm in the study, aliquot of 30 μl).

Inhibition study Ν83.

Stage 2.2.5.

A sample of the compounds was dissolved to 10 mM in DMSO, then diluted to 2.5 mM (1: 4) in DMSO. Typically, the compounds were added to the assay plate at a concentration of 2.5 mM obtained by diluting the initial concentration to 50 μM by the inhibition assay curve. Compounds were diluted sequentially in assay buffer to obtain low concentration test solutions.

Stage 2.2.6.

E.co11 N83 / N84A-2 was diluted to 4 nM Ν83 (1: 417.5 1.67 μM source - 18 μl 1.67 μM source + 7497 μl assay buffer).

Baculovirus N83 / N84A-2 was diluted to 6 nM Ν83 (1: 278.3 1.67 μM source - 24 μl 1.67 μM source + 6655 μl assay buffer).

Stage 2.2.7.

Using a manual multichannel pipetting device and avoiding the formation of bubbles in the plate, 50 μl of assay buffer was added to wells A01-H01 of a black Co81ag 96-well polypropylene storage plate.

Stage 2.2.8.

Using a multi-channel manual pipetting device and avoiding the formation of bubbles in the plate, 50 μl of the diluted N83 / N84A-2 from step 2.2.6 was added to the wells of A02-H12 of the tablet of step 2.2.7.

Stage 2.2.9.

Using a multichannel manual pipetting device and avoiding the formation of bubbles in the plate, 25 μl of the wells in the plate for diluting the compounds of stage 2.2.5 were transferred to the corresponding wells of the analytical tablet of stage 2.2.8. The tips of the multichannel pipetting device varied for each row of portable compounds.

Stage 2.2.10.

Using a multi-channel manual pipetting device and avoiding the formation of bubbles in the plate, the contents of the wells of the analytical plate of step 2.2.9 were mixed by suction and distribution of 35 of 75 μl in each well 5 times. The tips of the multichannel pipetting device varied for each row of portable compounds.

Stage 2.2.11.

The tablet was covered with a polystyrene tablet lid and the tablet of step 2.2.10, containing Ν83 protease and samples of the compounds, was previously aged for 10 minutes at room temperature.

While the tablet from step 2.2.11 was previously aged, the KET81 substrate was diluted in a 15 ml propylene centrifuge tube. KET81 substrate was diluted to 8 μM (1: 80.75 646 μM source — 65 μl 646 μM source + 5184 μl assay buffer).

After the plate in step 2.2.11 was previously aged, 25 μl of the substrate was added to all wells in the plate using a hand-held device. The contents of all wells were quickly mixed as in step 2.2.10, but by mixing 65 μl of 100 μl in the wells.

The tablet was read in a kinetic manner on a Sco1ci1a ^ Eeu1ce5 8pcu ^ aaax Set1sh X8 tablet reader. Reader settings: read time: 30 min, interval: 36 s, playback: 51,

- 189 012389 radiation λ: 335 nm, emission λ: 495 nm, boundary value: 475 nm, automix: disabled, calibration: 1 time, PMT: high, radiation / well: 6, V _max ρΐ8: 21 or 28/51 V depending on the length of the linearity of the reaction.

1C ₅₀ were determined using the empirical equation of a four-parameter curve and recalculating Κί'δ using the following Ksh'§:

the full length of E.coP N83-2.03 μM, the total length of the slave N83-1.74 μM, where K1 = 1C50 / (1+ [8] / Ksh).

Quantification by enzyme-linked immunosorbent assay (E8A) of selectable protein markers, Neomycin phosphotransferase II (ΝΡΉΙ) in the HCV subgenomic replicon, 684.3.

HCV subgenomic replicon (Ι377 / Ν83-3 ', entry No. A1242652), which is stably stored in human HNH-7 hepatoma cells, was created by Lobia et al. 8aeis 285: 110-113 (1999). Replicon-containing cell cultures, designated as 684.3, were obtained from Ig.SNgMorN 8deeg from the Institute for Research on Cancer, Roch SNache Saiseg Seyeg, Philadelphia, PA.

684.3 cells were maintained at 37 ° C, 5% CO ₂ , in IMEM (61Lco 11965-092) with L-glutamine 200 mM (100x) (61Lco25030-081), secondary amino acids (NELΛ) (Vu \\ 1Sh1akeg 13-114E) , thermally inactivated (ΗΙ) fetal bovine serum (PB8) (Hucloye 8H3007.03) and 750 μg / ml of geneticin (6418) (61bco 10131-035). Cells were subdivided 1: 3 or 4 every 2-3 days.

24 hours before the study, 684.3 cells were harvested, counted and plated in 96-well plates (Co §1ag 3585) at a density of 7500 cells / well in all standard stabilizing media (above) and maintained under the conditions indicated above. To start the study, the nutrient medium was removed, the cells were washed 1 time with physiological saline with phosphate buffer PB8 (61Lco 10010-023) and 90 ml of the research medium (IMEM, L-glutamine, No. AA, 10% H1PB8, without 6418) was added. The inhibitors were made as a 10x stock solution in a research medium (3-fold dilution from 10 μM to 56 pM final concentration, final concentration of IMSO 1%), 10 μl was added to the duplicate wells, the plates were shaken for mixing and aged as indicated above, within 72 hours

No. TP E8A kit was obtained from A6I1A, 1is. (E8A test system of compounds for neomycin phosphotransferase II, P8P 73000/4800). Manufacturer's instructions have been followed with some modifications. The 10x REV-1 lysis buffer was modified to include 500 pM phenylmethylsulfonyl fluoride (PM8P) (8x D7626, 50 mM stock solution in isopropanol). After 72 h of incubation, the cells were washed 1 time with physiological saline with phosphate-buffered saline buffer РВ8 and 150 μl of REV-1 with RMSP was added per well. The contents of the tablets were mixed for 15 min at room temperature, then frozen at -70 ° C. The plates were thawed, the lysates were thoroughly mixed and 100 μl was dispensed onto a No. TP E8A plate. A standard curve was built. The lysate from DMSO-treated control cells was collected, sequentially diluted with REB-1 with RMSP, and applied to duplicate wells of an E8A plate, in the range of the initial lysate amount of 150-2.5 μl. An additional 100 μl of buffer alone was duplicated as a control sample. The plates were hermetically sealed and gently mixed at room temperature for 2 hours. After aging, the plates were washed with 5x300 μl of PB8-T (0.5% Teteyi-20, PB8-T were provided in the E8A kit). To determine 1x, dilution with the enzyme conjugated diluent MK8-2 (5x) was carried out in PB8-T, to which 1: 100 diluted solutions of the enzyme conjugates A and B were added in accordance with the instructions. The plates were resealed and kept with stirring, coated and left at room temperature for 2 hours. Washing was repeated and 100 μl of room temperature TMB substrate was added. After about 30 minutes holding (room temperature, shaking, coating), the reaction was stopped with 50 μl of 3 M sulfuric acid. The tablets were read at 450 nm on a Molecular Arbitrary Tablet reader.

The inhibitory effect was expressed as a percentage of the IMCO-treated control signal and the inhibition curve was calculated using an equation with 4 parameters:

y = A + ((B-A) / (1 + ((C / x) ^L I))), where C represents half the maximum activity or EC ₅₀ .

- 190 012389

Examples of activity A are 1C ₅₀ or EC ₅₀ , as indicated, less than 50 μM; B is 1C ₅₀ or EC ₅₀ , as indicated, less than 10 μM; C is 1C ₅₀ or EC ₅₀ , as indicated, less than 1 μM; □ denotes 1C ₅₀ or EC ₅₀ , as indicated, less than 0.1 μM.

Compound Ν83 / Ν84Α-2 1C50 Replicon EC50 Compound Ν83 / Ν84Α- 2 1C50 Replica EC50 AK00220042 FROM Β AK00301383 IN No vault. AK00220122 BUT No vault. AK00301745 FROM IN AK00226824 IN No vault. AK00301746 ϋ ϋ AK00226825 IN No vault. AK00301747 ϋ ϋ AK00247310 from No vault. AK00301749 from IN AK00248687 from No vault. AK00301751 ϋ ϋ AK00248688 in No vault. AK00304000 from IN AK00248689 from No vault. AK00304008 ϋ ϋ AK00254906 ϋ FROM AK00304010 from in ΑΚΌ0261407 ϋ FROM AK00304012 ϋ from AK00261408 ϋ ϋ AK00304014 ϋ ϋ AK00261409 ϋ IN AK00304062 in No vault. AK00282131 ϋ ϋ AK00304063 FROM IN AK00287262 Β No vault. AK00220122 from IN AK00287266 ϋ FROM AK00304066 from IN AK00291871 Ώ FROM AK00304067 from IN AK00291875 FROM IN AK00304072 from in AK00294376 Β No vault. AK00304073 FROM in AK00294377 FROM IN AKOOZ 04074 FROM in AK00294378 FROM IN AK00304075 FROM in AK00294381 ϋ ϋ AK00304076 ϋ FROM AK00294382 FROM No vault. AK00304077 ϋ in AK00294383 Β No vault. AK00304078 ϋ from AK00294384 FROM IN AK00304079 ϋ from AK00294980 Β No vault. AK00304080 ϋ Ώ AK00298989 Β No vault. AK00304081 ϋ FROM AK00298990 Β No vault. AK00304082 ϋ ϋ AK00298996 ϋ ϋ AK00304103 Β in AK00298997 ϋ Ώ AK00304125 FROM in AK00301338 ϋ IN AK00304126 FROM in AK00304183 Α No vault. AKOOZ 04127 FROM in Not AK00311814 ϋ IN AK00304154 Β vault Not AK00311815 ϋ FROM AK00304158 Α vault Not AKOOZ 12023 FROM No vault. AK00304160 Α vault AKOOZ 12024 ϋ ϋ AK00304161 ϋ ϋ AKOOZ 12025 ϋ ϋ AK00304162 ϋ ϋ AKOOZ 12026 ϋ ϋ AK00304163 ϋ ϋ AKOOZ 14578 FROM No vault. AK00320123 FROM IN AKOOZ 14635 ϋ ϋ AK00320220 ϋ ϋ AKOOZ 14654 ϋ ϋ AK00320221 FROM Not

- 191 012389

AKOOZ 14656 ϋ ϋ ΑΚ00320222 vault Β AKOOZ 14685 BUT No vault. ΑΚ00320403 ϋ FROM AKOOZ 14719 ϋ ϋ ΑΚ00320445 Β Not vault AKOOZ 15997 FROM Β ΑΚ00320446 ο 0 AKOOZ 15998 FROM Β ΑΚ00320447 ϋ FROM AKOOZ 15999 FROM Β ΑΚ00320448 FROM in AK00320001 ϋ ϋ ΑΚ00320449 ϋ in AK00320002 from Β ΑΚ00320450 FROM in AK00320073 ϋ ϋ ΑΚ00320506 ϋ ϋ AK00320074 ϋ Β ΑΚ00320547 ϋ Ώ AK00320075 from Β ΑΚ00320548 ϋ ϋ AK00320076 from Β ΑΚ00320549 ϋ ϋ AK00320077 from Β ΑΚ00320556 ϋ ϋ AK00320078 ϋ Β ΑΚ00320557 ϋ ϋ AK00320079 ϋ ϋ ΑΚ00320574 ϋ ϋ AK00320080 ϋ FROM ΑΚ00320575 ϋ FROM AK00320081 ϋ ϋ ΑΚ00320576 Β Not vault AK00320082 ϋ ϋ ΑΚ00320577 FROM IN AK00320119 ϋ ϋ ΑΚ00320578 ϋ ϋ AK00320120 ϋ ϋ ΑΚ00320579 ϋ ϋ AK00320121 ϋ ϋ ΑΚ00320580 ϋ ϋ AK00320122 FROM Β ΑΚ00320581 ϋ ϋ AK00324375 FROM FROM ΑΚ00320582 E ϋ AK00334286 ϋ ϋ ΑΚ00320774 ϋ FROM AK00334385 ϋ ϋ ΑΚ00333833 ϋ ϋ AK00365387 ϋ ϋ ΑΚ00334191 ϋ ϋ AKOOZ 65425 ϋ No vault. ΑΚ00340479 ϋ ϋ AK00365572 ϋ ϋ ΑΚ00365388 ϋ Not vault AK00333802 ϋ ϋ ΑΚ00365426 IN

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AK00334188 ϋ FROM ΑΚ00333801 ϋ ϋ AK00334248 ϋ FROM ΑΚΟΟ3338Ο3 ϋ FROM AK00334250 ϋ ϋ ΑΚ00334247 1E FROM AK003 64266 ϋ FROM ΑΚ00334249 I) FROM AK00334339 ϋ ϋ ΑΚ.003 34341 η ϋ AK00365438 ϋ ϋ ΑΚΌ0365427 ο ϋ AK00365349 FROM FROM ΑΚΌ0365193 ο ϋ AK00340303 ϋ FROM ΑΚΌ0333842 FROM Β AK00340156 ϋ FROM ΑΚ00365381 FROM FROM AK00340188 ϋ FROM ΑΚ00340122 ο FROM AK00334399 ϋ ϋ ΑΚ00340178 ϋ ϋ AK.00338070 ϋ ϋ ΑΚ00334314 ϋ ϋ AK00341649 ϋ ϋ ΑΚΌ0338066 ϋ ϋ ΑΚΌ0333224 Β No vault. ΑΚ00338071 ϋ ϋ AK00333248 Β No vault. ΑΚ.00364936 ϋ FROM Not AK.00333277 Β No vault. ΑΚ00333225 Β vault Not ΑΚΌ0365083 ϋ ϋ ΑΚ00333276 Β vault AK00340494 ϋ ϋ ΑΚ00365369 ϋ FROM ΑΚΌ0365252 ϋ FROM ΑΚΌ0333831 ϋ ϋ ΑΚΌ0334220 ϋ FROM ΑΚΌ0365082 ϋ FROM AK00334225 ϋ FROM ΑΚΌ0334218 ϋ ϋ AK.00340173 ϋ IN ΑΚ00334222 ϋ ϋ AK00333462 ϋ ϋ ΑΚ00334226 ϋ ϋ AK00333463 ϋ ϋ ΑΚ.00340526 ϋ ϋ AK00345032 ϋ ϋ ΑΚ00345075 ϋ FROM AK00345090 ϋ ϋ ΑΚ00345094 Ρ ϋ AK00345095 ϋ ϋ ΑΚ00345096 ϋ Ρ Not ΑΚΌ0364924 ϋ ϋ ΑΚΌ0371946 ϋ vault Not ΑΚΌ0371947 FROM No vault. ΑΚ.003 71948 ϋ vault AK00340495 ϋ Ρ ΑΚ00365084 ϋ IN AK.00364989 ϋ ϋ ΑΚ00365019 ϋ ϋ

Specificity analysis.

When evaluating the compounds using specificity analysis, it was found that the compounds of formula G are selective, they did not show significant inhibition in cathepsin B, chymotrypsin, thrombin or leukocyte elastase.

Example 9. Pharmacokinetic analysis of compounds.

Ways.

Initially, the compounds were synthesized and tested for activity (HS50) in fluorogenic Ν83 / 4 protease analysis and on the cells of the HCV replicon system, as described in Example 8 above.

Plasma kinetic analysis in JaPiz sp. after GU administration, they were used together with stability studies of ίη νί human liver microsomes (HM) and hepatocytes to guide the design of metabolically stable compounds from compounds with activity <20 nM. These samples were then optimized for physical properties similar to drugs, and administered orally to JaPiz sp. to assess the concentration in the liver, heart and plasma.

Compounds were tested for elimination from the liver during the time following administration of an individual oral dose of 3 mg / kg to a rat. For any compound found in the liver 8 hours after administration, and at a concentration of at least 100 times greater than the concentration effective to inhibit 50% of the maximum inhibition in a replicon assay (EC ₅₀ replicon),

- 193 012389 an additional toxicological assessment was performed in rats, using doses of more than 30 mg / kg orally on the VGO scale for 7 days.

Results.

Compounds AK294381, AK261408, AK333833, and AK334191 had EC ₅₀ values of approximately 2 nM and showed ίη νίΙΐΌ stability in an incubation analysis of rat, dog, and human hepatocytes, the data of which indicate low to moderate liver excretion rates. Moreover, these compounds showed a high degree of selectivity with respect to a series of other protein proteases and did not show significant inhibition of cytochrome P450 isoforms or BEX activity channels even at the highest concentrations of the tested compounds. (10 μM).

For compounds AK294381, AK261408, AK333833 and AK334191, an individual oral dose of 30 mg / kg in Kayi5 5p. 24 hours after administration, gave concentrations in the liver that were at least 20 times greater than the corresponding EC50 values of the replicon.

Compound AK334191 yielded concentrations in the heart and plasma two orders of magnitude lower and kinetically correlated with liver concentrations in the same animals. At a clinically more reasonable oral dose (3 mg / kg), the AK334191 compound, 8 hours after administration, gave a concentration in the liver that was more than 100 times greater than the EC50 replicon value of the compound. After exposure of the compound AK334191 at a dose of 30 mg / kg orally on the GGO scale for 7 days, no changes in weight, anomalies in clinical chemistry, and mortality were observed in the treated animals.

Conclusion

Active, metabolically stable, orally available small molecules of Ν83 HCV protease inhibitors have been developed. At a moderate oral dosage (3 mg / kg), these compounds have a very high level in the liver (100 times more than their corresponding EC50 replicon values) 8 hours after the dose. Plasma and heart doses are two orders of magnitude lower than those observed in the liver, and such low concentrations reduce any potential systemic toxicological effect.

Compound AK334191 was not toxic in Kaip5 5p. at doses of 30 mg / kg on the VGO scale for 7 days, providing at least a 10-fold safety factor greater than the estimated effective dose (3 mg / kg), which gives a concentration in the liver that is 100 times greater than the EC50 value of the compound.

Obtaining viral inhibitors of section C.

The meaning of the terms and structural names used in this section is the same as the names and conditions of section C above. Any reference in this section to any number or designation should be considered in the context of the corresponding numbering or designation of symbols used in this section or section C above, in contrast to the context of a possibly similar or identical numbering or designation of symbols used here elsewhere if not specified otherwise.

Compounds of the formula ΧΣ-ΧΥΠ can be synthesized in accordance with the methods described below.

Methodology

Ν83 inhibitors, as shown in examples 1-35, were obtained in accordance with the chemical method illustrated in Scheme 1. Intermediates, 1 (K) -tertbutoxycarbonylamino-2 (8) -vinylcyclopropanecarboxylic acid ethyl ester, 2 (8) -tret β-butoxycarbonylaminonon-8-enoic acid and macrocyclic hydroxycyclic intermediates (step C) were prepared by the method as described in international application PCT / CA00 / 00353 (Publication No. AO 00/59929). 2 (8) -tert-butoxycarbonylamino-non-8-enoic acid was also purchased from K8P Atsho Ac1d5.

- 194 012389

Example 1-1 Synthesis of compound 101.

Scheme 1

1) 4Ν NS! (with nahapw)

2) ΗΑΤϋ, ϋΙΕΑ, OMR

VosCh

Sotroips! 101

Step A. Synthesis of 28- (1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl) 4K-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester.

Into a flask with ethyl (1K, 28) / (18.2K) -1-amino-2-vinylcyclopropylcarboxylate (1.0 g, 5.2 mmol), trans-Y- (tert-butoxycarbonyl) -4-hydroxy- L-proline (1.3 g, 1.1 eq.) And O- (7-azabenzotriazol-1-yl) 1,1,3,3-tetramethyluronium hexafluorophosphate (NATI) (2.7 g, 1.1 eq. .) added 30 ml of DMF to obtain a solution. The solution was then cooled to 0 ° C in an ice bath, after which a solution of Ν, Ν-diisopropylethylamine (EHEA) (4.4 ml, 4 equiv.) In DMF (15 ml) was slowly added with stirring. The reaction mixture was allowed to warm to room temperature and was stirred overnight.

After 16 hours, the reaction was completed as demonstrated by HPLC. The mixture was diluted with ethyl acetate ЕУАс (100 ml), washed with water (3x40 ml), saturated NaHCO ₃ solution (2x40 ml) and brine (2x40 ml), then dried over 2α ₂ 8Ο ₄ and concentrated to obtain a dark red oil. The mixture was purified on silica gel (eluent: acetone / hexane 3: 7) to give the pure desired product as a tan powder (770 mg, 32%).

Stage B. Synthesis of ethyl ester 1K - {[1- (28-tert-butoxycarbonylamino-non-8-enoyl) -4Khydroxypyrrolidine-28-carbonyl] amino} -28-vinylcyclopropanecarboxylic acid.

The dipeptide from step A (2.85 g, 7.7 mmol) was dissolved in 10 ml of 4N. HC1 (dioxane) and left at room temperature for 90 minutes to remove the Βοс-protecting groups. The solution was concentrated, then extracted with acetonitrile, then again concentrated twice. To the light brown precipitate was added 2 (8) -tert-butoxycarbonylamino-non-8-enoic acid (2.2 g, 8.1 mmol) and NATI (3.2 g, 8.5 mmol), after which 80 ml of DMF in the nitrogen atomosphere. The reaction was cooled in an ice bath for 15 minutes, after which 5 ml of a solution of Ν, Ν-diisopropylethylamine in DMF EHEA (5.4 ml, 30.9 mmol) was added dropwise to the reaction mixture with stirring. The ice bath was removed to slowly increase the temperature to room temperature and the reaction mixture was stirred overnight.

After 18 h, TLC showed completion of the reaction. The reaction mixture was diluted with EJAc (300 ml) and washed with water (3x150 ml), saturated NaHCO ₃ solution (2x150 ml), brine (150 ml), dried (Να ₂ 8Ο ₄ ) and the solvent removed. The product was purified on silica gel using flash chromatography on a 40M solid solution (eluent = 3 to 5% MeOH in 1) C \ 1) to obtain the desired product as a brown solid precipitate (3.5 g, 87%).

Stage C. Synthesis of ethyl ester (18.4K, 68.148.18K) -14-tert-butoxycarbonylamino-18-hydroxy2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-4 -carboxylic acid.

The product from step B (2.6 g, 5.0 mmol) was dissolved in 500 ml of dichloroethane Op8O1ue in a 1 L round bottom flask to give a solution. The solution was degassed by bubbling nitrogen for 1 h. Then, the Hoveid catalyst (0.25 equiv.) Was added at room temperature under a nitrogen atmosphere. The reaction mixture was placed in a preheated oil bath (50 ° C.) and stirred overnight. After

- 195 012389 h, the reaction mixture became dark brown. TLC (OSM / ESAAc 1: 1) showed complete conversion and the appearance of a new spot with a lower Kr value. The reaction mixture was concentrated and purified on silica gel. (Vyuade 40 M, eluent = BSM / E1OAc gradient from 1: 1 to 1: 2) to give product 10 as a yellow-brown powder (0.64 g, 52%).

¹ H NMR (СОС1 ₃ , 400 MHz) δ 1.21 (t, 1 = 7.0 Hz, 3Н), 1.43 (s, 9Н), 1.20-1.50 (m, 6Н), 1 53-1.68 (m, 2H), 1.83-1.96 (m, 2H), 1.98-2.28 (m, 4H), 2.60 (m, 1H), 3.13 (broad s, 1H), 3.68 (m, 1H), 3.94 (m, 1H), 4.01-4.19 (m, 2H), 4.48 (m, 1H), 4, 56 (br.s, 1H), 4.79 (m, 1H), 5.26 (t, 1 = 9.4 Hz, 1H), 5.36 (d, 1 = 7.8 Hz, 1H), 5.53 (m, 1H); 7.19 (br s, 1H).

MS t / e 494.0 (M ⁺ +1).

Stage Ό. Synthesis of ethyl ester (18.4K, 68.148.18K) -14-tert-butoxycarbonylamino-18- (1,3-dihydroisoindole-2-carbonyloxy) -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4.6 ] Nonadec-7-en-4-carboxylic acid.

The macrocyclic product from step C (110 mg, 0.22 mmol) was dissolved in dichloromethane (BSM) (2.2 ml), after which carbodiimide (0ΌΙ) (45 mg, 0.27 mmol) was added in one portion. The reaction mixture was stirred at room temperature overnight. After 15 hours, the reaction was completed as shown by TLC (BSM / MeOH 9: 1). Isoindoline (0.12 ml, 1.1 mmol) was added dropwise to the reaction mixture, and the reaction mixture was stirred at room temperature overnight. After 22 h, TLC showed completion of the reaction. The reaction mixture was diluted with dichloromethane (6 ml) and washed with 1N. aqueous HC1 (2x2 ml), saturated sodium bicarbonate solution (2 ml), brine (2 ml), dried (Na ₂ 8 O ₄ ) and concentrated. The product was purified on silica gel (Wuade 408, eluent: 2 to 4% MeOH in dichloromethane) to give the desired product as a pale yellow powder (131 mg, 90%).

Stage E. Synthesis of (18.4K, 68.148.18K) -14-tert-butoxycarbonylamino-18- (1,3-dihydro-1H-isoindole2-carbonyloxy) -2,15-dioxo-3,16-diazatricyclo [14.3. 0.0 ^4.6 ] nonadec-7-en-4-carboxylic acid.

The macrocyclic ether from stage Ό (60 mg, 0.092 mmol) was dissolved in 0.9 ml of a mixed solvent (THF / MeOH / H ₂ O 2: 1: 1), after which B1OH-H ₂ O (23 mg, 6 equiv. ) The mixture was stirred at room temperature overnight. After 18 h, TLC (BSM / MeOH 9: 1) showed the appearance of one new spot with less K _g . The reaction mixture was concentrated almost to dryness and was extracted with two 1N layers. aqueous HC1 (15 ml) and BSM dichloromethane (20 ml). The aqueous layer was again extracted with BSM (2x10 ml). The organic layers were combined, dried over IA ₂ 8O ₄ and concentrated to give the desired product as a white powder (50 mg, 87%).

¹ H NMR (SPS1 ₃ , 500 MHz) δ 1.21-1.44 (m, 8H), 1.32 (s, 9H), 1.54-1.62 (m, 2H), 1.78- 1.88 (m, 2H), 2.042.13 (m, 1H), 2.16-2.23 (m, 1H). 2.24-2.36 (m, 2H), 2.66-2.74 (m, 1H), 3.87-3.90 (m, 1H), 4.15 (d, 1 = 11.0 Hz, 1H), 4.37-4.43 (m, 1H), 4.61-4.77 (m, 5H), 5.18 (t, 1 = 10.3 Hz, 1H), 5.24 -5.31 (m, 1H), 5.40-5.45 (m, 1H), 5.585.66 (m. 1H), 7.11-7.30 (m, 4H).

MS t / ζ 611.0 (M ⁺ +1).

Stage R. Synthesis of (18.4K, 68.148.18K) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4-SH-dimethylsulfonylaminocarbonyl) -2.15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4.6 ] non-adec-7-en-18-yl ester (compound 101).

The macrocyclic product from step E (40 mg, 0.066 mmol) was dissolved in 0.7 ml of OCE, after which carbodiimide (0ΌΙ) (13 mg, 0.079 mmol) was added in one portion. The reaction mixture was stirred at 50 ° C in an oil bath for 2 hours. TLC (10% methanol in dichloromethane) showed that the starting acid disappeared and a new spot appeared with much higher K _g . Then, Ν, Ν-dimethyl sulfamide (12 mg, 0.098 mmol; purchased from TC1) was added to the reaction mixture, after which 7.11-diazabicyclo [5.4.0] undec-11-ene BVB (15 mg, 0.098 mmol) was added . Heating was continued at 50 ° C in an oil bath for 2 hours until TLC and chromatography-mass spectrometry showed that the reaction was complete and the product was formed. The reaction mixture was concentrated and directly loaded onto a silica gel 408 column. The product was purified using flash chromatography (eluent = 40% ethyl acetate in hexane with 1% formic acid) to give the desired product as a white solid (30 mg, 64%).

MS t / ζ 715.5 (ARSB, M-1).

The following compounds of Examples 2-35 were prepared according to the procedures described in Example 1 above, replacing Ν, Ν-dimethyl sulfamide with other corresponding sulfamides in step P and / or replacing isoindole with other amines. The sulfamides used herein were commercially purchased or prepared by Method A or Method B described in Scheme 2 below.

Methods similar to those described in method A are described in the literature (e.g.,

2001, 12 (1), 1-5). The reagent a) described in stage B was obtained in accordance with the method from the literature (KhMysht, B-U. E1 a1., Ogdashs Beyegk. 2001, 3, 2241-2243).

- 196 012389

Method A

Scheme 2

Method B

Synthesis of цик-cyclopropylsulfamide

To a stirred solution of chlorosulfonyl isocyanate (1 ml, 11.5 mmol) in 20 ml of dichloromethane ϋπ8ο1νυ anhydrous tert-butanol (1.1 ml, 1 equiv.) Was added at 0 ° C. After stirring for 90 minutes, the resulting solution of carbamatesulfamoyl chloride and 5 ml of triethanolamine TEM in 20 ml of dichloromethane was added dropwise to a solution of cyclopropylamine (0.66 g, 1 equiv.) In 25 ml of ESM and 3 ml of TEM. The temperature of the reaction mixture upon addition was kept below 5 ° C. The ice bath was removed after addition and the resulting mixture was stirred for 3 hours.

TLC (hexane / ethyl acetate 1: 1) showed one major spot with a higher%. Chromatography-mass spectrometry showed product formation. The reaction mixture was diluted with 100 ml ESM and washed with 0.1 n. HC1 (2x200 ml) and saline (150 ml). The organic layer was dried over No. ₂ 8O ₄ and concentrated, whereby a Βοο-protected sulfamide was obtained as a light yellow solid, 1.2 g. ¹ H-NMR spectroscopy confirmed that the obtained compound was the desired product with a small amount of impurity. The crude product was recrystallized from EA / hexane (room temperature up to 0 ° C) to obtain 0.64 g of a crystalline substance, off-white color.

'H NMR (СОС1 ₃ , 400 MHz) δ 0.71-0.77 (m, 4 N), 1.51 (s, 9 N), 2.44 (m, 1H), 5.58 (br. s, 1H), 7.42 (broad s, 1H).

MS t / ζ 234.7 (ARSG, M-1).

To remove the Βοο-protecting group, the product obtained above was dissolved in 10 ml of a 1: 1 mixture (by volume) of dichloromethane and trifluoroacetic acid and left at room temperature for 1 h. Then, the solution was concentrated on a rotary evaporator and then under high vacuum. The viscous oil solidified under high vacuum to obtain the above product off-white.

'H NMR (СОС1 ₃ , 400 MHz) δ 0.66-0.74 (m, 4 Н), 2.57-2.58 (m, 1Н), 5.29 (br.s, 2 N), 5.42 (broad s, 1H).

Synthesis of pyrrolidinosulfamide

The above compound was obtained in accordance with the same procedures as described above for the synthesis of Ν-cyclopropylsulfamide, replacing cyclopropylamine with pyrrolidine. For a βοβ-protected product 'H NMR (СОС1 ₃ , 400 MHz) δ 1.49 (s, 9H), 1.92-1.95 (m, 4H), 3.48-3.52 (m, 4H) 7.02 (br s, 1H).

MS t / ζ 249 (ARSG, M-1).

Synthesis of morpholinosulfamide ° ν °

H ₂ M Ν ^ k / O

The above compound was obtained in accordance with the same procedures as described above for the synthesis of Ν-cyclopropylsulfamide, replacing cyclopropylamine with morpholine. For a Βοβ-protected product 'H NMR (СОС1 ₃ , 400 MHz) δ 1.50 (s, 9H), 3.39 (t, 4H), 3.76 (t, 4H), 7.18 (br s , 1H).

MS t / ζ 265 (ARSG, M-1).

- 197 012389

Synthesis of thiazol-2-ylaminosulfamide o ^ o Η ₂ Ν ' ^δ Ν Ν ^ζ Η

The above compound was obtained in accordance with the same procedures as described above for the synthesis of Ν-cyclopropylsulfamide, replacing cyclopropylamine with 2-aminothiazole. However, the Boc-protected intermediate was not isolated due to the loss of the protecting group during the treatment of the reaction mass and subsequent recrystallization steps. The above product was isolated after silica gel column chromatography (40%, eluent = 5-10% MeOH in ESM).

¹ H NMR (b6-OMSO, 400 MHz) δ 6.52 (br.s, 2H), 6.75 (d, 1H), 7.19 (d, 1H), 12.1 (br.s, 1H )

MS t / ζ 180 (ES ⁺ , MH ⁺ ).

Synthesis of 4-methylpiperazinosulfamide η ₂ ν ³ 'ν ^

The above compound was obtained in accordance with method B in Scheme 2. 4-Methylpiperazine (0.15 g, 1.50 mmol) was dissolved in 3 ml of dichloromethane 1) n8o1 \ e in a 10 ml round-bottom flask, after which reagent a ( 0.45 g, 1.50 mmol). After about 5 minutes stirring, this reagent gradually dissolved, resulting in the formation of a clear and almost colorless solution. The solution was stirred at room temperature overnight. After 17 h, TLC showed complete completion of the reaction (OSM: MeOH 9: 1 with 1% TEM). The reaction mixture was concentrated and the resulting pinkish solid precipitate was purified on a Vyushka 40 8 silica gel column using flash chromatography (eluent = OSM: MeOH 10: 1 with 1% TEM) to give the Boc-protected title product as a white powder in almost quantitative yield .

¹ H NMR (COC1 ₃ , 400 MHz) δ 1.48 (s, 9H), 2.33 (s, 3H), 2.52 (t, 4H), 3.43 (t, 4H).

MS t / ζ 278 (APC1 ^- , M-1).

The Boc-protected group was removed in the same manner as described in the synthesis of Ν-cyclopropylsulfamide, and the resulting product was directly used in the following reaction steps without further purification.

Example 2

(18.4K, 68.148.18K) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (No. cyclopropylsulfonylaminocarbonyl) -2.15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4.6 ] non-adec-7-en-18-ethyl ester was synthesized according to the procedures described in Example 1, replacing Ν, Ν-dimethyl sulfamide with Ν-cyclopropyl sulfamide in step R.

MS t / ζ 728 (APC1 ^- , M-1).

- 198 012389

Example 3

(18,4B, 68,148,18B) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (pyrrolidinosulfonylaminocarbonyl) -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-18-ethyl ester was synthesized according to the procedures described in Example 1, replacing the Ν, Ν-dimethyl sulfamide with pyrrolidinosulfamide in step P.

MS t / ζ 742 (ARSG, M-1).

Example 4

(18,4B, 68,148,18B) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (morpholinosulfonylaminocarbonyl) -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-18-ethyl ester was synthesized according to the procedures described in Example 1, replacing Ν, Ν-dimethyl sulfamide with morpholinosulfamide in step P.

MS t / ζ 758 (ARSG, M-1).

Example 5

Compound 105 (18.4B, 68.148.18B) -1,3-Dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (thiazol-2-ylaminosulfonylaminocarbonyl) -2.15-dioxo-3,16-diazatricyclo [14.3 .0.0 ^4.6 ] nonadec-7-en18-yl ester was synthesized in accordance with the procedures described in example 1, replacing Ν, Ν-dimethyl sulfamide with thiazol-2-ylaminosulfamide in stage P.

¹ H NMR (400 MHz, 0 ₆ -acetone) δ 1.15 (s, 9H), 1.22-1.54 (m, 11H), 1.60 (m, 1H), 1.68-1, 88 (m, 2H), 2.352.45 (m, 3H), 2.57 (m, 1H), 3.85 (m, 1H), 4.15 (brd, 1H), 4.48 (m , 1H), 4.65 (m, 4H), 4.74 (t, 1H), 4.92 (t, 1H), 5.43-5.52 (m, 2H), 6.92 (d, 1H), 7.20-7.33 (m, 5H), 8.18 (s, 1H).

MS t / ζ 770 (ES ’, M-1).

- 199 012389

Example 6

(18.4K, 68.148.18K) -5-Fluoro-1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (X, X-dimethylsulfonylaminocarbonyl) -2.15-dioxo-3.16- diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7en-18-yl ester was synthesized in accordance with the procedures described in example 1, replacing isoindoline with 5-fluoroisoindoline in step Ό.

¹ H NMR (400 MHz, CO ₃ O) δ 7.31 (q, 1H), 7.13 (d, 1H), 7.03-6.97 (m, 2H), 6.63 (br s , 1H), 5.70 (q, 1H), 5.40 (br s, 1H), 5.07 (t, 1H), 4.78-4.51 (m, 7H), 4.10- 4.02 (m, 1H). 3.83 (d. 1H), 2.84 (s, 6H), 2.73-2.64 (m. 1H), 2.55-2.47 (m, 1H), 2.43-2, 29 (m, 3H), 1.84-1.67 (m, 4H), 1.64-1.57 (m, 2H), 1.13 (d, 9H). 0.94-0.82 (m, 4H).

MS t / ζ 733.4 (ARSG, M-1).

Example 7

Compound 107 (18.4K, 68.148.18K) -1-piperidin-1-methylmethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid

14-tert-butoxycarbonylamino-4- (X, X-dimethylsulfonylaminocarbonyl) -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester was synthesized in accordance with by the procedures described in Example 1, replacing isoindoline with 1-piperidin-1-ylmethyl-3,4-dihydro-1H-isoquinoline in step Ό.

¹ H NMR (400 MHz, CO ₃ O) δ 7.32-7.16 (m, 4H), 5.75-5.64 (m, 2H), 5.47 (br s, 1H), 5 05 (t, 1H), 4.524.45 (m, 2H), 4.39-4.17 (m, 3H), 4.12-4.02 (m, 1H), 3.99-3.88 (m, 1H), 3.70-3.38 (m, 6n), 3.14-3.00 (m, 4n), 2.83 (d, 6H), 2.59-2.24 (m , 4H), 2.08-2.01 (m, 2H), 1.98-1.65 (m, 10H), 1.63-1.51 (m, 4H), 1.23 (d, 9H ), 0.92-0.84 (m, 1H).

MS t / ζ 826.6 (ARSG, M-1).

Example 8

(18.4K, 68.148.18K) -1-piperidin-1-methylmethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (X-cyclopropylsulfonylaminocarbonyl) -2,15-dioxo 3,16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester was synthesized in accordance with the procedures described in example 1, replacing isoindoline with 1-piperidin-1-methyl-3,4-dihydro 1H-isoquinoline in stage

Ό and Ν, Ν-dimethyl sulfamide to Ν-cyclopropyl sulfamide in step G.

- 200 012389 ¹ N NMR (400 MHz. SP3СУ) δ 7.31-7.15 (m, 4H). 5.75-5.58 (m, 2H). 5.47 (broad s. 1H). 5.11 (t. 1H). 4.b24.57 (m. 1H). 4.52-4.45 (m, 1H). 4.41-4.17 (m, 3H). 4.15-3.84 (m, 3H). 3.73-3.34 (m, 5H). 3.1b-2.71 (m. 5H). 2.70-2.27 (m.bN). 2.13-2.b7 (m. 10H). 1.b5-1.24 (m. 15H). 0.73-0.47 (m, 4H).

MS t / ζ 838.4 (APC1 ^- . M-1).

Example 9

(18.4B.b8.148.18B) -1-piperidin-1-methylmethyl-3.4-dihydro-1H-isoquinoline-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (pyrrolidinosulphonylaminocarbonyl) -2.15-dioxo-3.1-diazatricyclic ⁴ . ^b ] non-adec-7-en-18-yl ester was synthesized in accordance with the procedures. described in example 1. replacing isoindoline with 1-piperidin-1 methylmethyl-3.4-dihydro-1H-isoquinoline in step O and K. K-dimethyl sulfamide with pyrrolidinosulfamide in step D.

¹ H NMR (400 MHz. SOzOE) δ 8.94 (d. 1H). 7.31-7.1b (m. 4H). 5.75-5.b2 (m. 2H). 5.48 (broad s. 1H). 5.084.99 (m, 1H). 4.bb-3.84 (m. 7H). 3.72-3.39 (m. 7H). 3.28-3.20 (m, 2H). 3.17-2.25 (m, 10H). 2.12-1.99 (m. 2H). 1.98-1.bb (m. 1H). 1.b4-1.22 (m. 15H).

MS t / ζ 852.5 (APC1 ^- . M-1).

Example 10

(18.4B.b8.148.18B) -1-piperidin-1-methylmethyl-3.4-dihydro-1H-isoquinoline-2-carboxylic acid

14-tert-butoxycarbonylamino-4- (morpholinosulfonylaminocarbonyl) -2.15-dioxo-3.1-diazatricyclo [14.3.0.0 ⁴ . ^b ] non-adec-7-en-18-yl ester was synthesized in accordance with the procedures. described in example 1. replacing isoindoline with 1-piperidin-1-ylmethyl-3.4-dihydro-1H-isoquinoline in step O and K. K-dimethyl sulfamide with morpholinosulfamide in step D.

¹ H NMR (400 MHz. SP3OP) δ 7.33-7.14 (m, 4H). 5.78-5.b3 (m. 2H). 5.47 (broad s. 1H). 5.11 (t. 1H). 4.b33.84 (m. 7H). 3.74-3.3b (m. 9H). 3.29-3.19 (m, 3H). 3.1b-2.14 (m, 11H). 2.13-1.23 (m. 24H). 0.94-0.81 (m, 1H).

MS t / ζ 8b8.b (APC1 ^- . M-1).

Example 11

Compound 111 (18.4B.b8.148.18B) -1-Morpholin-4-ylmethyl-3.4-dihydro-1H-isoquinoline-2-carboxylic acid

14-tert-butoxycarbonylamino-2.15-dioxo-4- (pyrrolidin-1-sulfonylaminocarbonyl) -3.1b-diazatricyclo [14.3.0.0 ⁴ . ^b ] non-adec-7-en-18-yl ester was synthesized in accordance with the procedures. described in example 1. replacing isoindoline with 1-morpholin-4-ylmethyl-3.4-dihydro-1H-isoquinoline at the stage

- 201 012389

Ό and Н ^ dimethyl sulfamide on pyrrolidinosulfamide at the stage of G. MS t / ζ 874.3 (ARSG, M + 18).

Example 12

(18.4K, 68.148.18K) - (2-Morpholin-4-yl-1-phenylethyl) carbamic acid 14-tert-butoxycarbonylamino-2.15-dioxo-4- (pyrrolidin-1-sulfonylaminocarbonyl) -3.16 -diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester was synthesized in accordance with the procedures described in example 1, replacing isoindoline with 2-morpholin-4-yl-1-phenylethylamine in stage Ό and ^^ dimethyl sulfamide to pyrrolidinosulfamide in stage G.

MS t / ζ 828.3 (ARSG, M-1).

Example 13

(18.4K, 68.148.18K) -5-Chloro-1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (H # dimethylsulfonylaminocarbonyl) -2.15-dioxo-3,1b-diazatricyclo [ 14.3.0.0 ^4,6 ] nonadec-7en-18-yl ester was synthesized in accordance with the procedures described in example 1, replacing isoindoline with 5-chloroisoindoline in step Ό.

MS t / ζ 651 (ARO ⁺ , M-Boc).

Example 14

(18.4K, 68.148.18K) -5-Chloro-1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (No. cyclopropylsulfonylaminocarbonyl) -2.15-dioxo-3,16-diazatricyclo [14.3 .0.0 ^4.6 ] nonadec7-en-18-yl ester was synthesized according to the procedures described in Example 1, replacing isoindoline with 5-chloroisoindoline in the Ό stage and ^^ dimethyl sulfamide with ^ cyclopropyl sulfamide in the stage G.

MS t / ζ 663 (ARO ⁺ , M-Boc).

- 202 012389

Example 15

(18,4J, 68,148,18J) -5-Chloro-1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (pyrrolidinosulfonylaminocarbonyl) -2,15-dioxo-3,16-diazatricyclo [14.3. 0.0 ^4.6 ] nonadec-7en-18-yl ester was synthesized in accordance with the procedures described in Example 1, replacing isoindoline with 5-chloroisoindoline in steps Ώ and Ν, Ν-dimethyl sulfamide with pyrrolidinosulfamide in step P.

MS t / ζ 677 (ARSG, M-Vos).

Example 16

(18,4J, 68,148,18J) -5-Chloro-1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (morpholinosulfonylaminocarbonyl) -2,15-dioxo-3,16-diazatricyclo [14.3. 0.0 ^4.6 ] nonadec-7en-18-yl ester was synthesized according to the procedures described in Example 1, replacing isoindoline with 5-chloroisoindoline in stage I) and Ν, Ν-dimethyl sulfamide with morpholinosulfamide in stage P.

MS t / ζ 693 (ARSG, M-Vos).

Example 17

(18,4J, 68,148,18J) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (azetidinosulfonylaminocarbonyl) -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-18-ethyl ester was synthesized according to the procedures described in Example 1, replacing Ν, Ν-dimethyl sulfamide with azetidine-1-sulfonamide in step P.

¹ H NMR (400 MHz, J6-acetone) δ 1.21 (s, 9H), 1.28-1.54 (m, 8H), 1.59-1.63 (m, 1H), 1.77 -1.89 (m, 3H), 2.38-2.42 (m, 1H), 2.46-2.52 (m, 2H), 3.77 (t, 2H), 3.84-3 94 (m, 3H), 4.14-4.22 (m, 3H), 4.50 (brd, 1H), 4.614.72 (m, 5H), 5.12 (t, 1H), 5.44 (br s, 1H), 5.78 (br, 1H), 6.17 (br d, 1H), 7.23-7.36 (m, 4H), 8.38 (s, 1H).

MS t / ζ 727.4 (ARSG, M-1).

- 203 012389

Example 17a

The title compound, azetidine-1-sulfonamide, was prepared according to method B in Scheme 2. Azetidine (0.16 g, 2.8 mmol) was dissolved in 5.6 ml of dichloromethane 1) n8o1 \ 'e in a 10 ml round bottom flask then reagent a (0.85 g, 2.8 mmol) was added. After approximately 5 minutes of stirring, the reagent a gradually dissolved to form a pure and almost colorless solution. The solution was stirred at room temperature overnight. After 17 h, TLC showed complete completion of the reaction ([) C \ 1: \ 1eO11 9: 1). The reaction mixture was concentrated and the resulting white solid precipitate was purified by flash chromatography on a Vnyads 40 8 silica gel column (eluent = 5-10% \ 1eO11 / ΙΧ Μ) to give the Boc-protected title product as a white powder with almost quantitative yield. The product was initially in the form of a viscous oil, which then gradually solidified overnight under high vacuum.

¹ H NMR (SES 13, 400 MHz) δ 1.52 (s, 9 N). 2.27 (m, 2H), 4.15 (t, 4H), 7.18 (br s, 1H).

The product from the previous step (0.4 g, 2 mmol) was dissolved in 10 ml of a mixture of trifluoroacetic acid and dichloromethane 1T / \ / [) С \ 1 (1: 1 by volume) and left at room temperature for 2 hours. Volatile substance has been deleted. The resulting oily precipitate was treated with diethyl ether and filtered. The white powder obtained after filtration was used in further reactions without further purification.

¹ H NMR (400 MHz, bb-acetone) δ 2.12-2.19 (m, 2H), 3.77 (t, 4H), 6.05 (br s, 2H).

Example 18

(18.4K, 68.148.18K) -1,3-Dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (4-methylpiperazin-1-sulfonylaminocarbonyl) -2.15-dioxo-3,16-diazatricyclo [14.3 .0.0 ^4,6 ] nonadec-7en-18-yl ester was synthesized according to the procedures described in example 1, replacing Ν, Ν-dimethyl sulfamide with 4-methylpiperazin-1-sulfonamide in step G.

¹ H NMR (400 MHz, b ₆ -acetone) δ 1.21 (s, 9H), 1.19-1.58 (m, 9H), 1.70-1.73 (m, 1H), 1, 85-1.88 (m, 2H), 2.24 (s, 3H), 2.36-2.48 (m, 7H), 2.53 (m, 1H), 3.24-3.29 ( m, 4H), 3.84-3.88 (m, 1H), 4.14-4.18 (m, 1H), 4.49 (brd, 1H), 4.60-4.72 ( m, 5H), 5.04 (br s, 1H), 5.71 (br, 1H), 6.16 (br d, 1H), 7.23-7 36 (m, 4H); 8.31 (s, 1H).

MS t / ζ 770.5 (APC1 ^- , Μ-1).

Example 19

(18.4K, 68.148.18K) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (4- (2-trimethylsilylethoxycarbonyl) piperazine-1-sulfonylaminocarbonyl) -2.15-dioxo-3, 16 diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester was synthesized according to the procedures described in example 1, replacing Ν, Ν-dimethyl sulfamide with 4- (2-trimethylsilylethoxycarbonyl) piperazin-1-sulfonamide at the stage of G.

- 204 012389 ¹ H NMR (400 MHz, d ₆ -acetone) δ 0.06 (s, 9H), 0.94-0.98 (m, 2H), 1.15 (s, 9 N), 1, 17-1.50 (m, 8H), 1.501.54 (m, 1H), 1.65-1.68 (m, 1H), 1.75-1.82 (m, 2n), 2.30- 2.44 (m, 3H), 2.56-2.68 (m, 1H), 3.17-3.26 (m, 4H), 3.44-3.47 (m, 4H), 3, 78-3.81 (m, 1H), 4.08-4.14 (m, 3H), 4.44 (brd, 1H), 4.54-4.66 (m, 5H), 4, 98 (t, 1H), 5.38 (br s, 1H), 5.56-5.63 (m, 1H), 6.12 (brd, 1H), 7.16-7.30 ( m, 4H); 8.26 (s, 1H).

MS t / ζ 901.3 (APC1 ^- , M-1).

Example 19a θ 'η / -Ν Ν-Зу ⁰ \ / ^/ —О 2— ^/ ΝΗ ₂ 8Ι- ⁷ /

The title compound, 4- (2-trimethylsilylethoxycarbonyl) piperazine-1-sulfonamide, was obtained in accordance with scheme 3 below

Scheme 3

° γ ° η <O N N osm ^1tA - ^pcm % O ^ ° oOo ^2TEA - ^0CM _o > (- ν ° ^ΝΗ: Υ Λ '-'Ύ'β' ^θ N a one Stage 1 Stage 2

Stage 1

tert-Butylpiperazine-1-carboxylate (1.0 g, 5.4 mmol) was dissolved in 10 ml of dichloromethane Er18O1ue in a 50 ml round bottom flask, after which reagent a (1.6 g, 5.4 mmol) was added. After about 5 minutes of stirring, the last reagent gradually dissolved to give a clear and almost colorless solution. The solution was stirred at room temperature overnight. After 17 h, TLC showed complete completion of the reaction (OSM: MeOH 20: 1). The reaction mixture was concentrated, and the resulting white solid precipitate was purified on a silica gel column of Büläge 40 M (eluent = 2% MeOH / OCM) to give the Boc-protected title product as a white powder.

¹ H NMR (400 MHz, de-acetone) δ 1.45 (s, 9H), 1.46 (s, 9H), 3.30-3.32 (m, 4H), 3.48-3.50 (m, 4H).

LC-MS t / ζ 364.1 (APC1 ^- , M-1).

Stage 2

The product from step 1 above (0.90 g, 2.5 mmol) was dissolved in approximately 20 ml of a 1: 1 (by volume) mixture of trifluoroacetic acid-dichloromethane and left at room temperature for 2 hours. The solid precipitate was extracted with acetonitrile and re-concentrated again. to obtain an unprotected product in the form of a finely divided white powder.

To this unprotected product was added 20 ml of 1) d8o1ue dichloromethane, after which 1 ml of TEA triethanolamine was added. To the resulting white suspension was added trimethylsilylethoxycarbonyl succinate (0.70 g, 2.7 mmol) in one portion and with stirring the white suspension quickly disappeared, the colorless solution was stirred at room temperature overnight. The reaction mass was concentrated and purified by column chromatography on silica gel (Vyulag 40 8, eluent = hexane: ethyl acetate 2: 1) to obtain a pure product in the form of a white solid precipitate, 0.65 g (85%).

¹ H NMR (400 MHz, d ₆ -acetone) δ 0.06 (s, 9H), 0.94-0.98 (m, 2H), 3.01 (t, 4H), 3.48 (t, 4H), 4.10-4.14 (m, 2H), 6.03 (br s, 2H).

LC-MS t / ζ 308.2 (APC1 ^- , M-1).

Example 20

R

Compound 120 (18.4K, 68.148.18K) -1,3-Dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (piperazine-1-sulfonylaminocarbonyl) -2.15-dioxo-3,16-diazatricyclo [14.3 .0.0 ^4.6 ] nonadec-7-en-18yl ether was synthesized by deprotection of compound 119. Compound 119

- 205 012389 (54.8 mg, 60.7 μmol) was first dissolved in 0.5 ml of tetrahydrofuran Op8O1ue, and then added

A 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (TBAP THP) (0.2 ml, 200 μmol). The reaction mixture was heated at 60 ° С in an oil bath for 2 h, and TLC showed that the reaction was completely completed. The reaction mass was purified by column chromatography on silica gel (Vyuade 12 M; eluent = 0-20% MeOH in 1) C \ '1) to give compound 120 as a white solid, 42.4 mg (92%).

MS t / ζ 756.4 (ARCE, M-1).

Example 21

(18,4B, 68,148,18B) -4-Fluoro-1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4- (No. cyclopropylsulfonylaminocarbonyl) -2.15-dioxo-3,16-diazatricyclo [14.3 .0.0 ^4.6 ] nonadec7-en-18-yl ester was synthesized in accordance with the procedures described in Example 1, replacing Ν, Ν-dimethyl sulfamide with Ν-cyclopropylsulfonamide in step P.

¹ H NMR (500 MHz, SOYUO) δ 8.91 (d, 1H), 7.32 (q, 1H), 7.14 (d, 1H), 7.01 (t, 1H), 5.63 ( q, 1H), 5.40 (br s, 1H), 5.13 (t, 1H), 4.80-4.68 (m, 4H), 4.61 (q, 1H), 4.56 -4.49 (m, 1H), 4.06 (t, 1H), 3.83 (br s, 1H), 3.72 (s, 1H), 3.22 (s, 1H), 2, 72-2.60 (m, 1H), 2.57-2.48 (m, 1H), 2.46-2.31 (m, 4H), 1.83-1.69 (m, 4H), 1.66-1.58 (m, 1H), 1.56-1.19 (m, 5H), 1.13 (d, 9H), 0.71-0.51 (m, 4n).

MS t / ζ 745.3 (ARCE, M-1).

Example 22

Compound 122 (18.4V, 68.148.18B) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (4-aminosulfonylaminocarbonyl) -2.15-dioxo-3.16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester was synthesized in accordance with the procedures described in example 1, replacing Ν, Ν-dimethyl sulfamide with sulfamide in stage P.

MS t / ζ 688.2 (ARCE, M-1).

Example 23

R

Compound 123 (18,4B, 68,148,18B) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (No. (1-cyanocyclopropyl) aminosulfonylaminocarbonyl) -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-18-yl ester was synthesized in accordance with the procedures described in example 1, replacing Ν, Ν-dimethyl sulfamide with 1-cyanocyclopropyl sulfamide in step P.

- 206 012389 ¹ H NMR (400 MHz, bb-acetone) δ 1.22 (s, 9H). 1.20-1.55 (m, 11H), 1.58-1.61 (m, 1H), 1.66-1.69 (m, 1H),

1.71-1.75 (m, 1H), 1.81-1.90 (m, 2H), 2.42-2.48 (m, 3H), 2.60-2.70 (m, 1H) ), 3.84-3.88 (m, 1H), 4.16-4.20 (m, 1H), 4.48 (brd, 1H), 4.58-4.71 (m, 5H) ), 5.07 (t, 1H), 5.44 (br s, 1H), 5.62 (br, 1H), 6.14 (brd, 1H), 7.227.36 (m, 4H) 7.88 (br s, 1H); 8.20 (s, 1H).

MS t / ζ 752.3 (ARSG, M-1).

Example 23 a

N

III

The title compound, 1-cyanocyclopropylsulfamide, was prepared according to the procedures described for Ν-cyclopropylsulfamide (method A, Scheme 2), replacing cyclopropylamine with 1-aminocyclopropanecarbonitrile hydrochloride.

Compound 124 (18.4K, 68.148.18K) -1,3-Dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (cyclopropyl (1-methylpiperidinyl-4-yl) aminosulfonylaminocarbonyl) -2.15-dioxo-3 , 16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester was synthesized in accordance with the procedures described in example 1, replacing Ν, Ν-dimethyl sulfamide with cyclopropyl (1-methylpiperidinyl-4yl) sulfamide at the stage of R.

Ή NMR (400 MHz, _6- acetone) δ 0.75-0.77 (m, 2H), 0.96-1.01 (m, 2H), 1.21 (s, 9H), 1.20 -1.57 (m, 7H), 1.60-1.66 (m, 1H), 1.71-1.74 (m, 1H), 1.80-1.92 (m, 3H), 1 97-2.06 (m, 1H), 2.38-2.60 (m, 5H), 2.68 (s, 3n),

2.88-3.02 (m, 2H), 3.32-3.41 (m, 2H), 3.90-3.96 (m, 2H), 4.17-4.23 (m, 2H) ), 4.41-4.47 (m, 2H), 4.59-4.72 (m,

5H), 5.10 (t, 1H), 5.45 (br.s, 1H), 5.63-5.70 (m, 1H), 6.11 (br. D, 1H), 6.95 (s, 1H), 7.19-7.35 (m, 4H), 8.42 (s, 1H).

MS t / ζ 824.4 (ARSG, M-1).

Example 24a

The title compound, cyclopropyl (1-methylpiperidinyl-4-yl) sulfamide, was prepared according to the procedures described in Example 17a, replacing azetidine with \ -cycloopropyl. L-1-methylpiperidin-4-amine.

¹ H NMR (400 MHz, b ^6- DMSO) δ 0.67-0.76 (m, 4H), 1.93-1.97 (m, 211), 2.07-2.18 (m, 211 ), 2.22-2.26 (m,

Compound 125

- 207 012389 (18.4K, 68.148.18K) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (2-cyanoethyl (cyclopropyl) aminosulfonylaminocarbonyl) -2.15-dioxo-3.16- diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-18-yl ester was synthesized in accordance with the procedures described in example 1, replacing Ν, Ν-dimethyl sulfamide with 2-cyanoethyl (cyclopropyl) sulfamide in stage P.

¹ H NMR (400 MHz, J6-acetone) δ 0.74-0.78 (m, 2H), 0.98-1.01 (m, 2H), 1.21 (s, 9H), 1.20 -1.54 (m, 7H), 1.59-1.63 (m, 1H), 1.74-1.77 (m. 1H), 1.82-1.87 (m, 2H), 2 41-2.65 (m, 6H), 2.79-2.83 (m, 2H), 3.49-3.56 (m, 1H), 3.84-3.88 (m, 1H) 3.97-4.04 (m, 1H), 4.14-4.18 (m, 1H), 4.50 (brd, 1H), 4.60-4.72 (m, 5H) , 5.05 (t, 1H), 5.45 (br.s, 1H), 5.68 (br, 1H), 6.15 (br. D, 1H), 7.22-7.36 (m 4H); 8.33 (s, 1H).

MS t / ζ 781.3 (ARSG, M).

Example 25 a

The title compound, 2-cyanoethyl (cyclopropyl) sulfamide, was prepared according to the procedures described in Example 17a, replacing azetidine with (3-cyclopropylamino) propanitrile.

¹ H NMR (400 MHz, Y6-DMSO) δ 0.68-0.76 (m, 4H), 2.36-2.37 (m, 1H), 2.78 (t, 2H), 3.35 (t, 2H), 7.05 (br s, 2H).

Example 26

(18.4K, 68.148.18K) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (^ No. Diisopropylaminosulfonylaminocarbonyl) -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^{4, 6} ] non-inadequate 7-en-18-yl ester was synthesized according to the procedures described in Example 1, replacing Ν, Ν-dimethyl sulfamide with Ν, Ν-diisopropyl sulfamide in step P.

¹ H NMR (400 MHz, ^6th Acetone) δ 1.21 (s, 9H), 1.25-1.53 (m, 20H), 1.68-1.71 (m, 1H), 1, 81-1.87 (m, 2H), 2.38-2.45 (m, 3H), 2.56-2.68 (m, 1H), 3.84-3.87 (m, 1H), 3.94-4.01 (m, 2H), 4.14-4.18 (m, 1H), 4.47 (brd, 1H), 4.58-4.68 (m, 5H), 5.03 (t, 1H), 5.44 (br.s, 1H), 5.62 (br, 1H), 6.11 (br. D, 1H), 7.23-7.36 (m, 4H), 8.24 (s, 1H), 10.29 (br s, 1H).

MS t / ζ 772.3 (ARSG, M).

Example 26a

The title compound, Ν, Ν-diisopropylsulfamide, was prepared according to the procedures described in Example 17a, replacing azetidine with diisopropylamine.

¹ H NMR (400 MHz, Y6-acetone) δ 1.23 (d, 12H), 3.70-3.77 (m, 2H), 5.67 (br s, 2H).

Example 27

(18.4K, 68.148.18K) -1,3-Dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (phenylaminosulfonylaminocarbonyl) -2.15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4.6 ] nonadec-7-en-18yl ether was synthesized in accordance with the procedures described in example 1, replacing

Ν, Ν-dimethyl sulfamide to phenyl sulfamide in step R.

- 208 012389 ¹ H NMR (400 MHz, _6th acetone) δ 1.20 (s, 9H), 1.20-1.50 (m, 8H), 1.60-1.70 (m, 2H) 1.78-1.86 (m, 1H), 2.30-2.44 (m, 4H), 3.81-3.85 (m, 1H), 4.12-4.17 (m, 1H), 4.45 (br.s.d, 1H), 4.54-4.75 (m, 6H), 5.28 (q, 1H), 5.43 (br.s, 1H), 6.11 (broad d, 1H), 7.14-7.35 (m, 9H), 8.22 (s, 1H), 8.97 (broad s, 1H), 10.80 (broad s, 1H )

MS t / ζ 764.3 (APC1 ^- , M).

Example 27 a

The title compound, phenyl sulfamide, was prepared according to the procedures described for Ν-cyclopropyl sulfamide (method A, Scheme 2), replacing cyclopropylamine with aniline.

¹ H NMR (400 MHz, _6th DMSO) δ 6.95-6.98 (m, 1H), 7.06 (br s, 2H), 7.14-7.16 (m, 2H), 7.24-7.28 (m, 2H); 9.46 (br s, 1H).

Example 28

Compound 128.

(18.4K, 68.148.18K) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (4-chlorophenylaminosulfonylaminocarbonyl) -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^{4, 6} ] non-adec-7-en18-yl ester was synthesized according to the procedures described in Example 1, replacing Ν, Ν-dimethyl sulfamide with 4-chlorophenyl sulfamide in step P.

¹ H NMR (400 MHz, _6th Acetone) δ 1.19 (s, 9H), 1.18-1.51 (m, 8H), 1.61-1.72 (m, 2H), 1, 76-1.87 (m, 1H), 2.32-2.44 (m, 4H), 3.82-3.86 (m, 1H), 4.12-4.16 (m, 1H), 4.45 (br.s.d, 1H), 4.54-4.72 (m, 6H), 5.28 (q, 1H), 5.43 (br.s, 1H), 6.10 (br. d, 1H), 7.22-7.38 (m, 8H), 8.24 (s, 1H).

MS t / ζ 798.2 (APC1 ^- , M).

Example 28a

The title compound, 4-chloro-phenylsulfamide, was prepared according to the procedures described for Ν-cyclopropylsulfamide (method A, Scheme 2), replacing cyclopropylamine with 4-chlorobenzeneamine.

¹ H NMR (400 MHz, _6th DMSO) δ 7.09-7.12 (m, 4H), 7.27 (d, 2H), 9.59 (br s, 1H).

Example 29

Compound 129.

(18.4K, 68.148.18K) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (4-methoxyphenylaminosulfonylaminocarbonyl) -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^{4, 6} ] nonadec-7en-18-yl ester was synthesized according to the procedures described in Example 1, replacing Ν, Ν-dimethyl sulfamide with 4-methoxyphenyl sulfamide in step P.

¹ H NMR (400 MHz, _6th Acetone) δ 1.20 (s, 9H), 1.18-1.54 (m, 8H), 1.64-1.87 (m, 3H), 2, 22-2.46 (m, 4H), 3.80 (s, 3H), 3.77-3.82 (m, 1H), 4.14 (m, 1H), 4.43 (br. D, 1H), 4.52-4.70 (m, 5H), 4.88 (t, 1H), 5.40-5.50 (m, 2H), 6.10 (br.s.d, 1H), 6 88-6.90 (d, 2H); 7.18-7.35 (m, 6H); 8.18 (s, 1H).

MS t / ζ 794.3 (ARSG, M).

- 209 012389

Example 29a

The title compound, 4-methoxyphenyl sulfamide, was prepared according to the procedures described for Ν-cyclopropyl sulfamide (method A, Scheme 2), replacing cyclopropylamine with 4-methoxybenzeneamine.

¹ H NMR (400 MHz, UH-DMSO) δ 3.71 (s, 3H), 6.85-6.87 (m, 4H), 7.11 (d, 2H), 9.01 (br.s ., 1H).

Example 30

(18.4K, 68.148.18K) -1.3 - Dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (4-methylphenylaminosulfonylaminocarbonyl) -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^{4, 6} ] nonadec-7en-18-yl ester was synthesized according to the procedures described in Example 1, replacing Ν, Ν-dimethyl sulfamide with 4-methylphenyl sulfamide in step P.

¹ H NMR (400 MHz, _6- acetone) δ 1.20 (s, 9H), 1.20-1.52 (m, 8H), 1.60-1.74 (m, 2H), 1, 76-1.87 (m, 1H), 2.26-2.42 (m, 4H), 2.31 (s, 3H), 3.81-3.84 (m, 1H), 4.14- 4.17 (m, 1H), 4.44 (br. D, 1H), 4.52-4.79 (m, 6H), 5.32 (br. 1H), 5.42 (br.s, 1H), 6.11 (br.s.d, 1H), 7.14-7.35 (m, 8H), 8.20 (s, 1H), 8.79 (br.s, 1H), 10.69 (broad s, 1H).

MS t / ζ 778.2 (ARSG, m).

Example 30a

The title compound, 4-methylphenyl sulfamide, was prepared according to the procedures described for Ν-cyclopropyl sulfamide (method A, Scheme 2), replacing cyclopropylamine with 4-methylbenzeneamine.

¹ H NMR (400 MHz, 06-DMSO) δ 2.18 (s, 3H), 6.91 (s, 2H), 7.01 (s, 4H), 9.20 (s, 1H).

Example 31

(18.4K, 68.148.18K) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (4-cyanophenylaminosulfonylaminocarbonyl) -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^{4, 6} ] non-adec-7en-18-yl ester was synthesized according to the procedures described in Example 1, replacing Ν, Ν-dimethyl sulfamide with 4-cyanophenyl sulfamide in step P.

¹ H NMR (400 MHz, _6- acetone) δ 1.20 (s, 9H), 1.18-1.53 (m, 8H), 1.60-1.70 (m, 2H), 1, 76-1.87 (m, 1H), 2.32-2.48 (m, 4H), 3.85-3.88 (m, 1H), 4.15-4.17 (m, 1H), 4.46 (br.s.d, 1H), 4.57-4.71 (m, 6H), 5.16 (q, 1H), 5.46 (br.s, 1H), 6.10 (br. d, 1H), 7.24-7.35 (m, 4H), 7.42 (d, 2H), 7.76 (d, 2H), 8.28 (s, 1H).

MS t / ζ 788.3 (ARSG, M-1).

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Example 31a

The title compound, 4-cyanophenyl sulfamide, was prepared according to the procedures described for Ν-cyclopropyl sulfamide (method A, Scheme 2), replacing cyclopropylamine with 4-aminobenzonitrile.

¹ H NMR (400 MHz, _6th DMSO) δ 7.22 (d, 2H), 7.40 (br s, 2H), 7.70 (d, 2H), 10.24 (br s, 1H).

Example 32

Compound 132.

(18.4J, 68.148.18J) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (4-trifluoromethylphenylaminosulfonylaminocarbonyl) -2.15-dioxo-3,16-diazatricyclo [14.3.0.0 ^{4, 6} ] nonadec-7-en-18-yl ester was synthesized in accordance with the procedures described in example 1, replacing Ν, Ν-dimethyl sulfamide with 4-trifluoromethylphenyl sulfamide in step R.

¹ H NMR (400 MHz, _6th Acetone) δ 1.19 (s, 9H), 1.18-1.64 (m, 10H), 1.82 (q, 1H), 2.30-2, 46 (m, 4H), 3.843.87 (m, 1H), 4.12-4.16 (m, 1H), 4.47 (brd, 1H), 4.57-4.71 (m. 6H), 5.11 (q, 1H), 5.45 (s, 1H), 6.12 (brd, 1H), 7.23-7.35 (m, 4H), 7.45 (d , 2H), 7.69 (d, 2H), 8.30 (s, 1H), 9.53 (br s, 1H), 11.06 (br s, 1H).

MS t / ζ 832.2 (ARSG, M).

Example 32a

The title compound, 4-trifluoromethylphenyl sulfamide, was prepared according to the procedures described for Ν-cyclopropyl sulfamide (method A, Scheme 2), replacing cyclopropylamine with 4-trifluoromethylbenzamine.

¹ H NMR (400 MHz, _6th DMSO) δ 7.26-7.30 (m, 4H), 7.59 (d, 2H), 10.05 (br s, 1H).

Example 33

Compound 133.

(18,4J, 68,148,18J) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (4-cyclobutylaminosulfonylaminocarbonyl) -2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^{4, 6} ] non-adec-7-en18-yl ester was synthesized according to the procedures described in Example 1, replacing Ν, Ν-dimethyl sulfamide with cyclobutyl sulfamide in step P.

¹ H NMR (400 MHz, _6th Acetone) δ 1.21 (s, 9H), 1.20-1.70 (m, 11H), 1.80-1.90 (m, 2H), 2, 02-2.09 (m, 2H),

2.21-2.30 (m, 2H), 2.41-2.47 (m, 3H), 2.58-2.68 (m, 1H), 3.75-3.87 (m, 2H) ), 4.15-4.18 (m, 1H), 4.47 (broad d, 1n),

4.57-4.72 (m, 5H), 5.11 (t, 1H), 5.44 (s, 1H), 5.63 (q, 1H), 6.14 (brd, 1H) 6.34 (brd. 1H); 7.23-7.36 (m, 4n),

8.18 (s, 1H).

MS t / ζ 741.4 (ARSG, M-1).

- 211 012389

Example 33a

The named connection. cyclobutyl sulfamide. was received in accordance with the procedures. described in example 17a. replacing azetidine with cyclobutanamine.

¹ H NMR (400 MHz. _B- DMSO) δ 1.20-1.b0 (m, 2H). 1.89-1.94 (m, 2H). 2.14-2.21 (m, 2H). 3.b7 (m. 1H). b.42 (broad s. 2 N). b.82 (broad s. 1H).

Example 34

Compound 133.

(18.4B.b8.148.18B) -1.3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (4-cyclopentylaminosulfonylaminocarbonyl) -2.15-dioxo-3.1b-diazatricyclo [14.3.0.0 ⁴ ^] non-in-7 en -18-yl ester was synthesized in accordance with the procedures. described in example 1. replacing Ν.Ν-dimethyl sulfamide with cyclopentyl sulfamide in stage G.

¹ H NMR (400 MHz. Yb-acetone) δ 1.21 (s. 9H). 1.20-1.73 (m. 15H). 1.87-1.9b (m. 4H). 2.41-2.49 (m. 3H). 2.5b-2.b8 (m. 1H). 3.55-3.b0 (m. 1H). 3.84-3.87 (m, 1H). 4.15-4.18 (m, 1H). 4.48 (broad d. 1H). 4.57-4.72 (m, 5H). 5.08 (t. 1H). 5.44 (s. 1H). 5.b3 (q. 1H). b.15 (br. d. 1H). b.24 (br. d. 1H). 7.23-7.35 (m. 4H). 8.25 (p. 1n). 10.25 (broad s. 1H).

MS t / ζ 755.4 (APC1 ^- . M-1).

Example 34a

The named connection. cyclopentyl sulfamide. was received in accordance with the procedures. described in example 17a. replacing azetidine with cyclopentanamine.

¹ NNMR (400 MHz. Th _b- DMSO) δ 1.43-1.b1 (m bn). 1.80-1.83 (m, 2H). 3.54 (m, 1H). b.42 (broad s. 3H). Example 35

Compound 135.

(18.4B.b8.148.18B) -1.3-Dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (4-cyclohexylaminosulphonylaminocarbonyl) -2.15-dioxo-3.1 b-diazatricyclo [14.3.0.0 ^{4 / |} ] non-adec-7en-18-yl ester was synthesized in accordance with the procedures. described in example 1. replacing Ν.Ν-dimethyl sulfamide with cyclohexyl sulfamide in stage G.

¹ H NMR (400 MHz. Yb-acetone) δ 1.21 (s. 9H). 1.14-2.0 (m. 21H). 2.41-2.48 (m, 3H). 2.57-2.b7 (m. 1H). 3.07-3.1b (m. 1H). 3.84-3.87 (m, 1H). 4.15-4.19 (m, 1H). 4.47 (broad d. 1H). 4.57-4.72 (m, 5H). 5.08 (t. 1H). 5.44 (s. 1H). 5.b4 (q. 1H). b.13-b.17 (m 2H). 7.23-7.3b (m. 4H). 8.23 (p. 1H). 10.30 (br. S. 1H).

MS t / ζ 7b9.4 (APC1 ^- . M-1).

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Example 35a

Compound 136.

(18.4K, 68.148.18K) -1,3-dihydroisoindole-2-carboxylic acid 14-tert-butoxycarbonylamino-4 (dimethylsulfonylaminocarbonyl) -2.15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4.6 ] non-adec-7-ene-18-ethyl ester, HCl salt (compound 136) was synthesized from compound 101 (79 mg), which was dissolved in 0.5 ml of 4 M HCl / dioxane and stirred at room temperature for 16 hours. Then the reaction the mixture was concentrated, extracted with acetonitrile and concentrated again. The hydrochloride was dried overnight under high vacuum to give a white solid precipitate (76 mg).

MS t / ζ 617.1 (APCE, M + 1).

Example 35H

The title compound, cyclohexyl sulfamide, was prepared according to the procedures described in Example 17a, replacing azetidine with cyclohexanamine.

¹ H NMR (400 MHz, UH-DMSO) δ 1.08-1.23 (m, 5H), 1.50-1.54 (m, 1H), 1.65-1.68 (m, 2H) 1.86-1.89 (m, 2H); 3.02 (m, 1H); 6.40 (br s, 3H).

Example 36. No. 3-No. 84A protease analysis.

Formation of complex N83 with No. 4A-2.

The full length recombinant N83 obtained with E. EOH or baculovirus was diluted to 3.33 μM with assay buffer, and the material was transferred to an Eppendorf tube and placed in a 4 ° C water bath in a refrigerator. An appropriate amount of N84A-2 diluted to 8.3 mM with assay buffer was added to the equivalent volume of N83 in step 2.1.1 (conversion factor 3.8 mg / 272 µl assay buffer). The material was transferred to an Eppendorf tube and placed in a 4 ° C water bath in the refrigerator.

After adjusting the system to 4 ° C, equal volumes of N83 and N84A-2 solutions were combined in an Eppendorf tube and carefully mixed with a manual pipetting device; the mixture was kept for 15 min in a water bath at 4 ° C. The final concentrations in the mixture were 1.67 μM N83, 4.15 mM \ 84A-2 (2485-fold molar excess No. 4A-2).

After 15 minutes at 4 ° C, the Eppendorf tube No. 3A84A-2 was taken out of the refrigerator and placed at room temperature in a water bath for 10 minutes. Material N83 / N84A-2 was separated without residue into the corresponding volumes and stored at -80 ° C (E. eoH N83 acts at 2 nM in the analysis, an aliquot of 25 μl. Baculovirus N83 acts at 3 nM in the study, an aliquot of 30 μl).

Example 37. Investigation of inhibition of N83.

Stage 2.2.5.

Samples of the compounds were diluted to 10 mM in DMSO, then diluted to 2.5 mM (1: 4) in DMSO. Typically, the compounds were added to the assay plate at a concentration of 2.5 mM obtained by diluting the initial concentration to 50 μM by the inhibition assay curve. Compounds were sequentially diluted in assay buffer to obtain low concentration test solutions.

Stage 2.2.6.

E. eoN No. 3A84A-2 was diluted to 4 nM N83 (1: 417.5 1.67 μM source - 18 μl 1.67 μM source + 7497 μl assay buffer). Baculovirus No. 3A84A-2 was diluted to 6 nM N83 (1: 278.3 1.67 μM source - 24 μl 1.67 μM source + 6655 μl assay buffer).

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Stage 2.2.7.

Using a manual multichannel pipetting device and avoiding the formation of bubbles in the plate, 50 μl of assay buffer was added to the wells of A01-H01 black CoDag 96-well polypropylene storage plate.

Stage 2.2.8. Using a multichannel manual pipetting device and avoiding the formation of bubbles in the plate, 50 μl of the diluted Ν83 / Ν84Λ-2 from step 2.2.6 was added to the wells of A02-H12 of the tablet of step 2.2.7.

Stage 2.2.9. Using a multichannel manual pipetting device and avoiding the formation of bubbles in the plate, 25 μl of the wells in the plate for diluting the compounds of stage 2.2.5 were transferred to the corresponding wells of the analytical tablet of stage 2.2.8. The tips of the multichannel pipetting device varied for each row of portable compounds.

Stage 2.2.10. Using a multi-channel manual pipetting device and avoiding the formation of bubbles in the plate, the contents of the wells of the analytical plate of step 2.2.9 were mixed by suction and distribution of 35 μl of 75 μl in each well 5 times. The tips of the multichannel pipetting device varied for each row of portable compounds.

Stage 2.2.11. The tablet was covered with a polystyrene tablet lid and the tablet of step 2.2.10 containing the N83 protease, and samples of the compounds were pre-aged for 10 minutes at room temperature.

While the tablet from step 2.2.11 was previously aged, the KET81 substrate was diluted in a 15 ml propylene centrifuge tube. KET81 substrate was diluted to 8 μM (1: 80.75 646 μM source - 65 μl 646 μM source + 5184 μl assay buffer).

After the plate in step 2.2.11 was pre-aged using a manual multichannel device, 25 μl of the substrate was added to all wells in the plate. The contents of all wells were quickly mixed, as in step 2.2.10, but by mixing 65 μl of 100 μl in the wells.

The tablet was read in a kinetic manner on a Mo1ci1ag Eéu1ce5 8res1gaMax 6etsh1 X8 tablet reader. Reader settings Reading time: 30 min, interval: 36 s, reproduction: 51, radiation λ: 335 nm, emission λ: 495 nm, limit value: 475 nm, automix: disabled, calibration: 1 time, PMT: high, radiation / well: 6,

Vtax p! §: 21 or 28/51 depending on the length of the linearity of the reaction.

^ 50 were determined using the empirical equation of the four-parameter curve and recalculating Κί'δ using the following Kt ':

full length E. soi N83-2.03 μm;

full length BV N83-1.74 μM, where Κι = ^ / (Н ^ / Кт).

Quantification by enzyme-linked immunosorbent assay (E8A) of selectable protein markers, neomycin phosphotransferase II (No. TP) in the HCV subgenomic replicon, 684.3.

HCV subgenomic replicon (677 / Ν83-3 ', entry No. A1242652), which is stably stored in human HNH-7 hepatoma cells, was created by Lobtapp et al. 8c1epse, 285: 110-113 (1999). Replicon-containing cell cultures, designated 684.3, were obtained from Ig. SNGSHchorN 8eedeg from the Institute for Research on Cancer, Goh Oe Sapseg Sep1eg, Philadelphia, PA.

684.3 cells were maintained at 37 ° C, 5% CO ₂ , in MEM medium in the modification of Dulbecco BMME (BiLesso'8 Moyshey Ead1e'Meisht) (61Lco 11965-092), supplemented with L-glutamine 200 mM (100x) (61Lco25030-081 ), minor amino acids (No. AA) (Vu ^ Yyakeg 13-114E), thermally inactivated (III) fetal bovine serum (HB8) (Huclope 8H3007.03) and 750 μg / ml geneticin (6418) (61bco 10131-035). Cells were subdivided 1: 3 or 4 every 2-3 days.

24 hours before the study, 684.3 cells were harvested, counted and plated in 96-well plates (Co §1ag 3585) at a density of 7500 cells / well in all standard stabilizing media (above) and maintained under the conditions indicated above. To start the study, the nutrient medium was removed, the cells were washed 1 time with physiological saline with phosphate buffer PB8 (61Lco 10010-023) and 90 μl of the research medium was added (BMEM, L-glutamine, NL, 10% III GW8, no 6418). The inhibitors were made as a 10x stock solution in a research medium (3-fold dilution from 10 μM to 56 pM final concentration, final BMSO concentration 1%), 10 μl was added to the duplicate wells, the plates were shaken for mixing and you

- 214 012389 held, as described above, for 72 hours

ΝΈΤΙΙ ЕЫ8А kit was received from ASI1A, 1ps. (compound directed by E8A test system for neomycin phosphotransferase II, P8P 73000/4800). The manufacturer's instructions were followed with some modifications. 10x REV-1 lysis buffer was modified to include 500 pM RYSE (81dtA P7626, 50 mM stock solution in isopropanol). After 72 h of incubation, the cells were washed 1 time with physiological saline with phosphate-buffered saline PB8 and 150 μl of REV-1 with PΜCE was added per well. The plates were shaken thoroughly for 15 minutes at room temperature, then frozen at -70 ° C. The plates were thawed, the lysates were thoroughly mixed, and 100 μl were transferred to a ΝΓΤΙΙ EY8A plate. A standard curve was built. The lysate from ^ ΜCΟ-treated control cells was collected, sequentially diluted with REB-1 with PΜCE and transferred to duplicate wells of an E8A plate in the range of the initial lysate amount of 150-2.5 μl. An additional 100 μl of buffer alone was used in duplicate as a control solution. The plates were hermetically sealed and gently mixed at room temperature for 2 hours. The next curing time, the plates were washed with 5 × 300 μl of PB8-T (0.5% T \ uep-20. PB8-T were provided in the E8A kit). To determine 1x, dilution with an enzyme conjugated with an enzyme, ΜΚ8-2 (5x) was performed in PB8-T, to which 1: 100 enzyme was added in conjugates A and B diluents in accordance with the instructions. The plates were resealed and kept at room temperature for 2 hours with stirring, coated. The washing was then repeated and 100 μl of substrate ΊΜΕ room temperature was added. After approximately 30 minutes (room temperature, stirring, assay), the reaction was stopped with 50 μl of 3 M sulfuric acid. The tablets were read at 450 nm on a Co1Ci1a2 Oeiseh Uegaat plate reader.

The inhibitory effect is expressed as a percentage of the ^ ΜСΟ-processed control signal and the inhibition curve was calculated using an equation with 4 parameters:

y = A + ((B-A) / (1 + ((C / x) ^l O))), where C represents half the maximum activity or EC ₅₀ .

Examples of activity.

A is 1C ₅₀ or EC ₅₀ , as indicated, less than 1 μM;

B is 1C ₅₀ or EC ₅₀ , as indicated, less than 0.1 μM.

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Table 3

Connection Ν83-Ν84 1C ₅₀ 101 V 102 V EU ₅₀ in 103 IN 104 in in 105 in No vault. 106 in IN 107 in IN 108 BUT IN 109 IN BUT BY BUT No vault. 111 IN No vault. 112 IN No vault. OF IN IN 114 IN IN 115 IN IN 116 IN BUT 117 IN IN 118 in IN 119 in IN 120 in No vault. 121 in IN 122 in IN 123 in No vault. 124 BUT IN 125 in IN 126 in IN 127 in in 128 in in 129 in in 130 in in 131 in in 132 in in 133 in in 134 in in 135 in in

Example 38. Specificity analysis.

When evaluating compounds using a specificity analysis, compounds of formula I were found to be selective in that they did not show significant inhibition in cathepsin B, chymotrypsin, thrombin, or leukocyte elastase.

Example 39. Pharmacokinetic analysis of compounds.

Initially, the compounds were synthesized and tested for activity (1C ₅₀ ) in a fluorogenic N83 / 4 protease assay and a system based on HCV replicon cells as described above. Plasma kinetic analysis in Ba11 from sp. The next IV introduction was then used in conjunction with stability studies of human liver microsomes (BAT) and hepatocytes to guide the design of metabolically stable compounds from compounds with activity <20 nM. These samples were then optimized in physical properties, like drugs, and orally administered with Ba11 sp. to assess the concentration in the liver, heart and plasma.

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Ways.

The compounds were initially synthesized and tested for activity ([C? ₅₀ ) in a fluorogenic Ν83 / 4 protease assay and a system based on HCV replicon cells, as described in Example 8 above. Plasma kinetic analysis in Vayik 5p. The next IV introduction was then used in conjunction with studies of the stability of human liver microsomes (HM) and hepatocytes ίη νίίΓΟ to guide the design of metabolically stable compounds from compounds with activity <20 nM. These samples were then optimized for physical properties similar to drugs and orally administered Vayik 5p. to assess the concentration in the liver, heart and plasma.

Compounds were tested for liver cleansing in the time following administration of an individual 3 mg / kg oral dose in rats. For any compound found to exhibit a concentration in the liver 8 hours after administration, which is at least 100 times greater than the concentration of a compound effective to inhibit 50% of the maximum inhibition in a replicon assay (EC ₅₀ replicon), additional toxicological assessment was carried out in rats using doses higher than 30 mg / kg orally for VGO for 7 days.

Results.

Compounds AB334187 had an EC ₅₀ value of approximately 2 nM and showed ίη νίίτο stability in an incubation assay of rat, dog, and human hepatocytes, which could predict low to moderate liver excretion rates. In addition, these compounds display a high degree of selectivity against a series of other protein proteases and do not show significant inhibition of cytochrome P450 or 11EBC activity channel isoforms even at the highest concentrations of the tested compounds (10 μM).

For compounds AB334187, an individual oral dose of 30 mg / kg in Vayik 5p. yielded liver concentrations 24 hours after administration, which were at least 20 times greater than their corresponding EC50 replicon values.

Compound AB334187 gave concentrations in the liver and plasma two orders of magnitude lower, which correlated kinetically with concentrations in the liver in the same animals. At a clinically more reasonable oral dose (3 mg / kg), compound AB334187 produced a concentration in the liver 8 hours after administration, which was more than 100 times greater than the replicon EC50 value of the compound. After exposure of compound AB334187 at a dose of 30 mg / kg orally with VGO for 7 days, no changes in weight, anomalies in clinical chemistry, and mortality were observed in the treated animals.

Conclusion

Active, metabolically stable, orally available small molecules of Ν83 HCV protease inhibitors have been developed. At a moderate oral dosage (3 mg / kg), these compounds display a very high level in the liver (100 times greater than the corresponding EC50 replicon values) 8 hours after the dose. Plasma and heart exposures are two orders of magnitude lower than those observed in the liver, and such low concentrations reduce any potential systemic toxicological effect.

Compound AB334187 did not show toxicity in Vayik 5p. at doses for 7 days at 30 mg / kg VGO, providing at least a 10-fold safety margin higher than the estimated effective dose (3 mg / kg), which gives a concentration in the liver that exceeds 100 times the excess of the EC50 replicon of the compounds.

Obtaining viral inhibitors of section Ό.

The meaning of the terms and structural names used in this section coincides with the names and conditions of section Ό above. Any reference in this section to any number or designation should be considered in the context of the corresponding numbering or designation of symbols used in this section or section Ό above, in contrast to the context of a possibly similar or identical numbering or designation of symbols used here elsewhere if not specified otherwise.

The compounds of formulas XVIII can be synthesized in accordance with the methods described below.

(28.4B) -4-amino-1- [benzyloxycarbonyl] pyrrolidin-2-methylcarboxylate hydrochloride was purchased from Aggau Würjagt, 2 (8) -tert-butoxycarbonylamino-non-8-enoic acid and ethyl ether

1 (B) -tert-butoxycarbonylamino-2 (8) -vinylcyclopropanecarboxylic acid were obtained by the method as described in international application PCT / CA00 / 00353 (Publication No. \ ¥ O 00/59929). 28- (tert-butoxycarbonylamino-non-8-enoic acid was also purchased from B8P Atsho Ac1J5.

Two key aminoproline macrocyclic intermediates were used to prepare Ν83 inhibitors, as shown in Examples 1-69.

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1. Obtaining aminoproline macrocyclic acylsulfonamide intermediate A.

Synthesis of (18.4K, 68.148.18K) - (18-amino-4-cyclopropanesulfonylaminocarbonyl-12,15-dioxo-3,16 diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-14-yl) carbamic acid tert butyl ether.

Scheme 1

TEM. RSM

Ρά / s

H ₂ , Meon

MNTeos

Stage A

Stage C go

P1EA.RSM

Stage G

TWAG, TO

50-C.

1.5% Noueuda 1s1 depegaOop sa1, PCM.

Step A. To a solution of (28.4K) -4-amino-1- [benzyloxycarbonyl] pyrrolidin-2 methylcarboxylate hydrochloride in methylene chloride (25 ml) was added 2- (trimethylsilyl) ethyl p-nitrophenyl carbonate (1.98 g, 6.99 mmol) and triethylamine (1.81 ml, 13.34 mmol). The reaction mixture was stirred for 3 days, placed on silica gel and the product was eluted with 40% ethyl acetate / hexane to give a colorless oil. The oil was dissolved in methanol (20 ml) and stirred with 10% palladium on charcoal in an atmosphere of hydrogen passed from a balloon. After stirring for 4 hours, the reaction mixture was filtered and concentrated. The resulting solid precipitate was dissolved in 1N. aqueous HC1 (75 ml) and extracted with methylene chloride (75 ml). By adding sodium hydroxide, the pH of the aqueous layer was adjusted to basic values and the aqueous layer was again extracted with methylene chloride (100 ml). The organic layers were combined, concentrated and the resulting precipitate was purified by silica gel column chromatography with eluent 10% methanol / methylene chloride to obtain a brown solid precipitate (1.29 g, 70%).

LC-MS = 289 (H ⁺ ).

Stage B. Solution of methyl ester of 4 (E) - (2-trimethylsilylethylcarbonylamino) pyrrolidin-2 (8) carboxylic acid (1.29 g, 4.50 mmol), 2 (8) -tert-butoxycarbonylamino-8-enoic acid ( 1.22 g, 4.51 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium NATI hexafluorophosphate (2.06 g, 5.41 mmol) and diisopropylethylamine (1, 18 ml, 6.76 mmol) in dimethylformamide (10 ml) was stirred overnight. The reaction mixture was diluted with ethyl acetate (150 ml), washed with 1N. aqueous HC1 (2x100 ml), dried over magnesium sulfate and concentrated. Column chromatography on silica gel gave an oil, which was stirred with lithium hydroxide (0.28 g, 6.76 mmol) in methanol (5 ml) for 2 hours. The reaction mixture was diluted with methylene chloride, washed with 1N. aqueous HC1 (2x100 ml), dried over magnesium sulfate and concentrated to obtain 1.2 g (49%) of the product.

Step C. To 1-E-tert-butoxycarbonylamino-2 (8) -vinylcyclopropanecarboxylic acid ethyl ester (0.70 g, 2.75 mmol) was added 4N. a solution of HC1 in dioxane (2.87 ml, 11.46 mmol). After stirring for 2 hours, the reaction mixture was concentrated to obtain a solid precipitate. To this solid precipitate was added 1- (2 (8) -tert-butoxycarbonylamino-non-8-enoyl) -4 (E) - (2trimethylsilylethylcarbonylamino) pyrrolidin-2 (8) -carboxylic acid (1.21 g, 2.29 mmol), NATI (1.05 g, 2.75 mmol), diisopropylethylamine (1.60 ml, 9.17 mmol) and methylene chloride (10 ml) and the reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was placed.

- 218 012389 on silica gel and eluted with 50% ethyl acetate / hexane to give the product as a colorless oil (1.27 g, 83%). 665 (And ⁺ )

Step E. Ethyl ester solution 1 - {[1- (2 (8) tert-butoxycarbonylamino-non-8-enoyl) -4 (K) - (2trimethylsilylethyl ethylcarbonylamino) pyrrolidine-2 (8) -carbonyl] amino} -2 ( 8) -vinylcyclopropane-1- (K) carboxylic acid (2.57 g, 3.87 mmol) in methylene chloride (500 ml) was degassed by passing through the solution for 1 h Ν ₂ . Ruthenium dichloro (o-isopropoxyphenylmethylene) (tricyclohexylphosphine) (11) (0.116 g, 0.193 mmol) was added to the reaction mixture and the reaction mixture was stirred at 40 ° C for 16 hours. The reaction mixture was concentrated, placed on silica gel and eluted with 50% ethyl acetate / hexane to give the product (2.01 g, 3.16 mmol, 82%). 637.0 (H ⁺ ).

Stage E. To a solution of ethyl ether (18.4K, 68.148.18K) - (14-tert-butoxycarbonylamino-2.15 dioxo-18- (2-trimethylsilanylethoxycarbonylamino) -3,16-diazatricyclo [14.3.0.0 ^4,6 ] non- -7-en-14yl) carboxylic acid (1.94 g, 3.04 mmol) in 10: 1 methanol / water (10 ml) lithium hydroxide (1.02 g, 24.37 mmol) was added and the reaction mixture was stirred at room temperature all night. The reaction mixture was treated with 1N. IS1 (50 ml) and was extracted with methylene chloride (2x50 ml). The combined organic layers were washed with brine (50 ml), dried over magnesium sulfate and concentrated to give a solid precipitate (1.78 g, 2.92 mmol). A solution of this acid and carbonyl diimidazole (0.711 g, 4.39 mmol) in dichloroethane was heated at 50 ° C. After 1 h, HPLC showed the presence of the starting material; therefore, an additional amount of carbonyldiimidazole (0.1 g) was added. After an additional 1 hour stirring at 50 ° C, HPLC showed complete disappearance of the starting material. A solution of cyclopropanesulfonyl chloride (0.46 g, 3.80 mmol) and EVI (0.57 g, 3.80 mmol) were added to the reaction mass, and the reaction mixture was heated at 50 ° C. After 1 h, the reaction was not completed, as indicated by HPLC, therefore, an additional amount of 0.07 g of cyclopropylsulfonamide and 0.1 g of EVI were added. After stirring for an additional 30 minutes, the reaction was completed. The reaction mixture was cooled, placed on silica gel and the product was eluted with a gradient from 3% methanol / dichloromethane to 7.5% methanol / dichloromethane as a white precipitate.

Chromatography-mass spectrum 710.5 (H ^- ).

Step R. Solution 1 (0.80 g, 1.124 mmol) and tetrabutylammonium fluoride (1.0 M solution in THF, 1.4 ml) were stirred at 50 ° C. for 1 h. The reaction mixture was cooled, placed on silica gel, and the product was eluted with a gradient of 5% methanol / dichloromethane to 25% methanol / dichloromethane as a white precipitate (0.51 g).

Chromatography-mass spectrum 568.0 (H ⁺ ).

2. Obtaining aminoproline macrocyclic ether of intermediate compound B.

Synthesis of ethyl ester (18.4K, 68.148.18K) -18-amino (14-tert-butoxycarbonylamino-2.15-dioxo3,16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-14-yl ) carboxylic acid.

Scheme 2

ΝΗΤβοο ΝΗ ₂

IN

Compound 1 of Scheme 1 above was treated with TBAP (1.0 M in THF, 1.5 eq.) And heated at 50 ° C. for 4 hours. The reaction mixture was placed on silica gel and eluted with 20% methanol / methylene chloride to give B in the form of a tan solid precipitate (yield 69%).

¹ NMR (СОС1 ₃ , 400 MHz) δ 1.06-1.66 (m, 17I), 1.85-1.95 (m, 2I), 2.0-2.1 (m, 1I), 2.1-2.2 (m, 1I), 2.22.3 (m, 1I), 2.65-2.75 (m, 1I), 3.40 (m, 1I), 3.73- 3.83 (m, 2I), 4.08-4.19 (m, 2I), 4.56 (m. 1i), 4.78 (d, 1 = 5.5 Hz, 1I), 5.20 (t, 1 = 8.1 Hz, 1I), 5.34 (d, 1 = 8.1 Hz, 1I), 5.47 (dt, 1 = 4.5, 10.8 Hz, 1I), 7 08 (s, 1I).

493 (I ⁺ ).

The Ν83 acylsulfonamide inhibitors in Examples 1-69 were then prepared using one of the following methods using the two intermediates A and B. All the Ν83 carboxylic acid inhibitors in the examples were prepared according to method 2 of Scheme 3.

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Scheme 3

Example 1. Synthesis of (18.4K, 68.148.18K) - (18 - [(3-chlorobenzo [b] thiophene-2-carbonyl) amino] -4cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo [14.3. 0.0 ^4.6 ] nonadec-7-en-14yl) carbamic acid tert-butyl ether

A solution of tert-butyl ether (18.4K, 68.148.18K) - (18-amino-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo [14.3.0.0 ^4,6 ] nonadec-7-en-14 -yl) carbamic acid (0.254 g, 0.44 mmol), 3-chlorobenzo [b] thiophene-2-carbonyl chloride (0.124 g, 0.54 mmol) and

Ν, Ν-diisopropylethylamine DIEA (0.087 g, 0.67 mmol) was stirred together in dichloromethane at room temperature. After 1 h, the reaction mixture was placed on silica gel and the product was eluted as a white solid using a gradient of 1% methanol / dichloromethane to 5% methanol / dichloromethane.

¹ H NMR (C ₆ Pb, 400 MHz) δ 7.66-7.70 (m, 1H), 7.22-7.24 (m, 1H), 7.04-7.07 (m, 2H) 6.97 (m, 1H), 6.83 (br s, 1H), 5.61 (d, 1H), 5.18 (t, 1H), 5.05 (d, 1H), 4, 48-4.50 (b, H), 4.26 (t, n), 3.8-4.0 (m, 1H), 3.65-3.74 (m, 1H), 3.20- 3.35 (m, 1H), 2.78-2.85 (m, 1H), 2.55-2.65 (m, 1H), 2.3-2.4 (m, 1H), 1, 95-2.15 (m, 2H), 1.75-1.85 (m, 1H), 1.20-1.40 (m, 6H), 0.95-1.15 (m, 5H), 0.4-0.5 (m, 1H), 0.25-0.35 (m, 1H).

LC-MS 662 (H ⁺ -Boc).

Examples 2-69.

The examples were carried out following the general procedures described for the synthesis in Example 1 by replacing the corresponding acid chlorides or carboxylic acids ^ ATi (O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphane) with 3-chlorobenzo [b] thiophene-2-carbonyl chloride or the following similar amides and acylsulfonamides, combining the procedures as described in example 1 and for synthesis A, but using method 2 of scheme 3 instead.

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Table 4

- 221 012389

- 222 012389

- 223 012389

_kka Y g · '1 * ”Mm yshg Y. <t 22 ¹ θ _ζ ο ₄ _α. > nn ' ^D \\ _ /' ^Ζ Χ) Ν ”\ 0 Ζλ Η V ⁷ n) 771.9 (H ⁺ ) 23 0 ΧΎ & O% A ~ Sy ί V AAD G 2Gy V and / 787.7 (H ⁺ ) 24 0 k-3 Н £ Г I ⁰ ° Υ ^Ν \ -Ν А V Ч Д I Д Λ'κ'θΎ? No. \ 0 <4 Η V ⁷ n) y 754.9 (H ¹ ) 25 0 ^s \ ΗΗ ^ Ν ~~ ^ 3 GT \ θ Μ H \ / N / \ 788.8 (H ⁺ ) 26 Well, Νθ ^ _α 0 ο ^ νΑη о о r Λ ^Λ Ν ..... to 0 DW V and? 788.9 (n ⁴ ) 27 722.0 (N ‘)

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 MP · (· 'ΐΓΐΗο Ιί · “ 28 ι 9 hTsl ϊ 4 / LaD 723.1 (H ⁺ ) 29th , about αΛ X y Lal Gai ν 721.3 (H-) thirty Oh Ν = Ζ l> Oh ° udd ϊ V 723.9 (H ⁺ ) 31 UD / O I O ° uCi Ϊ% r LaL g Ay V n? V 710.9 (N *) 32 • '—Ζ ..................... I1 ° A ^a / X A-xA ^' · \ o D Η ν ⁿ \ // 744.9 (n ¹ ) 33 o, ~~ / № ^{and <:} ι о АЧД 1V All rD> ⁿ </) 740.9 (ΙΓ)

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th ¹ 1n "and · ι · honor 'Pi!> η 34 '““ Ίί ............ ρ --------  (/ 728.9 (Η ^τ ) 35 Me ι ρ ° γ ^Ν ~ \ Α XV Αλα γΑαα 724.9 (Η ⁺ ) 36 o ΗΝ ^ ι ^ ΑΑ ι ίίΥνίν AAD o ^r 2gA? 794.9 (Η ⁺ ) 37 0, - ^ ΑθΜθ Н ^^ _m ^ А% ЭМе ₀ ΟγΝ-4 Η 0 ο ρ> Μ ^ 'Λ ο 2θΓ V 771.0 (Η *) 38 λΟο ην ^λ ^ ^α 'ν _ ό .. η _. 1 ρ ^υ Υ уДА V Л ^л Д <ΓΛ> ^Η / /) 710.9 (Η *) 39 LO ι Ο ^ο · ν ^Ν 4.ϊ1 Π V A _o l D u Αγν ^Η \ // 712.0 (Η ⁺ )

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- 227 012389

- 228 012389

- 229 012389

- 230 012389

Α ι ’b ··! 64 ΗΝ ULA % A L. d Л / γόη Ν '\ о (/ 658.9 (H ⁺ ) 65 ό ⁰¹ о> αχ у А О Ν '\ о н) \ 676.9 (H ⁺ ) 66 ην AAA ό o Ι O ° -ν ^Ν Α._Η A A 1 A L OH (l 609.0 (H ⁺ ) 67 "Asa about r 620.0 (H ⁺ ) 68 ⁰ / = \ // \! o 9 A A l D / \ ^he <O Ν '\ O (A 597.0 (H ⁺ ) 69 > \ L _y ..... <<g / s ^he 666.9 (H ⁺ )

Ν83-Ν84Α protease analysis.

Formation of complex Ν83 with Ν84Α-2

Recombinant Ν83 of the full length obtained with E.coN or Baculovirus was diluted to 3.33 μM with assay buffer and the material was transferred to an Eppendorf tube and placed in a water bath at 4 ° C in a refrigerator. An appropriate amount of N84Α-2 diluted to 8.3 mM with assay buffer was added to an equivalent volume of Ν83 in step 2.1.1 (conversion factor 3.8 mg / 272 µl assay buffer). The material was transferred to an Eppendorf tube and placed in a water bath at 4 ° C in a refrigerator.

After adjusting the system to 4 ° С, equal volumes of Ν83 and N84Α-2 solutions were combined in an Eppendorf tube and carefully mixed with a manual pipetting device; the mixture was kept for 15 min in a water bath at 4 ° С. The final concentrations in the mixture were 1.67 μM Ν83, 4.15 mM No. 4A-2 (2485-fold molar excess No. 4A-2).

After 15 minutes at 4 ° C, the Eppendorf tube No. 3 / No. 4A-2 was removed from the refrigerator and placed at room temperature in a water bath for 10 minutes. Material No. 3 / L84A-2 was separated without residue into the corresponding volumes and stored at -80 ° C (E.coN Ν83 acts at 2 nM in the analysis, aliquot of 25 μl. Baculovirus Ν83 acts at 3 nM in the study, aliquot of 30 μl) .

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Inhibition study N83.

Samples of the compounds were diluted to 10 mM in DMSO, then diluted to 2.5 mM (1: 4) in DMSO. Typically, the compounds were added to the assay plate at a concentration of 2.5 mM obtained by diluting the initial concentration to 50 μM by the inhibition assay curve. Compounds were sequentially diluted in assay buffer to obtain low concentration test solutions.

E.coI Zh3 / Zh4A-2 was diluted to 4 nM N83 (1: 417.5 1.67 μM source - 18 μl 1.67 μM source + 7497 μl assay buffer).

Baculovirus J3 / J4A-2 was diluted to 6 nM N83 (1: 278.3 1.67 μM source - 24 μl 1.67 μM source + 6655 μl assay buffer).

Using a manual multichannel pipetting device and avoiding the formation of bubbles in the plate, 50 μl of assay buffer was added to wells A01-H01 of a black Soz1ag 96-well polypropylene storage plate.

Using a multichannel manual pipetting device and avoiding the formation of bubbles in the plate, 50 μl of the diluted No. 3 / No. 4A-2 from step 2.2.6 was added to the wells A02-H12 of the tablet of step 2.2.7.

Using a multichannel manual pipetting device and avoiding the formation of bubbles in the plate, 25 μl of the wells in the plate for diluting the compounds of stage 2.2.5 were transferred to the corresponding wells of the analytical tablet of stage 2.2.8. The tips of the multichannel pipetting device varied for each row of portable compounds.

Using a multi-channel manual pipetting device and avoiding the formation of bubbles in the plate, the contents of the wells of the analytical plate of step 2.2.9 were mixed by suction and distribution of 35 of 75 μl in each well 5 times. The tips of the multichannel pipetting device varied for each row of portable compounds.

The tablet was covered with a polystyrene tablet lid and the tablet of step 2.2.10, containing the N83 protease and samples of the compounds, was previously aged for 10 minutes at room temperature.

While the tablet from step 2.2.11 was previously aged, the YET81 substrate was diluted in a 15 ml centrifuged propylene tube.

HET81 substrate was diluted to 8 μM (1: 80.75 646 μM source - 65 μl 646 μM source + 5184 μl assay buffer).

After the plate in step 2.2.11 was previously aged using a hand-held device, 25 μl of the substrate was added to all wells in the plate. The contents of all wells were quickly mixed, as in step 2.2.10, but by mixing 65 μl of 100 μl in the wells.

The tablets were read in a kinetic manner on a Mo1ci1ag OetKez 8res1gaMax Setin X8 tablet reader. Reader settings Reading time: 30 min, interval: 36 s, reproduction: 51, radiation λ: 335 nm, emission λ: 495 nm, boundary value: 475 nm, automix: disabled, calibration: 1 time,

PMT: high, radiation / well: 6,

Utach p1z: 21 or 28/51 depending on the length of the linearity of the reaction.

GS50 were determined using the empirical equation of a curve with four parameters, and recalculation of Κι using the following CT:

full length E.coI N83-2.03 μM;

the full length of the NL is N83-1.74 μM, where =ι = HS ₅₀ / (1+ [8] / Kt).

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Examples of activity.

A is 1C ₅₀ less than 10 μM, B is 1C ₅₀ less than 1 μM,

C is 1C ₅₀ less than 0.1 μM.

Compound Ν83 / Ν84Α-2 1C50 Compound Ν83 / Ν84Α-2 1C50 one FROM 35 FROM 2 FROM 36 FROM 3 FROM 37 FROM 4 FROM 38 FROM 5 FROM 39 FROM 6 FROM 40 FROM 7 FROM 41 FROM 8 FROM 42 FROM nine FROM 43 FROM 10 FROM 44 FROM eleven from 45 from 12 from 46 from thirteen from 47 from 14 from 48 from fifteen from 49 from sixteen from fifty from 17 from 51 from eighteen from 52 from nineteen g; 53 G ’ twenty FROM 54 from 21 FROM 55 from 22 FROM 56 from 23 FROM 57 from 24 FROM 58 from 25 FROM 59 BUT

26 FROM 60 BUT 27 FROM 61 BUT 28 from 62 IN 29th from 63 IN thirty from 64 IN 31 from 65 IN 32 from 66 IN 33 from 67 BUT 34 from 68 BUT 35 from 69 BUT

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Synthetic intermediates.

Some intermediates (intermediates) from synthesis schemes are included in embodiments of the invention.

Examples of useful intermediates are shown below.

where 0 is a central ring selected from

where the central ring may be unsubstituted or substituted by H, halogen, cyano, nitro, hydroxy, _C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl substituted with C _1-6 alkyl, C _1-6 alkoxy, substituted C _1-6 alkoxy, C ₆ or C ₁₀ -aryl, pyridinyl, pyrimidinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulfonamido, urea, thiourea, amido, keto, carboxyl, carbamyl, sulfide, sulfoxide, sulfone, amino, alkoxyamino, alkyloxyheterocyclyl, al ylamino, alkylcarboxy, carbonyl, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or spirocyclic cyclohexyl, or represents K ¹ -K ^2, where R ¹ represents C 1-6 alkyl, C 3-7 cycloalkyl, S4-10alkiltsikloalkil, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole or benzimidazole may be of up to three substituents ΝΚ ⁶ Κ ^7, halogen, cyano, nitro, hydroxy, C 1-6 alkyl, C _3- 7tsikloalkilov, C _4-10 alkylcycloalkyl, _C2-6 alkenyl, _C1-6 alkoxy, _hydroxy-C1-6 alkyl or C _1-6 alkyl, possibly substituted up to 5 fluorine atoms, C _1-6 alkoxy, possibly substituted up to 5 fluorine atoms; and K ² represents Η, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiazole, or benzimidazole, each of which may be substituted by one to three substituents ΝΚ ⁶ Κ ^7, halogen, cyano, nitro, hydroxy, C _1-6 alkyl, C _3- 7tsikloalkilov C ₄₁₀ alkylcycloalkyl, C _2-6 alkenyl, C _{1 -6} alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted with up to 5 fluorine atoms, C _1-6 alkoxy, optionally substituted with GOVERNMENTAL to 5 fluorine atoms;

K ⁴ represents H, C _1-6 alkyl, C _3- 7tsikloalkil, C _4-10 alkylcycloalkyl, phenyl or benzyl, said phenyl or benzyl can be substituted with from one to three halogen atoms, cyano, nitro, hydroxy, C _{1- 6} alkyl, C _3- 7tsikloalkilov, C _4-10 alkylcycloalkyl, _C2-6 alkenyl, _C1-6 alkoxy, hydroxy-C ₁₆ alkyls, C _1-6 alkyl optionally substituted with up to 5 fluorine atoms, C _1-6 alkoxy, possibly substituted with up to 5 fluorine atoms;

K ⁵ is C1-6 alkyl, C (O) Xk ⁶ K ⁷ , C (8) Xk ⁶ K ⁷ , -C (O) K ⁸ , C (O) OK ⁸ , 8 (O) 2K ^8, or ^ Ο ) ΟΗΚ ²¹ ΝΗΌΟ) Κ ²² ;

By ⁶ and R ⁷ each independently represent H, C _1-6 alkyl, C _3- 7tsikloalkil, C ₄ 10alkiltsikloalkil or phenyl, said phenyl may be substituted by one to three halogen atoms, cyano, nitro, hydroxy, C _{1 -6} alkyls, C _3-7 cycloalkyls, C _4-10 alkylcycloalkyls, C _2-6 alkenyls, C ₁ 6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl, possibly substituted up to 5 fluorine atoms, C 1-6 alkoxy, possibly substituted up to 5 fluorine atoms; or _K 6 and K ⁷ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

By ⁸ represents C _1-6 alkyl, C _3- 7tsikloalkil, C _4-10 alkylcycloalkyl, each of which may be substituted with from one to three times by halogen, cyano, nitro, hydroxy, C1-6 alkoxy, or phenyl; or

By ⁸ is a C ₆ or C ₁₀ -aryl which may be substituted by one to three halogen, cyano, nitro, hydroxy, C _1-6 alkyl, C _3- 7tsikloalkilov, C _4-10 alkylcycloalkyl, _C2-6 alkenyl, , C _1-

- 234 012389 ₆ alkoxy, hydroxy-C1 _-6 alkyl, Sc ₆ alkyl, possibly substituted up to 5 fluorine atoms, or C1 _-6 alkoxy, possibly substituted up to 5 fluorine atoms; or

By ⁸ represents a C1 _-6 alkyl group which may be substituted with up to 5 fluoro groups; or

K ⁸ represents a tetrahydrofuran ring bonded through the positions of the C ₃ or C ₄ tetrahydrofuran ring; or

K ⁸ is a tetrapyranyl ring bonded through the position of the C4-tetrapyranyl ring;

Υ represents -SOOK ^9, where R ⁹ represents a C1 _-6 alkyl;

p is 0 or 1;

V is selected from O, 8 or ΝΗ;

when V is selected from O or 8, W is selected from O, ΝΚ ^15, or SK ¹⁵ ;

when V represents ΝΗ, W is selected from ΝΚ ¹⁵ or IC ^15, where R ¹⁵ is H, S1_ ₆ alkyl, C _3-7 cycloalkyl, C _4- 1 ₀ alkylcycloalkyl or C1 _-6 alkyl which may be substituted by up to 5 fluorine atoms;

dashed line indicates a possible double bond;

By ²¹ is C1 _-6 alkyl, C _3-7 cycloalkyl, C _4- 1 ₀ alkylcycloalkyl, each of which may be substituted with from one to three times by halogen, cyano, nitro, hydroxy, C ^ ₆ alkoxy, C ^ ₆ alkyl optionally substituted with up to 5 fluorine atoms, or phenyl; or

K ²¹ is C ₆ or Cn-aryl, which may be substituted by one to three atoms of halogen, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _{4-1 0} alkylcycloalkyl, C _2-6 alkenyls, _C1-6 alkoxy, hydroxy _C1-6 alkyls, Sc ₆ alkyls, optionally substituted with up to 5 fluorine atoms, Sc ₆ alkoxy, possibly substituted with up to 5 fluorine atoms; or

K ²¹ represents pyridinyl, pyrimidinyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy or thiophenoxy and

By ²² is C1 _-6 alkyl, C _3-7 cycloalkyl or C _4- 1 ₀ alkylcycloalkyl, each of which may be substituted with from one to three times by halogen, cyano, nitro, hydroxy, C1 _-6 alkyl optionally substituted by up to 5 fluorine atoms, or phenyl.

The compound having the formula

where K ⁴ represents H, Sc ₆ alkyl, C _3-7 cycloalkyl, C _{4-1 0} alkylcycloalkyl, phenyl or benzyl, said phenyl or benzyl may be substituted by one to three atoms of halogen, cyano, nitro, hydroxy, C1 _{- 6} alkyls, C _3-7 cycloalkyls, C ₄ 1 ₀ alkylcycloalkyl, C _2-6 alkenyl, C ^ ₆ alkoxy, gidroksiS1 _-6 alkyl, C1 _-6 alkyl optionally substituted with up to 5 fluorine atoms, C1 _-6 alkoxy, optionally substituted with up to 5 fluorine atoms;

K ⁵ is H, Sc6alkyl, C (O) NK ⁶ K ⁷ , C (8) NK ⁶ K ⁷ , -C (O) K ⁸ , C (O) OK ⁸ , 8 (O) 2K ⁸ or (CO ) SNK ²¹ OH (CO) K ²² ;

_K 6 and K ⁷ each independently represent H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl or phenyl, said phenyl may be substituted with one to three atoms of halogen, cyano, nitro, hydroxy , C _1-6 alkyls, C _3-7 cycloalkyls, C _4-10 alkylcycloalkyls, C _2-6 alkenyls, C1-6 alkoxy, hydroxy- _C1-6 alkyls, _C1-6 alkyls, possibly substituted with up to 5 fluorine atoms, C1-6 alkoxy, possibly substituted up to 5 fluorine atoms; or _K 6 and _K ⁷ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

K ⁸ represents C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, each of which may be substituted one to three times by halogen, cyano, nitro, hydroxy, C1-6 alkoxy or phenyl; or

K ⁸ is C6 or C10 aryl, which may be substituted by one to three halogens, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyls, C _4-10 alkylcycloalkyls, C _2-6 alkenyls, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl, possibly substituted up to 5 fluorine atoms, or C1-6 alkoxy, possibly substituted up to 5 fluorine atoms; or

K ⁸ is C 1-6 alkyl which may be substituted with up to 5 fluorine groups; or

K ⁸ represents a tetrahydrofuran ring linked through the positions of the C3 or C4 tetrahydrofuran ring; or

K ⁸ is a tetrapyranyl ring bonded through the position of a C4-tetrapyranyl

- 235 012389 rings;

Υ represents —COOB ⁹ , where B ⁹ represents C _1-6 alkyl;

p is 0 or 1;

V is selected from OH, 8H or ΝΗ ₂ ;

dashed line indicates a possible double bond;

B ²¹ represents C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, each of which may be substituted one to three times by halogen, cyano, nitro, hydroxy, C _1-6 alkoxy, C _{1- 6 by} alkyl, possibly substituted with up to 5 fluorine atoms, or phenyl; or

B ²¹ represents C ₆ or C ₁₀ aryl, which may be substituted by one to three atoms of halogen, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyls, C _4-10 alkylcycloalkyls, C _{2- 6} alkenyls, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl, which may be substituted with up to 5 fluorine atoms, C ₁ 6 alkoxy, possibly substituted with up to 5 fluorine atoms; or

B ²¹ is pyridinyl, pyrimidinyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy or thiophenoxy and

B ²² is C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkylcycloalkyl, each of which may be substituted one to three times with halogen, cyano, nitro, hydroxy, C _1-6 alkyl, optionally substituted with 5 fluorine atoms, or phenyl.

Metabolites.

Some embodiments of the invention are metabolites of compounds of the formulas Ι-ΧΙΧ. In some cases, the metabolites themselves are compounds of the formulas Ι-ΧΙΧ.

Examples of beneficial metabolites are given below.

Metabolites of compounds of the formulas Ι-ΧΙΧ can be identified using the following procedures.

1. Suspend the hepatocytes in the KNV medium (Krzb-Nezbek buffer @ pH 7.3) at a density of approximately 2x10 ⁶ viable hepatocytes per ml.

2. Prepare stock solutions (20 μM) of 1TM # 187 (a strong inhibitor of N83 protease) and GGM # 191 in KN buffer.

3. Add 50 μl of 1TM # 187 or 1TM # 191 to 50 μl of hepatocyte suspension in a 96-well polypropylene plate. The final concentration of the substrate is 10 μM (~ 7 μg / ml).

4. Soak the tablet at 37 ° C, 5% CO ₂ environment saturated with moisture for 0 to 2 hours.

5. Stop the reaction by adding 100 μl of acetonitrile and shake the plate at 700 rpm for 30 s.

6. Immediately place the plate in a centrifuge (1,500 xd) and allow it to rotate for 10 minutes in order to centrifuge the denatured hepatocytes.

7. Transfer 180 μl of the supernatant to another plate.

8. Combine the contents of the wells, evaporate the solvent with nitrogen Ν ₂ at 37 ° C, dissolve the precipitate in 75/25 water / acetonitrile by volume and analyze by chromatography-mass spectrometry.

Since the present invention has been drawn up with reference to specific embodiments of the invention, one skilled in the art will appreciate that various changes can be made and equivalents can be used without departing from the true spirit and scope of the claims of this invention. Additionally, many modifications can be made in order to adapt to a specific situation, material, mixture of chemically related substances, process, stage or stages of the process for the purpose, nature and scope of the claims of the present invention. All such modifications are considered to be included in the scope of the claims indicated by the attached claims.

Claims (213)

Where O is a central ring selected from where the central ring may be unsubstituted or substituted with halogen, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, phenyl, thiazolyl, C (O) INSN ₂ CH3, C (O) OH, OC1ES1ΕΧΙ 1 (C | _ ₃ alkyl), OCH ^ H ^ SczalkylU, C ₂ -alkoxy containing imidazolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, CH ₂ CH ₂ U (CH ₃ as a substituent) ) ₂ , C (O) OCH ₂ CH ₃ , spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl or spirocyclic im cyclohexyl, or 0 represents K ¹ -K ² , where K ¹ represents phenyl, pyridine, furan, thiophene, thiazole, pyrazole, naphthyl, quinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole or benzimidazole, each of which may contain substituents from one to three tax codes. ⁶ K. ⁷ , halogen atoms, cyano, C ₁ . ₆ alkyls, C _1-6 alkoxy, C ₁ . ₆ alkyls, possibly substituted with up to 5 fluorine atoms, or C _1-6 alkoxy, possibly substituted with up to 5 fluorine atoms; and K ² represents H, or phenyl, or imidazole, each of which may contain from one to three halogen atoms as substituents; K ⁴ represents H; K ⁵ represents H, C (O) \ K ^: 1B, -C (O) K ⁸ , C (O) OK ⁸ or (CO) SNK ² ^ H (CO) K ²² ; K ⁶ and K ⁷ each independently represent H, C _1-6 alkyl, C _3-7 cycloalkyl or phenyl, said phenyl may contain from one to three halogen, cyano, C ₁ atoms as substituents. ₆ alkyls, C ₁ . ₆ alkyls, possibly substituted with up to 5 fluorine atoms, or C _1-6 alkoxy, which can be substituted with up to 5 fluorine atoms; or K ⁶ and K ⁷ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; K ⁸ represents C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, wherein said C _1-6 alkyl may contain phenyl as a substituent; or K ⁸ is C _1-6 alkyl, optionally substituted with up to 5 groups containing fluorine; or K ⁸ represents a tetrahydrofuran ring bonded through the positions of a C ₃ or C4 tetrahydrofuran ring; or K ⁸ is a tetrahydropyran ring linked through position C4 tetrahydropyran ring; Υ represents —C (O) IN8 (O) ₂ K ⁹ , where K ⁹ represents C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl; or K ⁹ represents phenyl or naphthyl, each of which may contain up to three substituents selected from halogen, cyano, nitro, C _1-6 alkyl or C _1-6 alkoxy; or K ⁹ is C _1-6 alkyl, optionally substituted with up to 5 fluorine containing groups, No.K. ⁶ TO ⁷ or HC. ^1a K ^1b ; or K ⁹ represents a monocyclic heteroaromatic ring containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, which may be substituted up to two times by halogen; or Υ represents a carboxyl group or a pharmaceutically acceptable salt, solvate or prodrug thereof; Where K ^1a and K ^1b , each independently, are H, C _1-6 alkyl or C _3-7 cycloalkyl, which may be substituted one to three times by cyano, or K ^1a and K ^1b each independently represent H, C ₆ aryl, which may contain from one to three halogen atoms, cyano, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 alkyl as substituents possibly substituted with up to 5 fluorine atoms, or K ^1a and K ^1b , each independently, are H or 5-, 6- or 7-membered saturated or - 237 012389 unsaturated heterocyclic molecule containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, or ΝΒ ^ Β ¹ ' ¹ is an alkyl cyclic secondary amine containing from 3 to 6 members, which may contain in the ring from one to three heteroatoms selected from the group consisting of nitrogen and oxygen; p is 0 or 1; V is selected from O, 8 or ΝΗ; when V is selected from O or 8, V is selected from O or ΝΒ ¹⁵ ; when V represents ΝΗ, V represents ΝΒ ¹⁵ , where B ¹⁵ represents H; dashed line indicates a possible double bond; In ²¹ represents a C1 _-6 alkyl or _C3-7 cycloalkyl, and At ²² is C1 _-6 alkyl; provided that the compounds having the formula I do not include a compound having the formula II, III or IV II III IV where (aa) B ¹ and B ² each independently represent H, halogen, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy C1-6 alkyl or C1-6 alkyl, possibly substituted with up to 5 fluorine atoms, C1-6 alkoxy, possibly substituted with up to 5 fluorine atoms, C6 or C10-aryl, pyridinyl, pyrimidinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, 8O ^ В ⁶ В ⁷ , central nervous system (О) CV ⁶ В ⁷ , ΝΗ ((8) ΝΒ ⁶ Β ⁷ , С (ОЖ ⁶ В ⁷ , ΝΒ ⁶ Β ⁷ , С (О) В ⁸ , С (О) ОВ ⁸ , CNS (O) B ⁸ , CNS (O) OV ⁸ , ⁸ Gb ⁸ , Ν ^^^ Β ⁸ , (CH2 ^ B ⁶ V ⁷ , O (CH2 ^ B ⁶ V ⁷ or O (CH 2) _η Β ⁹ ; ⁹ wherein B represents -imidazo yl or pyrazolyl, said thienyl, pyrimidinyl, furanyl, thiazolyl and oxazolyl in the definition of B ¹ and B ² may be substituted by one to two halo, cyano, nitro, hydroxy, C1-6alkyl, C3-7cycloalkyl, S4-10alkiltsikloalkilov , C2-6 alkenyl, C1-6 alkoxy, hydroxyC1-6 alkyl, C1-6 alkyl, possibly substituted with up to 5 fluorine atoms, or C1-6 alkoxy, possibly substituted with up to 5 fluorine atoms; the specified C6 or C; 0-aryl, pyridinyl, phenoxy and thiophenoxy in the definition of B ¹ and B ² may contain as substituents from one to three halogen atoms, cyano, nitro, hydroxy, C1-6 alkyl, C _3-7 cycloalkyls, C _{4-1 0} alkylcycloalkyls, C _2-6 alkenyls, _C1-6 alkoxy, hydroxy _C1-6 alkyl, _C1-6 alkyl, possibly substituted with up to 5 fluorine atoms, or _C1-6 alkoxy optionally substituted with up to 5 fluorine atoms; (B) m = 0, 1 or 2; (ss) A ⁴ represents H, C1 _-6 alkyl, C _3-7 cycloalkyl, C _4- 1 ₀ alkylcycloalkyl, phenyl or benzyl, said phenyl or benzyl can be substituted with from one to three halogen atoms, cyano, nitro, hydroxy C1 _-6 alkyls, C _3-7 cycloalkyls, C ₄ 1 ₀ alkylcycloalkyl, _C2-6 alkenyl, C1 _-6 alkoxy, hydroxy-C1 _-6 alkyl, C1 _-6 alkyl optionally substituted with up to 5 fluorine atoms, or _C1-6 alkoxy, optionally substituted with up to 5 fluorine atoms; (s) B ⁵ represents H, C1-6 alkyl, C (O) XB'B ⁷ , €. '(8) ΝΒ'Β ⁷ , -C (O) B ⁸ , C (O) OB ⁸ , 8 ( O) 2B ⁸ or (CO) START ² ^ H (CO) B ²² ; (her) B ⁶ and B ⁷ each independently represent H, C; _-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl or phenyl, said phenyl may contain as substituents from one to three halogen atoms, cyano, nitro, hydroxy, C1-6 alkyls, C3-7 cycloalkyls, C4-10 alkylcycloalkyls, C _2-6 alkenyls, hydroxy- _C1-6 alkyl or _C1-6 alkyl, possibly substituted with up to 5 fluorine atoms, - 238 012389 C _1-6 alkoxy, optionally substituted with up to 5 fluorine atoms; or K ⁶ and K ⁷ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; (ίί) K ⁸ represents C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, each of which may be substituted one to three times by halogen, cyano, nitro, hydroxy, C _1-6 alkoxy, or phenyl; or K ⁸ represents C6 or C10-aryl, which may contain as substituents from one to three atoms of halogen, cyano, nitro, hydroxy, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, C _{2- 6} alkenyls, C _1-6 alkoxy, hydroxy-C _1-6 alkyl or C _1-6 alkyl, possibly substituted with up to 5 fluorine atoms, C1-6 alkoxy, possibly substituted with up to 5 fluorine atoms; or K ⁸ is C 1-6 alkyl optionally substituted with up to 5 groups containing fluorine; or K ⁸ represents a tetrahydrofuran ring bonded through the positions of the C3 or C4 tetrahydrofuran ring; or K ⁸ represents a tetrahydropyranyl ring bonded through the position of the C4-tetrahydropyranyl ring; (dd) Υ represents ^^ Ν ^^) ^ ⁹ , where K ⁹ represents C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, each of which can be substituted from one to three times by halogen, cyano, nitro, hydroxy C1-6 alkoxy or phenyl; or K ⁹ represents C6 or C10-aryl, which may contain as substituents from one to three halogen atoms, cyano, nitro, hydroxy, C1-6 alkyl, C _3-7 cycloalkyl, C _4-1 alkyl alkyl cycloalkyl, C _2-6 alkenyls, C _1-6 alkoxy, hydroxy- _C1-6 alkyl or _C1-6 alkyl, possibly substituted with up to 5 fluorine atoms, C1-6 alkoxy, possibly substituted with up to 5 fluorine atoms; or K ⁹ is C1-6 alkyl optionally substituted with up to 5 fluorine containing groups; ΝΕ ⁶ ^ or (CO) OH; or K ⁹ represents a heteroaromatic ring which can be substituted up to two times with halogen, cyano, nitro, hydroxyl or C1-6 alkoxy; or Υ represents a carboxyl group or a pharmaceutically acceptable salt, solvate or prodrug thereof; (HH) K ¹⁰ and K ¹¹ each independently represent H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or C10-aryl, hydroxy-C1-6 alkyl, C1-6 alkyl, optionally substituted with up to 5 fluorine atoms , (SND ^^ K ⁷ , (CH2) _and C (O) OK ¹⁴ , where K ¹⁴ represents H, C _1-6 alkyl, C _3-7 cycloalkyl, C4-10 alkylcycloalkyl, each of which can be substituted from one up to three times by halogen, cyano, nitro, hydroxy, C1-6 alkoxy or phenyl, or a ¹⁴ is a C6 or C10 aryl which is optionally substituted by one to three halogen atoms, cyano, nitro, hydroxy, S1-6a Kil, C3-7cycloalkyls, C4-10alkylcycloalkyls, C2-6alkenyls, C1-6alkoxy, hydroxy-C1-6alkyls, C1-6alkyls, possibly substituted with up to 5 fluorine atoms, or C1-6alkoxy, possibly substituted with up to 5 fluorine atoms; said C6 or C10-aryl in the definition of K ¹⁰ and K ¹¹ may contain from one to three atoms of halogen, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy- as substituents _C1-6 alkyl, _C1-6 alkyl, optionally substituted with up to 5 fluorine atoms, or _C1-6 alkoxy, optionally substituted with up to 5 fluorine atoms; or K ¹⁰ and K ^11, together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or K ¹⁰ and K ¹¹ together represent O; (ίί) ρ = 0 or 1; (I) K ¹² and K ¹³ each independently represent H, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or C10-aryl, hydroxy-C1-6 alkyl, C1-6 alkyl, optionally substituted with up to 5 fluorine atoms , (SND ^^ K ⁷ , (CH2) _and C (O) OK ¹⁴ , where K ¹⁴ represents H, C _1-6 alkyl, C _3-7 cycloalkyl, C4-10 alkylcycloalkyl, each of which can be substituted from one up to three times by halogen, cyano, nitro, hydroxy, C1-6 alkoxy or phenyl, or a ¹⁴ is a C6 or C10 aryl which is optionally substituted by one to three halogen atoms, cyano, nitro, hydroxy, S1-6al sludges, C3-7cycloalkyl, S4-10alkiltsikloalkilov, S2-6alkenilov, C1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl optionally substituted with up to 5 fluorine atoms, or C _1-6 alkoxy optionally substituted with up to 5 fluorine atoms; said C6 or C10-aryl in the definition of K ¹² and K ¹³ may contain as substituents from one to three halogen atoms, cyano, nitro, hydroxy, C1-6 alkyls, C3-7 cycloalkyls, C4-10 alkylcycloalkyls, C2-6 alkenyls, C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl, possibly substituted with up to 5 fluorine atoms, or C1-6 alkoxy, possibly substituted with up to 5 fluorine atoms; or K ¹² and K ¹³ together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or K ¹² and K ¹³ , each independently, are C _1-6 alkyl optionally substituted with (CH 2) and OK ⁸ ; (kk) K ²⁰ represents H, _C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or C10-aryl, hydroxy-C _1-6 alkyl, C _1-6 alkyl, optionally substituted with up to 5 fluorine atoms, (ΟΗ ^ ΝΕ ⁶ ^, (CH ₂ ) _and C (O) OK ¹⁴ , where K ¹⁴ represents H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, each of which can be substituted one to three times by halogen, cyano, nitro, hydroxy, C _1-6 alkoxy or phenyl; or K ¹⁴ represents C6 or C10 aryl, which may contain from one to three halogen, cyano, nitro atoms as substituents , hydroxy, C1-6alkyls, Sz-7cy cloalkyls, C4-10alkylcycloalkyls, C2-6alkenyls, C1-6alkoxy, hydroxy-C1-6alkyls, C1-6alkyl, possibly substituted with up to 5 fluorine atoms, C1-6alkoxy, possibly substituted with up to 5 fluorine atoms; specified C6 or C10-aryl in the definition K ¹² and K ¹³ can be substituted by one to three halogen atoms, cyano, nitro, hydroxy, C1-6 alkyl, _C3-7 cycloalkyl, C4 _-10 alkylcycloalkyl, C2 _-6 alkenyl, _C1-6 alkoxy, hydroxy -C _1-6 alkyl, C _1-6 alkyl, possibly substituted up to 5 fluorine atoms, C _1-6 alkoxy, possibly substituted up to 5 fluorine atoms; (11) n = 1-4; (tm) V is selected from O, 8 or ΝΗ; (PP) when V represents O or 8, choose from O, ΝΚ ¹⁵ or SK ¹⁵ ; when V represents ΝΗ, selected from ΝΚ ¹⁵ or IC ^15, where R ¹⁵ represents H, C _1-6 alkyl, C _3-7 cycloalkyl, C4 _-10 alkylcycloalkyl or C _1-6 alkyl optionally substituted with up to 5 atoms fluoride ra; (oo) dashed line means a possible double bond; (pp) K ²¹ represents C _1-6 alkyl, C _3-7 cycloalkyl, alkylcycloalkyl, C4 _-10, each of which may be substituted with from one to three times by halogen, cyano, nitro, hydroxy, C _1-6 alkoxy, C _1-6 alkyl, optionally substituted with up to 5 fluorine atoms, or phenyl; or By ²¹ is C ₆ or C ₁₀ -aryl which may be substituted by one to three halogen atoms, cyano, nitro, hydroxy, C _1-6 alkyls, C _3-7 cycloalkyls, C4 _-10 alkylcycloalkyl, C2 _{- 6} alkenyls, C _1-6 alkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkyl, possibly substituted with up to 5 fluorine atoms, C _1-6 alkoxy, possibly substituted with up to 5 fluorine atoms; or By ²¹ is pyridinyl, pyrimidinyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy and (IC) ^22, K represents C _1-6 alkyl, C _3-7 cycloalkyl, alkylcycloalkyl, C4 _-10, each of which may be substituted one to three times with halogen, cyano, nitro, hydroxy, C _1-6 alkyl, optionally substituted with up to 5 fluorine atoms, or phenyl; (gg) Ζ is a system of condensed or bonded aryl or heteroaryl rings. 2. The compound according to claim 1, where the Central ring is a 3. Connection by 4. Connection by 5. Connection by claim 1, where the Central ring is a claim 1, where the Central ring is a claim 1 of the formula - 240 012389 6. The compound according to claim 1 of formula 1b - 241 012389 10. The compound according to claim 1 of the formula ΙΓ - 242 012389 15. The compound according to claim 1 of formula k 16. The compound according to claim 1, where Υ represents —C (O) MH8 (O) ₂ I ⁹ , where I ^{9 is} selected from the group consisting of C1.6 alkyl, C3.7 cycloalkyl, C4.10 alkylcycloalkyl, and NYa ^1a I ^1b , where I ^1a and I ^1b , each independently, represent H, C1. ₆ alkyl or C ₃ . ₇ cycloalkyl. 17. The compound according to claim 2, where Υ represents —C (O) MH8 (O) ₂ I ⁹ , where I ^{9 is} selected from the group consisting of C1.6 alkyl, C3.7 cycloalkyl, C4.10 alkylcycloalkyl, and NYa ^1a I ^1b , where I ^1a and I ^1b , each independently, represent H, C1. ₆ alkyl or C ₃ . ₇ cycloalkyl. 18. The compound according to claim 3, where Υ represents —C (O) MH8 (O) ₂ I ⁹ , where I ^{9 is} selected from the group consisting of C1.6 alkyl, C3.7 cycloalkyl, C4.10 alkylcycloalkyl, and NYa ^1a I ^1b , where I ^1a and I ^1b , each independently, represent H, C1. ₆ alkyl or C ₃ . ₇ cycloalkyl. 19. The compound according to claim 4, where Υ represents —C (O) MH8 (O) ₂ I ⁹ , where I ^{9 is} selected from the group consisting of C1.6 alkyl, C3.7 cycloalkyl, C4.10 alkylcycloalkyl, and NYa ^1a I ^1b , where I ^1a and I ^1b , each independently, represent H, C1. ₆ alkyl or C ₃ . ₇ cycloalkyl. 20. The compound according to claim 1, where the substituents at C ₁₃ -C ₁₄ double bonds are in the cis position. 21. A pharmaceutical composition for treating or preventing liver diseases, comprising: a) an effective amount of a compound according to claim 1 and b) a pharmaceutically acceptable carrier. 22. The pharmaceutical composition according to item 21, characterized by the absence of alcohols and polyols. 23. The pharmaceutical composition according to claim 22, characterized by the absence of sugar alcohols and poly (ethylene glycol) (PEG). 24. The pharmaceutical composition according to item 21 in aqueous form, characterized by the absence of an excipient that reduces the polarity of this aqueous form. 25. The pharmaceutical composition according to item 21 in the form of tablets. 26. The pharmaceutical composition according to item 21 in the form of a solid tablet in the form of a capsule. 27. The pharmaceutical composition according to item 21 in the form of a capsule. 28. A method of treating hepatitis C virus infection in a patient, comprising administering to the patient an effective amount of a compound according to claim 1. 29. The method of claim 28, wherein said effective amount is sufficient to provide a sustained viral response. 30. The method according to p, where the method also includes introducing the patient an effective amount of a nucleoside analogue. 31. The method according to clause 30, where the nucleoside analogue is selected from ribavirin, levovirin, viramidine, any L-nucleoside and isorbine. 32. The method according to p, where the method also includes introducing the patient an effective amount of an inhibitor of N85B RNA-dependent RNA polymerase. 33. The method according to p, where the method also includes introducing the patient an effective amount of thymosin-α. 34. The method according to p, where thymosin-α is administered subcutaneously 2 times a week in an amount of from about 1.0 to 1.6 mg. 35. The method according to p, where the method also includes introducing the patient an effective amount of interferon-gamma (IFN-γ). 36. The method according to clause 35, where IFN-γ is administered subcutaneously in an amount of from about 10 to 300 μg. 37. The method according to p, where the method also includes introducing the patient an effective amount of interferon-alpha (IFN-α). 38. The method according to clause 37, where IFN-α is a mono-PEGylated (30 kDa, linear) consensus IFN-α, administered at intervals of every 8 days to every 14 days. 39. The method according to clause 37, where IFN-α is a mono-PEGylated (30 kDa, linear) consensus IFN-α, administered 1 time every 7 days. 40. The method according to clause 37, where IFN-α is a GNΡEJAΟN consensus IFN-α. - 243 012389 41. The method of claim 28, further comprising administering an effective amount of an agent selected from 3'-azidothymidine, 2 ', 3'-dideoxyinosine, 2', 3'-dideoxycytidine, 2,3-didehydro-2 ', 3'-dideoxythymidine , combivir, abacavir, adefovir, dipoxyl, cidofovir and an inosine monophosphate dehydrogenase inhibitor. 42. A method for treating liver fibrosis in a patient, comprising administering to the patient an effective amount of a compound according to claim 1. 43. The method according to § 42, where the method also includes introducing the patient an effective amount of a nucleoside analogue. 44. The method according to item 43, where the nucleoside analogue is selected from ribavirin, levovirin, viramidine, any L-nucleoside and isotorbine. 45. The method according to § 42, where the method also comprises administering to the patient an effective amount of a Ν85Ε RNA-dependent RNA polymerase inhibitor. 46. The method according to § 42, where the method also includes administering to the patient an effective amount of thymosin-α. 47. The method according to item 46, where thymosin-α is administered subcutaneously 2 times a week in an amount of from about 1.0 to 1.6 mg. 48. The method according to § 42, where the method also includes administering to the patient an effective amount of interferon-gamma (IFN-γ). 49. The method according to p, where IFN-γ is administered subcutaneously in an amount of from about 10 to 300 μg. 50. The method according to § 42, where the method also includes administering to the patient an effective amount of interferon-alpha (IFN-α). 51. The method of claim 50, wherein IFN-α is a mono-PEGylated (30 kDa, linear) consensus IFN-α, administered at intervals of every 8 days to every 14 days. 52. The method according to item 50, where IFN-α is a mono-PEGylated (30 kDa, linear) consensus IFN-α, administered 1 time every 7 days. 53. The method of claim 50, wherein IFN-α is an INP-CXN consensus IFN-α. 54. The method according to § 42, further comprising administering an effective amount of an agent selected from 3'-azidothymidine, 2 ', 3'-dideoxyinosine, 2', 3'-dideoxycytidine, 2,3-didehydro-2 ', 3'-dideoxythymidine , combivir, abacavir, adefovir, dipoxyl, cidofovir and an inosine monophosphate dehydrogenase inhibitor. 55. A method of increasing liver function in a patient with hepatitis C virus infection, comprising administering to the patient an effective amount of a compound according to claim 1. 56. The method of claim 55, wherein the method also comprises administering to the patient an effective amount of a nucleoside analogue. 57. The method according to p, where the nucleoside analogue is selected from ribavirin, levovirin, viramidine, any L-nucleoside and isatorbin. 58. The method of claim 55, wherein the method also comprises administering to the patient an effective amount of an Ν85Ε RNA-dependent RNA polymerase inhibitor. 59. The method of claim 55, wherein the method also comprises administering to the patient an effective amount of thymosin-α. 60. The method according to § 59, where thymosin-α is administered subcutaneously 2 times a week in an amount of from about 1.0 to 1.6 mg. 61. The method of claim 55, wherein the method further comprises administering to the patient an effective amount of interferon-gamma (IFN-γ). 62. The method according to p, where IFN-γ is administered subcutaneously in an amount of from about 10 to 300 μg. 63. The method of claim 55, wherein the method also comprises administering to the patient an effective amount of interferon-alpha (IFN-α). 64. The method according to item 63, where IFN-α is a mono-PEGylated (30 kDa, linear) consensus IFN-α, administered at intervals of every 8 days to every 14 days. 65. The method according to item 63, where IFN-α is a mono-PEGylated (30 kDa, linear) consensus IFN-α, administered 1 time every 7 days. 66. The method of claim 63, wherein the IFN-α is an INP-CXN consensus IFN-α. 67. The method of claim 55, further comprising administering an effective amount of an agent selected from 3'-azidothymidine, 2 ', 3'-dideoxyinosine, 2', 3'-dideoxycytidine, 2,3-didehydro-2 ', 3'-dideoxythymidine , combivir, abacavir, adefovir, dipoxyl, cidofovir and an inosine monophosphate dehydrogenase inhibitor. - 244 012389 68. A compound having the formula XI wherein: a) K ^1a and R ^1b each independently represent H, C _1-6 alkyl or C ₃ _7tsikloalkil which may be substituted with from one to three times with cyano, or K ^1a and K ^1b , each independently, are H, C ₆ aryl, which may contain from one to three halogen, cyano, C ₁ atoms as substituents. ₆ alkyl, C _1-6 alkoxy or C ₁ . ₆ alkyls, possibly substituted with up to 5 fluorine atoms, or K ^1a and K ^1b , each independently, are H or a 5-, 6- or 7-membered saturated or unsaturated heterocyclic molecule containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, or NI ^1a To ^1b represents an alkyl cyclic secondary amine containing from 3 to 6 members, which may contain from one to three heteroatoms in the ring selected from the group consisting of nitrogen and oxygen; b) W represents O or XII; c) V is selected from O, 8 or XII; 4) when V is selected from O or 8, W is selected from O or ΝΚ ¹⁵ ; when V is OH, W is ΝΚ ¹⁵ , where K ¹⁵ is H; e) K ² is a bicyclic secondary amine of the structure where K ²¹ and K ²² each independently represent H, halogen, cyano, hydroxy, C1.6 alkyl, 1.6 alkoxy, C1.6 alkyl, possibly substituted with up to 5 fluorine atoms, thiazolyl, С (О) НК ⁶ К ⁷ , ΝΚ ⁶ Κ ⁷ , С (О) ОК ⁸ or МНС (О) К ⁸ ; said thiazolyl in the definition of K ²¹ and K ²² may contain C1-6 alkyl as a substituent; K ¹⁰ 'and K ¹¹ each independently represent H or C _1-6 alkyl or _K 10 and K ¹¹ together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; p is 0 or 1; _K 12 and K ¹³ each independently represent H or (CH ^ pNK'K ⁷ ; K ²⁰ represents H; n = 0-4; _K 6 and K ⁷ each independently represent H, C ₁ . ₆ alkyl or C ₃ .7 cycloalkyl or _K 6 and K ⁷ together with the nitrogen to which they are attached form piperidinyl, piperazinyl or morpholinyl; or K ² represents K ^2a K ^2b when W XII and ν ^, where K ^2a represents phenyl, pyridine, furan, thiophene, thiazole, pyrazole, naphthyl, quinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole or benzimidazole, each of which may contain from one to three XK ^2c K ²⁴ atoms as substituents halogen, cyano, C ₁ . ₆ alkyls, C ₁ . ₆ alkoxy, C ₁ . ₆ alkyls, possibly substituted with up to 5 fluorine atoms, or C ₁ . ₆ alkoxy, possibly substituted with up to 5 fluorine atoms; K ^2b represents H, phenyl or imidazole, each of which may contain from one to three halogen atoms as substituents; said K ^2c and K ²⁴ each independently represent H or C ₁ . ₆ alkyl or - 245 012389 K ^2c and K ^2a, together with the nitrogen to which they are attached, form morpholinyl; ί K ⁴ represents H; d) K ⁵ represents H, ('(Ο) ΝΙ \ Ί \ ⁷ , -C (O) K ⁸ or C (O) OK ⁸ ; j) K ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl or C _4-10 alkylcycloalkyl, wherein said C _1-6 alkyl may contain phenyl as a substituent; and 1) A dashed line indicates a possible double bond. 69. The compound of claim 68 having the formula XII wherein (a) K ^1a and R ^1b each independently represent H, C _1-6 alkyl, or C _3-7 sch1kloalkil _4- 1 ₀ alkilsch1kloalkil, each of which may contain as substituents from one to three atoms of halogen, cyano, nitro, C _1-6 alkoxy, amido or phenyl, or K ^1a and K ^1b , each independently, represent H or ₅ ^ Ν m B ^1s where K ^1s represents Η, or No.K. ^1a K ^1b represents an alkyl cyclic secondary amine containing from 3 to 6 members, which may have from one to three heteroatoms in the ring selected from the group consisting of nitrogen and oxygen; (b) K ²¹ and K ²² each independently represent H, halogen, cyano, hydroxy, C _1-3 alkyl, C1-3 alkoxy; (c) K ⁵ represents H, ('(Ο) ΝΙ \ Ί \ ⁷ , C (O) K ⁸ or C (O) OK ⁸ ; (ά) K ⁶ and K ⁷ each independently represent H, C _1-6 alkyl or C _3-7 cycloalkyl; (e) K ⁸ is C _1-6 alkyl, C _3-7 alkaloalkyl, C _4-10 alknocloalkyl or 3-tetrahydrofuryl; (ί) K ¹⁰ and K ¹¹ each independently represent H or C _1-3 alkyl or K ¹⁰ and K ^11, together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (e) K ¹² and K ¹³ each represent H and (d) the dashed line indicates a possible double bond. - 246 012389 70. The compound according to p, having the formula ΧΙΙΙ "? ^one Ν— / o about Ος ;. .......... <, о _{Л Л} у \? - ΝΗ ₄ | ί η5 I М / У. yx °, <A, th λ7— / \ ......... / d "1st xm where (a) ^{1a 1b} and B each independently represent H, C1 _-6 alkyl, _C3-7 cycloalkyl or S4-10alkiltsikloalkil, each of which may contain as substituents from one to three halogen atoms, cyano, nitro, C1-6 alkoxy, amido, or phenyl, or B ^1a and B ^1b each independently represent H or where B ^1c represents H, or HB ^1a B ^1b is an alkyl cyclic secondary amine containing from 3 to 6 members, which may have from one to three heteroatoms in the ring selected from the group consisting of nitrogen and oxygen; (b) B ²¹ and B ²² each independently represent H, halogen, cyano, hydroxy, C _{| -3} alkyl, C1 _-3 alkoxy; (c) B ⁵ represents H, C (O ^ B ⁶ B ⁷ , C (O) B ⁸ or C (O) OB ⁸ ; (b) B ⁶ and B ⁷ each independently represent H, C1 _-6 alkyl or _C3-7 cycloalkyl; (e) B ⁸ is C _3-6 alkyl, C _3-7 cycloalkyl, C ^ alkylcycloalkyl or 3-tetrahydrofuryl; (ί) A dashed line indicates a possible double bond. 71. The compound of claim 68 having the formula ΧΙν wherein (a) ^{1a 1b} and B each independently represent H, C1 _-6 alkyl or _C3-7 cycloalkyl which may be substituted by from one to three cyano , or B ^1a and B ^1b each independently represent H or where B ^1c represents H, or HB ^{1a to 1b} is an alkyl cyclic secondary amine containing from 3 to 6 members, which may contain from one to three heteroatoms in the ring selected from the group, including - 247 012389 containing nitrogen and oxygen; (b) K ^2a represents phenyl or naphthyl, each of which may contain from one to three ΝΚ ^{2ι as substituents;} Κ ^26, halo, cyano, S1_ ₆ alkyl S1_ ₆ alkoxy S1_ ₆ alkyl optionally substituted with up to 5 fluorine atoms or S1_ ₆ alkoxy optionally substituted with up to 5 fluorine atoms; said K ^2c and R ²⁶ represent S1_ ₆ alkyl; or K ^2a is an unsaturated 5- or 6-membered heteroaryl which may be fused to a different cycle, wherein said other cycle may be a heterocycle or any other cycle; (c) K ⁵ represents H, C (O) + K ⁶ K ⁷ , C (O) K ⁸ or C (O) OK ⁸ ; (6) To ⁶ and R ⁷ each independently represent H, S1_ ₆ alkyl or C _{3. 7} cycloalkyl; (e) To a ⁸ represents S1_ ₆ alkyl, C _{3. 7} cycloalkyl, C ₄ _1 ₀ alkylcycloalkyl or 3-tetrahydrofuryl; (ί) A dashed line indicates a possible double bond. 72. The compound of claim 1 having the formula XII wherein (a) K ^1a and R ^1b each independently represent H, S1_ ₆ alkyl or C _{3. 7} cycloalkyl, which may contain from one to three cyano as substituents, or K ^1a and K ^1b each independently represent H or νμ K ^1s ; where K ^1s represents H, or ΝΚ ^{Ι: ι} Κ ^ηι is an alkyl cyclic secondary amine containing from 3 to 6 members, which may contain from one to three heteroatoms in the ring selected from the group consisting of nitrogen and oxygen; (b) K ²¹ and K ²² each independently represent H, halo, cyano, hydroxy, S1_ ₃ alkyl S1-3alkoksi; (c) K ⁵ represents H, €. '(Ο) ΝΚ ⁶ Κ ⁷ , C (O) K ⁸ or C (O) OK ⁸ ; (6) To ⁶ and R ⁷ each independently represent H, S1_ ₆ alkyl or C _{3. 7} cycloalkyl; (e) K ⁸ is C1_6alkyl, C3-7cycloalkyl, C4_10alkylcycloalkyl or 3-tetrahydrofuryl; (ί) K ¹⁰ and K ¹¹ each independently represent H or C1_3 alkyl or K ¹⁰ and K ^11, together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (e) K ¹² and K ¹³ each represent H; (11) A dashed line indicates a possible double bond. - 248 012389 73. The compound according to claim 1, having the formula XIII where (a) K ^1a and K ^1b each independently represent H, C _1-6 alkyl or C _3-7 cycloalkyl, which may contain from one to three as substituents cyano, or _K 1a _and K ^1b each independently represents H or where K ^1c represents H, or LK ^1a to ^1b represents an alkyl cyclic secondary amine containing from 3 to 6 members, which may contain from one to three heteroatoms in the ring selected from the group consisting of nitrogen and oxygen; (b) K ²¹ and K ²² each independently represent H, halogen, cyano, hydroxy, C _1-3 alkyl, C1-3 alkoxy; (c) K ⁵ represents H, C ^ S ^ K ⁷ , C (O) K ⁸ or C (O) OK ⁸ ; (i) K ⁶ and K ⁷ each independently represent H or C _1-6 alkyl; (e) To ⁸ represents C _1-6 alkyl, C _3-7 cycloalkyl, C4 _-10 alkylcycloalkyl or 3-tetrahydrofuryl; (ί) A dashed line indicates a possible double bond. 74. The compound according to claim 1, having the formula XIV where (a) K ^1a and K ^1b each independently represent H, C _1-6 alkyl or C _3-7 cycloalkyl, which may contain from one to three as substituents cyano, or _K 1a and K ^1b , each independently, represent H or where K ^1c represents H, or LK ^1a to ^1b is an alkyl cyclic secondary amine containing from 3 to 6 members, which may contain from one to three heteroatoms in the ring selected from the group consisting of nitrogen and oxygen; (b) K ^2a represents phenyl or naphthyl, each of which may contain as substituents from one to three ΝΚ ^, ²⁰ , halogen atoms, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl optionally substituted with up to 5 fluorine atoms, or C1-6 alkoxy optionally substituted with up to 5 fluorine atoms; said K ^2c and K ²⁶ each are C _1-6 alkyl; or K ^2a is an unsaturated 5- or 6-membered heteroaryl which may be fused to a different cycle, wherein said other cycle may be a heterocycle or any other cycle; (c) K ⁵ represents H, C ^ MKK ⁷ , C (O) K ⁸ or C (O) OK ⁸ ; (6) K ⁶ and K ⁷ each independently represent H, C _1-6 alkyl or C _3-7 cycloalkyl; (e) K ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl or 3-tetrahydrofuryl; (ί) A dashed line indicates a possible double bond. 75. A pharmaceutical composition for treating or preventing liver diseases, comprising: a) an effective amount of a compound according to claim 68; b) a pharmaceutically acceptable carrier. 76. The pharmaceutical composition according to item 75, characterized by the absence of alcohols and polyols. 77. The pharmaceutical composition according p, characterized by the absence of sugar alcohols and poly (ethylene glycol) (PEG). 78. The pharmaceutical composition according to item 75 in aqueous form, characterized by the absence of an excipient that reduces the polarity of the aqueous form. 79. The pharmaceutical composition according to item 75 in the form of tablets. 80. The pharmaceutical composition according to item 75 in the form of a solid tablet in the form of a capsule. 81. The pharmaceutical composition according to item 75 in the form of a capsule. 82. A method for treating hepatitis C virus infection in a patient, comprising administering to the patient an effective amount of a compound according to claim 68. 83. The method of claim 82, wherein said effective amount is sufficient to provide a sustained viral response. 84. The method of claim 82, wherein the method also comprises administering to the patient an effective amount of a nucleoside analogue. 85. The method of claim 84, wherein the nucleoside analogue is selected from ribavirin, levovirin, viramidine, any L-nucleoside, and isotorbine. 86. The method of claim 82, wherein the method also comprises administering to the patient an effective amount of a Ν856 RNA-dependent RNA polymerase inhibitor. 87. The method of claim 82, wherein the method also comprises administering to the patient an effective amount of thymosin-α. 88. The method according to p, where thymosin-α is administered subcutaneously 2 times a week in an amount of from about 1.0 to 1.6 mg. 89. The method of claim 82, wherein the method also comprises administering to the patient an effective amount of interferon-gamma (IFN-γ). 90. The method according to p, where IFN-γ is administered subcutaneously in an amount of from about 10 to 300 μg. 91. The method of claim 82, wherein the method also comprises administering to the patient an effective amount of interferon-alpha (IFN-α). 92. The method of claim 91, wherein IFN-α is a mono-PEGylated (30 kDa, linear) consensus IFN-α, administered at intervals of every 8 days to every 14 days. 93. The method according to p, where IFN-α is a mono-PEGylated (30 kDa, linear) consensus IFN-α, administered 1 time every 7 days. 94. The method of claim 91, wherein the IFN-α is an I \ ΕΈΚ6EN consensus IFN-α. 95. The method of claim 82, further comprising administering an effective amount of an agent selected from 3'-azidothymidine, 2 ', 3'-dideoxyinosine, 2', 3'-dideoxycytidine, 2,3-didehydro-2 ', 3'- dideoxythymidine, combivir, abacavir, adefovir, dipoxyl, cidofovir and an inosine monophosphate dehydrogenase inhibitor. 96. A method for treating liver fibrosis in a patient, comprising administering to the patient an effective amount of a compound according to claim 68. 97. The method according to p, where the method also includes introducing the patient an effective amount of a nucleoside analogue. 98. The method of claim 97, wherein the nucleoside analogue is selected from ribavirin, levovirin, viramidine, any b-nucleoside, and isotorbine. 99. The method according to p, where the method also includes introducing the patient an effective amount of an inhibitor of Ν856 RNA-dependent RNA polymerase. - 250 012389 100. The method according to p, where the method also includes introducing the patient an effective amount of thymosin-α. 101. The method according to p, where thymosin-α is administered subcutaneously 2 times a week in an amount of from about 1.0 to 1.6 mg. 102. The method according to p, where the method also includes introducing the patient an effective amount of interferon-gamma (IFN-γ). 103. The method of claim 102, wherein IFN-γ is administered subcutaneously in an amount of about 10 to 300 micrograms. 104. The method according to p, where the method also includes introducing the patient an effective amount of interferon-alpha (IFN-α). 105. The method of claim 104, wherein the IFN-α is a mono-PEGylated (30 kDa, linear) consensus IFN-α, administered at intervals of every 8 days to every 14 days. 106. The method of claim 104, wherein the IFN-α is a mono-PEGylated (30 kDa, linear) consensus IFN-α administered 1 time every 7 days. 107. The method of claim 104, wherein the IFN-α is an INPΕΒΟΕN consensus IFN-α. 108. The method of claim 96, further comprising administering an effective amount of an agent selected from 3'-azidothymidine, 2 ', 3'-dideoxyinosine, 2', 3'-dideoxycytidine, 2,3-didehydro-2 ', 3'- dideoxythymidine, combivir, abacavir, adefovir, dipoxyl, cidofovir and an inosine monophosphate dehydrogenase inhibitor. 109. A method of increasing liver function in a patient with hepatitis C virus infection, comprising administering to the patient an effective amount of a compound according to claim 68. 110. The method of claim 109, wherein the method also comprises administering to the patient an effective amount of a nucleoside analogue. 111. The method according to p, where the nucleoside analogue is selected from ribavirin, levovirin, viramidine, any L-nucleoside and isatorbin. 112. The method of claim 109, wherein the method also comprises administering to the patient an effective amount of an X85B inhibitor of an RNA-dependent RNA polymerase. 113. The method of claim 109, further comprising administering to the patient an effective amount of thymosin-α. 114. The method according to p, where thymosin-α is administered subcutaneously 2 times a week in an amount of from about 1.0 to 1.6 mg. 115. The method of claim 109, wherein the method also comprises administering to the patient an effective amount of interferon-gamma (IFN-γ). 116. The method according to p. 115, where IFN-γ is administered subcutaneously in an amount of from about 10 to 300 μg. 117. The method of claim 109, further comprising administering to the patient an effective amount of interferon-alpha (IFN-α). 118. The method according to p. 117, where IFN-α is a mono-PEGylated (30 kDa, linear) consensus IFN-α, administered at intervals of every 8 days to every 14 days. 119. The method according to p. 117, where IFN-α is a mono-PEGylated (30 kDa, linear) consensus IFN-α, administered 1 time every 7 days. 120. The method of claim 117, wherein the IFN-α is an INPΕΒΟΕN consensus IFN-α. 121. The method of claim 109, further comprising administering an effective amount of an agent selected from 3'-azidothymidine, 2 ', 3'-dideoxyinosine, 2', 3'-dideoxycytidine, 2,3-didehydro-2 ', 3'-dideoxythymidine , combivir, abacavir, adefovir, dipoxyl, cidofovir and an inosine monophosphate dehydrogenase inhibitor. 122. The compound having the formula XVIII K ¹ o = ^ ΝΗ ju 11 XVIII where (a) B ¹ is phenyl, pyridine, furan, thiophene, thiazole, pyrazole, naphthyl, quinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole or benzimidazole, each of which may - 251 012389 contain from one to three ΝΕ / εΛ halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl, optionally substituted up to 5 fluorine atoms, or C _1-6 alkoxy as substituents possibly substituted with up to 5 fluorine atoms; (b) K ² represents H, phenyl, which may contain as substituents up to three halogen atoms, or imidazole; (c) K ³ represents H; (e) K ⁴ represents C (O) Mk ⁵ K ⁶ , —C (O) K ⁷ or C (O) OK ⁷ ; (e) K ⁵ and K ⁶ each independently represent H, C 1-6 alkyl or C 3-7 cycloalkyl, or K ⁵ and K ⁶ together with the nitrogen to which they are attached form morpholinyl; (ί) K ⁷ represents C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, wherein said _C1-6 alkyl may be substituted with phenyl; (e) K ⁸ represents C _1-3 alkyl, C _3-4 cycloalkyl or phenyl, which may contain as substituents from one to two halogen atoms, cyano, C _1-3 alkyl or C _1-3 alkoxy; and (B) the dotted line indicates a possible double bond; or a pharmaceutically acceptable salt of said compound. 123. The compound according to p. 122, where K ¹ represents phenyl, benzothiazole, benzothiophene, benzofuran or benzimidazole, each of which may contain from one to two IR substituents. ⁵ K ⁶ , halogen atoms, cyano, C _1-2 alkyl, C _1-6 alkoxy, C _1-6 alkyl, possibly substituted up to 5 fluorine atoms, or C _1-6 alkoxy, possibly substituted up to 5 fluorine atoms; K ² represents H or phenyl, which may contain from 1 to 2 halogen atoms as substituents; K ³ represents H; K ⁴ represents C (O) Mk ⁵ K ⁶ , -C (O) K ⁷ or C (O) OK ⁷ ; K ⁵ and K ⁶ each independently represent H, C _1-6 alkyl or C _3-7 cycloalkyl or K ⁵ and K ⁶ together with the nitrogen to which they are attached form morpholinyl; K ⁷ represents C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, wherein said C 1-6 alkyl may be substituted with phenyl; K ⁸ represents C1-3 alkyl, C3-4 cycloalkyl or phenyl, which may contain up to two halogen atoms, cyano, C _1-3 alkyl or C _1-3 alkoxy as substituents; the dotted line indicates a possible double bond. 124. The compound according to p. 122, where K ¹ represents phenyl, benzothiazole or benzothiophene, each of which may contain as substituents from one to two halogen atoms, C1-2 alkyls, C1-6 alkyls, possibly substituted up to 5 fluorine atoms, _C1-6 alkoxy, possibly substituted up to 5 fluorine atoms; K ² represents H or phenyl, optionally containing from one to two halogen atoms as substituents; K ³ represents H; K ⁴ represents C (O) Mk ⁵ K ⁶ , -C (O) K ⁷ or C (O) OK ⁷ ; K ⁵ represents hydrogen, and K ⁶ represents H, C _1-6 alkyl or C _3-7 cycloalkyl; K ⁷ represents C _1-6 alkyl or C _3-7 cycloalkyl, wherein said C _1-6 alkyl is optionally substituted with phenyl; K ⁸ represents C1-3 alkyl, C3-4 cycloalkyl or phenyl, which may contain from one to two halogen atoms, cyano, C _1-3 alkyl or C _1-3 alkoxy as substituents; the dotted line indicates a possible double bond. 125. A pharmaceutical composition for treating or preventing liver diseases, comprising: a) an effective amount of a compound according to p. 122 and b) a pharmaceutically acceptable carrier. 126. The pharmaceutical composition according p, characterized by the absence of alcohols and polyols. 127. The pharmaceutical composition according p, characterized by the absence of sugar alcohols and poly (ethylene glycol) (PEG). 128. The pharmaceutical composition according to p. 125 in aqueous form, characterized by the absence of an excipient that reduces the polarity of the aqueous form. 129. The pharmaceutical composition of claim 125 in tablet form. 130. The pharmaceutical composition according p in the form of a solid tablet in the form of a capsule. 131. The pharmaceutical composition according p in the form of a capsule. 132. A method for treating a hepatitis C virus infection in a patient, comprising administering to the patient an effective amount of a compound according to paragraph 122. 133. The method of claim 132, wherein said effective amount is sufficient to provide a sustained viral response. - 252 012389 134. The method according to p, where the method also includes introducing the patient an effective amount of a nucleoside analogue. 135. The method according to p, where the nucleoside analogue is selected from ribavirin, levovirin, viramidine, any L-nucleoside and isorbine. 136. The method according to p, where the method also includes the introduction of a patient an effective amount of an inhibitor of Ν85Ε RNA-dependent RNA polymerase. 137. The method according to p, where the method also includes introducing the patient an effective amount of thymosin-α. 138. The method according to p, where thymosin-α is administered subcutaneously 2 times a week in an amount of from about 1.0 to 1.6 mg. 139. The method according to p, where the method also includes introducing the patient an effective amount of interferon-gamma (IFN-γ). 140. The method according to p, where IFN-γ is administered subcutaneously in an amount of from about 10 to 300 μg. 141. The method according to p, where the method also includes the introduction of a patient an effective amount of interferon-alpha (IFN-α). 142. The method according to p, where IFN-α is a mono-PEGylated (30 kDa, linear) consensus IFN-α, administered at intervals of every 8 days to every 14 days. 143. The method according to p. 141, where IFN-α is a mono-PEGylated (30 kDa, linear) consensus IFN-α, administered 1 time every 7 days. 144. The method of claim 141, wherein the IFN-α is an INPK6EN consensus IFN-α. 145. The method according to p, also comprising administering an effective amount of an agent selected from 3'-azidothymidine, 2 ', 3'-dideoxyinosine, 2', 3'-dideoxycytidine, 2,3-didehydro-2 ', 3'-dideoxythymidine , combivir, abacavir, adefovir, dipoxyl, cidofovir and an inosine monophosphate dehydrogenase inhibitor. 146. A method of treating liver fibrosis in a patient, comprising administering to the patient an effective amount of a compound according to p. 147. The method of claim 146, further comprising administering to the patient an effective amount of a nucleoside analogue. 148. The method according to p, where the nucleoside analogue is selected from ribavirin, levovirin, viramidine, any L-nucleoside and isorbine. 149. The method of claim 146, wherein the method also comprises administering to the patient an effective amount of a Ν85Ε RNA-dependent RNA polymerase inhibitor. 150. The method according to p, where the method also includes introducing the patient an effective amount of thymosin-α. 151. The method according to p. 150, where thymosin-α is administered subcutaneously 2 times a week in an amount of from about 1.0 to 1.6 mg. 152. The method according to p, where the method also includes introducing the patient an effective amount of interferon-gamma (IFN-γ). 153. The method according to p, where IFN-γ is administered subcutaneously in an amount of from about 10 to 300 μg. 154. The method of claim 146, wherein the method also comprises administering to the patient an effective amount of interferon-alpha (IFN-α). 155. The method according to p. 154, where IFN-α is a mono-PEGylated (30 kDa, linear) consensus IFN-α, administered at intervals of every 8 days to every 14 days. 156. The method according to p. 154, where IFN-α is a mono-PEGylated (30 kDa, linear) consensus IFN-α, administered 1 time every 7 days. 157. The method according to p. 154, where IFN-α is INREK6EN consensus IFN-α. 158. The method of claim 146, further comprising administering an effective amount of an agent selected from 3'-azidothymidine, 2 ', 3'-dideoxyinosine, 2', 3'-dideoxycytidine, 2,3-didehydro-2 ', 3'-dideoxythymidine , combivir, abacavir, adefovir, dipoxyl, cidofovir and an inosine monophosphate dehydrogenase inhibitor. 159. A method of increasing liver function in a patient with hepatitis C virus infection, comprising administering to the patient an effective amount of a compound according to p. 122. 160. The method of claim 159, further comprising administering to the patient an effective amount of a nucleoside analogue. 161. The method according to p, where the nucleoside analogue is selected from ribavirin, levovirin, viramidine, any L-nucleoside and isatorbin. 162. The method of claim 159, wherein the method also comprises administering to the patient an effective amount of a Ν85Ε RNA-dependent RNA polymerase inhibitor. 163. The method of claim 159, further comprising administering to the patient an effective amount of thymosin-α. - 253 012389 164. The method according to p, where thymosin-α is administered subcutaneously 2 times a week in an amount of from about 1.0 to 1.6 mg. 165. The method according to p. 159, where the method also includes administering to the patient an effective amount of interferon-gamma (IFN-γ). 166. The method according to p, where IFN-γ is administered subcutaneously in an amount of from about 10 to 300 μg. 167. The method of claim 159, wherein the method also comprises administering to the patient an effective amount of interferon-alpha (IFN-α). 168. The method according to p. 167, where IFN-α is a mono-PEGylated (30 kDa, linear) consensus IFN-α, administered at intervals of every 8 days to every 14 days. 169. The method according to p, where IFN-α is a mono-PEGylated (30 kDa, linear) consensus IFN-α, administered 1 time every 7 days. 170. The method according to p, where IFN-α is a GNNEYAEN consensus IFN-α. 171. The method of claim 159, further comprising administering an effective amount of an agent selected from 3'-azidothymidine, 2 ', 3'-dideoxyinosine, 2', 3'-dideoxycytidine, 2,3-didehydro-2 ', 3'-dideoxythymidine , combivir, abacavir, adefovir, dipoxyl, cidofovir and an inosine monophosphate dehydrogenase inhibitor. 172. A compound of the formula wherein (a) Ζ represents a group capable of forming a hydrogen bond with an imidazole fragment of the H1z57 N83 protease and forming a hydrogen bond with the nitrogen atom of the O1u137 N83 protease; (b) P1 ′ is a group capable of participating in non-polar interaction with at least one fragment 81 ′ of the N83 protease pocket selected from the group consisting of LU8136, C1u137, 8eg139, H1z57, O1u58, 8eg42 and Pb43; (c) b represents a linker group containing from 1 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen and sulfur; (ά) P _{2 is} selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclyl and substituted heterocyclyl; the position of P _{2 is} determined by L with the formation of non-polar interaction with at least one fragment 82 of the N83 protease pocket selected from the group consisting of Hl357, Agd 155, Wa1178, Azr79, Ο1η80 and Azr81; (e) dashed line means a possible double bond; (ί) I ⁵ are selected from the group consisting of H, C (O ^ I ⁶ I ⁷ and C (O) OA ⁸ ; (e) I ⁶ and I ⁷ each independently represent H, C _3-6 alkyl or C _3-7 cycloalkyl, and (b) I ⁸ represents C _3-6 alkyl, C _3-7 cycloalkyl or C _{4- 30} alkylcycloalkyl, wherein said C1-6alkyl may be substituted with phenyl; or I ⁸ represents C1-6 alkyl, optionally substituted with up to 5 groups containing fluorine; or I ⁸ represents a tetrahydrofuran ring bonded through the positions of the C ₃ or C4 tetrahydrofuran ring; or I ⁸ is a tetrahydropyran ring linked through position C4-tetrahydropyran ring, provided that the compound does not include a compound having the formula GG, GGG or GU - 254 012389 Π III IV where (aa) K ¹ and K ² , each independently, are H, halogen, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy C1-6 alkyl, C1-6 alkyl, possibly substituted up to 5 fluorine atoms, C | -6 alkoxy, possibly substituted up to 5 fluorine atoms, C6 or C | 0-aryl, pyridinyl, pyrimidinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy , 8O2CC ⁶ K ⁷ , \ HC (O) \ K ⁶ K ', \ HC (8) \ 1 <1 <', C (O) CC ⁶ K ⁷ , CC ⁶ K ⁷ , C (O) K ⁸ , C (O) OK ⁸ , central nervous system (O) K ⁸ , central nervous system (O) OK ⁸ , ⁸ OTK ⁸ , ΝΗ8 (Ο) 2Ε ⁸ , (CH2) _P \ K ⁶ K ⁷ , O (CH2) P \ K ⁶ K ⁷ or O (CH2) _P K ⁹ ; where K ⁹ represents imidazolyl or pyrazolyl; the indicated thienyl, pyrimidinyl, furanyl, thiazolyl and oxazolyl in the definition of K ¹ and K ² may contain as substituents from one to two halogen atoms, cyano, nitro, hydroxy, _C1-6 alkyl, C _3-7 cycloalkyl, C _{4-1 0} alkylcycloalkyls, C _2-6 alkenyls, _C1-6 alkoxy, hydroxy _C1-6 alkyls, _C1-6 alkyl, possibly substituted with up to 5 fluorine atoms, _C1-6 alkoxy, possibly substituted with up to 5 fluorine atoms; the specified C ₆ or C ^ -aryl, pyridinyl, phenoxy and thiophenoxy in the definition of K ¹ and K ² may contain as substituents from one to three halogen atoms, cyano, nitro, hydroxy, _C1-6 alkyl, C _3-7 cycloalkyls, Since _4- 1 ₀ alkylcycloalkyl, _C2-6 alkenyl, C1 _-6 alkoxy, gidroksiS1 _-6 alkyl, C1 _-6 alkyl optionally substituted with up to 5 fluorine atoms, C | _-6 alkoxy, possibly substituted with up to 5 fluorine atoms; (B) m = 0, 1 or 2; (pp) K ⁴ represents H, C1 _-6 alkyl, C _3-7 cycloalkyl, C _4- 1 ₀ alkylcycloalkyl, or phenyl or benzyl, said phenyl or benzyl is optionally substituted with from one to three halogen atoms, cyano, nitro, , hydroxy, C1 _-6 alkyls, C _3-7 cycloalkyls, C ₄ 1 ₀ alkylcycloalkyl, _C2-6 alkenyl, C1 _-6 alkoksn, hydroxy-C1 _-6 alkyl, C1 _-6 alkyl optionally substituted with up to 5 fluorine atoms, C1 _-6 alkoksn optionally substituted with up to 5 fluorine atoms; (άά) K ⁵ represents H, C1-6 alkyl, C (O) \ K ⁶ K ⁷ , C (8) \ K ⁶ K ⁷ , -C (O) K ⁸ , C (O) OK ⁸ , 8 ( O) 2K ⁸ or (CO) SNK ²¹ \ N (CO) K ²² ; (ee) K ⁶ and K ⁷ each independently represent H, C1 _-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl or phenyl, said phenyl is optionally substituted with from one to three halogen atoms, cyano, , nitro, hydroxy, C1-6 alkyls, C3-7 cycloalkyls, C4-10 alkylcycloalkyls, C2-6 alkenyls, hydroxy-C1-6 alkyls, C1-6 alkyls, possibly substituted with up to 5 fluorine atoms, C1-6 alkoxy, possibly substituted with up to 5 fluorine atoms; or K ⁶ and K ⁷ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; (ίί) K ⁸ represents C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, each of which may be substituted one to three times by halogen, cyano, nitro, hydroxy, C1-6 alkoxy or phenyl; or K ⁸ represents C6 or C10-aryl, which may contain as substituents from one to three atoms of halogen, cyano, nitro, hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy C1-6 alkyl, C1-6 alkyl, possibly substituted with up to 5 fluorine atoms, _C1-6 alkoxy, possibly substituted with up to 5 fluorine atoms; or K ⁸ is C 1-6 alkyl optionally substituted with up to 5 groups containing fluorine; or K ⁸ is a tetrahydrofuran ring bonded through C ₃ or C4 tetrahydrofuran ring; or K ⁸ is a tetrahydropyran ring linked through position C4 tetrahydropyran ring; (dd) Υ represents -C (O) \ H8 (O) ₂ ⁹ K, where K ⁹ is a C 1 _-6 alkyl, C _3-7 cycloalkyl, - 255 012389 C4-10 alkylcycloalkyl, each of which may be substituted one to three times by halogen, cyano, nitro, hydroxy, C _1-6 alkoxy or phenyl, or K ⁹ represents C ₆ or C ₁₀ aryl, which may contain as substituents from one to three halogen atoms, cyano, nitro, hydroxy, C1 _-6 alkyls, C _3-7 cycloalkyls, C ₄ 1 ₀ alkylcycloalkyl, _C2-6 alkenyl, C1 _-6 alkoxy, hydroxy-C1-6alkyl, C1- 6 alkyls, possibly substituted with up to 5 fluorine atoms, C1-6 alkoxy, possibly substituted with up to 5 fluorine atoms; or K ⁹ is C1-6 alkyl, optionally substituted with up to 5 groups containing fluorine, IR. ⁶ TO ⁷ or (CO) OH; or K ⁹ represents a heteroaromatic ring which can be substituted up to two times with halogen, cyano, nitro, hydroxyl or C1-6 alkoxy; or Υ represents a carboxyl group or a pharmaceutically acceptable salt, solvate or prodrug thereof; (11) K ¹⁰ and K ¹¹ each independently represent I, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or C10-aryl, hydroxy-C1-6 alkyl, C1-6 alkyl, optionally substituted with up to 5 fluorine atoms , (LED ^ LK ^ ⁷ , (CH2) _P C (O) OK ¹⁴ , where K ¹⁴ is I, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, each of which can be substituted one to three times with halogen , cyano, nitro, hydroxy, C1-6 alkoxy or phenyl, or a ¹⁴ is C 6 or C ₁₀ -aryl which may be substituted by one to three halogen atoms, cyano, nitro, hydroxy, and C1 _-6 Kills, C _3-7 cycloalkyls, C ₄ 1 ₀ alkylcycloalkyl, _C2-6 alkenyl, C1 _-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally substituted with up to 5 fluorine atoms; the specified C6 or C10-aryl in the definition of K ¹⁰ and K ¹¹ may contain from one to three halogen, cyano, nitro, hydroxy, C1-6 alkyl, C3-7cycloalkyl, C4-10 alkylcycloalkyl, C2-6 alkenyls as substituents , C1-6 alkoxy, hydroxy-C1-6 alkyl, C1-6 alkyl, possibly substituted with up to 5 fluorine atoms, C1-6 alkoxy, possibly substituted with up to 5 fluorine atoms; or K ¹⁰ and K ^11, together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or K ¹⁰ and K ¹¹ together represent O; (ίί) p = 0 or 1; (β) K ¹² and K ¹³ each independently represent I, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or C10-aryl, hydroxy-C1-6 alkyl, C1-6 alkyl, optionally substituted with up to 5 fluorine atoms , (LED ^ I ^ K ⁷ , (CH2) _P C (O) OK ¹⁴ , where K ¹⁴ represents I, Cg _-6 alkyl, C _3-7 cycloalkyl, C4-10 alkylcycloalkyl, each of which can be substituted from one up to three times with halogen, cyano, nitro, hydroxy, C1-6 alkoxy or phenyl, or K ¹⁴ represents C6 or C10-aryl, which may contain as substituents from one to three atoms of halogen, cyano, nitro, hydroxy, C1-6a lkilov, C3-7cycloalkyl, S4-10alkiltsikloalkilov, S2-6alkenilov, C1-6alkoxy, hydroxy-C1-6alkyl, C1-6alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally substituted with up to 5 fluoro; said _C6 or C ₁₀ -aryl in the definition of K ¹² and K ¹³ may contain from one to three halogen atoms, cyano, nitro, hydroxy, C _1-6 alkyl, C3-7 cycloalkyls, C4-10 alkylcycloalkyls, C2-6 alkenyls, C1-6 alkoxy as substituents , hydroxy-C1-6 alkyls, C1-6 alkyls, possibly substituted with up to 5 fluorine atoms, C1-6 alkoxy, possibly substituted with up to 5 fluorine atoms; or K ¹² and K ¹³ together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or K ¹² and K ¹³ each represent C1 _-6 alkyl optionally substituted by (CH _{2) n} OK ^8; (kk) K ²⁰ represents I, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, C6 or Cn-aryl, hydroxy-C1-6 alkyl, Cg-6 alkyl, optionally substituted with up to 5 fluorine atoms, (CH2) PYK ⁶ K ⁷ , (CH2) _P C (O) OK ¹⁴ , where K ¹⁴ is I, C1-6 alkyl, C3-7 cycloalkyl, C4-10 alkylcycloalkyl, each of which can be substituted one to three times with halogen, cyano, nitro, hydroxy , C1-6 alkoxy or phenyl, or a ¹⁴ is C 6 or C ^ -aryl which may be substituted by one to three halogen atoms, cyano, nitro, hydroxy, C1 _-6 alkyl, C _3-7 cycloalkyl, a C ₄ 1 ₀ alkylcycloalkyl, _C2-6 alkenyl, C1 _-6 alkoxy, hydroxy-C1 _-6 alkyl, C1 _-6 alkyl optionally substituted with up to 5 fluoro, C1-6 alkoxy optionally substituted with up to 5 fluorine atoms; the specified C6 or C10-aryl in the definition of K ¹² and K ¹³ may contain as substituents from one to three halogen atoms, cyano, nitro, hydroxy, _C1-6 alkyl, C _3-7 cycloalkyls, C _{4-1 0} alkylcycloalkyls, C _2-6 alkenyls, _C1-6 alkoxy, hydroxy- _C1-6 alkyl, _C1-6 alkyl, possibly substituted up to 5 fluorine atoms, _C1-6 alkoxy, possibly substituted up to 5 fluorine atoms; (11) n = 1-4; (n) V is selected from O, 8 or ΝΗ; (pp) when V is O or 8, is selected from O, ΝΒ? ⁵ or SK ¹⁵ ; when V is ΝΗ, choose from ΝΒ? ⁵ or SK ¹⁵ , where K ¹⁵ represents And, C1 _-6 alkyl, C _3-7 cycloalkyl, C _4- 1 ₀ alkylcycloalkyl or C1 _-6 alkyl optionally substituted with up to 5 fluorine atoms; (oo) dashed line means a possible double bond; - 256 012389 (pp) K ²¹ is C1 _-6 alkyl, C _3-7 cycloalkyl, C _4- 1 ₀ alkylcycloalkyl, each of which may be substituted with from one to three times by halogen, cyano, nitro, hydroxy, C1 _-6 alkoxy, _C1-6 alkyl, optionally substituted with up to 5 fluorine atoms, or phenyl; or K ²¹ represents C ₆ or Cn-aryl, which may contain as substituents from one to three atoms of halogen, cyano, nitro, hydroxy, _C1-6 alkyls, C _3-7 cycloalkyls, C _{4-1 0} alkylcycloalkyls, C _{2 -6} alkenyls, _C1-6 alkoxy, hydroxy- _C1-6 alkyl, _C1-6 alkyl, possibly substituted up to 5 fluorine atoms, _C1-6 alkoxy, possibly substituted up to 5 fluorine atoms; or By ²¹ is pyridinyl, pyrimidinyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy and (ςς) K ²² is C1 _-6 alkyl, C _3-7 cycloalkyl, C _4- 1 ₀ alkylcycloalkyl, each of which may be substituted one to three times by halogen, cyano, nitro, hydroxy, _C1-6 alkyl, possibly substituted by up to 5 fluorine atoms, or phenyl; provided that the specified compound does not include a compound of the formula - 257 012389 - 258 012389 173. The compound according to p. 172, where b contains from 2 to 5 atoms. 174. The compound of claim 173, wherein b is selected from the group consisting of —OSH ₂ - and —CHCH ₂ -. 175. The compound of claim 173, wherein b is selected from the group consisting of —CH═CH and —C═C—. 176. The compound according to p, where b is selected from the group consisting of -8CH ₂ -, -8O ₂ - and -CH ₂ 8O-. 177. The compound according to Claim 173, wherein b is selected from the group consisting of - ^ C (= V) -NH-- and - # C (= '^ - O-, and where V and ^ are each independently selected from O , 8, ΝΗ. 178. The compound according to Claim 172, where b contains the group - ^ - 0 (= ^ -, where V and ^, each individually, are selected from O, 8 or ΝΗ. 179. The compound according to p. 172, where b represents a linking group containing from 1 to 5 atoms selected from the group comprising carbon, oxygen, nitrogen, hydrogen and sulfur. 180. The compound of claim 172, wherein P _{2 is} selected from the group consisting of an unsubstituted heterocycle and a substituted heterocycle. 181. The compound of claim 172, wherein b is selected from the group consisting of ester, amide, carbamate, thioester and thioamide. 182. The compound according to Claim 172, wherein the position of the P ₂ group is additionally determined by the L linker with the formation of a hydrogen bond with at least one fragment 82 of the Ν83 protease pocket selected from the group comprising H1§57, Arg155, Va1178, Arg79 , 61p80 and Ag. 81. 183. The compound according to p, where b is a linking group containing from 1 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen and sulfur. 184. The compound of claim 182, wherein P _{2 is} selected from the group consisting of an unsubstituted heterocycle and a substituted heterocycle. 185. The compound according to Claim 172, wherein the substituents at the C ₁₃ -C ₁₄ double bond are in the cis position. 186. The compound according to Claim 172, wherein P ₂ is - 259 012389 187. The compound according to 172 of the formula 188. The compound according to p, where B is a linking group containing from 1 to 5 atoms selected from the group consisting of nitrogen, hydrogen and sulfur. 189. The compound of claim 188, wherein P _{2 is} selected from the group consisting of an unsubstituted heterocycle and a substituted heterocycle. 190. The compound of claim 187, wherein B contains from 2 to 5 atoms. 191. The compound of claim 190, wherein B is selected from the group consisting of —OSH ₂ - and —CHCH ₂ -. 192. The compound of claim 190, wherein B is selected from the group consisting of —CH═CH and —C = C—. 193. The compound according to p. 190, where B is selected from the group consisting of -8CH ₂ -, -8O ₂ - and -CH ₂ 8O-. 194. The compound according to p. 190, where B is selected from the group consisting of-# C (= Y) -HY- and -> C (= Y) -O-, and where V and V are each independently selected from O , 8, ΝΗ. 195. The compound according to p, where B contains the group - ^ - C (= Y) -, where V and V, each individually, are selected from O, 8 or ΝΗ. 196. The compound of claim 188, wherein B is selected from the group consisting of ester, amide, carbamate, thioester and thioamide. 197. The compound of claim 188, wherein the position of the P ₂ group is further determined by linker B to form a hydrogen bond with at least one fragment 82 of the Ν83 protease pocket selected from the group consisting of ΗΪ557, Agd155, Va1178, Akr79, Ο1η80 and Akr81. 198. The compound according to Claim 179, wherein B is a linker group containing from 1 to 5 atoms selected from the group consisting of nitrogen, hydrogen and sulfur. 199. The compound of claim 179, wherein P2 is selected from the group consisting of an unsubstituted heterocycle and a substituted heterocycle. 200. The compound of claim 188, wherein the substituents at the C13-C14 double bond are in the cis position. 201. The compound according to 172 of the formula U 11 202. The compound of claim 201, wherein B is a linking group containing from 1 to 5 atoms selected from the group consisting of nitrogen, hydrogen and sulfur. 203. The compound of claim 201, wherein P _{2 is} selected from the group consisting of an unsubstituted heterocycle and a substituted heterocycle. 204. The compound of claim 201, wherein B contains from 2 to 5 atoms. 205. The compound of claim 204, wherein B is selected from the group consisting of —OSH ₂ - and —CHCH ₂ -. 206. The compound according to claim 204, wherein B is selected from the group consisting of —CH═CH and —C = C—. 207. The compound according to claim 204, wherein B is selected from the group consisting of -8CH ₂ -, -8O ₂ -, and -CH ₂ 8O-. 208. The compound according to claim 204, wherein B is selected from the group consisting of - ^ C (= Y) -HH- and - ^ C (= Y) -O-, and where V and V are each independently selected from O, 8, ΝΗ. 209. The compound of claim 179, wherein B contains the group - ^ - C (= Y) -, where V and V, each individually, are selected from O, 8 or ΝΗ. 210. The compound of claim 201, wherein B is selected from the group consisting of ester, amide, carbamate, thioester and thioamide. 211. The compound of claim 201, wherein the position of the P ₂ group is additionally determined by linker B with the formation of a hydrogen bond with at least one fragment 82 of the Ν83 protease pocket, selected - 260 012389 from the group including H1857, Agd155, Va1178, Azr79, O1n80 and Azr81. 212. The compound of claim 211, wherein b is a linker group containing from 1 to 5 atoms selected from the group consisting of nitrogen, hydrogen and sulfur. 213. The compound of claim 211, wherein P _{2 is} selected from the group consisting of an unsubstituted heterocycle and a substituted heterocycle. 214. The compound of claim 201, wherein the substituents at the C ₁₃ -C ₁₄ double bond are in the cis position. 215. A compound having the formula wherein O is a central ring selected from wherein the central ring may be unsubstituted or substituted with halogen, cyano, hydroxy, C ₁ -alkyl, C ₁ -balkoxy, phenyl, thiazolyl, C (O) CNSN ₂ CH ₃ , C (O) OH, ΟCH ₂ CH ₂ NH (C _1-3 alkyl), OCH ₂ CH ₂ X (C _1-3 alkyl) ₂ , C ₂ alkoxy containing imidazolyl, pyrazolyl, pyrrolidinyl as a substituent, piperidinyl, piperazinyl or morpholinyl, CH ₂ CH ₂ X (CH ₃ ) ₂ , C (O) OCH ₂ CH ₃ , spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl or spirocyclic cyclohexyl, or P represents K ¹ -K ² , where K ¹ represents phenyl, pyridine, furan, thiophene, thiazole, pyrazole, naphthyl, quinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole or benzimidazole, each of which may contain substituents from one to three CK ^{bK 7} , halogen atoms, cyano, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 alkyl, possibly substituted up to 5 fluorine atoms, C _1-6 alkoxy, possibly substituted up to 5 atoms fluorine; and K ² represents H, phenyl or imidazole, each of which may contain from one to three halogen atoms as substituents; K ⁴ represents H; K ⁵ represents C (O) XK ⁶ K ⁷ , -C (O) K ⁸ , C (O) OK ⁸ or (CO) SNK ²¹ XN (CO) K ²² ; K ⁶ and K ⁷ each independently represent H, C _1-6 alkyl, C _3-7 cycloalkyl or phenyl, said phenyl may contain from one to three halogen, cyano, C _1-6 alkyl, C atoms as substituents _1-6 alkyl, possibly substituted up to 5 fluorine atoms, or C _1-6 alkoxy, possibly substituted up to 5 fluorine atoms; or _K 6 and K ⁷ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; K ⁸ represents C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, wherein said C _1-6 alkyl may be substituted with phenyl; or K ⁸ is C _1-6 alkyl, optionally containing up to 5 fluorine groups as substituents; or K ⁸ represents a tetrahydrofuran ring bonded through the positions of a C ₃ or C4 tetrahydrofuran ring; or K ⁸ is a tetrahydropyran ring linked through position C4 tetrahydropyran ring; Υ represents —COOC ⁹ , where K ⁹ is C _1-6 alkyl; V is selected from O, 8 or XII; when V is selected from O or 8, W is selected from O, ΝΕ ^15, or SK ¹⁵ ; when V is XII, III is selected from ΝΕ ¹⁵ or SK ¹⁵ , where K ¹⁵ is H, C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl or C _1-6 alkyl, optionally substituted with up to 5 fluorine atoms; dashed line indicates a possible double bond; K ²¹ represents C _1-6 alkyl or C _3-7 cycloalkyl and K ²² represents C1-6 alkyl. - 261 012389 216. The compound according to claim 215 of the formula 217. A compound having the formula wherein K ⁴ is H; K ⁵ represents + (0) + 1 + 1 +, -C (O) K ⁸ , C (O) OK ⁸ or (CO) SNK ²¹ KN (CO) K ²² ; By ⁶ and R ⁷ each independently represent H, C1 _-6 alkyl, _C3-7 cycloalkyl or phenyl, said phenyl is optionally substituted with from one to three halogen, cyano, C1 _-6 alkyl, C1 _-6 alkyls, possibly substituted with up to 5 fluorine atoms, or _C1-6 alkoxy, possibly substituted with up to 5 fluorine atoms; or K ⁶ and K ⁷ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; By ⁸ represents a C1 _-6 alkyl, C _3-7 cycloalkyl, C _4- schalkiltsikloalkil, wherein said C _1-6 alkyl may be substituted by phenyl; or K ⁸ is C _1-6 alkyl optionally substituted with up to 5 fluorine containing groups; or K ⁸ represents a tetrahydrofuran ring bonded through the positions of a C ₃ or C4 tetrahydrofuran ring; or K ⁸ is a tetrahydropyran ring linked through position C4 tetrahydropyran ring; Υ represents -C (O) YN8 (O) ₂ ⁹ K, where K ⁹ is a C1 _-3 alkyl which may be substituted by 1 to 3 halogen atoms, C _3-7 cycloalkyl or phenyl, which may contain as substituents, from one to two atoms of halogen, cyano, nitro, C1-3 alkyl or C _1-3 alkoxy, or Υ represents a carboxyl group; V is selected from OH or ΝΗ ₂ ; dashed line indicates a possible double bond; K ²¹ represents C 1-6 alkyl or C 3-7 cycloalkyl and K ²² represents C 1-6 alkyl. 218. The compound according to claim 217 of the formula 219. A compound according to p.218, where Υ represents -C (O) YN8 (O) ₂ ⁹ K, where K ⁹ is selected from the group consisting of C1 _-3 alkyl, C _3-7 cycloalkyl or phenyl, which may contain substituted by one to two halo, cyano, nitro, C1 _-3 alkyl or C1 _-3 alkoxy, and wherein V is selected from OH and ΝΗ _2. - 262 012389 220. A compound having the formula where 0 is a central ring selected from where the central ring may be unsubstituted or substituted with halogen, cyano, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, phenyl, thiazolyl, C (O) No. HCH ₂ CH ₃ , C (O) OH, OCH ₂ CH ₂ NO (C _1-3 alkyl), OCH ₂ CH ^ (C _1-3 alkyl) ₂ , C ₂ -alkoxy containing imidazolyl, pyrazolyl as a substituent , pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, _CH2 ~ CH _{(CH3) 2,} C (O) OCH ₂ CH _3, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or pirotsiklicheskim cyclohexyl, or P represents B ¹ -B ² , where B ¹ represents phenyl, pyridine, furan, thiophene, thiazole, pyrazole, naphthyl, quinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole or benzimidazole, each of which may contain substituents from one to three Ν ^ Έ ⁷ , halogen atoms, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl, possibly substituted up to 5 fluorine atoms, or C _1-6 alkoxy, optionally substituted up to 5 fluorine atoms; and B ² represents H, phenyl or imidazole, each of which may contain from one to three halogen atoms as substituents; In ⁴ represents H; ⁵ represents C (OMHC, —C (O) B ⁸ , C (O) OB ⁸ or (CO) START ²¹ YAN (CO) B ²² ; _B 6 and B ⁷ each independently represent H, C _1-6 alkyl, C _3- 7tsikloalkil or phenyl, said phenyl is optionally substituted with from one to three halogen atoms, cyano, C _1-6 alkyls, C _{1 -6} alkyl, possibly substituted up to 5 fluorine atoms, C _1-6 alkoxy, possibly substituted up to 5 fluorine atoms; or B ⁶ and B ⁷ together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; B ⁸ is C _1-6 alkyl, C _3-7 cycloalkyl, C _4-10 alkylcycloalkyl, wherein said C 1-6 alkyl may be substituted with phenyl; or B ⁸ is C _1-6 alkyl, optionally containing up to 5 fluorine containing substituents; or B ⁸ is a tetrahydrofuran ring bonded through the positions of the C ₃ or C ₄ tetrahydrofuran ring; or B ⁸ is a tetrapyran ring linked through the position of a C ₄ -tetpiran ring; Υ represents —COOB ⁹ , where B ⁹ represents C1-6 alkyl; or Υ represents —C (O) IN8 (O) ₂ B ⁹ , where B ^{9 is} selected from the group consisting of C _1-3 alkyl, C _3-7 cycloalkyl or phenyl, which may contain one to two halogen atoms as a substituent , cyano, nitro, C1-3alkyl or C1-3alkoxy; or Υ represents a carboxyl group; V represents O or 8 and represents O or ΝΗ; dashed line indicates a possible double bond; B ²¹ is C _1-6 alkyl or C _3-7 cycloalkyl and B ²² is C _1-6 alkyl.