Macrocyclic serine protease inhibitors

Macrocyclic serine protease inhibitors

Macrocyclic serine protease inhibitor compounds and pharmaceutical compositions comprising the compounds are provided herein. Compounds are also provided for use in the treatment of an HCV infection in a host that needs it.

Hepatitis C virus (HCV) is known to cause at least 80% of posttransfusion hepatitis and a substantial proportion of sporadic acute hepatitis (Houghton et al., Science 1989, 244, 362-364; Thomas, Curr. Top. Microbiol, Immunol. 2000, 25-41). Preliminary evidence also involves HCV in many cases of "idiopathic" chronic hepatitis, "cryptogenic" cirrhosis and probably hepatocellular carcinoma not related to other hepatitis viruses, such as hepatitis B virus (Di Besceglie et al., Scientific American, 1999, October, 8085; Boyer et al., J. Hepatol. 2000, 32, 98-112).

HCV is a enveloped virus that contains a positive sense single-stranded RNA genome of approximately 9.4 kb (Kato et al., Proc. Natl. Acad. Sci. USA 1990, 87, 9524-9528; Kato, Acta Medica Okayama, 2001, 55, 133-159). The viral genome consists of a 5 'untranslated region (UTR), a long open reading frame that encodes a polyprotein precursor of approximately 3011 amino acids, a short 3' UTR. The 5 'UTR is the most highly conserved part of the HCV genome and is important for the initiation and control of polyprotein translation. The HCV genome translation is initiated by an independent cap mechanism known as an internal ribosome entrance. This mechanism involves the binding of ribosomes to an RNA sequence known as the internal ribosome entry site (IRES). It has recently been determined that a pseudo-RNA structure of RNA is an essential structural element of the HCV IRES. Protein viral structures include a nucleocapsid center protein (C) and two envelope glycoproteins, E1 and E2. HCV also encodes two proteases, a zinc-dependent metalloprotease encoded by the NS2-NS3 region and a serine protease encoded in the NS3 region. These proteases are necessary for cleavage of specific regions of the precursor polyprotein into mature peptides. The carboxylic half of non-structural protein 5, NS5B, contains RNA-dependent RNA polymerase. The function of the other non-structural proteins, NS4A and NS4B, and that of NS5A (the amino terminal half of the non-structural protein 5) remain unknown.

WO 2007/014926 describes certain macrocyclic compounds that are said to be HCV inhibitors.

Currently, the most effective therapy for HCV uses a combination of interferon alfa and ribavirin, which leads to sustained efficacy in approximately 40% of patients (Poynard et al., Lancet 1998, 352, 1426-1432). Recent clinical results demonstrate that pegylated alpha interferon is superior to unmodified alpha interferon as monotherapy. However, even with experimental therapeutic regimens involving combinations of pegylated interferon alpha and ribavirin, a substantial fraction of patients do not have a sustained reduction in viral load (Manns et al, Lancet 2001, 358, 958-965; Fried et al ., N. Engl. J. Med. 2002, 347, 975982; Hadziyannis et al., Ann. Intern. Med 2004, 140, 346-355). Therefore, there is a clear and unmet need to develop effective therapeutic products for the treatment of HCV infection.

Macrocyclic serine protease inhibitor compounds and pharmaceutical compositions comprising the compounds are provided herein. Compounds are also provided for use in the treatment of an HCV infection in a host that needs it.

In one embodiment, a compound of formula I is provided herein:

or an individual enantiomer, a racemic mixture or a mixture of diastereoisomers thereof; or a pharmaceutically acceptable salt or solvate thereof;

where:

R5 is -OH, -NR8R9, -NHS (O) 2R8, -NHS (O) 2NR8R9, NHC (O) R8, -NHC (O) NR8R9, -C (O) R9, or -C (O) NR8R9; where:

each R 8 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, heterocyclyl, (C 1-6 alkyl) - (C 3-7 cycloalkylene), - CH2NR8aR8b, -CH (R8c) NR8aR8b, -CHR8cCHR8dNR8aR8b, or -CH2CR8cR8dNR8aR8b, where:

each R8a, R8c, and R8d is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl, heterocyclyl, or (C6-14 aryl) - (alkylene C1-6); and

each R8b is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl, heterocyclyl, -S (O) kR11, -S (O) kNR11R12, - C (O) R11, -C (O) OR11, -C (O) NR11R12, or -C (= NR13) NR11R12; wherein each R11, R12, and R13 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl; or R11 and R12 together with the N atom to which they are attached form heterocyclyl; or

R8a and R8b together with the N atom to which they are attached form heterocyclyl; and

each R9 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl; or

R8 and R9 together with the N atom to which they are attached form heterocyclyl;

R 6 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl;

L is a bond, C1-6 alkylene, C3-7 cycloalkylene, C2-6 alkenylene, C2-6 alkynylene, X, or - (CR6aR6b) pX-; where p is an integer 1, 2 or 3; R6a and R6b are each independently hydrogen, halogen, cyano, hydroxyl, or alkoxy; and X is -O-, -C (O) -, -C (O) O-, -OC (O) O-, -C (O) NR14-, -C (= NR14) NR15-, -NR14- , -NR14C (O) NR15-, -NR14C (= NR15) NR16-, -NR14S (O) kNR11-, -S (O) k-, -S (O) kNR14-, -P (O) (OR14) -, or -OP (O) (OR14) -, where each R14, R15 and

R16

it is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl;

Q1 is -O-, -N (R17) -, -C (R18R19) -, or -CR17 (NR18R19) -; where:

each R17 and R18 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C614 aryl, heteroaryl, or heterocyclyl; and

each R19 is independently -R20, -C (O) R20, -C (O) OR20, -C (O) NR21R22, -C (= NR20) NR21R22 or -S (O) kR20; wherein each R20, R21 and R22 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl; or R21 and R22 together with the N atom to which they are attached form heterocyclyl; or

R18 and R19 together with the C or N atom to which they are attached form C3-7 cycloalkyl or heterocyclyl;

Q2 is C3-9 alkylene, C3-9 alkenylene or C3-9 alkynylene, each optionally containing 1 to 3 heteroatoms in the chain, independently selected from O, N, and S; and

each k is independently an integer 1 or 2;

wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, aryl, cycloalkyl, cycloalkylene, heterocyclyl and heteroaryl optionally is substituted with one or more groups, each independently selected from cyano, halogen or nitro; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more, in one embodiment, with 1, 2, 3 or 4 Q substituents; or -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (NR8) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O ) NRbRc, -OC (= NRa) NRbRc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rb, - NRaC (O) ORb, -NRaC (O) NRbRc, -NRaC (= NRd) NRbRc, -NRaS (O) Rb, -NRaS (O) 2Rb, -NRaS (O) NRbRc, -NRaS (O) 2NRc, - SRa, -S (O) Ra, or -S (O) 2Ra; wherein each Ra, Rb, Rc and Rd is independently hydrogen; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more, in one embodiment, with 1, 2, 3 or 4 Q substituents; or Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, with 1, 2, 3 or 4 substituents Q;

wherein each Q is independently selected from the group consisting of cyano, halogen or nitro; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl; or -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (NRe) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O ) NRfRg, -OC (= NRe) NRfRg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rf, - NReC (O) ORf, -NReC (O) NRfRg, -NReC (= NRh) NRfRg, -NReS (O) Rf, -NReS (O) 2Rf, = NReS (O) NRfRg, -NReS (O) 2NRfRg, - SRe, -S (O) Re, or -S (O) 2Re; where each Re, Rf; Rg; and Rh is independently hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl; or Rf and Rg together with the N atom to which they are attached form heterocyclyl.

Pharmaceutical compositions comprising a compound described herein, e.g., are also provided herein. eg, a compound of formula I, including an individual enantiomer, a

racemic mixture or a mixture of diastereoisomers thereof; or a pharmaceutically acceptable salt or solvate thereof; in combination with one or more pharmaceutically acceptable excipients or vehicles.

In addition, a compound described herein is provided herein, e.g. eg, a compound of formula I, including an individual enantiomer, a racemic mixture or a mixture of diastereoisomers thereof; or a pharmaceutically acceptable salt or solvate thereof for use in the treatment or prevention of an HCV infection.

Additionally, a compound described herein is provided herein, e.g. eg, a compound of formula I, including an individual enantiomer, a racemic mixture or a mixture of diastereoisomers thereof; or a pharmaceutically acceptable salt or solvate thereof for use in the treatment, prevention or improvement of one or more symptoms of a liver disease or disorder associated with an HCV infection.

A compound described herein is provided herein, e.g. eg, a compound of formula I, including an individual enantiomer, a racemic mixture or a mixture of diastereoisomers thereof; or a pharmaceutically acceptable salt or solvate thereof for use in inhibiting the replication of a virus in a host.

A compound of formula I, including an individual enantiomer, a racemic mixture or a mixture of diastereoisomers thereof, is provided herein; or a pharmaceutically acceptable salt or solvate thereof, for use in inhibiting the activity of a serine protease.

To facilitate the understanding of the description set forth herein, a series of terms are defined below.

In general, the nomenclature used herein and the laboratory procedures of organic chemistry, medical chemistry and pharmacology described herein, are those known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used in general herein have the same meaning as an expert in the art to which this description belongs. In the event that there is a plurality of definitions for a term used herein, those in this section prevail unless otherwise stated.

The term "subject" refers to an animal, including, but not limited to, a primate (eg, human being), cow, sheep, goat, horse, dog, cat, rabbit, rat or mouse. The terms "subject" and "patient" are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject.

The term "host" refers to a unicellular or multicellular organism in which a virus can replicate, but is not limited to a cell, cell line and an animal, such as humans.

The terms "treat", "treating" and "treatment" are understood to include alleviating or suppressing a disorder, disease or condition, or one or more of the symptoms associated with the disorder, disease or condition; or alleviate or eradicate the cause or causes of the disorder, disease or condition itself.

The terms "prevent", "which prevents" and "prevention" are understood to include a procedure to delay and / or prevent the onset of a disorder, disease or condition, and / or the accompanying symptom (s); prevent a subject from acquiring a disease: or reduce a subject's risk of acquiring a disorder, disease or condition.

The term "therapeutically effective amount" is understood to include the amount of a compound that, when administered, is sufficient to prevent the development or alleviate to some extent, one or more of the symptoms of the disorder, disease or condition being treated. The term "therapeutically effective amount" also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal or human being that a researcher, veterinarian, doctor or clinician seeks.

The term "IC50" refers to an amount, concentration or dosage of a compound, which is necessary for 50% inhibition of a maximum response in an assay that measures said response.

The term "pharmaceutically acceptable excipient", "physiologically acceptable carrier" or "physiologically acceptable excipient" refers to a pharmaceutically acceptable carrier, composition or carrier, such as a solid or liquid filler, diluent, excipient, solvent or encapsulation material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of a pharmaceutical formulation and suitable for use in contact with cells, tissues or organs of humans and animals, without excessive toxicity, irritation, response. allergic, immunogenicity, or other problems or complications, consistent with a reasonable benefit / risk ratio. See, Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004.

The term "approximately" means an acceptable error for a particular value determined by one skilled in the art, which depends in part on how the value is measured or determined. In some embodiments, the term "approximately" means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% , 0.5%, or 0.05% of a given value or range.

The terms "active ingredient" and "active substance" refer to a compound that is administered alone or in combination with one or more pharmaceutically acceptable excipients, to a subject to treat, prevent or ameliorate one or more symptoms of a disorder, disease or condition. As used herein, "active ingredient" and "active substance" may be an optically active isomer of a compound described herein.

The terms "drug", "therapeutic agent" and "chemotherapeutic agent" refer to a compound, or a pharmaceutical composition thereof, that is administered to a subject to treat, prevent or ameliorate one or more symptoms of a condition, disorder or disease.

The term "excipient that controls release" refers to an excipient whose main function is to modify the duration or site of release of an active substance in a pharmaceutical form compared to a conventional immediate release pharmaceutical form.

The term "excipient that does not control release" refers to an excipient whose main function does not include modifying the duration or site of release of an active substance in a pharmaceutical form compared to a conventional immediate release pharmaceutical form.

The term "alkyl" refers to a saturated, linear or branched monovalent hydrocarbon radical, in which the alkylene may be optionally substituted as described herein. In some embodiments, the alkyl is a linear saturated monovalent hydrocarbon radical, having from 1 to 20 (C1-20), from 1 to 15 (C1-15), from 1 to 10 (C1-10), or from 1 to 6 (C1-6) carbon atoms, or branched saturated monovalent hydrocarbon radical from 3 to 20 (C3-20), from 3 to 15 (C3-15), from 3 to 10 (C3-10), or from 3 to 6 (C3-6) carbon atoms. As used herein, branched C1-6 linear and C3-6 alkyl groups are also referred to as "lower alkyl." Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, sec-butyl, t -butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms). For example, C1-6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.

The term "alkylene" refers to a saturated, linear or branched divalent hydrocarbon radical, in which the alkylene may be optionally substituted as described herein. The term "alkylene" encompasses both linear and branched alkylene, unless otherwise specified. In some embodiments, the alkylene is a linear saturated divalent hydrocarbon radical, having 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (C1-6) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (C320), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 ( C3-6) carbon atoms. As used herein, the C1-6 linear and C3-6 branched alkylene groups are also referred to as "lower alkylene." Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene (including all isomeric forms), n-propylene, isopropylene, butylene (including all isomeric forms), n-butylene, isobutylene, t-butylene, pentylene (including all isomeric forms), and hexylene (including all isomeric forms). For example, C1-6 alkylene refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms.

The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, of 1 to 5 carbon-carbon double bonds. The alkenyl may be optionally substituted as described herein. The term "alkenyl" also encompasses radicals having "cis" and "trans" configurations, or alternatively, "Z" and "E" configurations, as those skilled in the art will appreciate. As used herein, the term "alkenyl" encompasses both linear and branched alkenyl, unless otherwise specified. For example, C2-6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In some embodiments, the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2- 6) carbon atoms, or a branched monovalent hydrocarbonate radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3- 6) carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propen-1-yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl.

The term "alkenylene" refers to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, of 1 to 5 carbon-carbon double bonds. Alkenylene may be optionally substituted as described herein. Similarly, the term "alkenylene" also encompasses radicals having "cis" and "trans" configurations, or alternatively, "Z" and "E" configurations. As used herein, the term "alkenylene" encompasses both linear and branched alkenylene, unless otherwise specified. For example, C2-6 alkenylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In some embodiments, the alkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2- 6) carbon atoms, or a branched divalent hydrocarbonate radical of 3 to 20 (C320), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms Examples of alkenylene groups include, but are not limited to, ethenylene, alylene, propenylene, butenylene, and 4-methylbutenylene.

5 The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, of 1 to 5 triple carbon-carbon bonds. The alkynyl may be optionally substituted as described herein. The term "alkynyl" encompasses both linear and branched alkynyl, unless otherwise specified. In some embodiments, the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2- 6) carbon atoms, or a hydrocarbonate radical

10 monovalent branched from 3 to 20 (C3-20), from 3 to 15 (C3-15), from 3 to 10 (C3-10), or from 3 to 6 (C3-6) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH) and propargyl (-CH2C≡CH). For example, C2-6 alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.

The term "alkynylene" refers to a linear or branched divalent hydrocarbon radical, which contains one or more,

fifteen in one embodiment, from 1 to 5 triple carbon-carbon bonds. The alkynylene may be optionally substituted as described herein. The term "alkynylene" encompasses both linear and branched alkynylene, unless otherwise specified. In some embodiments, the alkynylene is a linear divalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2- 6) carbon atoms, or a branched divalent hydrocarbonate radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3- 6) atoms of

twenty carbon. Examples of alkynylene groups include, but are not limited to, ethynylene (-C≡C-) and propargylene (-CH2C≡C-). For example, C2-6 alkynylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms.

The term "cycloalkyl" refers to a cyclic saturated monovalent hydrocarbon radical, bridged and / or bridged, which may be optionally substituted as described herein. In some

25 embodiments, the cycloalkyl has 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 7 (C3-7) carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl and adamantyl.

The term "cycloalkylene" refers to a cyclic saturated divalent hydrocarbon radical, with bridge and / or without bridge, which may be optionally substituted as described herein. In some

30 embodiments, the cycloalkylene has 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 7 (C3-7) carbon atoms. Examples of cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, decalinylene and adamantylene.

The term "aryl" refers to a monocyclic aromatic group and / or multicyclic monovalent aromatic group containing at least one aromatic hydrocarbon ring. In some embodiments, the aryl has 6 to 20 (C6-20), 6 35 to 15 (C6-15), or 6 to 10 (C6-10) ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, antryl, phenanthryl, pyrenyl, biphenyl and terphenyl. Aryl also refers to bicyclic or tricyclic carbon rings, in which one of the rings is aromatic and the others can be saturated, partially unsaturated or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In some embodiments, the aryl may also be optionally substituted with one or more substituents Q

40 as described herein.

The term "arylene" refers to a monocyclic and / or multicyclic divalent aromatic group containing at least one aromatic hydrocarbon ring. In some embodiments, arylene has 6 to 20 (C6-20), 6 to 15 (C6-15), or 6 to 10 (C6-10) ring atoms. Examples of arylene groups include, but are not limited to, phenylene, naphthylene, fluorethylene, azulenylene, antrylene, phenanthylene, pyrethylene, biphenylene and terphenylene. Arylene also refers to

Four. Five bicyclic or tricyclic carbon rings, in which one of the rings is aromatic and the others can be saturated, partially unsaturated or aromatic, for example, dihydronaphthylene, indenylene, indanylene, or tetrahydronaphthylene (tetralinyl). In some embodiments, arylene may also be optionally substituted as described herein.

The term "heteroaryl" refers to a monocyclic aromatic group and / or multicyclic aromatic group containing the

fifty at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S and N. Each ring of a heteroaryl group may contain one or two atoms of O, one or two atoms of Z and of one to four atoms of N, with the proviso that the total number of heteroatoms in each ring is 4 or less, and each ring contains at least one carbon atom. In some embodiments, the heteroaryl has 5 to 20, 5 to 15, or 5 to 10 ring atoms. The examples of groups

55 Monocyclic heteroaryls include, but are not limited to, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl. Examples of bicyclic heteroaryl groups include, but not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, isobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, purinyl, pyrrolopyridinyl,

60 furopyridinyl, thienopyridinyl, dihydroisoindolyl, and tetrahydroquinolinyl. Examples of tricyclic heteroaryl groups include, but are not limited to, carbazolyl, bencindolyl, phenantholinyl, acridinyl, phenanthridinyl and xanthenyl. In some embodiments, the heteroaryl may also be optionally substituted with one or more substituents Q as described herein.

The term "heterocyclyl" or "heterocyclic" refers to a non-aromatic monocyclic ring system and / or system of

5 multicyclic rings, containing at least one non-aromatic ring, wherein one or more of the atoms of the non-aromatic ring are heteroatoms independently selected from O, S or N; and the rest of the ring atoms are carbon atoms. In some embodiments, the heterocyclyl or heterocyclic group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. In some embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include a fused or fused ring system.

10 bridge, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic. The heterocyclyl can be attached to the main structure of any heteroatom or carbon atom that results in the creation of a stable compound. Examples of such heterocyclic radicals include, but are not limited to, acridinyl, azepinyl, benzimidazolyl, bencindolyl, benzoisoxazolyl, bencisoxazinyl,

fifteen benzodioxanyl, benzodioxolyl, benzofuranonyl, benzofuranyl, benzonaftofuranilo, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahidrotienilo, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzothiopyranyl, benzoxazinyl, benzoxazolyl, benzothiazolyl, β-carbolinyl, carbazolyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dibenzofuranyl, dihydrobenzothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydropyranyl, dioxolanyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrazzolyl, dihydropyrimidinyl,

twenty dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, imidazopyridinyl, imidazothiazolyl, indazolyl, indolinyl, indolizinyl, indolyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroindolyl, octahydroisoindolyl, oxadiazolyl, oxazolidinonyl, oxazolidinyl, oxazolopyridinyl, oxazolyl, oxyranyl, perimidinyl, phenanthridinyl, phenatrolinyl, fenarsazinyl, phenazinyl,

25 phenothiazinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, 4-piperidonyl, pteridinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridopyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuryl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, tetrazolyl, thiadiazolopyrimidinyl, thiadiazolyl, thiamorpholinyl, thiazolidinyl, thiazolyl, thienyl, triazinyl, triazolyl, and 1,3,5-trityanyl. In some embodiments, the heterocyclic may also be optionally substituted.

30 with one or more substituents Q as described herein.

The term "alkoxy" refers to a radical -OR, in which R is, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each as defined herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, n-propoxy, 2-propoxy, n-butoxy, isobutoxy, tert-butoxy, cyclohexyloxy, phenoxy, benzoxy, and 2-naphthyloxy. In some embodiments, the alkoxy may also be optionally substituted as

35 It is described herein.

The term "acyl" refers to a radical -C (O) R, wherein R is, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each as defined herein. Examples of acyl include, but are not limited to, acetyl, propionyl, butanoyl, isobutanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, dodecanoyl, tetradecanoyl, hexadecanoyl, octadecanoyl, eicosanoyl, docosanoyl, myristoleoyl,

40 palmitoleoyl, oleoyl, linoleoyl, arachidonoyl, benzoyl, pyridinylcarbonyl, and furoyl. In some embodiments, the acyl may also be optionally substituted as described herein.

The term "halogen", "halide" or "halogen-" refers to fluorine, chlorine, bromine and / or iodine.

The term "optionally substituted" is intended to mean that a group, such as an alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, heteroaryl, heterocyclyl, alkoxy, or acyl group, may be substituted with one or more substituents independently selected from, e.g. eg, alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, heteroaryl or heterocyclyl, each optionally substituted with one or more, in one embodiment, with 1, 2, 3 or 4 substituents Q ; halogen, cyano (-CN), nitro (-NO2), -SRa, -S (O) Ra, -S (O) 2Ra, -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (NRa) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc, -OC (= NRa) NRbRc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, 50 -OS (O) 2 NRbRc, -NRbRc, -NRaC (O) Rb, -NRaC (O) OR b, -NRaC (O) NRbRc, NRaC (= NRd ) NRbRc, NRaS (O) Rb, -NRaS (O) 2Rb, -NRaS (O) RbRc, or NRaS (O) 2RbRc; wherein each Ra, Rb, Rc, and Rd is independently hydrogen; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more, in one embodiment, with 1, 2, 3 or 4 Q substituents; or Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment,

55 with 1, 2, 3 or 4 substituents Q. As used herein, all groups that may be substituted are "optionally substituted" unless otherwise specified.

In one embodiment, each Q is independently selected from the group consisting of cyano, halogen and nitro; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl and heterocyclyl; and -C (O) Re, -C (O) ORc, -C (O) NRfRg, -C (NRe) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O ) NRfRg, -OC (= NRe) NRfRg, -OS (O) Re, -OS (O) 2Re, 60 -OS (O) NRfRg, -OS (O) 2NRfRg, NRfRg, -NReC (O) Rf, - NReC (O) ORf, -NReC (O) NRfRg, -NRcC (= NRh) NRfRg, -NReS (O) Rf, -NReS (O) 2Rf -NReS (O) NRfRg, -NReS (O) 2NRfRg, -SRe , -S (O) Rc and -S (O) 2Re; where each Re, Rf, Rg, and Rh is

independently hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl; or Rf and Rg together with the N atom to which they are attached form heterocyclyl.

In some embodiments, "optically active" and "enantiomerically active" refer to a collection of molecules, which have an enantiomeric excess not less than about 50%, not less than about 70%, not less than about 80%, not less than approximately 90%, not less than approximately 91%, not less than approximately 92%, not less than approximately 93%, not less than approximately 94%, not less than approximately 95%, not less than approximately 96%, not less than approximately 97%, not less than approximately 98%, not less than approximately 99%, not less than approximately 99.5%, or not less than approximately 99.8%. In some embodiments, the compound comprises about 95% or more of the desired enantiomer and about 5% or less of the less preferred enantiomer, based on the total weight of the racemate in question.

When an optically active compound is described, the prefixes R and S are used to indicate the absolute configuration of the molecule around its or its chiral centers. The (+) and (-) are used to indicate the optical rotation of the compound, that is, the direction in which the optically active compound rotates a plane of polarized light. The prefix (-) indicates that the compound is levorotatory, that is, the compound rotates the polarized plane of light to the left or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise. However, the sign of optical rotation, (+) and (-), is not related to the absolute configuration of the molecule, R and S.

The term "solvate" refers to a compound provided herein or a salt thereof, which also includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

Compounds

HCV has a positive single stranded RNA genome that is approximately 9.6 kb in length and encodes a large polyprotein that is approximately 3010 amino acids. This polyprotein precursor is then processed into a variety of structural proteins, which include the core protein, C, and envelope glycoproteins, E1 and E2; and non-structural proteins, which include NS2, NS3, NS4A, NS4B, NS5A and NS5B, by the host signal peptidases and two viral proteases, NS2-3 and NS3. The NS3 protein contains a trypsin-like serine protease domain at its N-terminus, while its C-terminal domain has helicase activity. Because of its vital role in viral replication, HCV NS3 serine protease has been actively pursued as a drug target to develop a new HCV therapy.

HCV NS3 protease inhibitors have been described which have been described that include linear and cyclic peptides and non-peptide molecules (Llinàs-Brunet et al., Bioorg. Med. Chem. Lett. 1998, 8, 17131718; Steinkühler et al., Biochemistry 1998, 37, 8899-8905; US Pat. No. 5,538,865; 5,990,276; 6,143,715; 6,265,380; 6,323,180; 6,329,379; 6,410,531; 6,420,380; 6,534,523; 6,608,027; 6,642,204; 6,653,295; 6,727,366; 6,838,475; 6,846,802; 6,867,185; 6,869,964; 6,872,805; 6,878,722; 6,908,901; 6,911,428; 6,995,174; 7,012,066; 7,041,698; 7,091,184; 7,169,760; 7,176,208; 7,208,600; U.S. patent application publications No.: 2002/0016294; 2002/0016442; 2002/0032175; 2002/0037998; 2004/0229777; 2005/0090450; 2005/0153877; 2005/176648; 2006/0046956; 2007/0021330; 2007/0021351; 2007/0049536; 2007/0054842; 2007/0060510; 2007/0060565; 2007/0072809; 2007/0078081; 2007/0078122; 2007/0093414; 2007/0093430; 2007/0099825; 2007/0099929; 2007/0105781; WO98 / 17679; WO98 / 22496; WO99 / ​​07734; WO00 / 09543; WO00 / 59929; WO02 / 08187; WO02 / 08251; WO02 / 08256; WO02 / 08198; WO02 / 48116; WO02 / 48157; WO02 / 48172; WO02 / 60926; WO03 / 53349; WO03 / 64416; WO03 / 64455; WO03 / 64456; WO03 / 66103; WO03 / 99274; WO03 / 99316; WO2004 / 032827; WO2004 / 043339; WO2005 / 037214; WO2005 / 037860; WO2006 / 000085; WO2006 / 119061; WO2006 / 122188; WO2007 / 001406; WO2007 / 014925; WO2007 / 014926; WO2007 / 015824, and WO2007 / 056120) .However, the citation of any reference herein is not an admission that said reference is prior art with respect to the present description.

Compounds that are useful for the treatment of HCV infection are provided herein, which, in one embodiment, may have activity as HCV serine protease inhibitors. Pharmaceutical compositions comprising the compounds, and compounds for use in the treatment of HCV infection in a host in need of treatment are also provided herein.

In one embodiment, a compound of formula I is provided herein:

or an individual enantiomer, a racemic mixture or a mixture of diastereoisomers thereof; or a pharmaceutically acceptable salt or solvate thereof;

where:

R5 is -OH, -NR8R9, -NHS (O) 2R8, -NHS (O) 2NR8R9, -NHC (O) R8, -NHC (O) NR8R9, -C (O) R9, or -C (O) NR8R9 ; where:

each R 8 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, heterocyclyl, (C 1-6 alkyl) - (C 3-7 cycloalkylene), - CH2NR8aR8b, -CH (R8c) NR8aR8b, -CHR8cCHR8dNR8aR8b, or -CH2CR8cR8dNR8aR8b, where:

each R8a, R8c, and R8d is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl, heterocyclyl, or (C6-14 aryl) - (alkylene C1-6); and

each R8b is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl, heterocyclyl, -S (O) kR11, -S (O) kNR11R12, - C (O) R11, -C (O) OR11, -C (O) NR11R12, or -C (= NR13) NR11R12; wherein each R 11, R 12, and R 13 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl; or R11 and R12 together with the N atom to which they are attached form heterocyclyl; or

R8a and R8b together with the N atom to which they are attached form heterocyclyl; and

each R9 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl; or

R8 and R9 together with the N atom to which they are attached form heterocyclyl;

R 6 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl;

L is a bond, C1-6 alkylene, C3-7 cycloalkylene, C2-6 alkenylene, C2-6 alkynylene, X, or - (CR6aR6b) pX-; where p is an integer 1, 2 or 3; R6a and R6b are each independently hydrogen, halo, cyano, hydroxyl, or alkoxy; and X is -O-, -C (O) -, -C (O) O-, -OC (O) O-, -C (O) NR14-, -NR14C (O) NR15-, -C (= NR14) NR15-, -NR14C (= NR15) NR16-, -

R14 R15R16

NR14S (O) kNR15-, -S (O) k-, -S (O) kNR14 -, - P (O) (OR14) -, or -OP (O) (OR14) -, where each, and is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl;

Q1 is -O-, -N (R17) -, -C (R18R19) -, or -CR17 (NR18R19) -; where:

each R17 and R18 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6 aryl

14, heteroaryl, or heterocyclyl; and each R19 is independently -R20, -C (O) R20, -C (O) OR20, -C (O) NR21R22, -C (= NR20) NR21R22, or -S (O) kR20; wherein each R20, R21 and R22 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl; or R21 and R22 together with the N atom to which they are attached form heterocyclyl; or

R18 and R19 together with the C or N atom to which they are attached form cycloalkyl or heterocyclyl;

Q2 is C3-9 alkylene, C3-9 alkenylene or C3-9 alkynylene, each optionally containing 1 to 3 heteroatoms in the chain, independently selected from O, N, and S; and each k is independently an integer 1 or 2; wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, aryl, cycloalkyl, cycloalkylene,

heterocyclyl and heteroaryl is optionally substituted with one or more groups, each independently selected from cyano, halogen, or nitro; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more, in one embodiment, with 1, 2, 3 or 4 Q substituents; or -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (NRa) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O ) NRbRc, 5 -OC (= NRa) NRbRc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, NRaC (O) Rb, - NRaC (O) ORb, -NRaC (O) NRbRc, -NRaC (= NRd) NRbRc, -NRaS (O) Rb, NRaS (O) 2Rb, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, -SRa , -S (O) Ra or -S (O) 2Ra; wherein each Ra, Rb, Rc and Rd is independently hydrogen; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more, in one embodiment, with 1, 2, 3 or 4 Q substituents; or Rb and Rc together with the atom of N to which they are attached form

10 heterocyclyl, optionally substituted with one or more, in one embodiment, with 1, 2, 3 or 4 substituents Q;

wherein each Q is independently selected from the group consisting of cyano, halogen, or nitro; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl; or -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (NRe) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O ) NRfRg, -OC (= NRe) NRfRg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rf, - NReC (O) ORf, -NReC (O) NRfRg, -NReC (= NRh) NRfRg, -NReS (O) Rf,

fifteen -NReS (O) 2Rf, -NReS (O) NRfRg, -NReS (O) 2NRfRg, -SRe, -S (O) Re or -S (O) 2Re; wherein each Re, Rf, Rg and Rh is independently hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl; or Rf and Rg together with the N atom to which they are attached form heterocyclyl.

In yet another embodiment, the compound of formula I has the structure of formula II:

twenty where:

R6, L, Q1, and Q2 are each as defined herein; and

R30

it is hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, heterocyclyl or (C 1-6 alkyl) - (C 3-7 cycloalkylene), each optionally substituted with one or more substituents Q; or -CH2NR30aR30b, -CHR30cNR30aR30b, -CHR30cCHR30dNR30aR30b, or -CH2CR30cR30dNR30aR30b, where:

25 each R30a, R30c and R30d is independently hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, heterocyclyl, or (C 6-14 aryl) - (C 1-6 alkylene), each optionally substituted with one or more substituents Q; and

each R30b is independently hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q; -S (O) kR11,

30 -S (O) kNR11R12, -C (O) R11, -C (O) OR11, -C (O) NR11R12, or -C (= NR13) NR11R12; wherein each R11, R12 and R13 is independently hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q; or R11 and R12 together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q; or

R30e and R30b together with the N atom to which they are attached form heterocyclyl or heteroaryl, each optionally substituted with one or more substituents Q.

In yet another embodiment, the compound of formula I has the structure of formula III: wherein:

R5, L, Q1, and Q2 are each as defined herein; and

Z is CR3 'or N;

5 R2 ', R3', R5 ', R6', R7 ', and R8' are each independently:

hydrogen, halogen, cyano, trifluoromethyl or nitro;

C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described herein; or

<dl><dt>-</dt><dd>C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (NRe) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc , -OC (= NRa) NRbRc, </dd></dl>

10 -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rb, -NRaC (O) ORb, -NRaC (O) NRbRc, NRaC (= NRd) NRbRc, NRaS (O) Rb, -NRaS (O) 2Rb, -NRaS (O) NRbRc, -NReS (O) 2NRbRc, -SRa, -S (O) Ra or -S (O ) 2Ra; wherein each Re, Rb, Rc and Rd is independently hydrogen; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described herein; or Rb and Rc together with the N atom to which they are attached form heterocyclyl,

fifteen optionally substituted with one or more substituents Q as described herein.

In yet another embodiment, the compound of formula I has the structure of formula IV:

wherein R30, R2 ', R3', R5 ', R6', R7 ', R8', L, Q1, Q2 and Z are each as defined herein.

In some embodiments, Q2 is C3-9 alkylene. In some embodiments, Q2 is C3-9 alkenylene. In some embodiments, Q2 is C3-9 alkenylene having a carbon-carbon double bond in cis or trans configuration. In some embodiments, Q2 is C3-9 alkenylene having a carbon-carbon double bond in cis configuration. In some embodiments, Q2 is C3-9 alkynylene.

In some embodiments, Q2 is selected from the group consisting of:

where:

Z is -O-, -S-, or N (RZ) -, where RZ is hydrogen, C1-6 alkyl, aryl, heteroaryl, heterocyclyl, -C (O) RZa, -C (O) ORZa, 10 - C (O) NRZbRZc, -S (O) 2NRZbRzc, or -S (O) 2RZa; and

each RZa, RZb and RZc is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl; or RZb and RZc together with the N atom to which they are attached form heterocyclyl or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl optionally is substituted with one or more substituents Q as described herein. In one embodiment, the compound of formula I has the structure of formula V:

wherein R5, R6, L and Q1 are each as defined herein; and 20 n is an integer 0, 1, 2, 3, 4 or 5. In yet another embodiment, the compound of formula V has the structure of formula VI:

wherein R6, R30, L, Q1 and n are each as defined herein. In yet another embodiment, the compound of formula V has the structure of formula VII:

wherein R5, R2 ', R3', R5 ', R6', R7 ', R8', L, Q1, Z and n are each as defined herein. In yet another embodiment, the compound of formula V has the structure of formula VIII:

wherein R30, R2 ', R3', R5 ', R6', R7 ', R8', L, Q ', Z and n are each as defined herein.

The groups R5, R6, R30, R2 ', R3', R5 ', R6', R7 ', R8', L, Q1, Q2 and n in formulas I, II, III, IV, V, VI, VII and VIII they are also as defined herein. All combinations of the embodiments provided herein for such groups are within the scope of this description.

In some embodiments, n is 0, 1, 2, 3, 4, or 5. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3 In some embodiments, n is 4. In some embodiments, n is 5.

In some embodiments, R6 is hydrogen. In some embodiments, R 6 is C 1-6 alkyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described herein. In some embodiments, R6 is C1-6 alkyl, optionally substituted with one or more Q substituents. In some embodiments, R6 is C2-6 alkenyl, optionally substituted with one or more Q substituents. In some embodiments, R6 is C2-6 alkynyl, optionally substituted with one or more substituents Q. In some embodiments, R6 is C3-7 cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R6 is C6-14 aryl , optionally substituted with one or more substituents Q. In some embodiments, R6 is heteroaryl, optionally substituted with one or more substituents Q. In some embodiments, R6 is heterocyclyl, optionally substituted with one or more substituents Q.

In some embodiments, R6 is selected from the group consisting of:

where

R2 ', R3', R5 ', R6', R7 'and R8' are each as defined herein;

R1 'is independently:

hydrogen, halogen, cyano, trifluoromethyl or nitro;

C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described herein; or

<dl><dt>-</dt><dd>C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (NRe) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc , -OC (= NRa) NRbRc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rb, NRaC (O ) ORb, -NRaC (O) NRbRc, -NRaC (= NRd) NRbRc, -NRaS (O) Rb, -NRaS (O) 2Rb, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, -SRa, - S (O) Ra, or -S (O) 2Ra; wherein each Ra, Rb, Rc and Rd is independently hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described herein; or Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q as described herein; and</dd></dl>

Each asterisk (*) represents the point of attachment.

In some embodiments, R 2 'is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described in This memory. In some embodiments, R2 'is C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described herein.

In some embodiments, R2 'is selected from the group consisting of:

where

each A is independently hydrogen, halogen, cyano or nitro; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more Q substituents as described herein; or -C (O) Ra, -C (O) ORa, -C (O) NRdRc, -C (NRa) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O ) NRbRc, -OC (= NRa) NRbRc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, NRaC (O) Rb, -NRaC (O) ORb, -NRaC (O) NRbRc, -NRaC (= NRd) NRbRc, NRaS (O) Rb, NRaS (O) 2Rb, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, -SRa, - S (O) Ra, or -S (O) 2Ra; wherein each Ra, Rb, Rc and Rd is independently hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each

fifteen optionally substituted with one or more substituents Q as described herein; or Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q as described herein;

each E is independently hydrogen; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described in 20 the present report; or -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (NRa) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc, -OC (= NRa) NRbRc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, NRaC (O) Rb, -NRaC (O) ORb, -NRaC (O) NRbRc, NRaC (= NRd) NRbRc, -NRaS (O) Rb, -NRaS (O) 2Rb, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, -SRa, -S (O) Ra, or -S (O) 2Ra; wherein each Ra, Rb, Rc and Rd is independently hydrogen; C1-6 alkyl, alkenyl C2-6, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one

25 or more substituents Q as described herein; or Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q as described herein;

and each asterisk (*) is the point of attachment.

In some embodiments, A is hydrogen, halogen, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, wherein each alkyl, alkenyl, Alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one or more substituents Q as described herein.

In some embodiments, A is hydrogen, halogen, cyano, or nitro; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, alkoxy

5 C1-6, C1-6 alkylamine (i.e. -NRbRc, where Rb is hydrogen and Rc is C1-6 alkyl), or di (C1-6 alkyl) amino (ie, -NRbRc, where Rb and Rc are each one independently C1-6 alkyl), each optionally substituted with one or more substituents Q as described herein.

In some embodiments, A is hydrogen or C1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, A is hydrogen. In some embodiments, A 10 is C 1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, A is C2-6 alkenyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, A is C2-6 alkynyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, A is C3-7 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, A is C6-14 aryl, optionally substituted with one or more substituents Q as described herein. In some embodiments, A is heteroaryl, optionally substituted with one or more substituents Q as described herein. In some embodiments, A is heterocyclyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, A is -ORa, where Ra is as defined herein. In some embodiments, A is -NRbRc, where Rb and Rc are

twenty each as defined herein. In some embodiments, A is isopropylamino.

In some embodiments, A is hydrogen, cyano, fluoro, methyl, ethyl, n-propyl, isopropyl, isobutyl, isopentyl, trifluoromethyl, ethenyl, ethynyl, cyclopropyl, cyclobutyl, benzyl, 2-morpholin-4-yl-ethyl, methoxy, ethoxy or isopropylamino. In some embodiments, A is hydrogen, cyano, methyl, isopropyl, isobutyl, trifluoromethyl, cyclopropyl, cyclobutyl, ethenyl, ethynyl, methoxy, ethoxy or isopropylamino.

25 In some embodiments, E is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heterocyclyl or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one or more substituents Q as described herein. In some embodiments, E is hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, isopentyl, trifluoromethyl, benzyl, 2-morpholin-4-yl-ethyl, cyclobutyl, ethynyl, methoxy, ethoxy or isopropylamino. In some embodiments, E is

30 hydrogen, methyl, ethyl, n-propyl, isopropyl, isobutyl, isopentyl, benzyl or 2-morpholin-4-yl-ethyl.

In some embodiments, R2 'is selected from the group consisting of: In some embodiments, L is a link. In some embodiments, L is C1-6 alkylene, optionally substituted with one or more substituents Q as described herein.

In some embodiments, L is - (CR6aR6b) pX-, wherein R6a, R6b, X and p are each as defined herein.

5 memory. In some embodiments, R6a and R6b are each independently hydrogen or halogen. In some embodiments, L is - (CR6aR6b) pO-, wherein R6a, R6b and p are each as defined herein. In some embodiments, L is - (CR6aR6b) pC (O) -, wherein R6a, R6b and p are each as defined herein. In some embodiments, L is - (CR6aR6b) pC (O) O- wherein R6a, R6b, and p are each as defined herein. In some embodiments, L is - (CR6aR6b) pOC (O) -, where R6a, R6b and p are each

10 as defined herein. In some embodiments, L is - (CR6aR6b) pOC (O) O-, wherein R6a, R6b and p are each as defined herein. In some embodiments, L is - (CR6aR6b) pC (O) NR14-, wherein R6a, R6b, R14 and p are each as defined herein. In some embodiments, L is - (CR6aR6b) pNR14C (O) -, wherein R6a, R6b, R14 and p are each as defined herein. In some embodiments, L is - (CR6aR6b) pNR14C (O) NR15-, where R6a, R6b, R14, R15 and p are each as

fifteen defined herein. In some embodiments, L is - (CR6aR6b) pC (= NR14) NR15-, where R6a, R6b, R14,

R15

and p are each as defined herein. In some embodiments, L is - (CR6aR6b) pNR14C (= NR15) -, where R6a, R6b, R14, R15 and p are each as defined herein. In some embodiments, L is - (CR6aR6b) pNR14C (= NR15) NR16-, wherein R6a, R6b, R14, R15, R16 and p are each as defined herein. In some embodiments, L is - (CR6aR6b) pS (O) k-, where R6a, R6b, kyp

they are each as defined herein. In some embodiments, L is - (CR6aR6b) pS (O) kNR14-, wherein R6a, R6b, R14, k and p are each as defined herein. In some embodiments, L is - (CR6aR6b) pNR14S (O) k-, wherein R6a, R6b, R14, k and p are each as defined herein. In some embodiments, L is - (CR6aR6b) pNR14S (O) kNR15-, wherein R6a, R6b, R14, R15, k and p are each as defined herein. In some embodiments, L is - (CR6aR6b) pP (O) OR14-, wherein R6a, R6b, R14, k and p are each as defined herein. In some embodiments, L is - (CR6aR6b) pOP (O) OR14-, wherein R6a, R6b, R14, k and p are each as defined herein.

In some embodiments, L is - (CH2) p-, where p is as defined herein. In some embodiments, -CH2-. L is in some embodiments, L is - (CH2) pCF2- or -CF2 (CH2) p-, where p is as defined herein. In some embodiments, L is -CF2-. In some embodiments, L is - (CH2) pO-, where p is as defined herein. In some embodiments, L is - (CH2) pC (O) -, where p is as defined herein. In some embodiments, L is - (CH2) pC (O) O-, where p is as defined herein. In some embodiments, L is - (CH2) pOC (O) -, where p is as defined herein. In some embodiments, L is - (CH2) pC (O) NR14-, where R14 and p are as defined herein. In some embodiments, L is - (CH2) pNR14C (O) -, wherein R14 and p are as defined herein. In some embodiments, L is - (CH2) pNR14C (O) NR15-, wherein R14, R15 and p are as defined herein.

In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

In some embodiments, L is C2-6 alkenylene, optionally substituted with one or more substituents Q. In some embodiments, L is C2-6 alkynylene, optionally substituted with one or more substituents Q. In some embodiments, L is C3-7 cycloalkylene , optionally substituted with one or more substituents Q.

In some embodiments, L is -X-, where X is as defined herein. In some embodiments, L is -O-. In some embodiments, L is -C (O) -. In some embodiments, L is -C (O) O-. In some embodiments, L is -OC (O) -. In some embodiments, L is -OC (O) O-. In some embodiments, L is -C (O) NR14-, where R14 is as defined herein. In some embodiments, L is -C (= NR14) NR15-, where R14 and R15 are each as defined herein. In some embodiments, L is -NR14-, where R14 is as defined herein. In some embodiments, L is -NR14C (O) -, where R14 is as defined herein. In some embodiments, L is -NR14C (O) NR15-, wherein R14 and R15 are each as defined herein. In some embodiments, L is -NR14C (= NR15) -, where R14 and R15 are each as defined herein. In some embodiments, L is -NR14C (= NR15) NR16-, wherein R14, R15 and R16 are each as defined herein. In some embodiments, L is -NR14S (O) k-, where R14 and k are each as defined herein. In some embodiments, L is -NR14S (O) kNR15-, where k, R14 and R15 are each as defined herein. In some embodiments, L is -S (O) k-, where k is as defined herein. In some embodiments, L is -S (O) kNR14-, where R14 and k are each as defined herein. In some embodiments, L is -P (O) (OR14) -, where R14 is as defined herein. In some embodiments, L is -OP (O) (OR14) -, where R14 is as defined herein.

In some embodiments, each R14 and R15 is independently hydrogen; C1-6 alkyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described herein. In some embodiments, each R14 and R15 is independently hydrogen; C1-6 alkyl, or C3-7 cycloalkyl, each optionally substituted with one or more substituents Q as described herein. In some embodiments, R14 and R15 are hydrogen.

In some embodiments, R3 'is hydrogen. In some embodiments, R5 'is hydrogen. In some embodiments, R3 'and R5' are hydrogen. In some embodiments, R5 'is methoxy.

In some embodiments, R6 'is hydrogen, hydroxyl, cyano or halogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described herein; or -ORa, wherein Ra is C1-6 alkyl, C26 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described in present memory

In some embodiments, R6 'is halogen or -ORa, where Ra is as defined herein. In some embodiments, R6 'is -ORa, where Ra is as defined herein. In some embodiments, R 8 is C 1-6 alkyl, C 3-7 cycloalkyl or C 6-14 aryl, each optionally substituted with one or more substituents Q as described herein. In some embodiments, Ra is C 1-6 alkyl or C 3-7 cycloalkyl, each optionally substituted with one or more substituents Q as described herein. In some embodiments, R6 'is methoxy. In some embodiments, R6 'is halogen. In some embodiments, R6 'is chlorine. In some embodiments, R6 'is fluoro. In some embodiments, R6 'is hydrogen.

In some embodiments, R 7 'is hydrogen, hydroxyl, cyano or halogen; C1-6 alkyl, C2-6 alkenyl, C26 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more

Q substituents as described herein; or -ORa, wherein Ra is C1-6 alkyl, C26 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described in present memory

In some embodiments, R7 'is halogen or -OR8, where Ra is as defined herein. In some embodiments, R7 'is -ORa, where Ra is as defined herein. In some embodiments, Ra is C 1-6 alkyl, C 3-7 cycloalkyl or C 6-14 aryl, each optionally substituted with one or more substituents Q as described herein. In some embodiments, Ra is C 1-6 alkyl or C 3-7 cycloalkyl, each optionally substituted with one or more substituents Q as described herein. In some embodiments, R7 'is methoxy. In some embodiments, R7 'is halogen. In some embodiments, R7 'is chlorine. In some embodiments, R7 'is fluoro. In some embodiments, R7 'is hydrogen.

In some embodiments, R6 'is -ORa and R7' is hydrogen, where Ra is as defined herein. In some embodiments, R6 'is methoxy and R7' is hydrogen.

In some embodiments, R6 'is hydrogen and R7' is -ORa, where Ra is as defined herein. In some embodiments, R6 'is hydrogen and R7' is methoxy.

In some embodiments, R8 'is hydrogen, hydroxyl, cyano or halogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described herein; or -ORa, wherein Ra is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-7 cycloalkyl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described In the present memory. In some embodiments, R8 'is hydrogen, halogen or C1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R8 'is hydrogen.

In some embodiments, R8 'is halogen. In some embodiments, R8 'is fluoro. In some embodiments, R8 'is chlorine. In some embodiments, R8 'is bromine. In some embodiments, R8 'is iodine.

In some embodiments, R8 'is C1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R8 'is methyl.

In some embodiments, R5 'is hydrogen or methoxy; R6 'is hydrogen or methoxy; R7 'is hydrogen, chlorine or methoxy; and R8 'is hydrogen, chlorine, fluoro, bromine or methyl. In some embodiments, R5 'is methoxy and R7' is fluoro. In some embodiments, R6 'is methoxy and R7' is chlorine. In some embodiments, R6 'is methoxy and R8' is methyl. In some embodiments, R7 'is methoxy and R8' is fluoro. In some embodiments, R7 'is methoxy and R8' is chlorine. In some embodiments, R7 'is methoxy and R8' is bromine. In some embodiments, R7 'is methoxy and R8' is methyl.

In some embodiments, R1 'is hydrogen.

In some embodiments, Q1 is -O-.

In some embodiments, Q1 is -N (R17) -, where R17 is as defined herein. In one embodiment, R17 is hydrogen; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described herein. In another embodiment, R17 is hydrogen; C1-6 alkyl or C3-7 cycloalkyl, each optionally substituted with one or more substituents Q as described herein. In yet another embodiment, R17 is hydrogen or C1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In yet another embodiment, R17 is hydrogen. In yet another embodiment, R17 is C1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In yet another embodiment, R17 is methyl.

In some embodiments, Q1 is -C (R18R19) -, where R18 and R19 are each as defined herein. In one embodiment, R18 and R19 are each independently hydrogen; C1-6 alkyl or C3-7 cycloalkyl, each optionally substituted with one or more substituents Q as described herein. In another embodiment, R18 is hydrogen. In yet another embodiment, R19 is hydrogen. In yet another embodiment, R18 and R19 are hydrogen. In another embodiment, R18 is C1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In yet another embodiment, R19 is C1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In yet another embodiment, R18 and R19 are each independently C1-6 alkyl, optionally substituted with one or more substituents Q as described herein.

In some embodiments, Q1 is -C (R18R19) -, wherein R18 and R19 together with the C atom to which they are attached form cycloalkyl, optionally substituted with one or more substituents Q as described herein.

In some embodiments, Q1 is -CR17 (NR18R19) -, where R17, R18 and R19 are each as defined herein. In one embodiment, R17 and R18 are each independently hydrogen; C1-6 alkyl or C3-7 cycloalkyl, each optionally substituted with one or more substituents Q as described in the

present memory In another embodiment, R17 is hydrogen or C1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In yet another embodiment, R17 is hydrogen. In yet another embodiment, R17 is C1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In yet another embodiment, R17 is methyl. In one embodiment, R18 is hydrogen or C1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In yet another embodiment, R18 is hydrogen. In yet another embodiment, R18 is C1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In yet another embodiment, R18 is methyl. In yet another embodiment, R17 and R18 are hydrogen.

In some embodiments, R19 is hydrogen, -C (O) R20, -C (O) OR20, -C (O) NR21R22, or -C (= NR20) NR21R22, wherein R20, R21 and R22 are each as defined herein. In some embodiments, R19 is hydrogen. In some embodiments, R19 is -C (O) R20, where R20 is as defined herein. In some embodiments, R19 is -C (O) NR21R22, wherein R21 and R22 are each as defined herein. In some embodiments, R19 is -C (= NR20) NR21R22, where R20, R21 and R22 are each as defined herein. In some embodiments, R21 and R22 together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q as described herein.

In some embodiments, R19 is -C (O) OR20, where R20 is as defined herein. In one embodiment, R20 is C1-6 alkyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described herein. In yet another embodiment, R20 is C1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In yet another embodiment, R20 is t-butyl. In yet another embodiment, R20 is C6-14 aryl, optionally substituted with one

or more substituents Q as described herein. In yet another embodiment, R20 is benzyl.

In some embodiments, R18 and R19 together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q as described herein.

In some embodiments, R5 is -OH.

In some embodiments, R5 is NR8R9, where R8 and R9 are as defined herein. In some embodiments, R8 and R9 together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q as described herein.

In some embodiments, R5 is -NHS (O) kR8, where R8 and k are each as defined herein. In some embodiments, R 8 is C 1-6 alkyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, heterocyclyl, or (C 1-6 alkyl) - (C 3-7 cycloalkylene), each optionally substituted with one or more substituents Q as described herein; or -CH2NR8aR8b, -CHR8cCHR8dR8aR8b or -CH2CR8cR8dNR8aR8b, where R8a, R8b, R8c and R8d are each as defined herein.

In some embodiments, R 8 is C 1-6 alkyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, heterocyclyl, or (C 1-6 alkyl) (C 3-7 cycloalkylene), each optionally substituted with one or more substituents Q as are described herein; or -CH2NR8aR8b, -CHR8cCHR8dNR8aR8b, or -CH2CR8cR8dNR8aR8b, where R8a, R8b, R8c and R8d are each as defined herein. In some embodiments, R 8 is C 1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R8 is methyl. In some embodiments, R8 is C3-7 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R8 is cyclopropyl, 1-methylcyclopropyl, 1-ethynylcyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R8 is C6-14 aryl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R8 is heteroaryl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R8 is heterocyclyl, optionally substituted with one or more substituents Q as described herein.

In some embodiments, R8 is -CH2NR8aR8b, where R8a and R8b are each as defined herein. In some embodiments, R8 is -CHR8cCHR8dNR8aR8b, where R8a, R8b, R8c and R8d are each as defined herein. In some embodiments, R8 is -CH2CR8cR8dNR8aR8b, where R8a, R8b, R8c and R8d are each as defined herein.

In some embodiments, R8 has the structure of

where R 'is hydrogen; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, halogen, heteroaryl

or heterocyclyl, each optionally substituted with one or more substituents Q as described herein. In one embodiment, R 'is C1-6 alkyl. In another embodiment, R 'is hydrogen. In yet another embodiment, R 'is methyl. In yet another embodiment, R 'is C2-6 alkynyl. In yet another embodiment, R 'is ethynyl.

55 Therefore, when R5 is -NHS (O) 2R8, R5 has the structure of

where R 'is as defined herein. In one embodiment, R 'is C1-6 alkyl. In another embodiment, R 'is hydrogen. In yet another embodiment, R 'is methyl. In yet another embodiment, R 'is C2-6 alkynyl. In yet another embodiment, R 'is ethynyl.

In some embodiments, R8a is hydrogen; C1-6 alkyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described herein. In some embodiments, R8a is hydrogen; C1-6 alkyl or C3-7 cycloalkyl, each optionally substituted with one or more substituents Q as described herein. In some embodiments, R8a is hydrogen. In some embodiments, R 8a is C 1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R8a is methyl. In some embodiments, R 8a is C 3-7 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R8a is C6-14 aryl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R8a is heteroaryl, optionally substituted with one

or more substituents Q as described herein. In some embodiments, R8a is heterocyclyl, optionally substituted with one or more substituents Q as described herein.

In some embodiments, R8b is hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described herein; or -S (O) kR11, -S (O) kNR11R12, -C (O) R11, -C (O) OR11, -C (O) NR11R12 or -C (= NR11) NR12R13, where R11, R12, R13 and k are each as defined herein. In some embodiments, R8b is hydrogen; C1-6 alkyl or C3-7 cycloalkyl, each optionally substituted with one or more substituents Q as described herein; or -C (O) R11, -C (O) OR11, or -C (O) NR11R12, wherein R11 and R12 are each as defined herein. In some embodiments, R8b is hydrogen. In some embodiments, R 8b is C 1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R8b is methyl, ethyl or isopropyl. In some embodiments, R 8b is C 3-7 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R8b is C6-14 aryl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R8b is phenyl, optionally substituted with one or more Q substituents. In some embodiments, R8b is (C6-14 aryl) - (C1-6 alkylene), each optionally substituted with one or more substituents Q as described herein. In some embodiments, R8b is benzyl. In some embodiments, R8b is -C (O) R11, where R11 is as defined herein. In some embodiments, R8b is -C (O) R11, and R11 is C1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R8b is acetyl. In some embodiments, R8b is -C (O) OR11, where R11 is as defined herein. In some embodiments, R8b is -C (O) OR11, and R11 is C1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R8b is -C (O) Ot-butyl (Boc). In some embodiments, R8b is -C (O) NR11R12, wherein R11 and R12 are each as defined herein.

In some embodiments, R8c is hydrogen; C1-6 alkyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described herein. In some embodiments, R8c is hydrogen; C1-6 alkyl or C3-7 cycloalkyl, each optionally substituted with one or more substituents Q as described herein. In some embodiments, R8c is hydrogen. In some embodiments, R8c is C1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R8c is methyl. In some embodiments, R8c is C3-7 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R8c is C6-14 aryl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R8c is heteroaryl, optionally substituted with one

or more substituents Q as described herein. In some embodiments, R8c is heterocyclyl, optionally substituted with one or more substituents Q as described herein.

In some embodiments, R8d is hydrogen; C1-6 alkyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described herein. In some embodiments, R8d is hydrogen; C1-6 alkyl or C3-7 cycloalkyl, each optionally substituted with one or more substituents Q as described herein. In some embodiments, R8d is hydrogen. In some embodiments, R8d is C1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R8d is methyl. In some embodiments, R8d is C3-7 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R8d is C6-14 aryl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R8d is heteroaryl, optionally substituted with one

or more substituents Q as described herein. In some embodiments, R8d is heterocyclyl, optionally substituted with one or more substituents Q as described herein.

In some embodiments, R30 is C1-6 alkyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl, heterocyclyl, or (C1-6 alkyl) (C3-7 cycloalkylene), each optionally substituted with one or more substituents Q as are described herein; or -CH2NR30aR30b, -CHR30cCHR30dNR30aR30b, or -CH2CR30cR30dNR30aR30b, where R30a, R30b, R30c and R30d are each as defined herein. In some embodiments, R30 is C1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R30 is methyl. In some embodiments, R30 is C3-7 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R30 is cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R30 is C6-14 aryl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R30 is heteroaryl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R30 is heterocyclyl, optionally substituted with one or more substituents Q as described herein.

In some embodiments, R30 is -CH2NR30aR30b, where R30a and R30b are each as defined herein. In some embodiments, R30 is -CH2CR30cR30dNR30aR30b, where R30a, R30b, R30c and R30d are each as defined herein. In some embodiments, R30 is -CHR30cCHR30dNR30aR30b, where R30a, R30b, R30c and R30d are each as defined herein.

In some embodiments, R30 has the structure of

where R 'is hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-7 cycloalkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q as described herein. In one embodiment, R 'is C1-6 alkyl. In another embodiment, R 'is hydrogen. In yet another embodiment, R 'is methyl. In yet another embodiment, R 'is C2-6 alkynyl. In yet another embodiment, R 'is ethynyl.

In some embodiments, R30a is hydrogen; C1-6 alkyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described herein. In some embodiments, R30a is hydrogen; C1-6 alkyl, or C3-7 cycloalkyl, each optionally substituted with one

or more substituents Q as described herein. In some embodiments, R30a is hydrogen. In some embodiments, R30a is C1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R30a is methyl. In some embodiments, R30a is C3-7 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R30a is C6-14 aryl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R30a is heteroaryl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R30a is heterocyclyl, optionally substituted with one or more substituents Q as described herein.

In some embodiments, R30b is hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described herein; or -S (O) kR11, -S (O) kNR11R12, -C (O) R11, -C (O) OR11, - (O) NR11R12, or -C (= NR11) NR12R13, where R11, R12, R13 and k are each as defined herein. In some embodiments, R30b is hydrogen; C1-6 alkyl or C3-7 cycloalkyl, each optionally substituted with one or more substituents Q as described herein; or -C (O) R11, -C (O) OR11, or -C (O) NR11R12, wherein R11 and R12 are each as defined herein. In some embodiments, R30b is hydrogen. In some embodiments, R30b is C1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R30b is methyl, ethyl or isopropyl. In some embodiments, R30b is C3-7 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R30b is C6-14 aryl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R30b is phenyl, optionally substituted with one or more substituents.

Q. In some embodiments, R30b is (C6-14 aryl) - (C1-6 alkylene), each optionally substituted with one or more Q substituents as described herein. In some embodiments, R30b is benzyl. In some embodiments, R30b is -C (O) R11, where R11 is as defined herein. In some embodiments, R30b is -C (O) R11, and R11 is C1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R30b is acetyl. In some embodiments, R30b is -C (O) OR11, where R11 is as defined herein. In some embodiments, R30b is -C (O) OR11, and R11 is C1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R30b is -C (O) Ot-butyl (Boc). In some embodiments, R30b is -C (O) NR11R12, where R11 and R12 are each as defined herein.

In some embodiments, R30c is hydrogen; C1-6 alkyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described herein. In some embodiments, R30c is hydrogen; C1-6 alkyl, or C3-7 cycloalkyl, each optionally substituted with one

or more substituents Q as described herein. In some embodiments, R30c is hydrogen. In some embodiments, R30c is C1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R30c is methyl. In some embodiments, R30c is C3-7 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R30c is C6-14 aryl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R30c is heteroaryl, optionally substituted with one or more Q substituents as described herein. In some embodiments, R30c is

10 heterocyclyl, optionally substituted with one or more substituents Q as described herein.

In some embodiments, R30d is hydrogen; C1-6 alkyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described herein. In some embodiments, R30d is hydrogen; C1-6 alkyl or C3-7 cycloalkyl, each optionally substituted with one

or more substituents Q as described herein. In some embodiments, R30d is hydrogen. In

fifteen Some embodiments, R30d is C1-6 alkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R30d is methyl. In some embodiments, R30d is C3-7 cycloalkyl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R30d is C6-14 aryl, optionally substituted with one or more substituents Q as described herein. In some embodiments, R30d is heteroaryl, optionally substituted.

twenty with one or more substituents Q as described herein. In some embodiments, R30d is heterocyclyl, optionally substituted with one or more substituents Q as described herein.

In some embodiments, k is 1. In some embodiments, k is 2.

In some embodiments, Z is CR3 '. In some embodiments, Z is CH. In some embodiments, Z is N.

In one embodiment, a compound of formula (IX) is provided herein:

wherein R17, R30, R2 ', R5', R6 ', R7', R8 ', L and n are each as defined herein; and Z is CH or N. In one embodiment, L is -O-. In another embodiment, R17 is C1-6 alkyl. In yet another embodiment, R17 is methyl. In yet another embodiment, R17 is C1-6 alkyl and L is -O-. In yet another embodiment, R17 is methyl and L is -O-.

In yet another embodiment, a compound of formula (X) is provided herein: wherein R18, R19, R30, R2 ', R5', R6 ', R7', R8 ', L and n are each as defined In the present memory; and Z is CH

or N. In one embodiment, L is -O-. In another embodiment, R18 is hydrogen. In yet another embodiment, R18 is hydrogen and L is -O-.

5 In one embodiment, the compound of formula IX or X is provided herein, wherein

each R17 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl;

each R30 is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl, heterocyclyl or (C1-6 alkyl) - (C3-7 cycloalkylene), each optionally substituted with one or more substituents Q; or

10 -CH2NR30aR30b, -CHR30cNR30aR30b, -CHR30cCHR30dNR30aR30b, or -CH2CR30cR30dNR30aR30b, where:

each R30a, R30c and R30d is independently hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, heterocyclyl, or (C 6-14 aryl) - (C 1-6 alkylene), each optionally substituted with one or more substituents Q; and

each R30b is independently hydrogen; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl,

fifteen heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q; -S (O) kR11, -S (O) kNR11R12, -C (O) R11, -C (O) OR11, -C (O) NR11R12, or -C (= NR13) NR11R12; wherein each R11, R12 and R13 is independently hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q; or R11 and R12 together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q; or

twenty R30a and R30b together with the N atom to which they are attached form heterocyclyl or heteroaryl, each optionally substituted with one or more substituents Q;

Each R2 ', R5', R6 ', R7, and R8' is independently:

hydrogen, halogen, cyano, trifluoromethyl or nitro;

C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q; or

<dl><dt>-</dt><dd>C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (NRa) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc , -OC (= NRa) NRbRc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rb, -NRaC ( O) ORb, -NRaC (O) NRbRc, -NRaC (= NRd) NRbRc, -NRaS (O) Rb, -NRaS (O) 2Rb, -NRaS (O) NRbRc, NRaS (O) 2NRbRc, -SRa, - S (O) Ra, or -S (O) 2Ra; wherein each Ra, Rb, Rc and Rd is independently hydrogen; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl</dd></dl>

30 C3-7, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described herein; or Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q;

each L is independently a bond, C1-6 alkylene, C3-7 cycloalkylene, C2-6 alkenylene, C2-6 alkynylene, X, or - (CR6aR6b) pX-; where p is an integer 1, 2 or 3; R6a and R6b are each independently hydrogen, halogen, cyano, hydroxyl or alkoxy; and X is -O-, -C (O) -, -C (O) O-, -OC (O) O-, -C (O) NR14-, -C (= NR14) NR15-, -NR14- ,

NR14C (O) NR15-, -NR14C (= NR15) NR16-, -NR14S (O) kNR15-, -S (O) k-, -S (O) kNR14-, -P (O) OR14-, or - OP (O) OR14-, where each R14, R15 and R16 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl;

each Z is independently CH or N; and Each n is independently an integer of 0, 1, 2, 3, 4 or 5. In another embodiment, the compound of formula IX or X is provided herein, wherein: each R17 is independently hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl; each R30 is independently C1-6 alkyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl, heterocyclyl, or (C1-6 alkyl)

(C3-7 cycloalkylene), each optionally substituted with one or more substituents Q; or -CH2NR30aR30b, -CHR30cNR30aR30b, -CHR30cCHR30dNR30aR30b, or -CH2CR30cR30dNR30aR30b, where:

each R30a, R30c and R30d is independently hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, heterocyclyl, or (C 6-14 aryl) - (C 1-6 alkylene), each optionally substituted with one or more substituents Q; and

each R30b is independently hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q; -S (O) kR11, -S (O) kNR11R12, -C (O) R11, -C (O) OR11, -C (O) NR11R12, or -C (= NR13) NR11R12; wherein each R11, R12 and R13 is independently hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q; or R11 and R12 together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q; or

R30a and R30b together with the N atom to which they are attached form heterocyclyl or heteroaryl, each optionally substituted with one or more substituents Q;

Each R2 ', R5', R6 ', R7' and R8 'is independently:

hydrogen, halogen, cyano, trifluoromethyl or nitro;

C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q; or

<dl><dt>-</dt><dd>C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (NRa) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc , -OC (= NRa) NRbRc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rb, -NRaC ( O) ORb, -NRaC (O) NRbRc, -NRaC (= NRd) NRbRc, -NRaS (O) Rb, -NRaS (O) 2Rb, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, -SRa, -S (O) Ra, or -S (O) 2Ra; wherein each Ra, Rb, Rc and Rd is independently hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described herein; or Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q;</dd></dl>

each L is independently a bond, X, or - (CR6aR6b) pX-; where p is an integer 1, 2 or 3; R6a and R6b are each independently hydrogen or halogen; and X is -O-, -C (O) -, -C (O) O-, -OC (O) O-, -C (O) NR14-, -C (= NR14) NR15-, -N- R14-, -NR14C (O) NR15-, NR14C (= NR15) NR16-, -NR14S (O) kNR15-, -S (O) k-, or -S (O) kNR14-, where each R14, R15 and R16 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl;

each Z is independently CH or N; and

Each n is independently an integer of 1, 2, 3, 4 or 5.

In yet another embodiment, the compound of formula IX or X is provided herein, wherein:

each R17 is independently hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl;

each R30 is independently C1-6 alkyl, C3-7 cycloalkyl, C6-14 aryl, or (C1-6 alkyl) - (C3-7 cycloalkylene), each optionally substituted with one or more substituents Q;

each R2 'is independently C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q;

each R5 ', R6', R7 'and R8' is independently hydrogen, halogen, cyano, methanesulfonamido, C1-6 alkyl or C3-7 cycloalkyl, each optionally substituted with one or more substituents Q; or -ORa, wherein each Ra is independently C1-6 alkyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q;

each L is independently a bond, X, or - (CR6aR6b) pX-; where p is an integer 1, 2 or 3; R6a and R6b are each independently hydrogen or halogen; and X is -O-, -C (O) -, -C (O) O-, -OC (O) O-, -C (O) NR14-, -C (= NR14) NR15-, -NR14- , -NR14C (O) NR15-, -NR14C (= NR15) NR16-, -NR14S (O) kNR15-, -S (O) k-, or -S (O) kNR14-, where each R14, R15 and R16 it is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl;

each Z is independently CH or N; and Each n is independently an integer of 1, 2, 3, 4 or 5. In yet another embodiment, the compound of formula IX or X is provided herein, wherein: each R17 is independently C1-6 alkyl or C3-7 cycloalkyl; each R30 is independently C1-6 alkyl, C3-7 cycloalkyl, C6-14 aryl or (C1-6 alkyl) - (C3-7 cycloalkylene), each

optionally substituted with one or more substituents Q;

each R2 'is independently C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q; each R5 ', R6', R7 'and R8' is independently hydrogen, halogen, cyano, C1-6 alkyl or C3-7 cycloalkyl, each

optionally substituted with one or more substituents Q; or -ORa, where each Ra is independently alkyl

C1-6 or C3-7 cycloalkyl, each optionally substituted with one or more substituents Q; each L is independently -O-, -C (O) -, -C (O) O-, -OC (O) O-, -C (O) NR14-, or -NR14-, where R14 is hydrogen, C1-6 alkyl or C3-7 cycloalkyl;

each Z is independently CH or N; and Each n is independently an integer of 1, 2, 3, 4 or 5. In yet another embodiment, the compound of formula IX or X is provided herein, wherein: each R17 is independently C1-6 alkyl; each R30 is independently C1-6 alkyl or C3-7 cycloalkyl optionally substituted with one or more substituents

Q;

each R2 'is independently C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q; each R5 ', R6', R7 'and R8' is independently halogen, cyano, methanesulfonamido, C1-6 alkyl or C3-7 cycloalkyl,

each optionally substituted with one or more substituents Q; or -ORa, where each Ra is independently C1-6 alkyl or C3-7 cycloalkyl, each optionally substituted with one or more substituents Q;

L is -O-; each Z is independently CH or N; and Each n is independently an integer of 1, 2 or 3. In yet another embodiment, the compound of formula IX or X is provided herein, wherein: each R17 is independently C1-6 alkyl; each R30 is independently C1-6 alkyl or C3-7 cycloalkyl optionally substituted with C1-6 alkyl or alkynyl

C2-6; each R2 'is independently C6-14 aryl or heteroaryl, each optionally substituted with one or more

substituents selected from the group consisting of cyano, fluoro, methyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, ethenyl and ethynyl; each R5 ', R6', R7 'and R8' is independently hydrogen, halogen, methanesulfonamido; C1-6 alkyl, optionally

substituted with 1 to 3 fluoro groups; -ORa, where Ra is C1-6 alkyl, optionally substituted with 1 to 3 groups fluoro; L is -O-; each Z is independently CH or N; and

Each n is independently an integer of 1, 2 or 3. In yet another embodiment, the compound of formula IX or X is provided herein, wherein: each R17 is independently methyl or ethyl; each R30 is independently methyl, cyclopropyl, 1-methylcyclopropyl or 1-ethynylcyclopropyl;

R2 '

5 each is independently phenyl, 4-fluorophenyl, 2-isopropylaminothiazol-4-yl, 2-isopropylthiazol-4-yl, 2trifluoromethylthiazol-4-yl, 4-cyanothiazol-2-yl, 4-methylthiazol-2-yl, 4-trifluoromethylthiazole -2-yl, 4-isopropylthiazol-2-yl, 4-cyclopropylthiazol-2-yl, 4-cyclobutylthiazol-2-yl, 4-ethenylthiazol-2-yl, 4-ethynylthiazol-2-yl, 3-isopropylpyrazol-1-yl , 3trifluoromethylpyrazol-1-yl or 5-isopropyl-isoxazol-3-yl;

each R5 'is independently hydrogen or methoxy;

10 each R6 'is independently hydrogen, chlorine or methoxy; each R7 'is independently hydrogen, methoxy, difluoromethoxy, trifluoromethoxy, methanesulfonamido or chlorine; each R8 'is independently hydrogen, methyl, difluoromethyl, fluoro, chloro or bromo; L is -O-; each Z is independently CH or N; and

fifteen each n is independently an integer of 1, 2 or 3. In still another embodiment, the compound of formula IX or X is provided herein, wherein: each R17 is independently methyl or ethyl; each R30 is independently methyl, cyclopropyl, 1-methylcyclopropyl or 1-ethynylcyclopropyl;

R2 '

each is independently phenyl, 4-fluorophenyl, 2-isopropylaminothiazol-4-yl, 2-isopropylthiazol-4-yl, 2

twenty trifluoromethylthiazol-4-yl, 4-cyanothiazol-2-yl, 4-methylthiazol-2-yl, 4-trifluoromethylthiazol-2-yl, 4-isopropylthiazol-2-yl, 4-cyclopropylthiazol-2-yl, 4-cyclobutylthiazol-2- ilo, 4-ethenylthiazol-2-yl, 4-ethynylthiazol-2-yl, 3-isopropylpyrazol-1-yl, 3-trifluoromethylpyrazol-1-yl or 5-isopropyl-isoxazol-3-yl;

each R5 'is independently hydrogen or methoxy; each R6 'is independently hydrogen or methoxy;

25 each R7 'is independently hydrogen, chlorine or methoxy; each R8 'is independently hydrogen, methyl, fluoro, chloro or bromine; L is -O-; each Z is independently CH or N; and each n is independently an integer of 1, 2 or 3.

30 In one embodiment, a compound selected from the group consisting of and pharmaceutically acceptable salts and solvates thereof is provided herein.

In yet another embodiment, there is provided herein a compound selected from the group consisting of

and pharmaceutically acceptable salts and solvates thereof.

In yet another embodiment, there is provided herein a compound selected from the group consisting of

and pharmaceutically acceptable salts and solvates thereof.

In yet another embodiment, the compound of formula I is selected from the group consisting of:

and pharmaceutically acceptable salts and solvates thereof;

In yet another embodiment, the compound of formula I is selected from the group consisting of

and pharmaceutically acceptable salts and solvates thereof;

where the * symbol indicates the junction point.

The compounds provided herein are intended to cover all possible stereoisomers, unless a particular stereochemistry is specified. When the compound provided herein contains an alkenyl or alkenylene group, the compound may exist as one or as a mixture of cis / trans (or Z / E) geometric isomers. When the structural isomers are interconvertible through a low energy barrier, the compound can exist as a single tautomer or as a mixture of tautomers. This may have the form of protonic tautomería in the compound that contains, for example, an amino, keto or oxime group; or the so-called Valencia tautomería in the compounds that contain an aromatic residue. It turns out that a

10 Only compound can have more than one type of isomerism.

The heterocyclic moiety that is fused to the macrocyclic ring in the compound provided herein contains two chiral centers indicated by the asterisk symbols. As a result, the heterocyclic moiety can exist in four different stereoisomeric forms as shown below, including two cis isomers, (i) and (ii), and two trans isomers, (iii) and (iv).

In some embodiments, the heterocyclic moiety in the compound provided herein is in a cis configuration, (i), (ii), or a mixture thereof. In some embodiments, the heterocyclic moiety in the compound provided herein is in the cis (i) configuration. In some embodiments, the heterocyclic moiety in the compound provided herein is in the cis (ii) configuration. In some

twenty embodiments, the heterocyclic moiety in the compound provided herein is in the cis (i) and (ii) configuration.

In some embodiments, the heterocyclic moiety in the compound provided herein in a

trans configuration, (iii), (iv), or a mixture thereof. In some embodiments, the heterocyclic moiety in the compound provided herein is in the trans (iii) configuration. In some embodiments, the heterocyclic moiety in the compound provided herein is in the trans (iv) configuration. In some embodiments, the heterocyclic moiety in the compound provided herein is in the trans (iii) and (iv) configuration.

In some embodiments, the heterocyclic moiety in the compound provided herein is in the configuration (i), (iii), or a mixture thereof. In some embodiments, the heterocyclic moiety in the compound provided herein is in configuration (i). In some embodiments, the heterocyclic moiety in the compound provided herein is in configuration (iii). In some embodiments, the heterocyclic moiety in the compound provided herein is in configuration (i) and (iii).

In some embodiments, the heterocyclic moiety in the compound provided herein is in the configuration (ii), (iv), or a mixture thereof. In some embodiments, the heterocyclic moiety in the compound provided herein is in configuration (ii). In some embodiments, the heterocyclic moiety in the compound provided herein is in configuration (iv). In some embodiments, the heterocyclic moiety in the compound provided herein is in the configuration (ii) and (iv).

The heterocyclic moiety of a particular configuration can be easily introduced by selecting a chiral starting material that will give the desired chirality. For example, several 4-hydroxy-prolines, including cis-4-hydroxy-D-proline, cis-4-hydroxy-L-proline and trans-4-L-proline, are commercially available.

The compounds provided herein may be enantiomerically pure, such as an individual enantiomer or an individual diastereoisomer, or they may be mixtures of stereoisomers, such as a racemic mixture or a mixture of diastereoisomers. As such, one skilled in the art will recognize that the administration of a compound in its form (R) is equivalent, for compounds that undergo epimerization in vivo, to the administration of the compound in its form (S). Conventional techniques for preparing / isolating individual enantiomers include synthesis from a suitable optically pure precursor, asymmetric synthesis from achiral starting materials, or the resolution of a mixture of enantiomers, for example, by chiral chromatography, recrystallization, resolution, formation of diastereoisomeric salts, or derivatization in diastereoisomeric adducts followed by separation.

When the compound provided herein contains an acidic or basic moiety, it can also be provided in the form of a pharmaceutically acceptable salt (See, Berge et al., J. Pharm. Sci. 1977, 66, 1-19; and " Handbook of Pharmaceutical Salts, Properties, and Use, "Stahl and Wermuth, Ed .; Wiley-VCH and VHCA, Zurich, 2002).

Acids suitable for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, Laspartic acid, benzenesulfonic acid, benzoic acid, acid. 4-acetamidobenzoic acid, boric acid, (+) - camphoric acid, camphorsulfonic acid, (+) - (1S) -field-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L -glutamic, α-oxyglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, iohydric acid, (+) - L-lactic acid, (±) -DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-) - L-malic acid, malonic acid, (±) -D-Mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, nadphthalene-1,5-disulfonic acid, 1-hydroxy-2naphthoic acid, nicotinic acid, nitric acid , oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicyclic acid, sebacic acid, stearic acid, succinic acid, acid sulfuric, tannic acid, (+) - L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

Suitable bases for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, inorganic bases such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide or sodium hydroxide; and organic bases such as primary, secondary, tertiary and quaternary, aliphatic and aromatic amines, which include L-arginine, benetamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2- (diethylamino) -ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, Nmethyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, morpholine, 4- (2-hydroxyethyl) -morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1- (2-hydroxyethyl) -pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2- (hydroxymethyl) -1,3-propanediol and tromethamine.

Synthesis methods

The compound provided herein can be prepared, isolated or obtained by any method known to one skilled in the art. For example, a compound of formula I can be prepared as shown in scheme 1.

The N-protected 4-hydroxyproline 1 with a desired stereochemistry is coupled with an amine with a carbon-carbon terminal double bond to form amide 2. Compound 2 is then converted to a free amine by removal of the N-protective group in its proline moiety with a Lewis acid, such as trifluoroacetic acid, followed by coupling with a cyclopropylamine to give compound 3, which is then protected with a hydroxyl protecting group 5, such as TBDMSCl, and is cycled in the presence of a metathesis catalyst to give macrocyclic compound 4. The hydroxyl protecting group of compound 4 is removed to give compound 5 with a free hydroxyl group. At this point, a variety of R6-L groups can be introduced at the hydroxyl position using different chemical procedures, such as coupling reactions to form an ester, carbonate

or carbamate with the hydroxyl group, or nucleophilic substitution reactions to form ether, amine or thioether. At

10 Scheme 1 illustrates a nucleotide substitution reaction to form an ether bond. Compound 5 reacts with R6OH under Mitsunobu conditions with reversal of the stereochemistry at the position of the hydroxyl group to produce compound 6 with oxy as L in formula I, as provided herein. The ethyl protecting group is removed from the carboxyl group of compound 6 to give a free acid, which readily couples with a variety of amines to form the desired macrocyclic serine protease inhibitors, such as the

fifteen sulfonamide 7.

Scheme 1

An alternative strategy is shown in Scheme 2, where double inversion of the stereochemistry at the hydroxyl group position is used to retain its original stereochemistry. Compound 5 first becomes the ester

twenty of para-nitrobenzoyl (GNP) 8 under Mitsunobu conditions with the first inversion of stereochemistry at the hydroxyl group position. The ester of PNB 8 is hydrolyzed and then reacts with R6OH under Mitsunobu conditions with the second inversion of the stereochemistry in the apposition of the hydroxyl group to give compound 10 with retention of its original stereochemistry at the position of the hydroxyl group.

The starting materials used in the synthesis of the compounds provided herein are commercially available or can be easily prepared. For example, beta-amino-sulfonamide is synthesized as shown in scheme 3 and quinoline derivatives are synthesized as shown in scheme 4, where A, R5 ', R6', R7 'and R8' are as are defined herein.

Scheme 2

Scheme 3

Scheme 4

For the synthesis of quinoline derivatives, dichloroquinolines are prepared by the condensation of aniline 39 and malonic acid. Selective substitution of the chlorine group in position 2 with pyrazole 86 gives compound 119 in a single step without a protective group. The chlorine in position 4 of compound 119 is then converted to hydroxylin in the presence of a base, including, but not limited to, NaOH, KOH, KOAc and NaOAc.

A method of preparing a quinoline having the structure of:

the method comprising the step (selective substitution) of reacting a dicoloroquinoline having the structure of:

with a pyrazole that has the structure of

to form a chloroquinoline that has the structure of:

wherein A, R5 ', R6', R7 'and R8' are each as defined herein.

Selective substitution can be carried out in the presence of NaH (1.1 eq.), DMF and compound 86 (1.1 eq.) At an elevated temperature, e.g. eg, 90 ° C. Selective substitution can be carried out in the presence of N5 methylpyrrolidine and DMF at an elevated temperature, e.g. eg, 200 ° C. Selective substitution can be carried out in the presence of Cs2CO3 and DMF at an elevated temperature, e.g. eg, 110 ° C Selective substitution can be carried out in the presence of TEA and ACN at an elevated temperature. Selective substitution can be carried out in the presence of EtN (iPr) 2 and dioxane at a temperature of room temperature to 140 ° C. Selective substitution can be carried out in toluene at an elevated temperature. Selective substitution can be carried out in the absence of

10 any solvent at an elevated temperature, e.g. eg, 120 ° C.

The method may further comprise the step of converting the chlorine into hydroxyl in the presence of a base. Suitable bases include, but are not limited to, NaOH, KOH, NaOAc and KOAc. The base can be NaOH. The base can be KOH. The base can be NaOAc. The base can be KOAc.

A method of preparing compound 129a is described herein. As shown in the scheme

fifteen 4a, the method comprises the steps of (a) reacting compound 127a with CDI to form compound 128a and (b) coupling compound 128a with compound 128b to form compound 129a.

Also described herein is a method for preparing a macrocyclic serine protease inhibitor provided herein, e.g. eg, compound 7, as shown in scheme 4b. The method comprises the step of converting compound 129a to compound 7 in the presence of a metathesis catalyst

twenty ring closure (RCM). The RCM catalyst can be Zhan catalyst 1B.

Scheme 4a

Scheme 4b

25 Pharmaceutical compositions

Pharmaceutical compositions are provided herein which comprise a compound provided herein as an active ingredient, including an individual enantiomer, a racemic mixture or a mixture of diastereoisomers thereof; or a pharmaceutically acceptable salt or solvate thereof, in combination with a pharmaceutically acceptable carrier, carrier, diluent or excipient, or a mixture thereof. In some embodiments, the pharmaceutical composition comprises at least one excipient or vehicle that controls the release. In some embodiments, the pharmaceutical composition comprises at least one excipient or vehicle that does not control the release. In some embodiments, the pharmaceutical composition comprises at least one excipient or vehicle that controls the release and at least one that does not control the release.

The compound provided herein may be administered alone, or in combination with one or more other compounds provided herein, one or more other active ingredients. Pharmaceutical compositions comprising a compound provided herein can be formulated in different pharmaceutical forms for oral, parenteral and topical administration. Pharmaceutical compositions can also be formulated as controlled release pharmaceutical forms, including delayed, extended, prolonged, sustained, pulsatile, controlled, accelerated and rapid, directed, programmed, and gastric retention release forms. These pharmaceutical forms can be prepared according to conventional methods and techniques known to those skilled in the art (See, Remington: The Science and Practice of Pharmacy, see above; Modified-Release Drug Deliver Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc .: New York, NY, 2003; Vol. 126).

In one embodiment, the pharmaceutical compositions are provided in a pharmaceutical form for oral administration, which comprises a compound provided herein, including an individual enantiomer, a racemic mixture or a mixture of diastereoisomers thereof; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and one or more pharmaceutically acceptable excipients or vehicles.

In another embodiment, the pharmaceutical compositions are provided in a pharmaceutical form for parenteral administration, which comprises a compound provided herein, including an individual enantiomer, a racemic mixture or a mixture of diastereoisomers thereof; or a pharmaceutically acceptable salt or solvate thereof; and one or more pharmaceutically acceptable excipients or vehicles.

In another embodiment, the pharmaceutical compositions are provided in a pharmaceutical form for topical administration, which comprises a compound provided herein, including an individual enantiomer, a racemic mixture or a mixture of diastereoisomers thereof; or a pharmaceutically acceptable salt or solvate thereof; and one or more pharmaceutically acceptable excipients or vehicles.

The pharmaceutical compositions provided herein may be provided in a unit dosage form or a multiple dosage form. A unit dosage form, as used herein, refers to a physically discrete unit for administration to a human and animal subject, individually packaged as is known in the art. Each unit dose contains a predetermined amount of the active ingredient (s) sufficient to produce the desired therapeutic effect, together with the pharmaceutically necessary carriers or excipients. Examples of a unit dosage form include an individually packed vial, syringe and tablet or capsule. A unit dosage form can be administered in fractions or multiples thereof. A multiple dosage form is a plurality of identical unit dosage forms packaged in a single container for administration in a separate unit dosage form. Examples of a multiple dosage form include a vial, bottle of tablets or capsules, or bottle of milliliters or liters.

The pharmaceutical compositions provided herein may be administered once or multiple times in time intervals. It is understood that the exact dosage and duration of treatment may vary with the age, weight and condition being treated in the patient, and can be determined empirically using known assay protocols or by extrapolation from in vivo or in vitro or diagnostic data. It is also understood that for any particular individual, specific dosing regimens should be adjusted over time according to the individual need and professional judgment of the person who administers or supervises the administration of the formulations.

A. Oral administration

The pharmaceutical compositions provided herein may be provided in solid, semi-solid or liquid pharmaceutical forms for oral administration. As used herein, oral administration includes oral, lingual and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pills, seals, pellets, medicinal chewing gums, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions , suspensions, solutions, wafers, sprinkles, elixirs and syrups. In addition to the active ingredient (s), the pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or excipients, including but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, migration migration inhibitors. dye, sweetening agents and

flavoring agents

Binders and granulators impart cohesion to a tablet to ensure that the tablet remains intact after compression. Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch and pregelatinized starch (e.g. eg, STARCH 1500); jelly; sugars such as sucrose, glucose, dextrose, molasses and lactose; natural and synthetic gums, ghatti gum, isabgol shells mucilage, carboxymethyl cellulose, methyl cellulose, polyvinyl pyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth and guar gum; celluloses such as ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC); microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical composition provided herein.

Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch and powdered sugar. Some diluents, such as mannitol, lactose, sorbitol, sucrose and inositol, when present in sufficient quantity, can impart properties to some pressed tablets that allow disintegration in the mouth by chewing. Such pressed tablets can be used as chewable tablets.

Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methyl cellulose and carboxymethyl cellulose; wood products; natural sponge; cation exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses, such as croscarmellose; crosslinked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate, potassium polyacryline; starches, such as corn starch, potato starch, tapioca starch and pregelatinized starches; clays; alginates; and mixtures thereof. The amount of a disintegrant in the pharmaceutical compositions provided herein varies with the type of formulation, and can be discerned by one skilled in the art. The pharmaceutical compositions provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.

Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin, sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talcum powder; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; zinc stearate; zinc oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSIL® 200 (WR Grace Co., Baltimore, MD) and CAB-O-SIL® (Cabot Co. of Boston, MA), and mixtures thereof. The pharmaceutical compositions provided herein may contain from about 0.1 to about 5% by weight of a lubricant.

Suitable glides include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co. of Boston, MA), asbestos-free talc. Coloring agents include any of the certified and approved dyes, water-soluble FD&amp;C and water-insoluble FD&amp;C dyes suspended in alumina hydrate, and dye lacquers, and mixtures thereof - A dye lacquer is a combination by adsorption of a soluble dye in water in an oxide of a hydrated heavy metal, which results in an insoluble form of the dye. Flavoring agents include natural flavors extracted from plants, such as fruits, and synthetic mixtures of compounds that produce a pleasant taste sensation, such as peppermint and methyl salicylate. Sweetening agents include sucrose, lactose, mannitol, syrups, glycerin and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifying agents include gelatin, gum arabic, tragacanth, bentonite and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene 80 sorbitan monooleate (TWEEN® 80) and triethanolamine oleate. Suspension and dispersion agents include sodium carboxymethyl cellulose, pectin, tragacanth, Veegum, gum arabic, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate and alcohol. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and lauryl ether and polyoxyethylene. Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Organic acids include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.

It should be understood that many vehicles and excipients may serve several functionalities, even within the same formulation.

The pharmaceutical compositions provided herein may be provided as pressed tablets, crushed tablets, chewable tablets, quick dissolving tablets, multiple pressed tablets, or enteric coated tablets, sugar coated tablets or film-coated tablets. Enteric coated tablets are pressed tablets coated with substances that resist the action of stomach acid, but dissolve or disintegrate in the intestine, thus protecting the active ingredients of the stomach acid environment. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, lacquers, ammonia lacquer, and acetate phthalates

5 of cellulose. Sugar-coated tablets are pressed tablets surrounded by a sugar coating, which can be beneficial by masking unacceptable flavors or odors and protecting the tablets from oxidation. Film-coated tablets are pressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. The film coating imparts some general characteristics such as sugar coating. Multiple pressed tablets are pressed tablets made for more than one compression cycle, including layered tablets, and coated-pressed and dried-coated tablets.

The pharmaceutical forms of tablets may be prepared from the active substance in powder, crystalline or granular form, alone or in combination with one or more carriers or excipients described herein.

fifteen memory, including binders, disintegrants, controlled release polymers, lubricants, diluents and / or dyes. Flavoring agents and sweeteners are especially useful in the formation of chewable tablets and tablets.

The pharmaceutical compositions provided herein can be provided as soft or hard capsules, which can be made of gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsule, also known as dry load capsule (DFC), consists of two sections, one that slides over the other, which completely enclose the active substance. The soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol or a similar polyol. Soft gelatin capsules may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those described herein, including methyl and propylparabenos, and acid

25 sorbic The liquid, semi-solid and solid pharmaceutical forms provided herein can be encapsulated in a capsule. Suitable liquid and semi-solid pharmaceutical forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be prepared as described in US Pat. No. 4,328,245; 4,409,239; and 4,410,545. The capsules can also be coated, as those skilled in the art know, in order to modify or maintain the dissolution of the active ingredient.

The pharmaceutical compositions provided herein may be provided in liquid and semi-solid pharmaceutical forms, including emulsions, solutions, suspensions, elixirs and syrups. An emulsion is a two-phase system, in which a liquid is dispersed in the form of small globules in another liquid, which can be oil in water or water in oil. Emulsions may include a liquid or solvent.

35 non-aqueous pharmaceutically acceptable, emulsifying agent and preservative. The suspensions may include a pharmaceutically acceptable suspending agent and a preservative. Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal such as di (lower alkyl) acetal of a (lower alkyl) -aldehyde, e.g. eg, acetaldehyde diethylacetal; and a water miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are hydroalcoholic, transparent and sweetened solutions. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative. For a liquid pharmaceutical form, for example, a solution of polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, e.g. eg, water, to measure it conveniently for administration.

Other useful liquid or semi-solid pharmaceutical forms include, but are not limited to, those containing the one or more

Four. Five active ingredients provided herein, and a dialkylated mono or polyalkylene glycol, including 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350 dimethyl ether, polyethylene glycol550 dimethyl ether, polyethylene glycol-750 dimethyl ether, wherein 350, 550 and 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations may further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hiroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, acid phosphoric, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administration may also be provided in the form of liposomes, micelles, microspheres or nanosystems. Micellar dosage forms can be prepared as described in US Pat. No. 6,350,458.

55 The pharmaceutical compositions provided herein may be provided in the form of effervescent or non-effervescent granules or powders, to be reconstituted in a liquid pharmaceutical form. Pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders may include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.

The coloring and flavoring agents can be used in all the above pharmaceutical forms.

The pharmaceutical compositions provided herein may be formulated as pharmaceutical forms of immediate or modified release, including delayed, sustained, pulsed, controlled, directed, and programmed release forms.

The pharmaceutical compositions provided herein can be co-formulated with other active ingredients that do not impair the desired therapeutic action, or with substances that complement the desired action.

B. Parenteral Administration

The pharmaceutical compositions provided herein may be administered parenterally by injection, infusion or implant, for local or systemic administration. Parenteral administration, as used herein, includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

The pharmaceutical compositions provided herein may be formulated in any pharmaceutical form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and solid forms suitable for solutions or suspensions in liquid before injection. . Such pharmaceutical forms can be prepared according to conventional methods known to the person skilled in the art of pharmaceutical science (see, Remington: The Science and Practice of Pharmacy, see above).

Pharmaceutical compositions directed to parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the development of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lioprotectors, thickening agents, pH adjusting agents and inert gases.

Suitable aqueous vehicles include, but are not limited to, water, saline solution, physiological saline solution or phosphate buffered saline solution (PBS), sodium chloride injection, Ringer injection, isotonic dextrose injection, sterile water injection, dextrose injection and injection of Ringer lactate. Non-aqueous vehicles include, but are not limited to, fixed oils of plant origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium chain triglycerides of coconut oil, and palm kernel oil. Water miscible vehicles include, but are not limited to, ethanol, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, N, N-dimethylacetamide , and dimethylsulfoxide.

Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl hydroxybenzoates, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl and propylparabenos and acid sorbic Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citrate. Suitable antioxidants are those described herein, including bisulfite and sodium metabisulfite. Local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are as described herein, including sodium carboxymethyl cellulose, hydroxypropyl methylcellulose and polyvinyl pyrrolidone. Suitable emulsifying agents include those described herein, which include polyoxyethylene sorbitan monolaurate, polyoxyethylene 80 sorbitan monooleate and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether of β-cyclodextrin, and 7-β-cyclodextrin sulfobutyl ether (CAPTISOL®, CyDex, Lenexa , KS).

The pharmaceutical compositions provided herein may be formulated for single or multiple dosage administration. Individual dosage formulations are packaged in a vial, vial or syringe. Parenteral multiple dosage formulations may contain an antimicrobial agent in bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as is known and practiced in the art.

In one embodiment, the pharmaceutical compositions are provided as sterile solutions ready to use. In another embodiment, the pharmaceutical compositions are provided as sterile dry soluble products, including lyophilized powders and hypodermic tablets, to be reconstituted with a vehicle before use. In yet another embodiment, the pharmaceutical compositions are provided as sterile suspensions ready to use. In yet another embodiment, the pharmaceutical compositions are provided as sterile dry insoluble products, to be reconstituted with a vehicle before use. In yet another embodiment, the pharmaceutical compositions are

they provide ready-to-use sterile emulsions.

The pharmaceutical compositions provided herein may be formulated as immediate or modified release dosage forms, including delayed, sustained, pulsed, controlled, directed, and programmed release forms.

The pharmaceutical compositions can be formulated as a suspension, solid, semi-solid or thixotropic liquid, for administration as an implanted reservoir. In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid internal matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids, but allows the active ingredient in the pharmaceutical compositions to diffuse through she.

Suitable inner matrices include poly (methyl methacrylate), poly (butyl methacrylate) or plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized poly (ethylene terephthalate), natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone-carbonate copolymers, hydrophilic polymers, such as hydrogels of acrylic and methacrylic acid esters, collagen, crosslinked polyvinyl alcohol, and partially hydrolyzed crosslinked polyvinyl acetate.

Suitable outer polymeric membranes include polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinyl chloride ), vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, poly (ethylene terephthalate) ionomer, butyl rubber, epichlorohydrin rubbers, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer.

C. Topical administration

The pharmaceutical compositions provided herein may be administered topically to the skin, holes or mucosa. Topical administration, as used herein, includes (intra) dermal, conjunctival, intracorneal, intraocular, ophthalmic, atrial, transdermal, nasal, vaginal, urethral, ​​respiratory and rectal administration.

The pharmaceutical compositions provided herein may be formulated in any pharmaceutical form that is suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, powder powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigation, sprays, suppositories, bandages, dermal patches. The topical formulation of the pharmaceutical compositions provided herein may also comprise liposomes, micelles, microspheres, nanosystems and mixtures thereof.

Pharmaceutically acceptable carriers and excipients for use in the topical formulations provided herein include, but are not limited to, aqueous vehicles, water miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, enhancers of solubility, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lipoprotectors, thickening agents and inert gases.

The pharmaceutical compositions can also be administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis or microneedle or needleless injection, such as POWDERJECT ™ (Chiron Corp., Emeryville, CA), and BIOJECT ™ (Bioject Medical Technologies Inc., Tualatin , OR).

The pharmaceutical compositions provided herein can be provided in the form of ointments, creams and gels. Suitable ointment vehicles include oil or hydrocarbon vehicles, including, butter, benzoin butter, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifiable or absorbing vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate and anhydrous lanolin; water removable vehicles, such as hydrophilic ointment; water soluble ointment vehicles, including polyethylene glycols of different molecular weights; emulsion vehicles, water-in-oil emulsions (AG / AC) or oil-in-water emulsions (AC / AG), including cetyl alcohol, glycerin monostearate, lanolin and stearic acid (see, Remington: The Science and Practice of Pharmacy , see before). These vehicles are emollients but generally require the addition of antioxidants and preservatives.

The appropriate cream base may be oil in water or water in oil. Cream vehicles can be washable with water, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase is also called the "internal" phase, which is generally comprised of petrolatum and a fatty alcohol such as cetyl alcohol.

or stearyl. The aqueous phase normally, although not necessarily, exceeds the oil phase by volume, and generally contains a humectant. The emulsifiers in a cream formulation may be a nonionic, anionic, cationic or amphoteric surfactant.

Gels are suspension systems, semi-solid. Single phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid vehicle. Suitable gelling agents include crosslinked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, CARBOPOL®; hydrophilic polymers, such as poly (ethylene oxides), polyoxyethylene-polyoxypropylene copolymers and polyvinyl alcohol; cellulosic polymers, such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate and methylcellulose; gums such as tragacanth and xanthan gum; sodium alginate; and jelly. In order to prepare a uniform gel, dispersing agents such as alcohol can be added

or glycerin, or the gelling agent can be dispersed by crushing, mechanical mixing and / or stirring.

The pharmaceutical compositions provided herein may be administered rectally, urethrally, vaginally or vaginally, in the form of suppositories, pessaries, catheters, plasters or poultices, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, buffers, gels, foams, sprayers or enemas. Pharmaceutical forms can be manufactured using conventional procedures as described in Remington: The Science and Practice of Pharmacy, see above.

Rectal, urethral and vaginal suppositories are solid bodies to insert into body holes, which are solid at normal temperatures but melt or soften at body temperature to release the active substance (s) within the holes. Pharmaceutically acceptable carriers used in rectal and vaginal suppositories include base or vehicles, such as hardening agents, which produce a melting point close to body temperature, when formulated with the pharmaceutical compositions provided herein; and antioxidants as described herein, including bisulfite and sodium metabisulfite. Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerinagelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax, and suitable mixtures of mono, di and triglycerides of fatty acids, hydrogels such as polyvinyl alcohol, hydroxyethyl methacrylate, poly (acrylic acid); glycerinated jelly. Combinations of different vehicles can be used. Rectal and vaginal suppositories can be prepared by the compression or molding method. The typical weight of a rectal or vaginal suppository is about 2 to about 3 g.

The pharmaceutical compositions provided herein can be administered ophthalmically in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, solution powders, gels, eye inserts and implants.

The pharmaceutical compositions provided herein may be administered intranasally or by inhalation to the respiratory tract. The pharmaceutical compositions may be provided in the form of an aerosol or solution to be supplied using a pressurized container, pump, sprayer, atomizer, such as an atomizer that uses electrohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a suitable propellant. , such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions can also be provided in the form of a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, including chitosan or cyclodextrin.

The solutions or suspensions for use in a pressurized container, pump, sprayer, atomizer or nebulizer may be formulated to contain ethanol, aqueous ethanol or an alternative agent suitable for dispersion, solubilization or prolonged release of the active ingredient provided herein, a propellant as solvent; and / or a surfactant, such as sorbitan trioleate, oleic acid and an oligolactic acid.

The pharmaceutical compositions provided herein may be micronized to a size suitable for inhalation delivery, such as about 50 micrometers or less, or about 10 micrometers or less. Particles of such sizes can be prepared using a milling method known to those skilled in the art, such as spiral jet mill milling, fluidized bed jet mill milling, supercritical fluid processing to form nanoparticles, homogenization to high pressure or spray drying.

Capsules, blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mixture of the pharmaceutical compositions provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as l-leucine, mannitol or magnesium stearate. Lactose can be anhydrous or in the form of monohydrate. Other suitable excipients or carriers include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. The pharmaceutical compositions provided herein for inhaled / intranasal administration may further comprise a suitable aroma, such as menthol or levomenthol, or sweeteners, such as saccharin or sodium saccharin.

The pharmaceutical compositions provided herein for topical administration may be formulated for immediate or modified release, including delayed, sustained, pulsed, controlled, directed and programmed release.

D. Modified release

The pharmaceutical compositions provided herein may be formulated as a modified release pharmaceutical form. As used herein, the term "modified release" refers to a pharmaceutical form in which the rate or site of release of the active ingredient (s) is different from that of the immediate pharmaceutical form when administered by it. via. Pharmaceutical forms of modified release include delayed, extended, prolonged, sustained, pulsed, forms of release.

5 controlled, accelerated and rapid, directed and programmed, and gastric retention. Pharmaceutical compositions in modified-release pharmaceutical forms can be prepared using a variety of modified-release devices and methods known to those skilled in the art, including, but not limited to, matrix-controlled release devices, osmotic controlled-release devices, devices. Multi-particle controlled release, ion exchange resins, enteric coatings, multilayer coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient (s) can also be modified by varying the particle size and the polymorphism of the active ingredient (s).

Examples of modified release include, but are not limited to, those described in US Pat. nº

3.845.770; 3.916.899; 3.536.809; 3.598.123; 4.008.719; 5.674.533; 5.059.595; 5.591.767; 5.120.548; 5.073.543; 5.639.476; 5.354.556; 5.639.480; 5.733.566; 5.739.108; 5.891.474; 5.922.356; 5.972.891; 5.980.945; 5.993.855;

fifteen 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; and 6,699,500

1. Matrix controlled release devices

The pharmaceutical compositions provided herein in a modified release pharmaceutical form can be manufactured using a matrix controlled release device known to those skilled in the art (see, Takada et al., In Encyclopedia of Controlled Drug Delivery; Vol 2 , Mathiowitz Ed .; Wiley: 1999).

In one embodiment, the pharmaceutical compositions provided herein in a modified release pharmaceutical form are formulated using an erodible matrix device, or soluble polymers, including synthetic polymers and natural and derivative polymers, such as polysaccharides and proteins.

Materials useful for the formation of an erodible matrix include, but are not limited to, chitin, chitosan,

25 dextran and pululane; agar gum, gum arabic, karaya gum, locust bean gum, tragacanth gum, carrageenans, ghatti gum, guar gum, xanthan gum and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphates such as lecithin; alginates; propylene glycol alginate; jelly; collagen; and cellulosics, such as ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropylmethylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropylmethylcellulose acetate trimellinate (HPMCAT), and ethylhydroxyethylcellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; poly (vinyl acetate); esters of fatty acid and glycerol; polyacrylamide; poly (acrylic acid); copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, NJ); poly (2-hydroxyethyl methacrylate); polylactides; copolymers of L-glutamic acid and L-glutamate

35 ethyl; degradable lactic acid-glycolic acid copolymers; poly (D - (-) - 3-hydroxybutyric acid); and other acrylic acid derivatives, such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate, and (trimethylaminoethyl) methacrylate chloride.

In further embodiments, the pharmaceutical compositions are formulated with a non-erodible matrix device. The active ingredient (s) dissolve or disperse in an inert matrix and are released mainly by diffusion through the inert matrix once administered. Suitable materials for use as a non-erodible matrix device include, but are not limited to insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, poly (methyl methacrylate), poly (butyl methacrylate), chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymers, ethylene-vinyl acetate copolymers, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, vinyl chloride copolymers with

Four. Five vinyl acetate, ethylene and propylene vinylidene chloride, poly (ethylene terephthalate) ionomer, butyl rubber, epichlorohydrin rubbers, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / copolymer / vinyloxyethanol, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers; and hydrophilic polymers, such as ethyl cellulose, cellulose acetate, crospovidone, and crosslinked partially hydrolyzed polyvinyl acetate; and fatty compounds, such as carnauba wax, microcrystalline wax and triglycerides.

In a matrix controlled release system, the desired release kinetics can be controlled, for example, by the type of polymer used, the viscosity of the polymer, the particle sizes of the polymer and / or the active ingredient (s), the ratio of the active ingredient (s) against the polymer, and other excipients or vehicles in the compositions.

55 The pharmaceutical compositions provided herein in a modified release pharmaceutical form may be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, melt granulation followed by compression.

two. Osmotic controlled release devices

The pharmaceutical compositions provided herein in a modified release pharmaceutical form may be manufactured using an osmotic controlled release device, including the one chamber system, two chamber system, asymmetric membrane technology (AMT) and core system of extrusion (ECS). In general, said devices have at least two components: (a) the core containing the active ingredient (s); and (b) a semipermeable membrane with at least one supply port, which encapsulates the core. The semipermeable membrane controls the influx of water to the core from an aqueous environment of use, so as to produce the release of drug by extrusion through the supply port (s).

In addition to the active ingredient (s), the core of the osmotic device optionally includes an osmotic agent, which creates a director outside for the transport of water from the environment of use to the core of the device. A class of osmotic agents that are water-swollen hydrophilic polymers, which are also called "osmopolymers" and "hydrogels," include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, poly (ethylene oxide). ) (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly (2-hydroxyethyl methacrylate), poly (acrylic acid), poly (methacrylic acid), polyvinyl pyrrolidone (PVP), crosslinked PVP, poly (vinyl alcohol) ( PVA), PVA / PVP copolymers, PVA / PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large blocks of PEO, croscarmellose sodium, carrageenan, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl HPMC), carboxymethyl cellulose (CMC) and carboxy ethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum and sodium starch glycolate.

The other class of osmotic agents are osmogens that are capable of immersing water to affect the osmotic pressure gradient through the barrier of the surrounding lining. Suitable osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulphite, lithium sulfate, potassium chloride, and sodium sulfate; sugars such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose and xylitol; organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof.

Osmotic agents of different dissolution rates can be used to influence how quickly the active ingredient (s) are initially supplied in the pharmaceutical form. For example, amorphous sugars, such as MANNOGEM ™ EZ (SPI Pharma, Lewes, DE) can be used to provide a faster supply during the first couple of hours to immediately produce the desired therapeutic effect, and gradually and continuously release the amount remaining to maintain the desired level of therapeutic or prophylactic effect over a prolonged period of time. In this case, the active ingredient (s) is released at a rate to replace the amount of active substance metabolized and excreted.

The core may also include a wide variety of other excipients and vehicles as described herein, to enhance the performance of the pharmaceutical form or promote stability or processing.

Materials useful for forming the semipermeable membrane include different qualities of acrylic, vinyl, ethers, polyamides, polyesters and cellulosic derivatives that are permeable to water and insoluble in water at physiologically relevant pH, or are capable of becoming insoluble in water by chemical alteration, such as crosslinking. Examples of suitable polymers useful for forming the coating include plasticized, unplasticized and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose butyrate (CAB), ethylcarbamate Ca, CAP, CA methylcarbamate, CA chloroacetate, Ca ethyl ethoxylate, CA methylsulfonate, CA butylsulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta-glucan acetate, beta-glucan triacetate, acetaldehyde dimethylacetate, locust bean gum triacetate, hydroxylated ethylene-vinyl acetate, EC, PEG, PPG, PEG / PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS , HPMCAT, poly (acids and acrylic esters) and poly (acids and methacrylic esters) and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrenes, poly (halides of vinyl), poly (vinyl esters and ethers), natural waxes and synthetic waxes.

The semipermeable membrane can also be a hydrophobic microporous membrane, where the pores are substantially filled with a gas and are not wetted by the aqueous medium, but are permeable to water vapor, as described in US Pat. No. 5,798,119. Said hydrophobic but water vapor permeable membrane is typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, poly (acrylic acid) derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, poly (vinyl halides), poly ( vinylidene fluoride), poly (vinyl esters and ethers), natural waxes and synthetic waxes.

The supply port or ports on the semipermeable membrane can be formed after coating by mechanical or laser drilling. The supply port (s) can also be formed at the site by erosion of a plug of water-soluble material or by breaking a thinner part of the membrane over a notch in the core. In addition, the supply ports can be formed during the coating process, as in the case of asymmetric membrane coatings of the type described in US Pat. No. 5,612,059 and 5,698,220.

The total amount of the active ingredient (s) released and the release rate can be substantially modulated by the thickness and porosity of the semipermeable membrane, the composition of the core and the number, size and position of the supply ports.

5 Pharmaceutical compositions in an osmotic controlled release pharmaceutical form may further comprise additional excipients and conventional carriers as described herein, to promote the performance or processing of the formulation.

Osmotic controlled release pharmaceutical forms can be prepared according to conventional methods and techniques known to those skilled in the art (see, Remington: The Science and Practice of

10 Pharmacy, see above; Santus and Baker, J. Controlled Release 1995, 35, 1-21; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J. Controlled Release 2002, 79, 7-27).

In some embodiments, the pharmaceutical compositions provided herein are formulated as an AMT controlled release pharmaceutical form, comprising an asymmetric osmotic membrane that covers a core comprising the active ingredient (s) and other pharmaceutically excipients or vehicles.

fifteen acceptable. See, U.S. Pat. No. 5,612,059 and WO 2002/17918. AMT controlled release pharmaceutical forms can be prepared according to conventional procedures and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation and a dip coating process.

In some embodiments, the pharmaceutical compositions provided herein are formulated.

twenty as a pharmaceutical controlled release form ESC, which comprises an osmotic membrane that covers a core comprising the active ingredient (s), a hydroxyethyl cellulose, and other pharmaceutically acceptable excipients or vehicles.

3. Multi-particle controlled release devices

The pharmaceutical compositions provided herein in a pharmaceutical release form

25 controlled can be manufactured as a multi-particle controlled release device, comprising a multiplicity of particles, granules or pellets, in the range of about 10 µm to about 3 mm, about 50 µm to about 2.5 mm, or about 100 μm to approximately 1 mm in diameter. Said multiparticles can be done by procedures known to the person skilled in the art, including wet and dry granulation, extrusion / spheronization, roller compaction, fusion

30 freezing, and spray coating of seed cores. See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

Other excipients or carriers described herein can be mixed with pharmaceutical compositions to aid in the processing and formation of multiparticles. The resulting particles may themselves constitute the multi-particle device or may be coated by different materials.

35 film formers, such as enteric polymers, water swelling and water soluble polymers. Multiparticles can also be processed as a capsule or tablet.

Four. Targeted Supply

The pharmaceutical compositions provided herein may also be formulated to be directed to a tissue, receptor or other area of ​​the particular body of the subject to be treated, and include systems of

40 Liposome supply, released and antibody-based erythrocytes. Examples include, but are not limited to, US Pat. No. 6,316,652; 6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; 6,060,082; 6,048,736; 6,039,975; 6,004,534; 5,985,307; 5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874.

Applications

A compound provided herein is provided herein, including a

Four. Five individual enantiomer, a racemic mixture or a mixture of diastereoisomers thereof; or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of a viral infection of hepatitis C. In one embodiment, the subject is a mammal. In another embodiment, the subject is a human being.

In addition, the compound of formula I is provided herein, including an individual enantiomer, a racemic mixture or a mixture of diastereoisomers thereof; or a salt or solvate thereof

fifty pharmaceutically acceptable, for use in inhibiting the replication of a virus from a host. In one embodiment, the host is a cell. In another embodiment, the host is a human cell. In yet another embodiment, the host is a mammal. In yet another embodiment, the host is a human being.

In some embodiments, the administration of a therapeutically effective amount of a compound provided herein, including an individual enantiomer, a racemic mixture or a mixture of

diastereoisomers thereof; or a pharmaceutically acceptable salt or solvate thereof, produces a reduction of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or more, of virus replication with respect to a subject without administration of the compound, determined 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 15 days, or 30 days after administration by a method known in the art ; p. eg, determination of viral titration.

In some embodiments, the administration of a therapeutically effective amount of a compound provided herein, including an individual enantiomer, a racemic mixture or a mixture of diastereoisomers thereof; or a pharmaceutically acceptable salt or solvate thereof, produces a reduction of 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100 times, of virus replication with respect to a subject without administration of the compound, determined 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 15 days, or 30 days after administration by a method known in the art.

In some embodiments, the administration of a therapeutically effective amount of a compound provided herein, including an individual enantiomer, a racemic mixture or a mixture of diastereoisomers thereof; or a pharmaceutically acceptable salt or solvate thereof, produces a reduction of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or more, of viral titre with respect to a subject without administration of the compound, determined 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 15 days, or 30 days after administration by a method known in the art.

In some embodiments, the administration of a therapeutically effective amount of a compound provided herein, including an individual enantiomer, a racemic mixture or a mixture of diastereoisomers thereof; or a pharmaceutically acceptable salt or solvate thereof, produces a reduction of 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100 times, of the viral titre with respect to a subject without administration of the compound, determined 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 15 days, or 30 days after administration by a method known in the art.

In addition, a compound provided herein is provided herein, including an individual enantiomer, a racemic mixture or a mixture of diastereoisomers thereof; or a pharmaceutically acceptable salt or solvate thereof, to inhibit the replication of an HCV virus.

In some embodiments, the contact of the virus with a therapeutically effective amount of a compound provided herein, including an individual enantiomer, a racemic mixture or a mixture of diastereoisomers thereof; or a pharmaceutically acceptable salt or solvate thereof, produces a reduction of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or more, of viral titration with respect to a virus without such contact, determined 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 15 days, or 30 days after initial contact, by a method known in the art.

In some embodiments, the contact of the virus with a therapeutically effective amount of a compound provided herein, including an individual enantiomer, a racemic mixture or a mixture of diastereoisomers thereof; or a pharmaceutically acceptable salt or solvate thereof, produces a reduction of 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100 times, of the viral titre with respect to the virus without said contact , determined 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 15 days, or 30 days after initial contact, by a method known in the art.

Also provided herein is the compound provided herein, including an individual enantiomer, a racemic mixture or a mixture of diastereoisomers thereof; or a pharmaceutically acceptable salt or solvate thereof for use in the treatment, prevention or improvement of one or more symptoms of a liver disease or disorder associated with an HCV infection. Non-limiting examples of diseases associated with HCV infection include chronic hepatitis, cirrhosis, hepatocarcinoma or extrahepatic manifestations.

A compound provided herein is provided herein, including an individual enantiomer, a racemic mixture or a mixture of diastereoisomers thereof; or a pharmaceutically acceptable salt or solvate thereof, to be used to inhibit the activity of a serine protease. In one embodiment, the serine protease is the NS3 protease of hepatitis C.

Depending on the condition, disorder or disease, to be treated and the condition of the subject, a compound provided herein, may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection or implant), inhalation, nasal, vaginal, rectal, sublingual or topical (e.g. eg transdermal or local), and can be formulated alone or in a suitable dosage unit together with pharmaceutically acceptable carriers, adjuvants and carriers for each route of administration.

The dose may be in the form of 1, 2, 3, 4, 5, 6 or more sub-doses that are administered at appropriate daily intervals. Doses or sub-doses may be administered in the form of dosage units containing from about 0.1 to about 1000 mg, from about 0.1 to about 500 mg, or from about 0.5 to about 100 mg, in principle (s ) active (s) per dosage unit, and if the patient's condition requires it, alternatively the dose can be administered as a continuous infusion.

In some embodiments, a suitable dosage level is from about 0.01 to about 100 mg per kg of the patient's body weight per day (mg / kg per day), from about 0.01 to about 50 mg / kg per day, from about 0.01 to about 25 mg / kg per day, or from about 0.05 to about 10 mg / kg per day, which can be administered in single or multiple doses. A suitable dosage level may be from about 0.01 to about 100 mg / kg per day, from about 0.05 to about 50 mg / kg per day, or from about 0.1 to about 10 mg / kg per day. Within this range, the dosage may be from about 0.01 to about 0.1, from about 0.1 to about 1.0, from about 1.0 to about 10, or from about 10 to about 50 mg / kg up to date.

Combination therapy

The compounds provided in the present invention can also be combined or used in combination with other therapeutic agents useful in the treatment and / or prevention of an HCV infection.

As used herein, the term "in combination" includes the use of one or more therapies (eg, one or more prophylactic and / or therapeutic agents). However, the use of the term "in combination" does not restrict the order in which the therapies are administered (eg, prophylactic and / or therapeutic agents) to a subject with a disease or disorder. A first therapy can be given (e.g. eg, a prophylactic or therapeutic agent such as a compound provided herein) before (e.g., 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 12 h, 24 h, 48 h, 72 h, 96 h, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), simultaneously, or later (p. e.g., 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 12 h, 24 h, 48 h, 72 h, 96 h, 1 week, 2 weeks, 3 weeks , 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks later) of the administration of a second therapy (eg, a prophylactic or therapeutic agent) to the subject. Triple therapy is also contemplated herein.

As used herein, the term "synergistic" includes a combination of a compound provided herein and other therapy (eg, prophylactic or therapeutic agent) that has been used or used simultaneously to treat, prevent or manage a disease or disorder, which is more effective than the additive effects of therapies. A synergistic effect of a combination of therapies (e.g. eg, a combination of prophylactic or therapeutic agents) allows the use of minor dosages of one or more of the therapies and / or the less frequent administration of said therapies to a subject with a disorder. The ability to use lower dosages of a therapy (e.g. eg, a prophylactic or therapeutic agent) and / or administering said therapy less frequently, reduces the toxicity associated with the administration of said therapy to a subject without reducing the effectiveness of said therapy in the prevention or treatment of a disorder). In addition, a synergistic effect may produce improved efficacy of the agents in the prevention or treatment of a disorder. Finally, a synergistic effect of a combination of therapy (e.g. eg, a combination of prophylactic or therapeutic agents) can prevent or reduce adverse or unwanted side effects associated with the use of any of the therapies alone.

The compound provided herein may be administered in combination or alternated with another therapeutic agent, such as an anti-HCV agent. In combination therapy, effective dosages of two or more agents are administered together, while alternate or sequential stage therapy, an effective dosage of each agent is administered serially or sequentially. The dosages given will depend on the rates of absorption, inactivation and excretion of the drugs, as well as other factors known to those skilled in the art. It should be noted that the dosage values ​​will also vary with the severity of the condition to be relieved. It should also be understood that for each particular subject, the specific dosage regimes and programs must be adjusted over time according to the individual need and professional criteria of the person administering or supervising the administration of the compositions.

It has been recognized that HCV drug resistant variants may arise after prolonged treatment with an antiviral agent. Drug resistance most typically occurs due to the mutation of a gene that encodes an enzyme used in viral replication. The efficacy of a drug against viral infection can be prologized, increased or restored by administering the compound in combination or alternating with a second, and perhaps a third antiviral compound that induces a mutation different from that caused by the main drug. Alternatively, the pharmacokinetics, biodistribution or other parameters of the drug can be altered by said combination or alternate therapy. In general, combination therapy is typically preferred over alternate therapy because it induces multiple simultaneous strains in the virus.

In some embodiments, the compound provided herein is combined with one or more agents selected from the group consisting of an interferon, ribavirin, amantadine, an interleukin, an NS3 protease inhibitor, a cysteine ​​protease inhibitor, a phenanthorequinone, a thiazolidine, a benzanilide, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a gliotoxin, a cerulenin , an antisense oligodeoxynucleotide phosphorothioate, an IRES-dependent translation inhibitor and a ribozyme.

In some embodiments, the compound provided herein is combined with an HCV protease inhibitor, including, but not limited to, the HCV protease inhibitor Medivir (Medivir / Tibotec); ITMN

191 (InterMune), SCH 503034 (Schering), VX950 (Vertex); NS3 substrate-based protease inhibitors as described in WO 98/22496; Attwood et al., Antiviral Chemistry and Chemotherapy 1999, 10, 259273; documents DE 19914474; WO 98/17679; WO 99/07734; non-substrate NS3 protease inhibitors such as 2,4,6-trihydroxy-3-nitro-benzamide derivatives (Sudo et al., Biochem. Biophys. Res. Commun. 1997, 238, 643-647), RD3-4082, RD3-4078, SCH 68631, and a phenanthorequinone (Chu et al., Tetrahedron Letters 1996, 37, 7229-7232); SCH 351633 (Chu et al., Bioorganic and Medicinal Chemistry Letters 1999, 9, 1949-1952); Eglin c, a potent serine protease inhibitor (Qasim et al., Biochemistry 1997, 36, 1598-1607).

Other protease inhibitors suitable for treatment against HCV include those described, for example, in US Pat. No. 6,004,933, which describes a class of HCV endopeptidase 2 cysteine ​​protease inhibitors.

Additional hepatitis C virus NS3 protease inhibitors include those described, for example in Llinàs-Brunet et al., Bioorg. Med. Chem. Lett. 1998, 8, 1713-1718; Steinkühler et al., Biochemistry 1998, 37, 8899-8905; US patents No. 5,538,865; 5,990,276; 6,143,715; 6,265,380; 6,323,180; 6,329,379; 6,410,531; 6,420,380; 6,534,523; 6,608,027; 6,642,204; 6,653,295; 6,727,366; 6,838,475; 6,846,802; 6,867,185; 6,869,964; 6,872,805; 6,878,722; 6,908,901; 6,911,428; 6,995,174; 7,012,066; 7,041,698; 7,091,184; 7,169,760; 7,176,208; 7,208,600; U.S. patent application publications No.: 2002/0016294, 2002/0016442; 2002/0032175; 2002/0037998; 2004/0229777; 2005/0090450; 2005/0153877; 2005/176648; 2006/0046956; 2007/0021330; 2007/0021351; 2007/0049536; 2007/0054842; 2007/0060510; 2007/0060565; 2007/0072809; 2007/0078081; 2007/0078122; 2007/0093414; 2007/0093430; 2007/0099825; 2007/0099929; 2007/0105781; WO 98/17679; WO 98/22496; WO 99/07734; WO 00/09543; WO 00/59929; WO 02/08187; WO 02/08251; WO 02/08256; WO 02/08198; WO 02/48116; WO 02/48157; WO 02/48172; WO 02/60926; WO 03/53349; WO 03/64416; WO 03/64455; WO 03/64456; WO 03/66103; WO 03/99274; WO 03/99316; WO 2004/032827; WO 2004/043339; WO 2005/037214; WO 2005/037860; WO 2006/000085; WO 2006/119061; WO 2006/122188; WO 2007/001406; WO 2007/014925; WO 2007/014926; WO 2007/015824 and WO 2007/056120.

Other protease inhibitors include thiazolidine derivatives, such as RD-1-6250, RD4 6205 and RD4 6193, which show relevant inhibition in a reverse phase HPLC assay with a NS3 / 4A fusion protein and NS5A / 5B substrate ( Sudo et al., Antiviral Research 1996, 32, 9-18); thiazolidines and benzanilides identified in Kakiuchi et al., FEBS Lett. 1998, 421, 217-220; Takeshita et al., Analytical Biochemistry 1997, 247, 242-246.

Suitable helicase inhibitors include, but are not limited to, those described in US Pat. nº

5,633,358; and WO 97/36554.

Nucleotide polymerase inhibitors include, but are not limited to, gliotoxin (Ferrari et al., Journal of Virology 1999, 73, 1649-1654), and the natural product cerulenin (Lohmann et al., Virology 1998, 249, 108-118) .

Suitable interfering RNA (RNAi) based antivirals include, but are not limited to, short interfering RNA (RNAi) based antivirals, such as Sirna-034 and those described in WO / 03/070750, WO 2005/012525 and patent USA No. 2004/0209831.

Suitable antisense oligodeoxynucleotide (S-ODN) phosphorothioates complementary to the 5 'non-coding (NCR) sequence sections of the HCV virus include, but are not limited to, those described in Alt et al., Hepatology 1995, 22, 707 -717, and nucleotides 326-348 comprising the 3 'end of the NCR and nucleotides 371-388 located in the coding region of the HCV RNA core (Alt et al., Archives of Virology 1997, 142, 589-599 ; Galderisi et al., Journal of Cellular Physiology 1999, 181, 251-257).

Suitable IRES-dependent translation inhibitors include, but are not limited to, those described in Japanese Patent Publications No. JP 08268890 and JP 10101591.

Suitable ribozymes include those described, for example, in US Pat. No. 6,043,077; 5,869,253 and

5.610.054.

Suitable nucleoside analogs include, but are not limited to, the compounds described in US Pat. No. 6,660,721; 6,777,395; 6,784,166; 6,846,810; 6,927,291; 7,094,770; 7,105,499; 7,125,855; and 7,202,224; US patent publications No. 2004/0121980; 2005/0009737; 2005/0038240; and 2006/0040890; WO 99/43691; WO 01/32153; WO 01/60315; WO 01/79246; WO 01/90121, WO 01/92282, WO 02/18404; WO 02/32920, WO 02/48165, WO 02/057425; WO 02/057287; WO 2004/002422, WO 2004/002999 and WO 2004/003000.

Other various compounds that can be used as second agents include, for example, aminoalkylcyclohexanes (U.S. Patent No. 6,034,134), alkyl lipids (U.S. Patent No. 5,922,757), vitamin E and other antioxidants (U.S. Patent No. 5,922,757), squalene, amantadine, bile acids (U.S. Patent No. 5,846,964), N- (phosphonacetyl) -L-aspartic acid (U.S. Patent No. 5,830,905), benzenedicarboxamides (US Pat. No. 5,633,388), polyadenyl acid derivatives (U.S. Patent No. 5,496,546), 2 ', 3'-dideoxyinosine (U.S. Patent No. 5,026,687), benzimidazoles (U.S. Pat. No. 5,891,874), plant extracts (U.S. Patent No. 5,725,859; 5,837,257; and 6,056,961), and piperidines (U.S. Patent No. 5,830,905).

In some embodiments, one or more compounds provided herein are administered in combination or alternated with a hepatitis C antivirus interferon, including, but not limited to INTRON® A (interferon alfa-2b) and PEGASYS® (Peg-interferon alfa -2a); ROFERON® A (recombinant interferon alfa-2a), INFERGEN® (interferon alfacon-1), and PEG-INTRON® (pegylated interferon alfa-2b). In one embodiment, hepatitis C antivirus interferon 5 is INFERGEN®, IL-29 (PEG-Interferon lambda), R7025 (Maxy-alpha), BELEROFON®, oral alpha interferon, BLX-883 (LOCTERON®), omega interferon , MULTIFERON®, Medusa interferon, ALBUFERON®,

or REBIF®.

In some embodiments, one or more compounds provided herein are administered in combination or alternated with a hepatitis C antivirus polymerase inhibitor, such as ribavirin, viramidine,

10 NM 283 (valopicitabine), PSI-6130, R1626, HCV-796 or R7128.

In some embodiments, one or more compounds provided herein are administered in combination with ribavirin and a hepatitis C antivirus interferon, such as INTRON® A (interferon alfa-2b), PEGASYS® (Peg-interferon alfa-2a) , ROFERON® A (recombinant interferon alfa-2a), INFERGEN® (interferon alfacon-1), and PEG-INTRON® (pegylated interferon alfa-2b).

fifteen In some embodiments, one or more compounds provided herein are administered in combination or alternated with a hepatitis C antivirus protease inhibitor, such as ITMN-191, SCH 503034, VX950 (telaprevir), or HCV protease inhibitor. Measure

In some embodiments, one or more compounds provided herein are administered in combination or alternated with a hepatitis C antivirus vaccine, including, but not limited to, TG4040,

twenty PEVIPRO ™, CGI-5005, HCV / MF59, GV 1001, IC41, and INNO0101 (E1).

In some embodiments, one or more compounds provided herein are administered in combination or alternated with a hepatitis C antivirus monoclonal antibody, such as AB68 or XTL-6865 (formerly HepX-C); or a polyclonal hepatitis C antibody, such as cicavir.

In some embodiments, one or more compounds provided herein are administered in

25 combination or alternated with a hepatitis C antivirus immunomodulator, such as ZADAXIN® (thymalfasin), NOV-205, or oglufanide.

In some embodiments, one or more compounds provided herein are administered in combination or alternated with NEXAVAR®, doxorubicin, PI-88, amantadine, JBK-122, VGX-410C, MX-3253 (celgosivir), SUVUS® (BIVN -401 or virostat), PF-03491390 (formerly IDN-6556), G126270, UT-231B, DEBIO30 025, EMZ702, ACH-0137171, MitoQ, ANA975, AVI-4065, bavituximab (tarvacina), ALINIA® (nitrazoxanide) PYN17.

In some embodiments, the compounds provided herein may be combined with one or more steroidal drugs known in the art, including, but not limited to, the group that includes aldosterone, beclomethasone, betamethasone, deoxycorticosterone acetate, fludrocortisone, hydrocortisone (cortisol). , prednisolone, prednisone, methylprednisolone, dexamethasone and triamcinolone.

35 In some embodiments, the compounds provided herein may be combined with one or more antibacterial agents known in the art, including, but not limited to, the group that includes amikacin, amoxicillin, ampicillin, arsfenamine, azithromycin, aztreonam, azlocillin, bacitracin. , carbenicillin, cefaclor, cefadroxil, cefamandol, cefazolin, cefalexin, cefdinir, cefditorine, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol,

40 cilastin, ciprofloxacin, clarithromycin, clindamycin, cloxacillin, colistin, dalfopristin, demeclocycline, dicloxacillin, dirithromycin, doxycycline, erythromycin, enrofloxacin, ertepenem, ethambutol, flucloxacillin, fosfomycin, furazolidone, gatifloxacin, geldanamycin, gentamicin, herbimycin, imipenem, isoniazid, kanamycin, levofloxacin, linezolid, lomefloxacin, loracarbef, mafenide, moxifloxacin, meropenem, metronidazole, mezlocillin, minocycline, mupirocin, nafcillin, neomycin, netilmicin, nitrofurantoin, norfloxacin, ofloxacin, oxytetracycline, penicillin, piperacillin,

Four. Five platensimycin, polymyxin B, Prontocil, pyrazinamide, quinupristin, rifampin, roxithromycin, spectinomycin, streptomycin, sulfacetamide, sulfamethizol, sulfamethoxazole, teicoplanin, telithromycin, tetracycline, ticarcillin, tobimycin, tropromycin, trophocinine, trimethoxycin, trophocinine, trophocinine, trimethoxycin, trophocinine, trimethoxycin, trophocinine, trophocinine, trophocinine, trophocinine, trophocinine, trophocinine, trophocinine, trophocinine, trophocinine, trophocinine, trophocinine, trophocinine, trophocinine, trophocinin, trophamine, trophocinin, trophocinine, trophocinin, trophocinin, trophocinin, trophocinin, trophocinin, trophocinin, trophocinic acid

In some embodiments, the compounds provided herein may be combined with one or more antifungal agents known in the art, including, but not limited to, the group that includes amorolfine,

fifty Amphotericin B, anidulafungin, bifonazole, butenaphine, butoconazole, caspofungin, cyclopirox, clotrimazole, econazole, fenticonazole, filipin, fluconazole, isoconazole, itraconazole, ketoconazole, micafungin, miconazole, naphthyrine, natamycin oconazole, rhizimconazole, rhizimconazole, oxaconazole , sulconazole, terbinafine, terconazole, thioconazole and voriconazole.

In some embodiments, the compounds provided herein may be combined with one or

55 more anticoagulants known in the art, including, but not limited to, the group that includes acenocoumarol, argatroban, bivalirudin, lepirudin, fondaparinux, heparin, fenindione, warfarin and ximelagatran.

In some embodiments, the compounds provided herein may be combined with one or more thrombolytics known in the art, including, but not limited to, the group that includes anistreplase, reteplasa, t-PA (alteplase activase), streptokinase, tenecteplase and urokinase

In some embodiments, the compounds provided herein may be combined with one or

5 more non-steroidal anti-inflammatory agents known in the art, including, but not limited to, aceclofenac, acemetacin, amoxiprine, aspirin, azapropazone, benorilate, bromfenac, carprofen, celecoxib, choline and magnesium salicylate, diclofenac, diflunisal, etodolac, etoxyllaminate fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam, metamizol, methyl salicylate, magnesium salicylate, nabumetone, naproxen,

10 nimesulide, oxyphebutazone, parecoxib, phenylbutazone, piroxicam, salicylic salicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam, thiaprofenic acid and tolmetine.

In some embodiments, the compounds provided herein may be combined with one or more antiplatelet agents known in the art, including, but not limited to, abciximab, cilostazol, clopidogrel, dipyridamole, ticlopidine and thyrofibin.

fifteen The compounds provided herein may also be administered with other classes of compounds, including, but not limited to, endothelin converting enzyme (ECE) inhibitors, such as phosphoramidone; thromboxane receptor antagonists, such as ifetroban; potassium channel opening agents; thrombin inhibitors, such as hirudin; growth factor inhibitors, such as modulators of PDGF activity; platelet activating factor (PAF) antagonists; antiplatelet agents, such as

twenty GPIIb / IIIa blockers (e.g., abciximab, eptifibatide and tirofiban), P2I (AC) antagonists (e.g. eg, clopidogrel, ticlopidine and CS-747), and aspirin; anticoagulants, such as warfarin; low molecular weight heparins, such as enoxaparin; Factor VIIa inhibitors and Factor Xa inhibitors; renin inhibitors; neutral endopeptidase (NEP) inhibitors; vasopeptidase inhibitors (double NEP-ACE inhibitors), such as omapatrilat and gemopatrilat; HMG-CoA reductase inhibitors, such as pravastatin, lovastatin, atorvastatin,

25 simvastatin, NK-104 (also known as itavastatin, nisvastatin or nisbastatin), and ZD-4522 (also known as rosuvastatin, atavastatin or visastatin); squalene synthetase inhibitors; fibrates; bile acid sequestrants, such as questrán; niacin; anti-atherosclerotic agents, such as ACAT inhibitors; MTP inhibitors; calcium channel blockers, such as amlodipine besylate; potassium channel activators; alpha-adrenergic agents; beta-adrenergic agents, such as carvedilol and metoprolol;

30 antiarrhythmic agents; diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzothiazide, ethacrynic acid, ticrinaphene, chlorthalidone, furosenide, muzolimine, ammonium amide, muzolimine, ammonium amide, sponaimide amine, ammonium amide, sponaimide, ammonium amide, ammonium bromide thrombolytic agents such as tissue plasminogen activator (tPA), recombinant tPA, streptoqunase, urokinase, prourokinase, and anisoylated plasminogen and streptokinase activator complex (APSAC); agents

35 antidiabetics, such as biguanides (e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulins, meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide and glipizide ), thiozolidinediones (p. eg, troglitazone, rosiglitazone and pioglitazone), and PPAR-gamma agonists; mineralocorticoid receptor antagonists, such as spironolactone and eplerenone; growth hormone secretagogues; aP2 inhibitors; phosphodiesterase inhibitors such as PDE III inhibitors (eg, cilostazol) and inhibitors

40 PDE V (eg, sildenafil, tadalafil and vardenafil); protein tyrosine kinase inhibitors; anti-inflammatories; antiproliferatives, such as methotrexate, FK506 (tacrolimus), mycophenolate mofetil; chemotherapeutic agents; immunosuppressants; anti-cancer agents and cytotoxic agents (e.g. eg, alkylating agents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, and triazenes); antimetabolites, such as folate antagonists, purine analogs and pyrimidine analogs; antibiotics such as anthracyclines, bleomycins, mitomycin,

Four. Five dactinomycin, and plicamycin; enzymes, such as L-asparaginase; farnesyl protein transferase inhibitors; hormonal agents such as glucocorticoids (e.g. eg, cortisone), estrogens / antiestrogens, androgens / antiandrogens, progestins, and luteinizing hormone-releasing hormone antagonists, and octreotide acetate; microtubule disrupting agents, such as ecteinascidines; microtubule stabilizing agents, such as pacitaxel, docetaxel and epothilones AF; plant-derived products such as alkaloids

fifty of vinca, epipodophyllotoxins, and taxanes; and topoisomerase inhibitors; inhibitors of prenyl protein transferase; and cyclosporins; steroids, such as prednisone and dexamethasone; cytotoxic drugs such as azathioprine and cyclophosphamide; TNF-alpha inhibitors, such as tenidap; anti-TNF antibodies or soluble TNF receptor, such as etanercept, rapamycin and leflunimide; and cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and rofecoxib; and varied agents such as, hydroxyurea, procarbazine, mitotane, hexamethylmelamine,

55 Gold compounds, platinum coordination complexes, such as cisplatin, satraplatin and carboplatin.

In some embodiments, the pharmaceutical compositions provided herein comprise a second antiviral agent described herein. In one embodiment, the second antiviral is selected from the group consisting of an interferon, ribavirin, an interleukin, an NS3 protease inhibitor, a cysteine ​​protease inhibitor, a phenanthorequinone, a thiazolidine, a benzanilide, a helicase inhibitor, a polymerase inhibitor 60, a nucleotide analog, a gliotoxin, a cerulenin, an antisense oligodeoxynucleotide phosphorothioate, an IRES-dependent translation inhibitor, and a ribozyme. In another embodiment, the second antiviral agent is an interferon. In yet another embodiment, interferon t is selected from the group consisting of pegylated interferon alfa 2a, interferon alfacon-1, natural interferon, ALBUFERON®, interferon beta-1a, interferon

omega, interferon alfa, interferon gamma, interferon tau, interferon delta, and interferon gamma-1b.

The compounds provided herein can also be provided as an article of manufacture using packaging materials known in the art. See, p. eg, U.S. Patent Nos. 5,323,907; 5,052,558; and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for a selected formulation and mode of administration and treatment to which It is aimed.

Kits are also provided herein in which, when used by a physician, it can simplify the administration of adequate amounts of the active ingredients to a subject. In some embodiments, the kit provided herein includes a package and a pharmaceutical form of a compound provided herein, including an individual enantiomer, a racemic mixture or a mixture of diastereoisomers thereof; or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the kit includes a package comprising a pharmaceutical form of the compound provided herein, including an individual enantiomer, a racemic mixture or a mixture of diastereoisomers thereof; or a pharmaceutically acceptable salt or solvate thereof, in a package comprising one or more other therapeutic agents described herein.

The kits provided herein may further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, drip bags, needleless injectors, patches and inhalers. The kits provided herein also include condoms for the administration of the active ingredients.

The kits provided herein may further include pharmaceutically acceptable carriers that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit may comprise a sealed container of a suitable vehicle in which the active principle can be dissolved to form a sterile solution without particles that It is suitable for parenteral administration. Examples of pharmaceutically acceptable carriers include, but are not limited to: aqueous vehicles, including, but not limited to, water for USP injection, sodium chloride injection, Ringer injection, dextrose injection, dextrose and sodium chloride injection and Ringer lactate injection ; water miscible vehicles, including, but not limited to, ethyl alcohol, polyethylene glycol and polypropylene glycol; and non-harassing vehicles, including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate.

The invention will be summarized by the following points:

1. A compound of formula 1:

or an individual enantiomer, a racemic mixture or a mixture of diastereoisomers thereof; or a pharmaceutically acceptable salt or solvate thereof; where:

R5 is -OH, -NR8R9, -NHS (O) 2R8, -NHS (O) 2NR8R9, -NHC (O) R8, -NHC (O) NR8R9, -C (O) R9, or -C (O) NR8R9 ; where:

each R8 is independently hydrogen C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-4 aryl, heteroaryl, heterocyclyl, (C1-6 alkyl) - (C3-7 cycloalkylene), -CH2NR8aR8b , -CH (R8c) NR8aR8b, -CHR8cCHR8dNR8aR8b, or -CH2CR8cR8dR8aR8b, where:

each R8a, R8c, and R8d is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-4 aryl, heteroaryl, heterocyclyl, or (C6-14 aryl) - (alkylene C1-6); and

each R8b is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-4 aryl, heteroaryl, heterocyclyl, -S (O) kR11, -S (O) kNR11R12, - C (O) R11, -C (O) OR11, -C (O) NR11R12, or -C (= NR13) NR11R12; in

wherein each R11, R12, and R13 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-4 aryl, heteroaryl, or heterocyclyl; or R11 and R12 together with the N atom to which they are attached form heterocyclyl; or

R8a and R8b together with the N atom to which they are attached form heterocyclyl; and

each R9 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-4 aryl, heteroaryl, or heterocyclyl; or

R8 and R9 together with the N atom to which they are attached form heterocyclyl;

R 6 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-4 aryl, heteroaryl, or heterocyclyl;

L is a bond, C1-6 alkylene, C3-7 cycloalkylene, C2-6 alkenylene, C2-6 alkynylene, X, or - (CR6aR6b) pX-; where p is an integer 1, 2 or 3; R6a and R6b are each independently hydrogen, halogen, cyano, hydroxyl, or alkoxy; and X is -O-, -C (O) -, -C (O) O-, -OC (O) O-, -C (O) NR14-, -NR14-, -NR14C (O) NR15-, -C (= NR14) NR15-, -NR14C (= NR15) NR16-, -S (O) k-, -S (O) kNR14-, -NR14S (O) kNR15-, -P (O) (OR14) -, or -OP (O) (OR14) -, where each R14, R15, and

R16

it is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-4 aryl, heteroaryl, or heterocyclyl; and each k is independently an integer 1 or 2;

Q1 is -O-, -N (R7) -, -C (R18R19) -, or -CR17 (NR18R19) -; where:

each R17 and R18 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C64 aryl, heteroaryl, or heterocyclyl; and

each R19 is independently -R20, -C (O) R20, -C (O) OR20, -C (O) NR21R22, -C (= NR20) NR21R22, or -S (O) kR20; wherein each R20, R21 and R22 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-4 aryl, heteroaryl, or heterocyclyl; or R21 and R22 together with the N atom to which they are attached form heterocyclyl; or

R18 and R19 together with the C or N atom to which they are attached form C3-7 cycloalkyl or heterocyclyl;

Q2 is C3-9 alkylene, C3-9 alkenylene, or C3-9 alkynylene, each optionally containing 1 to 3 heteroatoms in the chain, independently selected from O, N and S; and

each k is independently an integer 1 or 2;

wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, aryl, cycloalkyl, cycloalkylene, heterocyclyl and heteroaryl optionally is substituted with one or more groups, each independently selected from cyano, halogen, or nitro; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-4 aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (NRa) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O ) NRbRc, -OC (= NRa) NRbRc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rb, - NRaC (O) ORb, -NRaC (O) NRbRc, -NRaC (= NRd) NRbRc, -NRaS (O) Rb, -NRaS (O) 2Rb, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, - SRa, -S (O) Ra, or -S (O) 2Ra; wherein each Ra, Rb, Rc, and Rd is independently hydrogen; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-4 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q; or Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q;

wherein each Q is independently selected from the group consisting of cyano, halogen, or nitro; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-4 aryl, heteroaryl, or heterocyclyl; or -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (NRe) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O ) NRfRg, -OC (= NRe) NRfRg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rf, - NReC (O) ORf, -NReC (O) NRfRg, -NReC (= NRh) NRfRg, -NReS (O) Rf, -NReS (O) 2Rf, -NReS (O) NRfRg, -NReS (O) 2NRfRg, - SRe, -S (O) Re, or -S (O) 2Re; wherein each Re, Rf, Rg and Rh is independently hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-4 aryl, heteroaryl or heterocyclyl; or Rf and Rg together with the N atom to which they are attached form heterocyclyl.

two. The compound of item 1, which has the structure of formula II:

where:

R30 is hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, heterocyclyl or (C 1-6 alkyl) - (C 3-7 cycloalkylene), each optionally substituted with one or more substituents Q; or 5 -CH2NR30aR30b, -CHR30cNR30aR30b, -CHR30cCHR30dNR30aR30b, or -CH2CR30cR30dNR30aR30b, where:

each R30a, R30c and R30d is independently hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, heterocyclyl, or (C 6-14 aryl) - (C 1-6 alkylene), each optionally substituted with one or more substituents Q; and

each R30b is independently hydrogen; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl,

10 heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q; -S (O) kR11, -S (O) kNR11R12, -C (O) R11, -C (O) OR11, -C (O) NR11R12, or -C (= NR13) NR11R12; wherein each R11, R12 and R13 is independently hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q; or R11 and R12 together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q; or

fifteen R30e and R30b together with the N atom to which they are attached form heterocyclyl or heteroaryl, each optionally substituted with one or more substituents Q.

3. The compound of item 1, which has the structure of formula III:

where: 20 Z is CR3 'or N; and

R2 ', R3', R5 ', R6', R7 'and R8' are each independently:

hydrogen, halogen, cyano, trifluoromethyl or nitro;

C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described herein; or

<dl><dt>-</dt><dd>C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (NRe) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc , -OC (= NRa) NRbRc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rb, -NRaC ( O) ORb, -NRaC (O) NRbRc, NRaC (= NRd) NRbRc, NRaS (O) Rb, -NRaS (O) 2Rb, -NRaS (O) NRbRc, -NReS (O) 2NRbRc, -SRa, -S (O) Ra or -S (O) 2Ra; wherein each Re, Rb, Rc and Rd is independently hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q; or Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q.</dd></dl>

Four. The compound of item 1, which has the structure of formula IV:

10 where

Z is CR3 'or N; and

R2 ', R3', R5 ', R6', R7 and R8 'are each independently:

hydrogen, halogen, cyano, trifluoromethyl, or nitro;

fifteen C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-4 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q; or

<dl><dt>-</dt><dd>C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (NRa) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc , -OC (= NRa) NRbRc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rb, -NRaC ( O) ORb, -NRaC (O) NRbRc, -NRaC (= NRd) NRbRc, -NR3S (O) Rb, -NRaS (O) 2Rb, -NR3S (O) NRbRc, -NRaS (O) 2NRbRc, -SRa, -S (O) Ra, or -S (O) 2Ra; in</dd></dl>

twenty where each Ra, Rb, Rc, and Rd is independently hydrogen; or C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-4 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q; or Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q.

5. The compound of any of items 1 to 4, wherein Q2 is C3-9 alkylene.

25 6. The compound of any of items 1 to 4, wherein Q2 is C3-9 alkenylene or C3-9 alkynylene.

7. The compound of any of items 1 to 4, where Q2 is selected from the group consisting of: where:

Z1 is -O-, -S-, or N (RZ) -, where RZ is hydrogen, C1-6 alkyl, aryl, heteroaryl, heterocyclyl, -C (O) RZa, -C (O) ORZa, -C (O) NRZbRZc, -S (O) 2NRZbRzc, or -S (O) 2RZa; and

each RZa, RZb and RZc is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl; or

RZb and RZc together with the N atom to which they are attached form heterocyclyl or heteroaryl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is independently optionally substituted with one or more substituents Q, each Q independently selected from the group that It consists of cyano, halogen, oxo, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-4 aryl, 10 heteroaryl, heterocyclyl, -C (O) Re, -C (O) ORe, -C (O) NRfRg, -C (NRe) NRfRg, -ORe, -OC (O) Re, -OC (O) ORe, -OC (O) NRfRg, -OC (= NRe) NRfRg, -OS (O) Re, -OS (O) 2Re, -OS (O) NRfRg, -OS (O) 2NRfRg, -NRfRg, -NReC (O) Rf, -NReC (O) ORf, -NReC (O) NRfRg, -NReC (= NRh) NRfR8, -NReS (O) Rf, -NReS (O) 2Rf, -NReS (O) NRfRg, -NReS (O) 2NRfRg, -SRe, -S (O) Re, -S (O) 2Re, and -S (O) 2NRfR8, where each Re, Rf, Rg and Rh is independently hydrogen, alkyl C1-6, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-4 aryl, heteroaryl or heterocyclyl; or Rf and Rg are linked together

fifteen to form heterocyclyl, together with the N atom to which they are attached.

8. The compound of item 1, which has the structure of formula V:

where n is an integer 0, 1, 2, 3, 4 or 5.

9. The compound of item 2, which has the structure of formula VI:

where n is an integer 0, 1, 2, 3, 4 or 5.

<dl><dt>10.</dt><dd> The compound of item 3, which has the structure of formula VII: </dd></dl>

where n is an integer 0, 1, 2, 3, 4 or 5.

<dl><dt>11.</dt><dd> The compound of item 4, which has the structure of formula VIII: </dd></dl>

5 where n is an integer 0, 1, 2, 3, 4 or 5.

<dl><dt>12. </dt><dd>The compound of any of items 1, 2 and 5 to 9, wherein R 6 is C 1-6 alkyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q. </dd></dl>

<dl><dt>13.</dt><dd> The compound of item 12, wherein R6 is C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q. </dd></dl>

10 14. The compound of item 12, where R6 is selected from the group consisting of: where

Each R2 ', R3', R5 ', R6', R7 'and R8' is independently:

hydrogen, halogen, cyano, trifluoromethyl or nitro;

5 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q as described herein; or

<dl><dt>-</dt><dd>C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (NRe) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O) NRbRc , -OC (= NRa) NRbRc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, -NRaC (O) Rb, NRaC (O ) ORb, -NRaC (O) NRbRc, -NRaC (= NRd) NRbRc, -NRaS (O) Rb, -NRaS (O) 2Rb, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, -SRa, - S (O) Ra, or -S (O) 2Ra; in</dd></dl>

10 where each Ra, Rb, Rc and Rd is independently hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q; or Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q.

<dl><dt>15.</dt><dd> The compound of any of points 1 to 14, wherein Q1 is -O-. 15 16. The compound of any of items 1 to 14, wherein Q1 is -C (R18R19) -.</dd></dl>

<dl><dt>17.</dt><dd> The compound of item 16, wherein R18 and R19 are each independently hydrogen; C1-6 alkyl or C3-7 cycloalkyl, each optionally substituted with one or more substituents Q.</dd></dl>

<dl><dt>18.</dt><dd> The compound of item 16, wherein R18 and R19 are hydrogen. </dd></dl>

<dl><dt>19.</dt><dd> The compound of any of points 1 to 14, wherein Q1 is -N (R17) -. 20 20. The compound of item 11, which has the structure of formula IX:</dd></dl>

twenty-one. The compound of item 19 or 20, wherein R17 is hydrogen; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heterocyclyl or heteroaryl, each optionally substituted with one or more substituents Q.

<dl><dt>22.</dt><dd> The compound of item 21, wherein R17 is hydrogen; C1-6 alkyl or C3-7 cycloalkyl, each optionally substituted with one or more substituents Q.</dd></dl>

<dl><dt>23.</dt><dd> The compound of item 21, wherein R17 is hydrogen or methyl. </dd></dl>

<dl><dt>24.</dt><dd> The compound of item 21, wherein R17 is methyl. </dd></dl>

<dl><dt>25.</dt><dd> The compound of any of items 1 to 14, wherein Q1 is -CR17 (NR18R19) -. </dd></dl>

<dl><dt>26.</dt><dd> The compound of item 25, wherein R17 and R18 are each independently hydrogen; C1-6 alkyl or C3-7 cycloalkyl, each optionally substituted with one or more substituents Q.</dd></dl>

<dl><dt>27.</dt><dd> The compound of item 25, wherein R17 is hydrogen. </dd></dl>

<dl><dt>28.</dt><dd> The compound of item 11, which has the structure of formula X: </dd></dl>

<dl><dt>29.</dt><dd> The compound of any of points 25 to 28, wherein R18 is hydrogen or methyl. </dd></dl>

<dl><dt>30.</dt><dd> The compound of any of points 25 to 29, wherein R19 is hydrogen, -C (O) R20, -C (O) OR20, -C (O) NR21R22, or -C (= NR20) NR21R22. </dd></dl>

<dl><dt>31.</dt><dd> The compound of item 30, wherein R19 is -C (O) OR20. </dd></dl>

32 The compound of item 30 or 31, wherein R20 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heterocyclyl or heteroaryl, each optionally substituted with one or more substituents Q.

<dl><dt>33.</dt><dd> The compound of item 32, wherein R20 is C1-6 alkyl. </dd></dl>

<dl><dt>34.</dt><dd> The compound of item 32, wherein R20 is t-butyl. </dd></dl>

<dl><dt>35.</dt><dd> The compound of item 32, wherein R20 is C6-14 aryl. </dd></dl>

<dl><dt>36.</dt><dd> The compound of item 32, wherein R20 is benzyl. </dd></dl>

10 37. The compound of any of items 3 to 7, 10, 11, and 14 to 36, wherein R 2 'is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6- aryl 14, heterocyclyl or heteroaryl, each optionally substituted with one

or more substituents Q.

38. The compound of item 37, wherein R2 'is C6-14 aryl, heterocyclyl or heteroaryl, each optionally substituted with one or more substituents Q.

fifteen 39. The compound of item 37, wherein R2 'is selected from the group consisting of:

where

each A is independently hydrogen, halogen, cyano, or nitro; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more Q substituents; or -C (O) Ra, -C (O) ORa, -C (O) NRdRc, -C (NRa) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O ) NRbRc, -OC (= NRa) NRbRc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, NRaC (O) Rb, -NRaC (O) ORb, -NRaC (O) NRbRc, -NRaC (= NRd) NRbRc, NRaS (O) Rb, NRaS (O) 2Rb, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, -SRa, - S (O) Ra, or -S (O) 2Ra; wherein each Ra, Rb, Rc and Rd is independently hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more Q substituents; or Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally

substituted with one or more substituents Q; and

each E is independently hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q; or -C (O) Ra, -C (O) ORa, -C (O) NRbRc, -C (NRa) NRbRc, -ORa, -OC (O) Ra, -OC (O) ORa, -OC (O ) NRbRc, -OC (= NRa) NRbRc, -OS (O) Ra, -OS (O) 2Ra, -OS (O) NRbRc, -OS (O) 2NRbRc, -NRbRc, NRaC (O) Rb, -NRaC (O) ORb, -NRaC (O) NRbRc, NRaC (= NRd) NRbRc, -NRaS (O) Rb, -NRaS (O) 2Rb, -NRaS (O) NRbRc, -NRaS (O) 2NRbRc, -SRa, -S (O) Ra, or -S (O) 2Ra; wherein each Ra, Rb, Rc and Rd is independently hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q; or Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q.

40 The compound of item 39, wherein A is hydrogen, halogen, cyano, or nitro; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl, or heterocyclyl; each optionally substituted with one

or more substituents Q.

<dl><dt>41.</dt><dd> The compound of item 39, wherein A is hydrogen or C1-6 alkyl, optionally substituted with one or more substituents Q. </dd></dl>

<dl><dt>42.</dt><dd> The compound of item 39, wherein A is hydrogen, methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, ethenyl or ethynyl. </dd></dl>

<dl><dt>43.</dt><dd> The compound of item 39, wherein A is isopropyl. </dd></dl>

<dl><dt>44.</dt><dd> The compound of item 39, wherein A is trifluoromethyl. </dd></dl>

<dl><dt>45.</dt><dd> The compound of item 39, wherein A is -NRbRc. </dd></dl>

<dl><dt>46.</dt><dd> The compound of item 39, wherein A is isopropylamino. </dd></dl>

<dl><dt>47.</dt><dd> The compound of any of points 39 to 46, wherein E is hydrogen or cyano; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heterocyclyl or heteroaryl, each optionally substituted with one</dd></dl>

or more substituents Q.

<dl><dt>48.</dt><dd> The compound of item 47, wherein E is hydrogen or methyl. </dd></dl>

<dl><dt>49.</dt><dd> The compound of item 47, where E is hydrogen. </dd></dl>

<dl><dt>50.</dt><dd> The compound of any of items 3 to 7, 10, 11, and 14 to 49, wherein R7 is hydrogen, cyano, or halogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q; or -ORa, where Ra is hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl; each optionally substituted with one</dd></dl>

or more substituents Q.

<dl><dt>51.</dt><dd> The compound of item 50, wherein R7 'is hydrogen, halogen or -ORa. </dd></dl>

<dl><dt>52.</dt><dd> The compound of point 50, where R7 'is -ORa. </dd></dl>

<dl><dt>53.</dt><dd> The compound of item 51 or 52, wherein Ra is C1-6 alkyl, C3-7 cycloalkyl or C6-14 aryl, each optionally substituted with one or more substituents Q. </dd></dl>

<dl><dt>54.</dt><dd> The compound of item 53, wherein Ra is C1-6 alkyl, optionally substituted with one or more substituents Q. </dd></dl>

<dl><dt>55.</dt><dd> The compound of item 53, wherein R 7 'is methoxy, difluoromethoxy or trifluoromethoxy. </dd></dl>

<dl><dt>56.</dt><dd> The compound of any of points 3 to 7, 10, 11, and 14 to 49, wherein R 7 'is methanesulfonamido. </dd></dl>

<dl><dt>57.</dt><dd> The compound of any of points 3 to 7, 10, 11, and 14 to 56, wherein R 8 'is hydrogen, hydroxyl, cyano or halogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q; or -ORa, wherein Ra C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q.</dd></dl>

<dl><dt>58.</dt><dd> The compound of item 57, wherein R8 'is hydrogen, halogen or C1-6 alkyl, optionally substituted with one </dd></dl>

or more substituents Q.

<dl><dt>59.</dt><dd> The compound of item 57, wherein R8 'is methyl. </dd></dl>

<dl><dt>60.</dt><dd> The compound of any of points 3 to 7, 10, 11, and 14 to 59, wherein R 6 'is hydrogen, cyano or halogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q; or -ORa, where Ra is hydrogen; C1-6 alkyl, alkenyl</dd></dl>

C2-6, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, heteroaryl or heterocyclyl, each optionally substituted with one

or more substituents Q.

<dl><dt>61.</dt><dd> The compound of item 60, wherein R6 'is hydrogen, halogen or -ORa. </dd></dl>

<dl><dt>62.</dt><dd> The compound of item 61, wherein Ra is C 1-6 alkyl, C 3-7 cycloalkyl or C 6-14 aryl. </dd></dl>

5 63. The compound of item 61, wherein R6 'is methoxy.

<dl><dt>64.</dt><dd> The compound of point 61, wherein R6 'is chlorine. </dd></dl>

<dl><dt>65.</dt><dd> The compound of any of points 3 to 7, 10, 11, and 14 to 64, wherein R5 'is hydrogen or -ORa. </dd></dl>

<dl><dt>66.</dt><dd> The compound of item 65, wherein R5 'is methoxy. </dd></dl>

<dl><dt>67.</dt><dd> The compound of any of points 3 to 7, 10, 11, and 14 to 66, wherein R3 'is hydrogen. </dd></dl>

10 68. The compound of any of items 3 to 7, 10, 11, and 14 to 36, wherein R2 'is selected from the group consisting of:

<dl><dt>69.</dt><dd> The compound of any of points 1 to 68, where L is a bond; C1-6 alkylene or C3-7 cycloalkylene, each optionally substituted with one or more substituents Q; or -O-, - (CH2) p-, -C (O) -, - (CH2) pC (O) -, -C (O) O-,</dd></dl>

-C (O) NR14-, -C (= NR14) NR15-, -NR14-, -S (O) k-, or -S (O) kNR15-; where p is an integer 1, 2 or 3.

<dl><dt>70.</dt><dd> The compound of item 69, where L is a bond. </dd></dl>

<dl><dt>71.</dt><dd> The compound of item 69, where L is -Oo -NR14-. </dd></dl>

<dl><dt>72.</dt><dd> The compound of item 69, wherein L is C1-6 alkylene, optionally substituted with one or more substituents </dd></dl>

Q.

<dl><dt>73.</dt><dd> The compound of item 69, wherein L is methylene. </dd></dl>

<dl><dt>74.</dt><dd> The compound of item 69, wherein L is ethylene. </dd></dl>

<dl><dt>75.</dt><dd> The compound of item 69, wherein L is - (CH2) p-. </dd></dl>

<dl><dt>76.</dt><dd> The compound of item 69, wherein L is - (CH2) pCF2-. </dd></dl>

<dl><dt>77.</dt><dd> The compound of item 69, where L is -CF2-. </dd></dl>

<dl><dt>78.</dt><dd> The compound of item 69, where L is -C (O) -. </dd></dl>

<dl><dt>79.</dt><dd> The compound of item 69, where L is -C (O) O-. </dd></dl>

<dl><dt>80.</dt><dd> The compound of item 69, wherein L is -C (O) NR14-. </dd></dl>

<dl><dt>81.</dt><dd> The compound of item 71 or 80, wherein R14 is hydrogen or C1-6 alkyl. </dd></dl>

<dl><dt>82.</dt><dd> The compound of item 69, wherein L is -C (O) NH-. </dd></dl>

<dl><dt>83.</dt><dd> The compound of any of points 8 to 82, where n is 1, 2 or 3. </dd></dl>

<dl><dt>84.</dt><dd> The compound of any of points 1, 3, 5 to 8, 10, and 12 to 83, wherein R5 is -OH. </dd></dl>

<dl><dt>85.</dt><dd> The compound of any of points 1, 3, 5 to 8, 10, and 12 to 83, wherein R5 is -NR7S (O) kR8. </dd></dl>

<dl><dt>86.</dt><dd> The compound of item 85, wherein R8 is C1-6 alkyl, C6-14 aryl or C3-7 cycloalkyl, each optionally substituted with one or more substituents Q; or -CH2NR8aR8b, -CHR8cCHR8dNR8aR8b, or -CH2CR8cR8dNR8aR8b.</dd></dl>

<dl><dt>87.</dt><dd> The compound of item 85, wherein R8 is C3-7 cycloalkyl, optionally substituted with one or more substituents Q. </dd></dl>

<dl><dt>88.</dt><dd> The compound of item 85, wherein R8 is methyl, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. </dd></dl>

<dl><dt>89.</dt><dd> The compound of any of points 2, 4 to 7, 9, and 11 to 88, wherein R30 is C1-6 alkyl, C6-14 aryl or C3-7 cycloalkyl, each optionally substituted with one or more substituents Q; or -CH2NR30aR30b, -CHR30cCHR30dNR30aR30b, or -CH2CR30cR30dNR30aR30b.</dd></dl>

<dl><dt>90.</dt><dd> The compound of item 89, wherein R30 is C3-7 cycloalkyl, optionally substituted with one or more substituents Q. </dd></dl>

<dl><dt>91.</dt><dd> The compound of item 89, wherein R30 is cyclopropyl, 1-methylcyclopropyl, 1-ethynylcyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. </dd></dl>

<dl><dt>92.</dt><dd> The compound of any of items 3 to 7, 10, 11, and 15 to 91, where Z is CH. </dd></dl>

<dl><dt>93.</dt><dd> The compound of any of items 3 to 7, 10, 11, and 15 to 91, where Z is N. </dd></dl>

<dl><dt>94.</dt><dd> The compound of point 4, selected from the group consisting of </dd></dl>

and pharmaceutically acceptable salts and solvates thereof.

<dl><dt>95.</dt><dd> The compound of point 4, selected from the group consisting of </dd></dl>

and pharmaceutically acceptable salts and solvates thereof.

<dl><dt>96.</dt><dd> The compound of point 4, selected from the group consisting of </dd></dl>

and pharmaceutically acceptable salts and solvates thereof.

<dl><dt>97.</dt><dd> The compound of point 4, selected from the group consisting of </dd></dl>

and pharmaceutically acceptable salts and solvates thereof.

98. The compound of point 4, selected from the group consisting of

and pharmaceutically acceptable salts and solvates thereof.

where the * symbol indicates the junction point.

99. A pharmaceutical composition comprising the compound of any of items 1 to 98, and one or more pharmaceutically acceptable carriers.

5 100. The pharmaceutical composition of item 99, which further comprises a second antiviral agent.

101. The pharmaceutical composition of item 100, wherein the second antiviral agent is selected from the group consisting of an interferon, ribavirin, an interleukin, an NS3 protease inhibitor, a cysteine ​​protease inhibitor, a phenanthorequinone, a thiazolidine, a benzanilide, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a gliotoxin, a cerulenin, an oligodeoxynucleotide phosphorothioate

10 antisense, an IRES-dependent translation inhibitor and a ribozyme.

<dl><dt>102.</dt><dd> The pharmaceutical composition of item 100, wherein the second antiviral agent is an interferon. </dd></dl>

<dl><dt>103.</dt><dd> The pharmaceutical composition of item 102, wherein the interferon is selected from the group consisting of pegylated interferon alpha 2a, alphacon-1 interferon, natural interferon, albuferon, beta-1a interferon, omega interferon, alpha interferon, gamma interferon, tau interferon, interferon delta and interferon gamma-1b. </dd></dl>

fifteen 104. The pharmaceutical composition of any of items 99 to 103, wherein the composition is formulated for single dose administration.

105. The pharmaceutical composition of any of items 99 to 104, wherein the composition is formulated as an oral, parenteral or intravenous dosage form.

106. The pharmaceutical composition of item 105, wherein the oral pharmaceutical form is a tablet or a capsule.

<dl><dt>107.</dt><dd> The pharmaceutical composition of any of items 99 to 106, wherein the compound is administered in a dose of about 0.5 mg to about 1,000 mg daily. </dd></dl>

<dl><dt>108.</dt><dd> The pharmaceutical composition of any of items 1 to 98 or the pharmaceutical composition of any of items 99 to 107, for use in the treatment or prevention of an HCV infection. </dd></dl>

<dl><dt>109.</dt><dd> The pharmaceutical composition of any of items 1 to 98 or the pharmaceutical composition of any of items 99 to 107, for use in the treatment, prevention or improvement of one or more symptoms of a disease </dd></dl>

or liver disorder associated with HCV infection.

<dl><dt>110.</dt><dd> The compound for use of item 108 or 109, wherein the compound is to be administered with a second antiviral agent, in combination or alternate form. </dd></dl>

<dl><dt>111.</dt><dd> The compound for use of item 110, wherein the second antiviral agent is selected from the group consisting of interferon, ribavirin, amantadine, an interleukin, an NS3 protease inhibitor, a cysteine ​​protease inhibitor, a phenanthrenoquinone, a thiazolidine, a benzanilide , a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a gliotoxin, a cerulenin, an antisense oligodeoxynucleotide phosphorothioate, an IRES-dependent translation inhibitor and a ribozyme. </dd></dl>

<dl><dt>112.</dt><dd> The compound for use of item 110, wherein the second antiviral agent is an interferon. </dd></dl>

<dl><dt>113.</dt><dd> The compound for use of item 112, wherein the interferon is selected from the group consisting of pegylated interferon alpha 2a, alphacon-1 interferon, natural interferon, albuferon, beta-1a interferon, omega interferon, alpha interferon, gamma interferon, tau interferon , interferon delta and interferon gamma-1b. </dd></dl>

<dl><dt>114.</dt><dd> The compound of any of items 1 to 98 or the pharmaceutical composition of any of items 99 to 107, for use in inhibiting the replication of a virus in a host, which comprises contacting the host with the compound of any of items 1 to 98 or the pharmaceutical composition of any of items 99 to 107. </dd></dl>

<dl><dt>115.</dt><dd> The compound for use of item 114, wherein the host is a human being. </dd></dl>

<dl><dt>116.</dt><dd> The compound for use of item 114, wherein the host is a cell. </dd></dl>

<dl><dt>117.</dt><dd> The compound of any of items 1 to 98 or the pharmaceutical composition of any of items 99 to 107, for use in inhibiting the replication of a virus, which comprises contacting the virus with the compound of any of the points 1 to 98, or the pharmaceutical composition of any of items 99 to 107. </dd></dl>

<dl><dt>118.</dt><dd> The compound of any of items 1 to 98 or the pharmaceutical composition of any of items 99 to 107, for use in inhibiting the activity of a serine protease, which comprises contacting the protease with the compound of any of the items 1 to 98, or the pharmaceutical composition of any of items 99 to 107. </dd></dl>

<dl><dt>119.</dt><dd> The compound for use of item 118, wherein the serine protease is an NS3 HCV protease. </dd></dl>

The description will be better understood by the following non-limiting examples.

Examples

As used herein, the symbols and conventions used in these procedures, schemes and examples, regardless of their particular abbreviation is specifically defined, are consistent with those used in contemporary scientific literature, for example the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, but not limited to, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); ml (milliliters); μl (microliters); mM (millimolar); μM (micromolar); Hz (Hertz); MHz (megahertz); mmol (millimoles); eq. (equivalent); hour or hours (h); min (min); MS (mass spectrometry); NMR (nuclear magnetic resonance); ESI (electrospray ionization); ACN, (acetonitrile); CDCl3 (deuterated chloroform); DCE (dichloroethane); DCM (dichloromethane); DMF (N, N-dimethylformamide); DMSO (dimethylsulfoxide); DMSO-d6 (deuterated dimethylsulfoxide); EtOAc (ethyl acetate); MeOH (methanol); THF (tetrahydrofuran); DIPEA (N, N-diisopropylethylamine); ASD (triethylamine); DBU (1,8diazabicyclo [5.4.0] undec-7-eno; CDI (carbonyldiimidazole); EDCI or EDC (N'-ethyl-N- (3-dimethylaminopropyl) -carbodiimide); P2O5, (phosphorus pentoxide); TBAF (tetrabutylammonium fluoride); TBTU (O- (benzotriazol-1-yl) N, N, N ', N'-tetramethyluronium tetrafluoroborate); Me (methyl); Et (ethyl); iPr, (isopropyl); tBu (tert-butyl); Boc (tert-butoxycarbonyl); Bn (benzyl); PMB (p-methoxybenzyl); TsO (tosylate); DEAD (diethylazodicarboxylate), DIAD (diisopropylazodicarboxylate), PPh3 (triphenylphosphine), PNBA (p-nitrobenzoic acid), PNB (p-nitrobenzoyl), and Zhan IB catalyst ((1,3-dimethylimimidazolidin-2-yl) (5- ( N, N-dimethylsulfamoyl) -2-isopropoxybenzylidene) ruthenium (V)).

For all of the following examples, conventional treatment and purification methods known to those skilled in the art can be used. Unless otherwise indicated, all temperatures are expressed in ° C (degrees Celsius). All reactions were carried out at room temperature unless otherwise indicated. The synthetic methodologies illustrated in Schemes 4 to 18 are intended to illustrate the applicable chemistry throughout the use of the specific examples and are not indicative of the scope of the description.

Example 1

Preparation of N-methyl-ω-alkenyl-1-amine tosylate salts 32

Syntheses of N-methyl-ω-alkenyl-1-amine 32 tosylate salts are shown in Scheme 5

Stage A: Preparation of 2,2,2-trifluoro-N- (hex-5-enyl) -N-methylacetamide 31a. Sodium hydride (60% dispersion in mineral oil, 31.5 g, 1.28 eq.) Was slowly added under nitrogen to a solution of N-methyl-2,2,2-trifluoroacetamide (100 g, 1,28 eq .) in DMF (500 ml) at 0 ° C. The reaction mixture was stirred for 90 min at 0 ° C, and then 6-bromo-1-hexene (100 g, 1 eq.) Was added dropwise over 45 min. The reaction mixture was allowed to warm to room temperature and stirred for 3 days at room temperature. Then the reaction mixture was poured into water and extracted 3 times with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield compound 31a as a colorless oil with 56% yield.

1H NMR (DMSO-d6, 400 MHz) δ 1.27-1.38 (m, 2H), 1.48-1.60 (m, 2H), 2.00-2.06 (m, 2H), 2.93-3.07 (2m, 3H), 3,353.40 (m, 2H), 4.92-5.04 (m, 2H), 5.73-5.83 (m, 1H).

Scheme 5

Stage B: N-Methylhex-5-en-1-amine tosylate salt 32a. At room temperature, compound 31a (71.88 g, 1 eq.) And p-toluenesulfonic acid (74.4 g, 1.2 eq.) Were dissolved in MeOH (640 ml). The reaction mixture was heated at reflux for 7 days. Then the solvent was removed in vacuo and the residue was crystallized from acetone. The product was isolated by filtration, dried over P2O5 to give compound 32a as a white powder in 76% yield.

1H NMR (CDl3, 400 MHz): δ 1.38 (q, J = 7.76 Hz, 2H), 1.71 (q, J = 7.76 Hz, 2H), 1.99 (q, J = 6.98 Hz, 2H), 2.38 (s, 3H), 2.70 (t, J = 5.17 Hz, 3H), 2.87-2.93 (m, 2H), 4.92- 4.99 (m, 2H), 5.67-5.73 (m, 1H), 7.20 (d, J = 7.76 Hz, 2H), 7.75 (d, J = 7.76 Hz , 2H), 8.62 (wide s, 2H).

Stage C: N-Methylhept-5-en-1-amine tosylate salt 32b. Compound 32b was synthesized from 7-bromoheptene as a white solid with quantitative yield, following the procedure described for compound 32a.

1H NMR (CDCl3, 400 MHz) δ 1.38 (q, J = 7.76 Hz, 2H), 1.71 (q, J = 7.76 Hz, 2H), 1.80 (q, J = 6 , 98 Hz, 2H), 1.99 (q, J = 6.98 Hz, 2H), 2.38 (s, 3H), 2.70 (t, J = 5.17 Hz, 3H), 2, 87-2.93 (m, 2H), 4.92-4.99 (m, 2H), 5.67-5.73 (m, 1H), 7.20 (d, J = 7.76 Hz, 2H), 7.75 (d, J = 7.76 Hz, 2H), 8.62 (wide s, 2H).

Stage D: N-Methyloct-5-en-1-amine tosylate salt 32c. Compound 32c was synthesized from 7-bromooctene as a white powder with quantitative yield, following the procedure described for compound 32a.

1H NMR (CDCl3, 400 MHz) δ 1.38 (q, J = 7.76 Hz, 2H), 1.71 (q, J = 7.76 Hz, 2H), 1.80 (q, J = 6 , 98 Hz, 2H), 1.90 (q, J = 6.9 Hz, 2H), 1.99 (q, J = 6.98 Hz, 2H), 2.38 (s, 3H), 2, 70 (t, J = 5.17 Hz, 3H), 2.87-2.93 (m, 2H), 4.92-4.99 (m, 2H), 5.67-5.73 (m, 1H), 7.20 (d, J = 7.76 Hz, 2H), 7.75 (d, J = 7.76 Hz, 2H), 8.62 (wide s, 2H).

Example 2

Preparation of iodide of 1 - ((1R, 2S) -1- (ethoxycarbonyl) -2-vinylcyclopropylcarbamoyl) -3-methyl-1H-imidazol-3-io Iodide synthesis of 1 - ((1R, 2S) -1 - (ethoxycarbonyl) -2-vinylcyclopropylcarbamoyl) -3-methyl-1H-imidazol-3-io 34 is shown in scheme 6.

Scheme 6

Stage A: Preparation of (1R, 2S) - (1H-imidazole-1-carboxamido) -2-vinylcyclopropanecarboxylate 33. Under a nitrogen atmosphere, the tosylate salt of (1R, 2S) -1-amino- Ethyl 2-vinylcyclopropanecarboxylate (5 g, 1 eq.) And CDI (2.7 g, 1.1 eq.) In THF (50 ml) containing ASD (2.3 ml, 1.1 eq.). Then, the reaction mixture was heated at reflux overnight. The solvent was removed under reduced pressure. The residue was dissolved in DCM, and was

10 washed twice with water. The organic layer was dried over sodium sulfate and then concentrated. The residue was purified by silica gel chromatography to give compound 33 as a pale yellow oil in 70% yield.

1H NMR (DMSO-d6, 400 MHz): δ 1.13 (t, J = 7.11 Hz, 3H), 1.54 (dd, J = 5.43 and 9.57 Hz, 1H), 1, 74 (dd, J = 5.43 and 8.28 Hz, 1H), 2.35 (q, J = 8.54 Hz, 1H), 4.08-4.13 (q, J = 7.11 Hz , 2H), 5.13-5.16 (dd, J = 10.41 and 1.84 Hz, 1H), 5.32

fifteen 5.36 (dd, J = 17.13 and 1.73 Hz, 1H), 5.63-5.71 (m, 1H), 7.02 (s, 1H), 7.65 (s, 1H) , 8.23 ​​(s, 1 H), 9.31 (s, 1 H); MS (ESI +): m / z = 250.2 (MH +).

Stage B: Preparation of iodide of 1 - ((1R, 2S) -1- (ethoxycarbonyl) -2-vinylcyclopropyl-carbamoyl) -3-methyl-1H-imidazol-3-ioe

3. 4. Under a nitrogen atmosphere, methyl iodide (1.9 ml, 4 eq.) Was added to a solution of compound 33 (2 g, 1 eq.) In ACN (16 ml). The reaction mixture was stirred at room temperature for 2 h. The solvent was separated

twenty under reduced pressure to give compound 34 as a yellow oil, which was used directly in the next step without further purification.

Example 3

Preparation of quinolin-4-oles substituted with 2- (4-isopropylthiazol-2-yl) 43 The syntheses of compounds 43 are shown in schemes 7 to 9, where R5 ', R6', R7 'and R8' in the Compounds 39 to 42 and 45 to 47 are as defined in compounds 43.

Method 1

5 Step A: Preparation of 1-bromo-3-methylbutan-2-one 35. To a solution of 3-methyl-2-butanone (40.7 g, 1 eq.) In ethanol (391 ml) bromine (62 , 4 g, 0.83 eq.) Under a nitrogen atmosphere at 0 ° C for 30 min. The reaction mixture was stirred at 0 ° C for 4 h, and then quenched with 1 M aqueous sodium metabisulfite (100 ml) and extracted with petroleum ether (750 ml). The organic layer was washed twice with water (100 ml), twice with a cold saturated aqueous bicarbonate solution and then brine. The organic layer was dried over sodium sulfate and

10 then it was concentrated under reduced pressure. The product was purified by vacuum distillation to give compound 35 as a colorless oil with 42% yield.

1H NMR (CDCl3, 400 MHz): δ 1.17 (d, J = 6.98 Hz, 6H), 2.99 (m, J = 6.98 Hz, 1H), 3.99 (s, 2H) .

Scheme 7 Scheme 8

Step B: Preparation of ethyl 4-isopropylthiazol-2-carboxylate 36. A solution of compound 35 (3.5 g, 1.25 eq.) And ethylthioxamate (2.3 g, 1 eq.) In ethanol (40 ml ) was heated at 80 ° C for 6 h, and then cooled to 0 ° C. The reaction mixture was diluted with water and EtOAc, and then neutralized to pH 7 with NH3 (28%). The aqueous layer was extracted with EtOAc. The combined organic layers were dried over sodium sulfate and then separated under reduced pressure. The residue was purified by silica gel chromatography to give compound 36 as a yellow oil with quantitative yield.

1H NMR (DMSO-d6, 400 MHz): δ 1.25 (d, J = 6.73 Hz, 6H), 1.31 (t, J = 7.24 Hz, 3H), 3.11 (hep, J = 6.73 Hz, 1H), 4.35 (q, J = 7.24 Hz, 2H), 7.72 (s, 1H).

Step C: Preparation of 4-isopropylthiazol-2-carboxylic acid, lithium salt 37. To a solution of compound 36 (26 g, 1 eq.) In a mixture of MeOH (78 ml) and THF (260 ml), added lithium hydroxide (2.8 g, 0.9 eq.). The reaction mixture was stirred at room temperature overnight. Then, the solvents were removed under reduced pressure. The residue was triturated with petroleum ether (500 ml), filtered, washed with petroleum ether and dried in vacuo to give compound 37 as a beige solid in 56% yield.

1H NMR (DMSO-d6, 400 MHz): δ 1.21 (d, J = 6.73 Hz, 6H), 2.95 (hep, J = 6.73 Hz, 1H), 7.19 (s, 1 HOUR).

Step D: Preparation of 4-isopropylthiazol-2-carbonyl chloride 38. Oxalyl chloride (2.9 g, 1.5 eq.) Was added dropwise under a nitrogen atmosphere at 0 ° C to a suspension of compound 37 (1.8 g, 1 eq.) In DCM (25 ml) and DMF (50 μl). The reaction mixture was stirred at 0 ° C for 30 min and then at room temperature for an additional 90 min. The lithium chloride salt was separated from the reaction mixture by filtration. The solvent was then removed under reduced pressure to give compound 38 as a yellow oil with quantitative yield, which was stored under a nitrogen atmosphere and used directly in the next step without further purification.

Stage E: Preparation of 1- (2-amino-4-methoxyphenyl) ethanone 40a. Trichloroborane (1 M) in DCM (82 ml, 1 eq.) Was added dropwise to a solution of meta-anisidine 39a (10 g, 1 eq.) In toluene (56 ml) under a nitrogen atmosphere at 0-5 ° C over 1 h. After stirring for 10 min at 0 ° C, ACN (5.2 ml, 1.20 eq.) Was added. After stirring the reaction mixture for an additional 1 h at 0 ° C, aluminum (III) chloride (11.9 g, 1.1 eq.) Was added at 0 ° C. The reaction mixture was stirred at 50 ° C for 16 h. Then, the reaction mixture was cooled to 0 ° C, and propan-2-ol (38 ml) was added over 10 min, followed by the addition of water (110 ml) over 30 min. The reaction mixture was heated at 50 ° C for 3 h. After cooling to 0 ° C, aqueous sodium hydroxide solution (25%) was added. The aqueous layer was extracted with toluene (100 ml). The combined organic layers were washed with NaOH (25%), brine, and dried over sodium sulfate. The solvent was removed to give compound 40a as a yellow solid in 63% yield.

1H NMR (CDCl3, 400 MHz): δ 2.52 (s, 3H), 3.80 (s, 3H), 6.07 (d, J = 2.43, 1H), 6.23 (dd, J = 2.43 and 8.98 Hz, 1H), 6.43 (wide s, 2H), 7.63 (d, J = 8.98 Hz).

Step F: Preparation of 1- (2-amino-3-methyl-4-methoxyphenyl) ethanone 40b. Compound 40b was synthesized from 3-methoxy-2-methylaniline 39b as a yellow solid in 23% yield, according to the procedure described for compound 40a.

MS (ESI, EI +): m / z = 180 (MH +).

Step G: Preparation of 1- (2-amino-4-chloro-5-methoxy-phenyl) -ethanone 40g. Compound 40g was synthesized from 3-chloro-4-methoxy-aniline 39g as a brown solid in 50% yield, according to the procedure described for compound 40a.

MS (ESI, EI +): m / z = 200 (MH +).

Step H: Preparation of N- (3,5-dimethoxy-phenyl) -4-isopropylthiazol-2-carboxamide 41e. To a stirred solution of compound 37 (1.38 g, 7.8 mmol) in DCM (50 ml) under a nitrogen atmosphere, oxalyl chloride (1.16 g, 9.1 mmol) was added. The reaction mixture was stirred at room temperature for 90 min. The solution was filtered under a nitrogen atmosphere and washed with DCM. The filtrate was concentrated under reduced pressure and the residue was dissolved in dioxane (20 ml). 3,5-Dimethoxyaniline (1 g, 6.5 mmol) in dioxane (9 ml) was added dropwise. The reaction mixture was stirred at room temperature for 90 min. The solvent was removed under reduced pressure and the crude material was purified by silica gel chromatography (EtOAc / DCM) to give compound 41e as a white solid in 90% yield.

1H NMR (CDCl3, 400 MHz) δ 1.35 (s, 3H), 1.37 (s, 3H), 3.14-3.17 (m, 1H), 3.82 (s, 6H), 6 , 30 (wide s, 1H), 6.97 (d, J = 2.30 Hz, 2H), 7.19 (s, 1H); MS (ESI, EI +) m / z = 307 (MH +).

Stage I: Preparation of N- (2-acetyl-5-methoxyphenyl) -4-isopropylthiazol-2-carboxamide 42a. Under a nitrogen atmosphere, a solution of compound 40a (3 g, 1 eq.) In 1,4-dioxane (30 ml) was added at 0 ° C to a solution of compound 38 (4.1 g, 1.2 eq .) in 1,4-dioxane. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography to give compound 42a as a beige solid in 75% yield.

1H NMR (CDCl3, 400 MHz): δ (ppm) 1.43 (d, J = 6.98 Hz, 6H), 2.65 (s, 3H), 3.26 (hep, J = 6.98 Hz , 1H), 3.92 (s, 3H), 6.69 (dd, J = 2.59 and 8.80 Hz, 1H), 7.2 (d, J = 0.84, 1H), 7, 87 (d, J = 8.9 Hz, 1H), 8.58 (d, J = 2.59 Hz, 1H), 13.5 (wide s, 1H); MS (ESI, EI +): m / z = 319 (MH +).

Step J: Preparation of N- (6-acetyl-2-methyl-3-methoxyphenyl) -4-isopropylthiazol-2-carboxamide 42b. Compound 42b was synthesized from compound 40b and compound 38 in the form of a beige solid in 66% yield, according to the procedure described for compound 42a.

MS (ESI, EI +): m / z = 333 (MH +).

Step K: Preparation of N- (6-acetyl-2-fluoro-3-methoxyphenyl) -4-isopropylthiazol-2-carboxamide 42c. Compound 42c was synthesized from 1- (2-amino-3-fluoro-4-methoxyphenyl) ethanone and compound 38 as a beige solid in 84% yield, according to the procedure described for compound 42a.

MS (ESI, EI +): m / z = 337 (MH +).

Step L: Preparation of N- (6-acetyl-2-chloro-3-methoxyphenyl) -4-isopropylthiazol-2-carboxamide 42d. Compound 42d was synthesized from 1- (2-amino-3-chloro-4-methoxyphenyl) ethanone and compound 38 as a beige solid in 80% yield, according to the procedure described for compound 42a.

1H NMR (CDCl3, 400 MHz) δ (ppm) 1.47 (s, 3H), 1.48 (s, 3H), 2.57 (s, 3H), 3.34-3.41 (quint, J = 6.90 Hz, 1H), 3.98 (s, 3H), 6.86 (d, J = 8.48 Hz, 1H), 7.64 (d, J = 8.48 Hz, 1H), 8.07 (s, 1 H); MS (ESI, EI-) m / z = 351 (MH-); MS (ESI, EI +): m / z = 353 (MH +).

Step M: Preparation of N- (2-acetyl-3,5-dimethoxy-phenyl) -4-isopropylthiazol-2-carboxamide 42e. To a suspension of Et2AlCl (1.61 g, 12.04 mmol) in DCM at 0 ° C was added acetyl chloride (630 mg, 8.02 mmol). The mixture was stirred at 0 ° C for 30 min. Compound 41e (1.23 g, 4.01 mmol) was added and the reaction mixture was stirred at 80 ° C for 90 min. The reaction was poured on ice and DCM was added. The organic layers were separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (EtOAc / DCM) to give compound 42e as a white solid in 82% yield.

1H NMR (CDCl3, 400 MHz) δ 1.41 (s, 3H), 1.43 (s, 3H), 2.63 (s, 3H), 3.20-3.27 (m, 1H), 3 , 89 (s, 3H), 3.90 (s, 3H), 6.27 (d, J = 2.30, 1H), 7.19 (s, 1H), 8.12 (d, J = 2 , 30 Hz, 1H).

Step N: Preparation of N- (6-acetyl-3-chloro-4-methoxyphenyl) -4-isopropylthiazol-2-carboxamide 42g. Compound 42g was synthesized from compounds 38 and 40g in the form of a beige solid in 69% yield, according to the procedure described for compound 42a.

MS (ESI, EI +): m / z = 354 (MH +).

Stage O: Preparation of 2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-ol 43a. To a solution of compound 42a (4,312 g, 1 eq.) In tBuOH (60 ml) was added potassium t-butoxide (3.8 g, 2.5 eq.) Under a nitrogen atmosphere. The mixture was stirred at 70 ° C for 16 h, and then cooled to 0 ° C and quenched with MeOH (10 ml) and acetic acid (2.5 ml). The solvent was removed under reduced pressure and the residue was triturated in a MeOH / water mixture, isolated by filtration, washed with ACN and then petroleum ether to give compound 43a as a yellow solid in 71% yield. .

1H NMR (DMSO-d6, 400 MHz): δ 1.32 (d, J = 6.98 Hz, 6H), 3.14 (m, 1H), 3.89 (s, 3H), 7.06 ( s wide, 1H), 7.50-7.66 (m, 3H), 8 (d, J = 9.05 Hz, 1H), 11.62 (wide s, 1H); MS (ESI, EI +): m / z = 301 (MH +).

Step P: Preparation of 2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methylquinolin-4-ol 43b. Compound 43b was synthesized from compound 42b as a yellow solid in 60% yield, according to the procedure described for compound 43a.

MS (ESI, EI +): m / z = 315 (MH +).

Stage Q: Preparation of 2- (4-isopropylthiazol-2-yl) -8-fluoro-7-methoxyquinolin-4-ol 43c. Compound 43c was synthesized from compound 42c as a yellow solid in 90% yield, according to the procedure described for compound 43a.

MS (ESI, EI +): m / z = 319 (MH +).

Step R: Preparation of 2- (4-isopropylthiazol-2-yl) -5,7-dimethoxyquinolin-4-ol 43e. Compound 43e was synthesized from compound 42e as a yellow solid in 60% yield, according to the procedures described for compound 43a.

1H NMR (CDCl3, 400 MHz) δ 1.37 (s, 3H), 1.39 (s, 3H), 3.15-3.22 (m, 1H), 3.95 (s, 3H), 4 , 05 (s, 3H), 6.45 (s, 1H), 7.03 (s, 2H), 7.62 (broad s, 1H), 9.55 (s, 1H); MS (ESI, EI +): m / z = 331 (MH +).

Step S: Preparation of 7-chloro-2- (4-isopropylthiazol-2-yl) -6-methoxyquinolin-4-ol 43g. Compound 43g was synthesized from compound 42g as a yellow solid in 70% yield, according to the procedures described for compound 43a.

MS (ESI, EI +): m / z = 335 (MH +).

Stage T: Preparation of 8-bromo-7-methoxy-2- (4-isopropyl-thiazol-2-yl) -quinolin-4-ol 43h. Compound 43h was synthesized according to the procedures described for compounds 42a and 43a and in WO 2007014919.

MS (ESI, EI +): m / z = 380 (MH +).

Method B:

Step AA: Preparation of 4-isopropyl-2-tributylstananyl-thiazole 44. To a stirred solution of 4-isopropylthiazole (9 g, 71 mmol) in anhydrous THF (100 ml) at -78 ° C was added nBuLi (40 ml, 99 mmol). The reaction was stirred for 1 h and the temperature reached -40 ° C. The reaction mixture was cooled to -78 ° C and tri-n-butyltin chloride (23 g, 71 mmol) was added. The reaction mixture was stirred at room temperature for 48 h. Water was added and the solvent was evaporated under reduced pressure. The residue was partitioned between water and EtOAc. The organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 44 as a colorless oil in 55% yield.

1H NMR (CDCl3, 400 MHz) δ 0.88-1.62 (m, 27H), 1.40 (s, 3H), 1.42 (s, 3H), 3.17-3.24 (m, 1 HOUR).

Stage AB: Preparation of 2,4,8-trichloro-7-methoxyquinoline 45d. A mixture of 2-chloro-3-methoxyaniline hydrochloride 39d (15 g, 1 eq.), Malonic acid (12.06 g, 1.5 eq.) And phosphorus oxychloride (80 ml) was heated at reflux for 16 h. The reaction mixture was slowly poured into water and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified on a silica pad eluted with DCM, to give compound 45d as a white solid in 74% yield.

1H NMR (CDCl3, 376 MHz) δ 4.10 (s, 3H), 7.43 (t, J = 4.88 Hz, 2H), 8.12 (d, J = 9.48 Hz, 1H).

Step AC: Preparation of 2,4-dichloro-8-methyl-7-methoxyquinoline 45b. Compound 45b was synthesized from 2-methyl-3-methoxyaniline 39b hydrochloride and malonic acid, in the form of a white powder with 43% yield, following the procedure described for compound 45d.

1H NMR (CDCl3, 376 MHz) δ 2.62 (s, 3H), 4.03 (s, 3H), 7.34 (s, 1H), 7.37 (d, J = 9.02 Hz, 1H ), 8.05 (d, J = 9.02 Hz, 5 1H).

Scheme 9

Stage AD: Preparation of 2,4-dichloro-6-methoxy-8-methyl-quinoline 45f. A mixture of 4-methoxy-2-methylaniline 39f (5 g, 36.45 mmol), malonic acid (5.68 g, 54.67 mmol) in phosphorus trichloride oxide (36 ml) was heated to reflux

10 for 16 h. Then, the reaction mixture was poured dropwise into cold water (400 ml), extracted with ethyl acetate, washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure, and purified on chromatography. silica gel (DCM) to give compound 45f as a beige solid in 43% yield.

1H NMR (CDCl3, 400 MHz) δ 2.72 (s, 3H), 3.95 (s, 3H), 7.27-7.28 (m, 2H), 7.47 (s, 1H).

fifteen Stage AE: Preparation of 2,8-dichloro-7-methoxy-4- (4-methoxy-benzyloxy) -quinoline 46d. NaH (60% in oil) (670 mg, 1.2 eq.) Was added portionwise to a stirred solution of p-methoxybenzyl alcohol (2.31 g, 1.2 eq.) And 15-crown5 (3, 32 ml, 1.2 eq.) In anhydrous DMF (10 ml). The mixture was stirred at room temperature for 30 min. Compound 45d (3.66 g, 1 eq.) In anhydrous DMF (25 ml) was then added and the reaction mixture was stirred at room temperature for 16 h. Then, the reaction mixture was poured into water (300 ml), extracted with EtOAC, dried

twenty over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (petroleum ether / DCM, 50/50) to give compound 46d as a yellow solid in 38% yield.

1H NMR (CDCl3, 376 MHz) δ 3.86 (s, 3H), 4.05 (s, 3H), 5.20 (s, 2H), 6.77 (s, 1H), 6.98 (d , J = 8.53 Hz, 2H), 7.23 (d, J = 9.41, 1H), 7.42 (d, J = 8.53 Hz, 2H), 8.08 (d, J = 9.41 Hz, 1H).

25 Stage AF: Preparation of 2-chloro-8-methyl-7-methoxy-4- (4-methoxy-benzyloxy) -quinoline 46b. Compound 46b was synthesized from compound 45b as a white powder in 50% yield, following the procedure described for compound 46d.

1H NMR (CDCl3, 376 MHz) δ 2.60 (s, 3H), 3.85 (s, 3H), 3.97 (s, 3H ), 5.18 (s, 2H), 6.69 (s , 1H), 6.97 (d, J = 8.57 Hz, 1H), 7.19 (d, J = 8.57 Hz, 1H), 7.42 (d, J = 8.57 Hz, 1H ), 8.02 (d, J = 8.57 Hz, 1H).

Stage AG: Preparation of 2-chloro-6-methoxy-4- (4-methoxybenzyloxy) -8-methyl-quinoline 46f. Compound 46f was synthesized from compound 45f as a white solid in 58% yield, following the procedure described for compound 46a.

1H NMR (CDCl3, 400 MHz) δ 2.68 (s, 3H), 3.80 (s, 3H), 3.83 (s, 3H), 5.11 (s, 2H), 6.72 (s , 1H), 6.97 (d, J = 9.03 Hz, 5 2H), 7.15 (dd, J = 3.01 Hz and J = 0.96 Hz, 1H), 7.20 (d, J = 3.00 Hz, 1 H), 7.40 (d, J = 9.03 Hz, 2H).

Step AH: Preparation of 2- (4-isopropyl-thiazol-2-yl) -6-methoxy-4- (4-methoxy-benzyloxy) -8-methyl-quinoline 47f. Compound 44 (100 mg, 0.29 mmol), compound 46f (242 mg, 0.35 mmol) and potassium carbonate (48 mg, 0.35 mmol) in degassed anhydrous DMF were stirred under microwave radiation at 80 ° C for 1 h. The solvent was removed under reduced pressure and the crude material was purified by silica gel chromatography (petroleum ether / DCM)

10 to give compound 47f in the form of a yellow powder with 63% yield.

1H NMR (CDCl3, 400 MHz) δ 1.40 (s, 3H), 1.42 (s, 3H), 2.80 (s, 3H), 3.17-3.24 (m, 1H), 3 , 85 (s, 3H), 3.89 (s, 3H), 5.31 (s, 2H), 6.99 (d, J = 9.10 Hz, 2H), 7.00 (s, 1H) , 7.21 (m, 1H), 7.31 (d, J = 2.93 Hz, 1H), 7.49 (d, J = 9.10 Hz, 2H), 7.79 (s, 1H) .

Stage AI: Preparation of 4-hydroxy- [2- (4-isopropyl-thiazol-2-yl)] - 6-methoxy-8-methyl-quinoline 43f. Compound 47f (1.23

fifteen g, 2.82 mmol), cesium trichloride (1.58 g, 4.23 mmol) and sodium iodide (423 mg, 2.82 mmol) in ACN (26 ml) were stirred at 85 ° C for 1 h . The mixture was then filtered through celite and the solvent was evaporated. The brown solid obtained was suspended in water, the pH was adjusted to 5 with 1 N HCl. The mixture was extracted with DCM, dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (petroleum ether / DCM) to give compound 43f as a brown solid with 55 % yield

twenty 1H NMR (CDCl3, 400 MHz) δ 1.40 (d, J = 6.91 Hz, 6H), 2.80 (s, 3H), 3.17-3.24 (m, 1H), 3.89 (s, 3H), 7.00 (s, 1H), 7.21 (m, 1H), 7.55 (s, 1H), 7.79 (s, 1H), 9.56 (wide s, 1H ).

Example 4

Preparation of macrocyclic compounds 56

25 The synthesis of the macrocyclic compounds 56 are illustrated in scheme 10, where R5 ', R6', R7 'and R8' in the

Scheme 10

Step A: Preparation of (2S, 4R) -2- (N- (hex-5-enyl) -N-methyl-carbamoyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

48. To a cold solution of cis-N-Boc-4-hydroxy-L-proline (10 g. 1 eq.), O- (benzotriazol-1-yl) -N, N, N 'tetrafluoroborate was added dropwise , N'-tetramethyluronium (TBTU 15.5 g, 1.12 eq.) And compound 32a (13.6 g, 1.1 eq.) In DMF (80 ml) containing DIPEA (29.4 ml, 3 , 9 eq.) Under a nitrogen atmosphere at 0 ° C. The reaction mixture was stirred overnight at room temperature, and then quenched with water and extracted with diethyl ether. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound 48 as a pink powder in 95% yield.

1H NMR (DMSO-d6, 400 MHz): δ 1.29-1.3 (m, 9H), 1.33-1.55 (m, 4H), 1.70-1.80 (m, 1H) , 1.97-2.12 (m, 3H), 2,772.97 (m, 3H), 3.15-3.40 (m, 4H), 4.22 (broad s, 1H), 4.50- 4.62 (m, 1H), 4.90-5.04 (m, 3H), 5.71-5.83 (m, 1H); MS (ESI +): m / z = 327 (MH +).

Step B: Preparation of (2S, 4R) -N- (hex-5-enyl) -4-hydroxy-N-methylpyrrolidine-2-carboxamide 49. Trifluoroacetic acid was added dropwise to a solution of compound 48 (1 g , 1 eq.) In DCM (10 ml). The reaction mixture was stirred for 3 h at room temperature, and then the trifluoroacetic acid was removed under reduced pressure. The residue was coevaporated with toluene to give compound 49 as a pale yellow oil with quantitative yield.

MS (ESI +): m / z = 227 (MH +).

Stage C: Preparation of the ethyl ester of (1R) -1 - {[2 (S) - (hex-5-enyl-methyl-carbamoyl) -4 (R) -hydroxy-pyrrolidine-Ncarbonyl] amino} -2 ( R) -vinyl-cyclopropanecarboxylic 50. Triethylamine (1.3 ml, 3 eq.) Was added at room temperature under a nitrogen atmosphere to a mixture of compound 34 (0.7 g, 1 eq.) And compound 49 (1, 2 g, 1 eq.) In DCM (15 ml). The reaction mixture was stirred overnight at room temperature and then quenched with 1 M aqueous hydrochloric acid. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound 50 as a white solid in 70% yield.

1H NMR (DMSO-d6, 400 MHz): δ 1.10-1.14 (td, J = 7.07 and 2.01 Hz, 3H), 1.15-1.17 (m, 1H), 1 , 22-1,30 (m, 1H), 1,331.41 (m, 2H), 1.42-1.50 (m, 1H), 1.54-1.57 (m, 1H), 1.71 -1.79 (m, 1H), 1.97-2.07 (m, 4H), 2.74 (s, 1H), 2.97 (s, 2H), 3.11 (d, J = 10 , 24 Hz, 1H), 3.15-3.21 (m, 1H), 3.43-3.48 (m, 1H), 3.91-4.07 (m, 2H), 4.29- 4.30 (m, 1H), 4.65-4.69 (d, J = 6.50 Hz, 1H), 4.90-4.96 (m, 3H), 5.00-5.06 ( m, 2H), 5.19-5.25 (dd, J = 17.04 and 6.50 Hz, 1H), 5.51-5.61 (m, 1H), 5.71-5.83 ( m, 1H), 7.08 (s, 1H); MS (ESI-): m / z = 406 (MH-).

Stage D: Preparation of the ethyl ester of (1R) -1 - {[2 (S) - (hex-5-enyl-methyl-carbamoyl) -4 (R) -terc-butyldimethylsilyloxypyrrolidine-N-carbonyl] -amino} -2 (R) -vinyl-cyclopropanecarboxylic 51. Under a nitrogen atmosphere, tert-butyldimethylsilyl chloride was added to a solution of compound 50 (750 mg, 1 eq.) And TEA (537 μl, 1 eq.) In DCM ( 6 ml) The reaction mixture was stirred overnight at room temperature and quenched with water. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound 51 in 70% yield.

1H NMR (DMSO-d6, 400 MHz): δ 0.03 (s, 6H), 0.83 (s, 9H), 1.09-1.13 (td, J = 7.09 and 2.24 Hz , 3H), 1.14-1.18 (m, 1H), 1.21-1.29 (m, 2H), 1.32-1.41 (m, 2H), 1.54-1.57 (m, 2H), 1.80-1.86 (m, 2H), 1.91-2.09 (m, 4H), 2.75 (s, 1H), 2.97 (s, 2H), 3.06-3.19 (m, 2H), 3.47-3.57 (m, 1H), 3.94-4.07 (m, 2H), 4.48-4.52 (m, 1H ), 4.66-4.71 (m, 1H), 4.90-5.06 (m, 2H), 5.19-5.25 (dd, J = 17.24 and 7.39 Hz, 1H ), 5.51-5.61 (m, 1H), 5.75-5.83 (m, 1H), 7.12 (s, 1H); MS (ESI +): m / z = 522 (MH +).

Stage E: Preparation of (Z) - ethyl ester (4R, 6S, 15S, 17R) -2,14-dioxo-13-N-methyl-17-tert-butyldimethylsilyloxy1,3,13-triazatricyclo [13.3.0.0 ] octadec-7-eno-4-carboxylic 52. To a solution of compound 51 (708 mg, 1 eq.) in DCE (700 ml) (degassed for 45 min by bubbling with nitrogen), the catalyst (catalyst of 2nd generation Hoveyda-Grubbs) (6%). The reaction mixture was purged with nitrogen for 15 min. After heating at reflux for 3 h, the reaction mixture was cooled to room temperature and poured onto a silica pad and eluted with EtOAc and then with EtOAc / MeOH. The crude product was purified by silica gel chromatography to give compound 52 as a yellow powder in 51% yield.

1H NMR (DMSO-d6, 400 MHz): δ 1.05 (s, 6H), 0.85 (s, 9H), 1.01-1.07 (m, 1H), 1.11-1.15 (t, J = 7.29 Hz, 3H ), 1,161.21 (m, 1H), 1.22-1.28 (m, 1H), 1.39-1.43 (m, 2H), 1.55-1.59 (m, 1H), 1.63-1.77 (m, 2H), 1.87-2.02 (m, 3H), 2,532.60 (m, 1H), 2.89 (s, 3H), 3.02-3, 05 (dd, J = 9.67 and 2.97 Hz, 1H), 3.50-3.53 (dd, J = 10.04 and 6.01 Hz, 1H), 3.90-3.99 ( m, 1H), 4.00-4.11 (m, 1H), 4.28-4.34 (td, J = 13.20 and 3.04 Hz, 1H), 4.58-4.60 ( m, 1H), 4.66-4.69 (dd, J = 13.20 and 3.04 Hz, 1H), 5.32-5.38 (m, 1H), 5.40-5.47 ( m, 1H), 7.04 (s, 1H); MS (ESI, EI +): m / z = 494 (MH +).

Stage F: Preparation of the ethyl ester of acid (Z) - (4R, 6S, 15S, 17R) -2,14-dioxo-17-hydroxy-13-N-methyl-1,3,13triazatricyclo [13.3.0.0] octadec -7-ene-4-carboxylic 53. Under a nitrogen atmosphere and at room temperature, a solution of TBAF (1 M in THF, 1.3 ml, 2 eq.) Was added dropwise to a solution of compound 52 (330 mg, 1 eq.) in THF (2 ml). The reaction mixture was stirred for 2 h at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in DCM, washed twice with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography to give compound 53 as a brown solid in 94% yield.

1H NMR (DMSO-d6, 400 MHz): δ 1.02-1.07 (m, 1H), 1.12-1.15 (t, J = 6.89 Hz, 3H), 1.20-1.27 (m, 2H), 1.33 -1.38 (m, 1H), 1.40-1.43 (dd, J = 4.50 and 4.76 Hz, 1H), 1.56-1.59 (dd, J = 4.50 and 4.96 Hz, 1H), 1.65-1.69 (m, 1H), 1.73-1.79 (m, 2H), 1.94-2.05 (m, 2H), 2.54 -2.66 (m, 1H), 2.89 (s, 3H), 3.07 (d, J = 10.32 Hz, 1H), 3.34-3.37 (dd, J = 4.97 and 4.90 Hz, 1H), 3.90-3.98 (m, 1H), 4.04-4.12 (m, 1H), 4.29-4.33 (m, 1H), 4, 36-4.38 (m, 1H), 4.65-4.68 (dd, J = 5.55 and 2.60 Hz, 1H), 5.00 (d, J = 4.68 Hz, 1H) , 5.32-5.37 (m, 1 H), 5.40-5.47 (m, 1H), 6.95 (s, 1H); MS (ESI, EI +): m / z = 380 (MH +).

Step G: Preparation of (Z) - (4R, 6S, 15S, 17S) ethyl ester -17- [8-fluoro-7-methoxy-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] - 13-N-methyl-2,14-dioxo-1,3,13-triazatricyclo- [13.3.0.0] octadec-7-eno-4-carboxylic acid 54c. To a solution of compound 53 (240 mg, 1 eq.), Compound 43c (201 mg, 1 eq.) And triphenylphosphine (331 mg, 2 eq) in THF (60 ml) DIAD (249 μl) was added dropwise 2 eq.) Under nitrogen atmosphere 0 ° C. The reaction mixture was stirred at room temperature overnight. Then the solvent was evaporated. The residue was dissolved in EtOAc, washed with a saturated solution of NaHCO3 and brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography to give compound 54c in 61% yield.

MS (ESI, EI +): m / z = 680 (MH +).

Step H: Preparation of (Z) - (4R, 6S, 15S, 17S) ethyl ester -17- [7-methoxy-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] -13-N- methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic 54a. Compound 54a was synthesized from compound 53 and compound 43a in 68% yield, following the procedure described for compound 54c.

MS (ESI, EI +): m / z = 662 (MH +).

Stage I: Preparation of (Z) - (4R, 6S, 15S, 17S) ethyl ester -17- [7-methoxy-8-methyl-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] - 13-N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic acid 54b. Compound 54b was synthesized from compound 53 and compound 43b in 42% yield, following the procedure described for compound 54c.

MS (ESI, EI +): m / z = 676 (MH +)

Step J: Preparation of ethyl ester of (Z) - (4R, 6S, 15S, 17S) -17- [8-chloro-7-methoxy-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] - 13-N-methyl-2,14-dioxo-1,3,13-triazatricyclo- [13.3.0.0] octadec-7-eno-4-carboxylic acid 54d. Compound 54d was synthesized from compound 53 and compound 43d in 48% yield, following the procedure described for compound 5c.

MS (ESI, EI +): m / z = 696 (MH +).

Step K: Preparation of (Z) - (4R, 6S, 15S, 17S) ethyl ester -17- [5,7-dimethoxy-2- (4-isopropylthiazol-2-yl) quinolin4-yloxy] -13- N-methyl-2,14-dioxo-1,3,13-triazatricyclo- [13.3.0.0] octadec-7-eno-4-carboxylic acid 54e. Compound 54e was synthesized from compound 53 and compound 43e in 89% yield, following the procedure described for compound 54c.

MS (ESI, EI +): m / z = 693 (MH +).

Stage L: Preparation of ethyl ester of (Z) - (4R, 6S, 15S, 17S) -17- [6-methoxy-8-methyl-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] - 13-N-methyl-2,14-dioxo-1,3,13-triazatricyclo- [13.3.0.0] octadec-7-eno-4-carboxylic acid 54f. Compound 54f was synthesized from compound 53 and compound 43f in the form of a beige solid with 60% yield, following the procedure described for compound 54c.

MS (ESI, EI +): m / z = 676 (MH +).

Stage M: Preparation of (Z) - (4R, 6S, 15S, 17S) ethyl ester -17- [7-chloro-6-methoxy-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] - 13-N-methyl-2,14-dioxo-1,3,13-triazatricyclo- [13.3.0.0] octadec-7-eno-4-carboxylic acid 54g. Compound 54g was synthesized from compound 53 and compound 43g as a white solid in 57% yield, following the procedure described for compound 54c.

MS (ESI, EI +): m / z = 696 (MH +).

Stage N: Preparation of (Z) - (4R, 6S, 15S, 17S) ethyl ester -17- [8-bromo-7-methoxy-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] - 13-N-methyl-2,14-dioxo-1,3,13-triazatricyclo- [13.3.0.0] octadec-7-eno-4-carboxylic acid 54h. Compound 54h was synthesized from compound 53 and compound 43h in the form of a beige solid in 80% yield, following the procedure described for compound 54c.

MS (ESI, EI +): m / z = 740 (MH +).

Step O: Preparation of (Z) - (4R, 6S, 15S, 17S) -17- [8-fluoro-7-methoxy-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] -13N acid -methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic 55c. A solution of compound 54c (453 mg, 1 eq.) And LiOH (75.8 mg, 5 eq.) In water / THF was stirred overnight at room temperature. THF was evaporated and the aqueous layer was acidified to pH = 6 with 1 M aqueous hydrochloric acid. The product was extracted 3 times with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound 55c as a white powder in 44% yield.

MS (ESI, EI +): m / z = 652 (MH +).

Step P: Preparation of acid (Z) - (4R, 6S, 15S, 17S) -17- [7-methoxy-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] -13-N-methyl2 , 14-dioxo-1,3,13-triazatricyclo- [13.3.0.0] octadec-7-eno-4-carboxylic 55a. Compound 55a was synthesized from compound 54a as a white solid in 22% yield, following the procedure described for compound 55c.

1H NMR (CDCl3, 400 MHz): δ 1.20-1.26 (m, 2H), 1.28-1.34 (m, 2H), 1.08 (d, J = 6.77 Hz, 6H), 1.55-1.62 (m, 2H), 1.81-1.86 (t, J = 7.20 Hz, 1H), 1.90-1.93 (m, 1H), 2.23-2.37 (m, 2H ), 2.63 (d, J = 13.90 Hz, 1H), 2.82-2.90 (m, 1H), 2.96-3.02 (m, 1H), 3.05 (s, 3H), 3.18-3.25 (m, 1H), 3.79-3.83 (t, J = 7.79 Hz, 1H), 3.97 (s, 3H), 4.01-4 , 05 (t, J = 7.75 Hz, 1H), 4.59-4.65 (td, J = 14.00 and 2.70 Hz, 1H), 4.89-4.92 (t, J = 10.50 Hz, 1H), 4.97-5.00 (m, 1H), 5.14 (s, 1H), 5.48-5.55 (m, 1H), 5.63-5, 69 (td, J = 11.00 and 4.47 Hz, 1H), 7.07 (s, 1H), 7.11-7.14 (dd, J = 9.20 and 2.40 Hz, 1H), 7.37 (dd, J = 2.40 Hz, 1H), 7 , 55 (s, 1H), 8.01 (d, J = 9.20 Hz, 1H); MS (ESI, EI +): m / z = 634 (MH +).

Step Q: Preparation of (Z) - (4R, 6S, 15S, 17S) -17- [7-methoxy-8-methyl-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] -13N -methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic 55b. Compound 55b was synthesized from compound 54b as a white solid in 25% yield, following the procedure described for compound 55c.

1H NMR (CDCl3, 400 MHz): δ 0.84-0.89 (m, 2H), 1.20-1.23 (t, J = 6.90 Hz, 2H), 1.28-1.34 (m, 2H), 1.40 (d, J = 6.93 Hz, 6H), 1.56-1.58 (m, 2H), 1.81-1.85 (t, J = 7.00 Hz, 1H), 1.86- 1.93 (m, 1H), 2.21-2.27 (m, 1H), 2.62 (d, J = 13.20 Hz, 1H), 2.70 (s, 3H), 2.82 -2.90 (m, 1H), 3.04 (s, 3H), 3.17-3.24 (m, 1H), 3.46-3.51 (q, J = 6.85 Hz, 1H ), 3.78-3.82 (t, J = 7.60 Hz, 1H), 3.99 (s, 3H), 4.59-4.65 (t, J = 13.29 Hz, 1H) , 4.89-4.99 (m, 2H), 5.11 (s, 1H), 5.47-5.54 (m, 1H), 5.63-5.69 (td, J = 5, 54 and 4.45 Hz, 1H), 7.05 (s, 1H), 7.23 (d, J = 9.20 Hz, 1H), 7.50 (s, 1H), 7.98 (d, J = 9.20 Hz, 1H); MS (ESI, EI +): m / z = 648 (MH +).

Step R: Preparation of (Z) - (4R, 6S, 15S, 17S) -17- [8-chloro-7-methoxy-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] -13N acid -methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic 55d. Compound 55d was synthesized from compound 54d as a white solid in 15% yield, following the procedure described for compound 55c.

1H NMR (CDCl3, 400 MHz): δ 1.26-1.34 (m, 2H), 1.39-1.41 (d, J = 6.40 Hz, 6H), 1.55-1.61 (m, 6H), 1.82-1.90 (m, 2H), 2.23-2.36 (m, 1H), 2.63 (d, J = 14.03 Hz, 1H), 2, 81-2.90 (m, 1H), 3.05 (s, 3H), 3.18-3.26 (m, 1H), 3.81-3.86 (t, J = 7.68 Hz, 1H), 4.03-4.05 (m, 1H), 4.08 (s, 3H), 4.58-4.64 (td, J = 13.40 and 2.34 Hz, 1H), 4 , 89-4.95 (t, J = 10.69 Hz, 1H), 4.97-5.01 (dd, J = 5.01 and 4.01 Hz, 1H), 5.15 (s, 1H ), 5.50-5.57 (m, 1H), 5.63-5.70 (td, J = 10. 81 and 4.47 Hz, 1H), 7.10 (s, 1H), 7.27 (d, J = 9.20 Hz, 1H), 7.59 (s, 1H), 8.06 (d, J = 9.20 Hz, 1H); MS (ESI, EI +): m / z = 668 (MH +).

Step S: Preparation of (Z) - (4R, 6S, 15S, 17S) -17- [5,7-dimethoxy-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] -13-Nmethyl acid -2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic 55e. Compound 55e was synthesized from compound 54e as a white solid in 36% yield, following the procedure described for compound 55c.

MS (ESI, EI +): m / z = 664 (MH +).

Step T: Preparation of (Z) - (4R, 6S, 15S, 17S) -17- [6-methoxy-8-methyl-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] -13N -methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic 55f. Compound 55f was synthesized from compound 54f as a white solid in 10% yield, following the procedure described for compound 55c.

MS (ESI, EI +): mlz = 648 (MH +).

Step U: Preparation of (Z) - (4R, 6S, 15S, 17S) -17- [7-chloro-6-methoxy-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] -13N acid -methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic 55g. Compound 55g was synthesized from compound 54g as a white solid in 40% yield, following the procedure described for compound 55c.

MS (ESI, EI +): m / z = 668 (MH +).

Stage V: Preparation of (Z) - (4R, 6S, 15S, 17S) -17- [8-bromo-7-methoxy-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] -13N acid -methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic acid 55h. Compound 55h was synthesized from compound 54h in the form of a beige solid in 90% yield, following the procedure described for compound 55c.

MS (ESI, EI +): m / z = 713 (MH +).

Stage W: Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [8-fluoro-7-methoxy-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] -13 -Nmethyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-en-4-yl] carbonyl (1-methyl-cyclopropyl) sulfonamide 56c. Under a nitrogen atmosphere, a solution of compound 55c (76 mg, 1 eq.) And CDI (37.6 mg, 2 eq.) In THF (6 ml) was heated with microwave radiation at 80 ° C for 50 min. Then, 1-methyl-cyclopropylsulfonamide (31.32 mg, 4 eq.) And DBU (35.3 mg, 2 eq.) Were added under a nitrogen atmosphere. The reaction mixture was heated with microwave radiation at 80 ° C for an additional 90 min. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography to give compound 56c as a white solid in 22% yield.

1H NMR (DMSO-d6, 400 MHz): δ 0.86 (m, 2H), 1.09-1.12 (m, 1H), 1.21-1.23 (m, 1H), 1.34 (d, J = 6.54 Hz, 6H ), 1.39 (s, 3H), 1.45-1.58 (m, 5H), 1.83-1.85 (m, 1H), 2.00-2.03 (m, 1H), 2.20-2.25 (m, 2H), 2.55-2.59 (m, 1H), 2.71 (s, 1H), 2.75-2.80 (m, 1H), 2, 87 (s, 1H), 2.90-2.95 (m, 1H), 2.97 (s, 3H), 3.12-3.18 (m, J = 6.87 Hz, 1H), 3 , 49-3.53 (m, 1H), 4.00 (s, 3H), 4.08-4.12 (t, J = 8.20 Hz, 1H), 4.39-4.45 (t , J = 12.97 Hz, 1H), 4.78-4.83 (t, J = 10.45 Hz, 1H), 4.91-4.95 (m, 1H), 5.52-5, 54 (m, 1H), 5.65 (wide s, 1H), 7.57-7.60 (m, 3H), 7.86-7.89 (d, J = 9.52 Hz, 1H), 11.70 (s, 1H); MS (ESI, EI +): m / z = 769 (MH +).

Stage X. Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [7-methoxy-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] -13-N-methyl -2,14 dioxo-1,3,13-triazatricyclo- [13.3.0.0] octadec-7-en-4-yl] carbonyl (1-methyl-cyclopropyl) sulfonamide 56a. Compound 56a was synthesized from compound 55a as a white solid in 20% yield, following the procedure described for compound 56c.

1H NMR (CDCl3, 400 MHz): δ 0.74 (m, 2H), 1.10-1.22 (m, 3H), 1.32 (d, J = 6.51 Hz, 6H), 1.53 (s, 3H), 1, 50-1.64 (m, 6H), 1.73-1.85 (m, 2H), 2.14-2.19 (m, 1H), 2.36-2.37 (m, 1H), 2.51-2.54 (m, 1H), 2.77-2.81 (m, 1H), 2.97 (s, 3H), 3.13-3.15 (m, 1H), 3, 69-3.71 (m, 1H), 3.89 (s, 3H), 3.92-3.97 (m, 1H), 4.51-4.5 8 (t, J = 13.51 Hz , 1H), 4.81-4.88 (m, 2H), 4.98 (s, 1H), 5.42-5.45 (m, 1H), 5.55-5.60 (m, 1H ), 6.98 (s, 1H), 7.03-7.06 (d, J = 8.64 Hz, 1H), 7.19 (s, 1H), 7.49 (s, 1H), 7 , 93 (d, J = 8.64 Hz, 1H), 11.08 (s, 1H); MS (ESI, EI +): m / z = 751 (MH +).

Step Y: Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [7-methoxy-8-methyl-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] -13 -Nmethyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-en-4-yl] carbonyl (1-methyl-cyclopropyl) sulfonamide 56b. Compound 56b was synthesized from compound 55b as a white solid in 14% yield, following the procedure described for compound 56c.

1H NMR (CDCl3, 400 MHz): δ 0.82-0.89 (m, 6H), 1.40 (d, J = 6.60 Hz, 6H), 1.53 (s, 3H), 1.65-1.76 (m, 2H ), 1.81-1.84 (m, 1H), 1.91-1.95 (m, 2H), 2.19-2.25 (m, 1H), 2.41-2.49 (m , 1H), 2.21-2.25 (m, 1H), 2.59-2.63 (d, J = 13.63 Hz, 1H) 2.70 (s, 3H), 2.86 (d , J = 5.52 Hz, 1H), 2.90-3.03 (m, 2H), 3.06 (s, 3H), 3.21-3.24 (m, 1H), 3.75- 3.79 (t, J = 7.60 Hz, 1H), 4.00 (s, 3H), 4.60-4.66 (t, J = 13.30 Hz, 1H), 4.89-4 , 98 (m, 2H), 5.04 (s, 1H), 5.49-5.53 (m, 1H), 5.61-5.68 (m, 1H), 7.05 (s, 1H ), 7.21-7.24 (d, J = 9.09 Hz, 1H), 7.54 (s, 1H), 7.97-8.00 (d, J = 9.07 Hz, 1H), 11.16 (s, 1H); MS (ESI, EI +): m / z = 765 (MH +).

Step Z: Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [8-chloro-7-methoxy-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] -13 -Nmethyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-en-4-yl] carbonyl (1-methyl-cyclopropyl) sulfonamide 56d. Compound 56d was synthesized from compound 55d as a white solid in 15% yield, following the procedure described for compound 56c.

1H NMR (CDCl3, 400 Hz): δ 0.82 (m, 2H), 1.28 (s, 2H), 1.40 (d, J = 6.93 Hz, 6H), 1.57 (m, 8H), 1.87-1, 93 (m, 2H), 2.22-2.24 (m, 1H), 2.43-2.46 (m, 1H), 2.60 (d, J = 13.85 Hz, 1H), 2 , 84-2.90 (m, 1H), 2.97-3.00 (m, 1H), 3.06 (s, 3H), 3.20-3.23 (m, 1H), 3.79 -3.81 (m, 1H), 4.04-4.06 (m, 1H), 4.07 (s, 3H), 4.37 (d, J = 6.93 Hz, 1H), 4, 5 8-4.66 (t, J = 13.85 Hz, 1H), 4.89-4.95 (m, 2H), 5.06 (s, 1H), 5.52-5.54 (m , 1H), 5.64-5.66 (m, 1H), 7.10 (s, 1H), 7.21-7.24 (d, J = 9.70 Hz, 1H), 7.59 ( s, 1H), 8.05 (d, J = 9.70 Hz, 1H), 11.13 (s, 1 H); MS (ESI, EI +): m / z = 785 (MH +).

Stage AA: Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [5,7-dimethoxy-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] -13-N -methyl2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-en-4-yl] carbonyl (1-methyl-cyclopropyl) sulfonamide 56e. Compound 56e was synthesized from compound 55e as a white solid in 48% yield, following the procedure described for compound 56c.

MS (ESI, EI +): m / z = 781 (MH +).

Stage AB: Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [6-methoxy-8-methyl-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] -13 -Nmethyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-en-4-yl] carbonyl (1-methyl-cyclopropyl) sulfonamide 56f. Compound 56f was synthesized from compound 55f as a white solid in 23% yield, following the procedure described for compound 56c.

MS (ESI, EI +): m / z = 765 (MH +).

Step AC: Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [7-chloro-6-methoxy-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] -13 -Nmethyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-en-4-yl] carbonyl (1-methyl-cyclopropyl) sulfonamide 56g. Compound 56g was synthesized from compound 55g as a white solid in 20% yield, following the procedure described for compound 56c.

MS (ESI, EI +): m / z = 785 (MH +). Stage AD: Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [8-bromo-7-methoxy-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] -13 -Nmethyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-en-4-yl] carbonyl (1-methyl-cyclopropyl) sulfonamide 56h. He

compound 56h was synthesized from compound 55h in the form of a white solid with 18% yield, following the procedure described for compound 56c. MS (ESI, EI +): m / z = 831 (MH +). Example 5 Preparation of macrocyclic compounds 61

10 The syntheses of macrocyclic compounds 61 are illustrated with compound 61d as shown in scheme 11, wherein R5 ', R6', R7 'and R8' in compounds 59 and 60 are the same defined for compounds 61. The same procedures are also applicable to other compounds 61.

Scheme 11

Stage A: Preparation of ethyl ester of (Z) - (4R, 6S, 15S, 17S) -2,14-dioxo-13-N-methyl-17- (4-nitrobenzoyloxy) 1,3,13-triazatricyclo [ 13.3.0.0] octadec-7-eno-4-carboxylic 57. To a stirred solution of compound 52 (500 mg, 1

5 eq.), 4-nitro-benzoic acid (290 mg, 1.2 eq.) and triphenylphosphine (450 mg, 1.2 eq.) in dry THF (10 ml) DEAD (300 mg, 1.2 eq. .) under a nitrogen atmosphere at 0 ° C. The reaction mixture was stirred for 3 h at room temperature and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel to give compound 57 in 16% yield.

MS (ESI, EI +): m / z = 529 (MH +).

10 Stage B: Preparation of ethyl ester of acid (Z) - (4R, 6S, 15S, 17S) -2,14-dioxo-17-hydroxy-13-N-methyl-1,3,13triazatricyclo [13.3.0.0] octadec -7-ene-4-carboxylic 58. A solution of compound 57 (700 mg, 1 eq.) And LiOH (75.8 mg, 5 eq.) In water / THF was stirred at room temperature until the reaction was complete. THF was evaporated and the aqueous layer was acidified to pH = 6 with 1 M aqueous hydrochloric acid. The product was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography to give compound 58 in 70% yield.

MS (ESI, EI +): m / z = 380 (MH +).

Step C: Preparation of ethyl ester of (Z) - (4R, 6S, 15S, 17R) -17- [8-chloro-7-methoxy-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] - 13-N-methyl-2,14-dioxo-1,3,13-triazatricyclo [3,3,0,0] octadec-7-eno-4-carboxylic acid 59d. Compound 59d was synthesized from compound 58 and compound 43d in 50% yield, following the procedure described for compound 54c.

MS (ESI, EI +): m / z = 696 (MH +).

Stage D: Preparation of (Z) - (4R, 6S, 15S, 17R) -17- [8-chloro-7-methoxy-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] -13- Nmethyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic acid 60d. Compound 60d was synthesized from compound 59d in the form of a white solid in 40% yield, following the procedure described for compound 55c.

1H NMR (DMSO-d6, 400 MHz): δ 1.26-1.34 (m, 4H), 1.33 (d, J = 6.40 Hz, 6H), 1.41-1.50 (m , 3H), 1.82-1.90 (m, 2H), 1.97-2.01 (m, 1H), 2.23-2.36 (m, 2H), 2.63 (d, J = 14.03 Hz, 2H), 2.96 (s, 3H), 3.12-3.15 (m, 1H), 3.62-3.65 (d, J = 11.30 Hz, 1H) , 3.77-3.81 (m, 1H), 4.02 (s, 3H), 4.58-4.64 (td, J = 13.40 and 2.34 Hz, 1H), 4.89 -4.95 (t, J = 10.69 Hz, 1H), 5.25 (s, 1H), 5.44 (m, 1H), 5.65 (s, 1H), 7.51 (s, 1H), 7.54 (s, 1H), 7.56 (d, J = 9.78, 1H), 8.17 (d, J = 9.78 Hz, 1H); MS (ESI, EI +): m / z = 668 (MH +).

Stage E: Preparation of (Z) - (4R, 6S, 15S, 17R) - [17- [8-chloro-7-methoxy-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] -13 -Nmethyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-en-4-yl] carbonyl (1-methyl-cyclopropyl) sulfonamide 61d. Compound 61d was synthesized from compound 60d as a white solid in 15% yield, following the procedure described for compound 56c.

1H NMR (DMSO-d6, 400 MHz): δ 0.82 (m, 2H), 1.06-1.09 (t, J = 7.50 Hz, 2H), 1.21-1.26 (m, 2H), 1.34 (d, J = 6.93 Hz, 6H), 1.37 (s, 3H), 1.44-1.59 (m, 5H), 1.85-1.88 (t, J = 13.26 Hz, 1H) , 2.16-2.20 (q, J = 9.36 Hz, 1H), 2.22-2.24 (m, 1H), 2.56-2.60 (d, J = 13.26 Hz , 2H), 2.66-2.77 (m, 3H), 3.00 (s, 3H), 3.12-3.18 (m, 1H), 3.34-3.39 (q, J = 7.02 Hz, 1H), 3.67-3.70 (d, J = 10.94 Hz, 1H), 3.81-3.85 (dd, J = 5.53 and 4.57 Hz, 1H), 4.02 (s, 3H), 4.39-4.45 (t, J = 13.46 Hz, 1H), 4.78-4.84 (t, J = 9.80 Hz, 1H ), 5.08-506 (t, J = 7.04 Hz, 1H), 5.52-5.54 (m, 1H), 5.66-5.68 (m, 1H), 7.52 (s, 1H), 7.55-7 , 57 (d, J = 9.53 Hz, 1H), 7.59 (s, 1H), 8.18 (d, J = 9.53 Hz, 1H), 11.66 (s, 1H); MS (ESI, EI +): m / z = 785 (MH +).

Example 6

Preparation of macrocyclic compounds 62 The syntheses of macrocyclic compounds 62 are illustrated with compounds 62b, 62d and 62f. The same procedures are also applicable to other compounds 62.

Stage A: Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [7-methoxy-8-methyl-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] -13 -N

5 methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-en-4-yl] carbonyl (cyclopropyl) sulfonamide 62b. Compound 62b was synthesized from compound 55b and cyclopropylsulfonamide as a beige solid in 52% yield, following the procedure described for compound 56c.

MS (ESI, EI +): m / z = 751 (MH +).

Stage B: Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [8-chloro-7-methoxy-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] -13 -N

10 methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-en-4-yl] carbonyl (cyclopropyl) sulfonamide 62d. Compound 62d was synthesized from compound 55d and cyclopropylsulfonamide as a white solid in 15% yield, following the procedure described for compound 56c.

MS (ESI, EI +): m / z = 771 (MH +).

Stage C: Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [6-methoxy-8-methyl-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] -13 -N

fifteen methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-en-4-yl] carbonyl (cyclopropyl) sulfonamide 62f. Compound 62f was synthesized from compound 55f and cyclopropylsulfonamide as a white solid in 37% yield, following the procedure described for compound 56c.

MS (ESI, EI +): m / z = 751 (MH +).

Example 7

twenty Preparation of macrocyclic compound 63 Syntheses of macrocyclic compounds 63 illustrate compound 63b. The same procedures are also applicable to other compounds 63.

Preparation of (Z) - (4R, 6S, 15S, 17S) -17- [7-methoxy-8-methyl-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] -13-N-methyl -2.14

5 dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-en-4-yl] carbonyl-methylsulfonamide 63b. Compound 63b was synthesized from compound 55b and methanesulfonamide as a white solid in 24% yield, following the procedure described for compound 56c.

MS (ESI, EI +): m / z = 725 (MH +).

Example 8

10 Preparation of substituted quinolines 65 The syntheses of substituted quinolines 65 are illustrated below with compounds 65b and 65d. The same procedures are also applicable to other compounds 65. The substituents in intermediate compounds 64 are the same as in compounds 65.

5 Preparation of N- (6-acetyl-3-methoxy-2-methylphenyl) -4-trifluoromethylthiazol-2-carboxamide 64b. Compound 64b was synthesized from 4- (trifluoromethyl) -1,3-thiazol-2-carboxylic acid and 1- (2-amino-4-methoxy-3-methylphenyl) -ethanone in the form of a beige solid with 74 % yield, following the procedure described for compound 42a.

1H NMR (CDCl3, 400 MHz) δ 2.15 (s, 3H), 2.58 (s, 3H), 3.94 (s, 3H), 6.82 (d, J = 8.55 Hz, 1H ), 7.78 (d, J = 8.55 Hz, 1H), 8.01 (s, 1H), 11.25 (s, 1H).

10 Preparation of N- (6-acetyl-2-chloro-3-methoxyphenyl) -4-trifluoromethylthiazol-2-carboxamide 64d. Compound 64d was synthesized from 4- (trifluoromethyl) -1,3-thiazol-2-carboxylic acid and 1- (2-amino-3-chloro-4-methoxyphenyl) -ethanone in the form of a beige solid with 65 % yield, following the procedure described for compound 42a.

Preparation of 7-methoxy-8-methyl-2- (4-trifluoromethyl-thiazol-2-yl) -quinolin-4-ol 65b. Compound 65b was synthesized from compound 64b as a yellow powder in 73% yield, following the procedure described for

fifteen compound 43a.

MS (ESI, EI +) m / z = 341 (MH +).

Preparation of 8-chloro-7-methoxy-2- (4-trifluoromethyl-thiazol-2-yl) -quinolin-4-ol 65d. Compound 65d was synthesized from compound 64d in the form of a yellow powder in 70% yield, following the procedure described for compound 43a.

twenty MS (ESI, EI +) m / z = 361 (MH +).

Example 9

Preparation of the macrocyclic compound 68 The syntheses of macrocyclic compounds 68 are illustrated below with compounds 68b and 68d, as shown in Scheme 12. The same procedures are also applicable to other macrocyclic compounds.

68. The substituents in intermediate compounds 66 and 67 are the same as in compounds 68. The same procedures are also applicable to other compounds 68.

Stage A: Preparation of (Z) - (4R, 6S, 15S, 17S) ethyl ester - [17- [7-methoxy-8-methyl-2- (4-trifluoromethythiazol-2-yl) quinolin-4-yloxy] -13-N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-en-4-yl] carboxylic acid 66b. Compound 66b was synthesized from compounds 53 and 65b as a white solid in 60% yield, following the procedure described for compound 54c.

10 MS (ESI, EI +) m / z = 702 (MH +).

Scheme 12

Stage B: Preparation of (Z) - (4R, 6S, 15S, 17S) ethyl ester - [17- [8-chloro-7-methoxy-2- (4-trifluoromethylthiazol-2-yl) quinolin-4-yloxy] -13-N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-en-4-yl] carboxylic acid 66d. Compound 5 66d was synthesized from compounds 53 and 65d as a pink solid in 90% yield, following the procedure described for compound 54c.

MS (ESI, EI +) m / z = 724 (MH +).

Step C: Preparation of acid (Z) - (4R, 6S, 15S, 17S) - [17- [7-methoxy-8-methyl-2- (4-trifluoromethythiazol-2-yl) quinolin-4-yloxy] -13- N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-en-4-yl] carboxylic acid 67b. Compound 67b was synthesized from compound 66b as a white solid in 38% yield, following the procedure described for compound 55c.

MS (ESI, EI +) m / z = 674 (MH +).

Stage D: Preparation of acid (Z) - (4R, 6S, 15S, 17S) - [17- [8-chloro-7-methoxy-2- (4-trifluoromethylthiazol-2-yl) quinolin-4-yloxy] 13 -N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-en-4-yl] carboxylic acid 67d. Compound 67d was synthesized from compound 66d as a white solid in 16% yield, following the procedure described for compound 55c.

MS (ESI, EI +) m / z = 694 (MH +).

Step E: Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [7-methoxy-8-methyl-2- (4-trifluoromethylthiazol-2-yl) quinolin-4-yloxy] -13 -Nmethyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-en-4-yl] carbonyl (1-methylcyclopropyl) sulfonamide 68b. Compound 68b was synthesized from compound 67b and 1-methylcyclopropylsulfonamide as a white solid in 40% yield, following the procedure described for compound 56c. 1H NMR (CDCl3, 400 MHz): δ 0.737 (m, 2H), 1.10-1.21 (m, 2H), 1.26-1.33 (m, 2H), 1.44 (s, 3H ), 1.41-1.53 ​​(m, 1H), 1.56-1.65 (m, 1H), 1.71-1.76 (m,

1H), 1.84 (dd, J = 6.2 and 8.1 Hz, 2H), 2.11 (dt, J = 5.7 and 13.5 Hz, 1H), 2.36 (dd, J = 9.3 and 18.9 Hz, 1H), 2.53 (dd, J = 3.0 and 13.5 Hz, 1H), 2.61 (s, 3H), 2.81 (ddd, J = 4.7, 12.4 and 17.1 Hz, 1H), 2.90-2.96 (m, 1H), 2.98 (s, 3H), 3.73 (dd, J = 7.0 and 8.3 Hz, 1H), 3.92 (s, 3H), 3.96 (t, J = 7.7, 1H), 4.54 (dd, J = 2.6 and 13.7 Hz, 1H ), 4.84 (t, J = 10.7 Hz, 1H), 4.89 (dd, J = 5.3 and 8.9 Hz, 1H), 5.10 (s, 1H), 5.41 (q, J = 7.0 Hz, 1H), 5.56 (td, J = 5.8 and 10.8 Hz, 1H), 7.18 (d, J = 9.2 Hz,

5 1H), 7.42 (s, 1H), 7.80 (s, 1H), 7.94 (d, J = 9.2 Hz, 1H), 11.12 (s, 1H); MS (ESI, EI +) m / z = 791 (MH +).

MS (ESI, EI +) m / z = 791 (MH +).

Step F: Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [8-chloro-7-methoxy-2- (4-trifluoromethylthiazol-2-yl) quinolin-4-yloxy] -13 -Nmethyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-en-4-yl] carbonyl (1-methylcyclopropyl) sulfonamide 68d. A solution of compound 67d (502 mg, 1 eq.) And EDCI (200 mg, 1.4 eq.) In dry DCM (10 ml) was stirred at temperature

10 ambient for 16 h. Then DBU (445 mg, 4 eq.) And 1-methylcyclopropylsulfonamide (402 mg, 4 eq.) Were added and mixed again for 16 h. The crude material was purified by silica gel chromatography to give compound 68d as a white solid in 37% yield.

1H NMR (CDCl3, 400 MHz): δ 0.73-0.81 (m, 2H), 1.10-1.21 (m, 2H), 1.26-1.34 (m, 2H), 1 , 45 (s, 3H), 1.42-1.46 (m, 1H), 1.57-1.65 (m, 1H), 1.72-1.76 (m, 1H), 1.86 (dd, J = 8.45 and 6.07 Hz, 2H), 2.13 (dt, J = 13.65 and 5.38 Hz, 1H), 2.36

fifteen (dd, J = 19.27 and 9.31 Hz, 1H), 2.51-2.55 (m, 1H), 2.76-2.88. (m, 1H), 2.91-2.98 (m, 1H), 2.99 (s, 3H), 3.76 (dd, J = 8.41 and 6.72 Hz, 1H), 3, 97 (t, J = 7.80, 1H), 4.02 (s, 3H), 4.54 (dd, J = 13.75 and 2.63 Hz, 1H), 4.85 (t, J = 10.7 Hz, 1H), 4.91 (dd, J = 8.91 and 5 Hz, 1H), 5.04 (s, 1H), 5.42-5.49 (m, 1H), 5, 57 (td, J = 10.72 and 5.79 Hz, 1H), 7.24 (d, J = 9.2 Hz, 1H), 7.50 (s, 1H), 7.85 (s, 1H ), 8.02 (d, J = 9.25 Hz, 1H), 11.05 (s, 1H); MS (ESI, EI +) m / z = 811 (MH +).

MS (ESI, EI +) m / z = 811 (MH +).

twenty Example 10

Preparation of the macrocyclic compound 69

Syntheses of macrocyclic compounds 69 are illustrated below with compounds 69b. The same procedure is also applicable to other macrocyclic compounds 69.

25 Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [7-methoxy-8-methyl-2- (4-trifluoromethylthiazol-2-yl) quinolin-4-yloxy] -13-N- methyl2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-en-4-yl] carbonyl (cyclopropyl) sulfonamide 69b. Compound 69b was synthesized from compound 67b and cyclopropylsulfonamide as a white solid in 49% yield, following the procedure described for compound 68d. 1H NMR (CDCl3, 400 MHz): δ 0.78-0.90 (m, 2H), 0.991.12 (m, 3H), 1.17-1.24 (m, 3H), 1.26-1 , 62 (m, 4H), 1.87 (dd, J = 6.1 and 8.5 Hz, 2H), 2.12 (dt, J = 5.8 and 13.5 Hz, 1H),

5 2.36 (dd, J = 9.3 and 19.2 Hz, 1H), 2.49-2.55 (m, 1H), 2.77-2.95 (m, 3H), 2.98 ( s, 3H), 3.73 (m, 1H), 3.92 (s, 3H), 3,964.01 (m, 1H), 4.54 (dd, J = 2.8 and 13.9 Hz, 1H ), 4.81-4.89 (m, 2H), 5.02 (s, 1H), 5.42 (qt, J = 7.0 Hz, 1H), 5.57 (td, J = 5, 7 and 10. 7 Hz, 1H), 7.19 (d, J = 9.3 Hz, 1H), 7.42 (s, 1H), 7.80 (s, 1H), 7.94 (d, J = 9.3 Hz, 1H), 11.13 (s, 1H); MS (ESI, EI +) m / z = 777 (MH +).

MS (ESI, EI +) m / z = 777 (MH +).

10 Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [8-chloro-7-methoxy-2- (4-trifluoromethylthiazol-2-yl) quinolin-4-yloxy] -13-N- methyl2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-en-4-yl] carbonyl (cyclopropyl) sulfonamide 69d. Compound 69d was synthesized from compound 67d and cyclopropylsulfonamide, following the procedure described for compound 68d. 1H NMR (CDCl3, 400 MHz): δ 0.90-0.98 (m, 1H), 1.06-1.19 (m, 2H), 1.23-1.31 (m, 3H), 1 , 35-1.54 (m, 4H), 1,871.94 (m, 1H), 1.95 (dd, J = 8.48 and 6.05 Hz, 2H), 2.21 (dt, J = 13 , 54 and 5.50 Hz, 1H), 2.58-2.63 (m, 1H), 2.89-2.96 (m,

fifteen 1H), 2.98-3.04 (m, 1H), 3.05 (s, 3H), 3.83 (dd, J = 8.31 and 6.76 Hz, 1H), 4-4.05 (m, 1H), 4.09 (s, 3H), 4.57-4.65 (m, 1H), 4.89-4.94 (m, 1H), 4.95-4.98 (m , 1H), 5.05 (s, 1H), 5.53 (qt, J = 6.86 Hz, 1H), 5.65 (td, J = 10.75 and 5.65 Hz, 1H), 7 , 31 (d, J = 9.27 Hz, 1H), 7.57 (s, 1H), 7.92 (s, 1H), 8.09 (d, J = 9.27 Hz, 1H), 11 , 14 (s, 1 H).

Example 11

Preparation of macrocyclic compounds 76

The syntheses of macrocyclic compounds 76 are shown in scheme 13, where R5 ', R6', R7 'and R8' in compounds 74 and 75 are as defined in compounds 76.

Scheme 13

Step A: Preparation of (2S, 4R) -2- (N- (hept-6-enyl) -N-methylcarbamoyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl 70a. Compound 70a was synthesized from compound 32b and cis-N-Boc-4-hydroxy-L-proline, in the form of an orange oil with quantitative yield, following the procedure described for compound 48.

1H NMR (DMSO-d6, 400 MHz) δ 1.29-1.3 (m, 9H), 1.33-1.55 (m, 4H), 1.70-1.80 (m, 1H), 1.97-2.12 (m, 4H), 2.77-2.97 (m, 4H), 3.15-3.40 (m, 4H), 4.22 (wide s, 1H), 4 , 50-4.62 (m, 1H), 4.90-5.04 (m, 3H), 5.71-5.83 (m, 1H).

Step B: Preparation of (2S, 4R) -2- (N- (oct-6-enyl) -N-methylcarbamoyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl 70b. Compound 70b was synthesized from compound 32c and cis-N-Boc-4-hydroxy-L-proline, in the form of a yellow oil with quantitative yield, following the procedure described for compound 48.

1H NMR (DMSO-d6, 400 MHz) δ 1.29-1.3 (m, 9H), 1.33-1.55 (m, 4H), 1.70-1.80 (m, 1H), 1.97-2.12 (m, 4H), 2,772.97 (m, 4H), 3.01-3.10 (m, 2H), 3.15-3.40 (m, 4H), 4, 22 (broad s, 1H), 4.50-4.62 (m, 1H), 4.90-5.04 (m, 3H), 5,715.83 (m, 1H).

Step C: Preparation of (2S, 4R) -2-N- (hept-6-enyl) -4-hydroxy-N-methyl pyrrolidine-2-carboxamide 71a. Compound 71a was synthesized from compound 70a in the form of a yellow oil in 35% yield, following the procedure described for compound 49.

MS (ESI, EI +) m / z = 241 (MH +).

Step D: Preparation of (2S, 4R) -2-N- (oct-6-enyl) -4-hydroxy-N-methyl pyrrolidine-2-carboxamide 71b. Compound 71b was synthesized from compound 70b as a yellow oil in 51% yield, following the procedure described for compound 49.

MS (ESI, EI +) m / z = 255 (MH +).

Stage E: Preparation of ethyl ester of (1R) -1 - {[2 (S) - (hept-5-enyl-methyl-carbamoyl) -4 (R) -hydroxy-pyrrolidine-Ncarbonyl] amino} -2 ( R) -vinyl-cyclopropanecarboxylic 72a. Compound 72a was synthesized from compounds 34 and 71a in the form of a beige solid in 38% yield, following the procedure described for compound 50.

MS (ESI, EI +) mlz = 422 (MH +).

Stage F: Preparation of ethyl ester of (1R) -1 - {[2 (S) - (oct-5-enyl-methyl-carbamoyl) -4 (R) -hydroxy-pyrrolidine-Ncarbonyl] amino} -2 ( R) -vinyl-cyclopropanecarboxylic 72b. Compound 72b was synthesized from compounds 34 and 71b in the form of a beige solid in 48% yield, following the procedure described for compound 50.

MS (ESI, EI +) m / z = 436 (MH +).

Stage G: Preparation of ethyl ester of acid (Z) - (4R, 6S, 16S, 18R) -2,15-dioxo-18-hydroxy-14-N-methyl-1,3,14triazatricyclo [14.3.0.0] nonadec -7-eno-4-carboxylic 73a. Compound 73a was synthesized from compound 72a as a white solid in 42% yield, following the procedure described for compound 52.

MS (ESI, EI +) m / z = 394 (MH +).

Step H: Preparation of (Z) - (4R, 6S, 17S, 19R) -2,16-dioxo-19-hydroxy-15-N-methyl-1,3,15triazatricyclo [15.3.0.0] ethyl acid ethyl ester -7-eno-4-carboxylic 73b. Compound 73b was synthesized from compound 72b as a white solid with 71% yield, following the procedure described for compound 52. MS (ESI, EI +) m / z = 408 (MH +).

Stage I: Preparation of ethyl ester of (Z) - (4R, 6S, 16S, 18R) -2,15-dioxo-18- [7-methoxy-8-methyl-2- (4isopropylthiazol-2-yl) quinolin -4-yloxy] -14-N-methyl-1,3,14-triazatricyclo [14.3.0.0] nonadec-7-eno-4-carboxylic acid 74a. Compound 74a was synthesized from compounds 43b and 73a in the form of a beige solid in 89% yield, following the procedure described for compound 54c.

MS (ESI, EI +) m / z = 690 (MH +).

Step J: Preparation of ethyl ester of (Z) - (4R, 6S, 17S, 19R) -2,16-dioxo-19- [7-methoxy-8-methyl-2- (4isopropylthiazol-2-yl) quinolin -4-yloxy] -15-N-methyl-1,3,15-triazatricyclo [15.3.0.0] eicos-7-eno-4-carboxylic acid 74b. Compound 74b was synthesized from compounds 43b and 73b as a white solid in 93% yield, following the procedure described for compound 54c.

MS (ESI, EI +) m / z = 704 (MH +).

Step K: Preparation of acid (Z) - (4R, 6S, 16S, 18R) -2,15-dioxo-18- [7-methoxy-8-methyl-2- (4-isopropylthiazol-2-yl) quinolin4- yloxy] -14-N-methyl-1,3,14-triazatricyclo [14.3.0.0] nonadec-7-eno-4-carboxylic acid 75a. Compound 75a was synthesized from compound 74a as a white solid in 32% yield, following the procedure described for compound 55c.

MS (ESI, EI +) m / z = 662 (MH +).

Stage L: Preparation of acid (Z) - (4R, 6S, 17S, 19R) -2,16-dioxo-19- [7-methoxy-8-methyl-2- (4-isopropylthiazol-2-yl) quinolin4- yloxy] -15-N-methyl-1,3,15-triazatricyclo [15.3.0.0] nonadec-7-eno-4-carboxylic acid 75b. Compound 75b was synthesized from compound 74b as a white solid in 36% yield, following the procedure described for compound 55c.

MS (ESI, EI +) m / z = 676 (MH +).

Stage M: Preparation of (Z) - (4R, 6S, 16S, 18R) - [2,15-dioxo-18- [7-methoxy-8-methyl-2- (4-isopropylthiazol-2-yl) quinolin- 4iloxy] -14-N-methyl-1,3,14-triazatricyclo [14.3.0.0] nonadec-7-en-4-yl] carbonyl (1-methyl-cyclopropyl) sulfonamide 76a. Compound 76a was synthesized from compound 75a and 1-methyl-cyclopropylsulfonamide as a white solid in 12% yield, following the procedure described for compound 56c.

MS (ESI, EI +) m / z = 779 (MH +).

Stage N: Preparation of (Z) - (4R, 6S, 17S, 19R) - [2,16-dioxo-19- [7-methoxy-8-methyl-2- (4-isopropylthiazol-2-yl) quinolin- 4iloxy] -15-N-methyl-1,3,15-triazatricyclo [15.3.0.0] nonadec-7-en-4-yl] carbonyl (1-methyl-cyclopropyl) sulfonamide 76b. Compound 76b was synthesized from compound 75b and 1-methyl-cyclopropylsulfonamide as a white solid in 27% yield, following the procedure described for compound 56c.

MS (ESI, EI +) m / z = 793 (MH +).

Example 12

Preparation of cyclopropanesulfonamide 82

The synthesis of cyclopropanesulfonamide 82 is illustrated in scheme 14.

10 Step A: Preparation of N-Boc-cyclopropanesulfonamide 77. To a stirred solution of cyclopropanesulfonamide (10.72 g, 88.6 mmol), TEA (13.9 ml, 100.4 mmol) and (4-dimethylamino) pyridine ( 1.11 g, 9.07 mmol) in DCM (160 ml) was added dropwise a solution of Boc2O (21.88 g, 100.4 mmol) in DCM (100 ml) at 0 ° C over 30 min. The mixture was allowed to warm to room temperature and stirred for 3 h. The mixture was washed with 1 N HCl, water and brine. The organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure, and

fifteen crushed with hexane to give compound 77 as a white powder with 87% yield. 1H NMR (CDCl3, 400 MHz) δ 0.92 (td, J = 1.72 Hz and J = 6.40 Hz, 2H), 1.49 (s, 9H), 1.59 (td, J = 1 , 72 and 6.40 Hz, 2H), 1.95 (m, 2H).

Scheme 14

twenty Step B: Preparation of N-Boc-1-benzyloxy-cyclopropanesulfonamide 78. To a solution of compound 77 (500 mg, 2.26 mmol) in anhydrous THF (5 ml) at -80 ° C nBuLi was added dropwise ( 2.26 ml, 5.65 mmol). The mixture was stirred at -80 ° C for 10 min and bromomethylbenzene (271 µL, 3.39 mmol) was added dropwise at -80 ° C. The mixture was then allowed to warm to -30 ° C. Then water was added slowly followed by EtOAc. The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by gel chromatography.

25 silica (EtOAc / DCM) to give compound 78 as a white powder in 30% yield.

1H NMR (CDCl3, 400 MHz) δ 1.04 (td, J = 1.72 Hz and J = 6.40 Hz, 2H), 1.49 (s, 9H), 1.73 (td, J = 1 , 72 and 6.40 Hz, 2H), 3.78 (s, 2H), 4.56 (s, 2H), 7.07 (wide s, 1H), 7.30-7.38 (m, 5H ).

Step C: Preparation of N-Boc-1-hydroxymethyl-cyclopropanesulfonamide 79. Compound 78 (2 g, 5.87 mmol) was reacted in an H-Cube® (Thales Technology) with a 10 / Pd / C cartridge % at 20 bar and 50 ° C. The material

30 Crude was purified by silica gel chromatography (EtOAc / DCM) to give compound79 in 70% yield.

1H NMR (CDCl3, 400 MHz) δ 1.09 (t, J = 6.32 Hz, 2H), 1.49 (s, 9H), 1.61 (t, J = 6.32 Hz, 2H), 3.72 (s, 1H), 3.89 (s, 2H), 8.23 ​​(wide s, 1H).

Step D: Preparation of N-Boc-1-formyl-cyclopropanesulfonamide 80. To a stirred solution of compound 79 (100 mg, 0.39 mmol) in DCM (2 ml) was added pyridinium chlorochromate (130 mg, 0.60 mmol). Then, the mixture was stirred at room temperature for 16 h and filtered through a silica column with DCM, and the solution

5 Organic was concentrated under reduced pressure to give compound 80 in 66% yield.

1H NMR (CDCl3, 400 MHz) δ 1.49 (s, 9H), 1.76 (m, 2H), 2.01 (m, 2H), 9.91 (s, 1H).

Step E: Preparation of N-Boc-1-ethynyl-cyclopropanesulfonamide 81. To a stirred solution of compound 80 (230 mg, 0.92 mmol) in MeOH (5 ml) at 0 ° C was added K2CO3 (255 mg, 1 , 84 mmol), and Ohira-Bestmann reagent (215 g, 1.10 mmol) (Tetr. Lett, 2008, 49, 4454). The mixture was stirred at room temperature for 16 h and concentrated to

10 reduced pressure Water, EtOAc and citric acid were added to bring the pH to 4-5. The organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 81 in 85% yield.

1H NMR (CDCl3, 400 MHz) δ 1.50 (m, 2H), 1.53 (s, 9H), 1.92 (m, 2H), 2.37 (s, 1H), 7.15 (s wide, 1H).

Step F: Preparation of 1-ethynyl-cyclopropanesulfonamide 82. A mixture of compound 81 (200 mg, 0.81 mmol) and

fifteen TFA (0.3 ml) in DCM (5 ml) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the crude material was purified by silica gel chromatography (MeOH / DCM) to give compound 82 in 70% yield.

1H NMR (CDCl3, 400 MHz) δ 1.43 (td, J = 2.90 and 4.80 Hz, 2H), 1.70 (td, J = 2.90 and 4.80 Hz, 2H), 2 , 38 (s, 1H), 4.79 (s, 2H).

twenty Example 13

Preparation of macrocyclic compounds 83

The syntheses of macrocyclic compounds 83 are illustrated with compound 83b as shown in scheme 15, where R5 ', R6', R7 'and R8' in compound 83 are as defined in compound 56. The same procedures 25 also they are applicable to other compounds 83.

Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [7-methoxy-8-methyl-2- (4-isopropylthiazol-2-yl) quinolin-4-yloxy] -13-N- methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-en-4-yl] carbonyl (1-ethynylcyclopropyl) sulfonamide 83b. Compound 83b was synthesized from compounds 55b and 82 as a white solid in 30% yield, following the procedure described for compound 56c.

MS (ESI, EI +) m / z = 775 (MH +).

Scheme 15

Example 14 Preparation of substituted quinolines 88

The syntheses of substituted quinolines are illustrated in scheme 16, where R8 'and A in compound 87 are the same as those defined in compounds 88.

Step A: Preparation of 4-ethoxy-trifluoro-but-3-en-2-one 84. Ethyl vinyl ether (5 g, 1 eq.) Was added dropwise at -10 ° C and under a nitrogen atmosphere , to a stirred solution of trifluoroacetic anhydride (10 ml, 1.05 eq.) and 415 dimethylaminopyridine (80 mg, 0.06 eq.) in DCM (90 ml). The reaction mixture was stirred at 0 ° C for 8 h and allowed to warm to room temperature overnight. Then, the mixture was poured into cold aqueous NaHCO3 solution. The organic layer was separated, washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 84 as a brown oil in 87% yield. 1H NMR (CDCl3, 400 MHz) δ 1.39-1.43 (t, J = 7.04 Hz, 3H), 4.08-4.13 (q, J = 7.04 Hz, 2H), 5 , 86 (d, J = 12.40 Hz,

twenty 1H), 7.90 (d, J = 12.40 Hz, 1H).

Scheme 16

5 residue. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 86a as a brown solid in 86% yield.

1H NMR (CDCl3, 376 MHz) δ 6.66 (d, J = 2.30 Hz, 1 H), 7.72 (d, J = 2.30 Hz, 1H);

19 F NMR (CDCl 3, MHz) δ 61.41 (s, 3F).

Step C: Preparation of 1-dimethylamino-4-methyl-pent-1-en-3-one 85. 3-methylbutan-2-one (2.5 g, 1 eq.)

10 and diethyl acetal of dimethylformamide (7.46 ml, 1.5 eq.) at 100 ° C for 4 days to give compound 85 as a viscous yellow oil in 80% yield, which was used directly without further purification In the next stage.

1H NMR (DMSO-d6, 400 MHz) δ 0.94 (s, 3H), 0.95 (s, 3H), 2.52 (s, 1H), 2.74 (wide s, 3H), 3, 01 (s wide, 3H), 4.96 (d, J = 12.97 Hz, 1H), 7.45 (d, J = 12.97 Hz, 1H).

fifteen Stage D: Preparation of 3-isopropyl-1H-pyrazole 86b. Compound 85 (6.6 g, 1 eq.) Was added dropwise to a stirred solution of hydrazine monohydrochloride (3.2 g, 1 eq.), Sulfuric acid (1.13 ml) and H2O (6 ml ). The reaction mixture was stirred at 68 ° C for 2 h. Then, the mixture was neutralized with 1 N NaOH and extracted with diethyl ether. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 86b as a beige solid in 94% yield.

twenty 1H NMR (DMSO-d6, 400 MHz) δ 1.17 (s, 3H), 1.19 (s, 3H), 2.87-2.93 (m, 1H), 5.99 (s, 1H) , 7.40 (s, 1H), 1.39-1.43 (t, J = 7.04 Hz, 3H), 4.08-4.13 (q, J = 7.04 Hz, 2H), 5.86 (d, J = 12.40 Hz, 1H), 7.90 (d, J = 12.40 Hz, 1H).

Step E: Preparation of 8-chloro-7-methoxy-4- (4-methoxy-benzyloxy) -2- (3-trifluoromethyl-1 H -pyrazol-1-yl) -quinoline 87a. To a stirred solution of compound 86a (821 mg, 1.1 eq.) In anhydrous DMF (20 ml) at 0 ° C NaH (241 mg, 1.1 eq.) Was added portionwise. Then, the reaction mixture was stirred for 1 h at room temperature, compound 46d (2g, 1 eq) was added and the mixture was stirred at 90 ° C for 16 h. After cooling the reaction mixture to room temperature, EtOAc was added. The organic phase was washed with HCl (2.5 N), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (petroleum ether / DCM, 50/50) to give compound 65a as a white solid in 51% yield. MS (ESI, EI-) m / z = 461.9 (MH-).

Step F: Preparation of 7-methoxy-4- (4-methoxy-benzyloxy) -8-methyl-2- (3-trifluoromethyl-1H-pyrazol-1-yl) -quinoline 87c. Compound 87c was synthesized from compounds 46b and 86a following the procedure described for compound 86a, in the form of a white solid in 19% yield.

1H NMR (CDCl3, 400 MHz) δ 2.64 (s, 3H), 3.86 (s, 3H), 3.99 (s, 3H), 5.33 (s, 2H), 6.75 (d , J = 2.58 Hz, 1H), 6.98 (d, J = 8.78 Hz, 2H), 7.20 (d, J = 9.22 Hz, 1H), 7.48 (d, J = 8.78 Hz, 2H), 7.57 (s, 1H), 8.07 (d, J = 9.08 Hz, 1H), 8.88 (s, 1H).

Step G: Preparation of 8-chloro-4-hydroxy-7-methoxy-2- (3-trifluoromethyl-1H-pyrazol-1-yl) -quinoline 88a. Compound 87 (800 mg, 1 eq.), CeCl3 · 7H2O (965 mg, 1.5 eq.) And NaI (258 mg, 1 eq.) In ACN (10 ml) was stirred at 85 ° C for 1 h with microwave irradiation. Water was added and the mixture was acidified with 1 N HCl at pH 5. The reaction mixture was extracted with diethyl ether. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (MeOH / DCM) to give compound 86 as a beige solid in 96% yield.

1H NMR (DMSO-d6, 400 MHz) δ 4.02 (s, 3H), 7.07 (s, 1H), 7.43 (s, 1H), 7.51 (d, J = 9.11 Hz , 1H), 8.11 (d, J = 9.11 Hz, 1H), 8.88 (s, 1H); MS (ESI, EI +) m / z = 343.9 (MH +).

Step H: Preparation of 4-hydroxy-7-methoxy-8-methyl-2- (3-isopropyl-pyrazol-1-yl) -quinoline 88b. A solution of compound 86b (350 mg, 1 eq.) And compound 46b (480 mg, 6 eq.) In N-methylpyrrolidone (5 ml) was heated at 200 ° C for 30 min. After cooling the reaction mixture to room temperature, water was added. The mixture was extracted with EtOAc, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (EtOAc / DCM). Recrystallization from diethyl ether gave compound 88b as a white solid in 49% yield.

1H NMR (CDCl3, 376 MHz) δ 1.35 (s, 3H), 1.36 (s, 3H), 2.85 (s, 3H), 3.97 (s, 3H), 6.40 (d , J = 2.65 Hz, 2H), 7.01 (d, J = 9.00 Hz, 1H), 8.00 (wide s, 1H), 8.23 ​​(d, J = 9.00 Hz, 1H), 9.81 (broad s, 1H); MS (ESI, EI +) m / z = 298 (MH +).

Step I: Preparation of 4-hydroxy-7-methoxy-8-methyl-2- (3-trifluoromethyl-1H-pyrazol-1-yl) -quinoline 88c. A mixture of compound 87c (885 mg, 1.99 mmol), ammonium formate (629 mg, 9.98 mmol), and Pd / C (89 mg, 10% by weight) in EtOH (16 ml) was heated to reflux for 1 h. Then, the reaction was filtered through celite and concentrated under reduced pressure. The residue was diluted with DCM and washed with water. The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (petroleum ether / EtOAc) to give compound 88c as a white solid in 93% yield. 1H NMR (DMSO-d6, 400 MHz) δ 2.54 (s, 3H), 3.94 (s, 3H), 7.06 (d, J = 2.48 Hz, 1H), 7.37-7 , 40 (m, 2H), 8.02 (d, J = 9.18 Hz, 1H), 8.97 (s, 1H), 11.89 (s, 1H).

Step J: Preparation of 8-chloro-4-hydroxy-7-methoxy-2- (3-isopropyl-1H-pyrazol-1-yl) -quinoline 88d. A mixture of compound 46a (500 mg, 1.37 mmol) and compound 86b (452 ​​mg, 4.11 mmol) in N-methylpyrrolidone (2 ml) was stirred at 200 ° C for 30 min with microwave radiation. After cooling the reaction mixture to room temperature, water was added. The reaction mixture was then extracted with EtOAc, dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (DCM / EtOAc) to give compound 88d as a white solid with 35% yield

1H NMR (DMSO-d6, 400 MHz) δ 1.26 (s, 3H), 1.28 (s, 3H), 2.98-3.01 (m, 1H), 4.00 (s, 3H) , 6.46 (m, 1H), 7.16 (d, 9.32 Hz, 1H), 7.89 (d, J = 9.32 Hz, 1H), 8.05 (d, J = 10, 85 Hz, 1H), 8.60 (m, 1H), 10.69 (s, 1H).

Example 15

Preparation of macrocyclic compounds 91 The syntheses of macrocyclic compounds 91 are illustrated in Scheme 17, where R8 'and A in compounds 89 and 90 are as defined in compounds 91.

Stage A: Preparation of (Z) - (4R, 6S, 15S, 17S) ethyl ester -17- [8-chloro-7-methoxy-2- (3-trifluoromethyl-1H)

5 pyrazol-1-yl) quinolin-4-yloxy] -13-N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13,3,0,0] octadec-7-eno-4-carboxylic 89a. Compound 89a was synthesized from compounds 53 and 88a in the form of a beige solid in 40% yield, following the procedure described for compound 54c.

MS (ESI, EI +) m / z = 705 (MH +).

Scheme 17 5 following the procedure described for compound 54c.

MS (ESI, EI +) m / z = 659 (MH +).

Stage C: Preparation of (Z) - (4R, 6S, 15S, 17S) ethyl ester -17- [7-methoxy-8-methyl-2- (3-trifluoromethyl-1Hpyrazol-1-yl) quinolin-4- yloxy] -13-N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic acid 89c. Compound 89c was synthesized from compounds 53 and 88c in the form of a brown foam with 80% of

10 yield, following the procedure described for compound 54c.

MS (ESI, EI +) m / z = 685 (MH +).

Stage D: Preparation of (Z) - (4R, 6S, 15S, 17S) ethyl ester -17- [8-chloro-7-methoxy-2- (3-isopropyl-1H-pyrazol-1-yl) quinolin-4 -yloxy] -13-N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic acid 89d. Compound 89d was synthesized from compounds 53 and 88d in the form of a brown foam with 90% yield,

fifteen following the procedure described for compound 54c.

MS (ESI, EI +) m / z = 679 (MH +).

Step E: Preparation of (Z) - (4R, 6S, 15S, 17S) -17- [8-chloro-7-methoxy-2- (3-trifluoromethyl-1H-pyrazol-1-yl) quinolin-4-yloxy] -13-N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic 90a. Compound 90a was synthesized from compound 89a as a white solid in 77% yield, following the procedure described for compound 55c.

MS (ESI, EI +) m / z = 677 (MH +).

Step F: Preparation of (Z) - (4R, 6S, 15S, 17S) -17- [8-methyl-7-methoxy-2- (3-isopropyl-1H-pyrazol-1-yl) quinolin-4-yloxy] -13-N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic 90b. Compound 90b was synthesized from compound 89b as a yellow solid in 50% yield, following the procedure described for compound 55c.

MS (ESI, EI +) m / z = 631 (MH +).

Step G: Preparation of (Z) - (4R, 6S, 15S, 17S) -17- [7-methoxy-8 methyl-2- (3-trifluoromethyl-1H-pyrazol-1-yl) quinolin-4-yloxy] - 13-N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic 90c. Compound 90c was synthesized from compound 89c as a pale yellow solid in 18% yield, following the procedure described for compound 55c.

MS (ESI, EI +) m / z = 657 (MH +).

Step H: Preparation of (Z) - (4R, 6S, 15S, 17S) -17- [8-chloro-7-methoxy -2- (3-isopropyl-1H-pyrazol-1-yl) quinolin-4-yloxy] -13-N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic 90d. Compound 90d was synthesized from compound 89d as a pale yellow solid in 36% yield, following the procedure described for compound 55c.

MS (ESI, EI +) m / z = 650 (MH +).

Stage I: Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [8-chloro-7-methoxy-2- (3-trifluoromethyl-1H-pyrazol-1-yl) quinolin-4- yloxy] 13-N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-yl] carbonyl (1-methylcyclopropyl) sulfonamide 91a. Compound 91a was synthesized from compound 90a and 1-methylcyclopropylsulfonamide as a white solid in 12% yield, following the procedure described for compound 56c.

MS (ESI, EI +) m / z = 794 (MH +).

Step J: Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [8-methyl-7-methoxy-2- (3-isopropyl-1H-pyrazol-1-yl) quinolin-4- yloxy] -1,3N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-yl] carbonyl (1-methylcyclopropyl) sulfonamide 91b. Compound 91b was synthesized from compound 90b and 1-methylcyclopropylsulfonamide as a white solid in 30% yield, following the procedure described for compound 56c.

MS (ESI, EI +) m / z = 748 (MH +).

Step K: Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [7-methoxy-8-methyl-2- (3-trifluoromethyl-1H-pyrazol-1-yl) quinolin-4- yloxy] 13-N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-yl] carbonyl (1-methylcyclopropyl) sulfonamide 91c. Compound 91c was synthesized from compound 90c and 1-methylcyclopropylsulfonamide as a white solid in 9% yield, following the procedure described for compound 56c.

MS (ESI, EI +) m / z = 774 (MH +).

Stage L: Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [8-chloro-7-methoxy-2- (3-isopropyl-1H-pyrazol-1-yl) quinolin-4- yloxy] -13N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-yl] carbonyl (1-methylcyclopropyl) sulfonamide 91d. Compound 91d was synthesized from compound 90d and 1-methylcyclopropylsulfonamide as a white solid in 28% yield, following the procedure described for compound 56c.

MS (ESI, EI +) m / z = 768 (MH +).

Stage M: Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [8-chloro-7-methoxy-2- (3-trifluoromethyl-1H-pyrazol-1-yl) quinolin-4- yloxy] 13-N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-yl] carbonyl (cyclopropyl) sulfonamide 91e. Compound 91e was synthesized from compound 90a and cyclopropylsulfonamide as a beige solid in 46% yield, following the procedure described for compound 56c.

MS (ESI, EI +) m / z = 780 (MH +).

Stage N: Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [8-methyl-7-methoxy-2- (3-isopropyl-1H-pyrazol-1-yl) quinolin-4- yloxy] -13N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-yl] carbonyl (cyclopropyl) sulfonamide 91f. Compound 91f was synthesized from compound 90b and cyclopropylsulfonamide as a white solid in 30% yield, following the procedure described for compound 56c.

MS (ESI, EI +) m / z = 734 (MH +).

Stage O: Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [7-methoxy-8-methyl-2- (3-trifluoromethyl-1H-pyrazol-1-yl) quinolin-4- yloxy] 13-N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-yl] carbonyl (cyclopropyl) sulfonamide 91g. Compound 91g was synthesized from compound 90c and cyclopropylsulfonamide as a white solid with

46% yield, following the procedure described for compound 56c. MS (ESI, EI +) m / z = 760 (MH +). Example 16 Preparation of macrocyclic compounds 96

Syntheses of macrocyclic compounds 96 are illustrated with compound 96d as shown in Scheme 18, where R5 ', R6', R7 'and R8' in compounds 92 to 96 are as defined in compounds 56. The same procedures They are also applicable to other compounds 96.

Stage A: Preparation of N- (6-acetyl-2-chloro-3-methoxyphenyl) -5-isopropylisoxazole-3-carboxamide 92d. To a solution

10 5-Isopropylisoxazol-3-carboxylic acid (3.5 g, 22.6 mmol) in DCM (35 ml) was added anhydrous DMF (a few drops) and oxalyl chloride (3.82 ml, 43.2 mmol) at 0 ° C under nitrogen atmosphere. At the end of the gas outlet, the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 2 h and evaporated. Dioxane (70 ml) was added under a nitrogen atmosphere, followed by a solution of 1- (2-amino-3-chloro-4-methoxy-phenyl) -ethanone 40d (4.10 g, 20.6 mmol) in dioxane (15 ml). The reaction mixture is

fifteen stirred at room temperature for 16 h. Then NaHCO3 was added. The reaction mixture was extracted with EtOAc. The organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was triturated in Et2O to give compound 92d as a brown solid in 60% yield.

1H NMR (CDCl3, 400 MHz) δ 1.47 (s, 3H), 1.48 (s, 3H), 1.76 (wide s, 1H), 2.57 (s, 3H), 3.34- 3.40 (m, 1H), 3.98 (s, 3H), 6.86 (d, J = 8.53 Hz, 1H), 7.64 (d, J = 8.53 Hz, 1H), 8.07 (s, 1 H).

Scheme 18

Stage B: Preparation of 8-chloro-2 (5-isopropyl-isoxazol-3-yl) -7-methoxy-quinolin-4-ol 93d. Compound 93d was synthesized from compound 92d in the form of a white solid with quantitative yield, following the procedure 5 described for compound 43a.

1H NMR (CDCl3, 400 MHz) δ 1.39 (s, 3H), 1.41 (s, 3H), 3.17-3.31 (m, 1H), 4.06 (s, 3H), 6 , 36 (s, 1H), 6.59 (s, 1H), 7.06 (d, J = 8.48 Hz, 1H), 8.28 (d, J = 8.48 Hz, 1H), 9 , 42 (s, 1 H).

Stage C: Preparation of (Z) - (4R, 6S, 15S, 17S) ethyl ester -17- [8-chloro-7-methoxy-2- (5-isopropylisoxazol-3-yl) quinolin-4-yloxy] - 13-N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic 94d. Compound 10 94d was synthesized from compounds 53 and 93d as a beige solid with 56% yield, following the procedure described for compound 54c.

MS (ESI, EI +) m / z = 680 (MH +).

Step D: Preparation of (Z) - (4R, 6S, 15S, 17S) -17- [8-chloro-7-methoxy-2- (5-isopropylisoxazol-3-yl) quinolin-4-yloxy] 13- N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic 95d. Compound 95d was synthesized at

starting from compound 94d in the form of a white solid with 10% yield, following the procedure described for compound 55c. MS (ESI, EI +) mlz = 652 (MH +). Stage E: Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [8-chloro-7-methoxy-2- (5-isopropylisoxazol-3-yl) quinolin-4-yloxy] -13 -N

5 methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-yl] carbonyl (1-methylcyclopropyl) sulfonamide 96d. Compound 96d was synthesized from compound 95d as a white solid in 16% yield, following the procedure described for compound 56c.

MS (ESI, EI +) m / z = 769 (MH +). Example 17 Preparation of macrocyclic compounds 101

The syntheses of macrocyclic compounds 101 are illustrated with compound 101d as shown in Scheme 19, where R5 ', R6', R7 'and R8' in compounds 92 to 96 are as defined in compounds 56. The same procedures They are also applicable to other compounds 101.

fifteen Stage A: Preparation of N- (6-acetyl-2-chloro-3-methoxyphenyl) -2-isopropylthiazol-4-carboxamide 97d. To a stirred solution of 2-isopropyl-1,3-thiazol-4-carboxylic acid (3.5 g, 20.4 mmol) in DCM (35 ml) was added oxalyl chloride (3.46 ml, 40.9 mmol) with a few drops of anhydrous DMF at 0 ° C. At the end of the gas outlet, the mixture was allowed to warm to room temperature and then stirred for 2 h. The reaction mixture was concentrated under reduced pressure and solubilized in dioxane (70 ml). Then, a solution of 1- (2-amino-3-chloro-4-methoxy-phenyl) was added slowly

twenty 40d ethanone (3.71 g, 18.6 mmol) in dioxane (15 ml). The mixture was stirred at room temperature for 16 h. NaHCO3 was added. The mixture was extracted with EtOAc, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was triturated in diethyl ether to give compound 97b in 60% yield.

1H NMR (CDCl3, 400 MHz) δ 1.47 (s, 3H), 1.48 (s, 3H), 2.57 (s, 3H), 3.34-3.41 (quint, J = 6, 90 Hz, 1H), 3.98 (s, 3H), 6.86 (d, J = 8.48 Hz, 1H), 7.64 (d, J = 8.48 Hz, 1H), 8.07 (s, 1 H); MS (ESI, EI-) m / z = 351 (MH-).

Scheme 19

Stage B: Preparation of 8-chloro-2- (2-isopropyl-thiazol-4-yl) -7-methoxy-quinolin-4-ol 98d. Compound 97d (352 mg, 1 mmol) and potassium tert-butoxide (236 mg, 2.1 mmol) in tert-butyl alcohol (10 ml) were stirred in a vessel

5 sealed at 120 ° C for 1 h with microwave radiation. The mixture was poured into diethyl ether, acidified with 2.5 N HCl at pH 5 and extracted with ethyl acetate, and concentrated under reduced pressure to give compound 98b in 82% yield.

1H NMR (CDCl3, 400 MHz) δ 1.49 (s, 3H), 1.51 (s, 3H), 3.38-3.45 (quint, J = 6.90 Hz, 1H), 4.06 (s, 3H), 6.70 (wide s, 1H), 7.05 (d, J = 9.35 Hz, 1H), 7.76 (s, 1H).

10 Step C: Preparation of (Z) - (4R, 6S, 15S, 17S) ethyl ester -17- [8-chloro-7-methoxy-2- (2-isopropylthiazol-4-yl) quinolin-4-yloxy] - 13-N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic 99d. Compound 99d was synthesized from compounds 53 and 98d as a white solid in 31% yield, following the procedure described for compound 54c.

MS (ESI, EI +) m / z = 696 (MH +).

Stage D: Preparation of (Z) - (4R, 6S, 15S, 17S) -17- [8-chloro-7-methoxy-2- (2-isopropylthiazol-4-yl) quinolin-4-yloxy] -13N acid -methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic 100d. Compound 100d was synthesized from compound 99d as a white solid in 47% yield, following the procedure described for compound 55c.

5 MS (ESI, EI +) m / z = 668 (MH +).

Stage E: Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [8-chloro-7-methoxy-2- (2-isopropythiazol-4-yl) quinolin-4-yloxy] -13 -Nmethyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-yl] carbonyl (1-methylcyclopropyl) sulfonamide 101d. Compound 101d was synthesized from compound 100d as a white solid in 38% yield, following the procedure described for compound 56c.

10 MS (ESI, EI +) m / z = 785 (MH +).

Example 18

Preparation of macrocyclic compounds 110

The syntheses of the macrocyclic compounds 110 are illustrated with compound 110d as shown in the schemes 20 and 21 where R5 ', R6', R7 'and R8' in compounds 102 to 110 are as defined in the compounds

56. The same procedures are also applicable to other compounds 110.

Stage A: Preparation of N- (2-chloro-3-methoxyphenyl) -2-hydroxyimino-acetamide 102d. To a stirred solution of sodium sulfate (58.5 g, 412 mmol) in water (100 ml) was added a solution of chloral hydrate (9.36 g, 56.6 mmol) in water (120 ml). Chloroanisidine 39d (10g, 51.5 mmol) was added followed by 37% HCl (20 ml). Later

twenty A solution of hydroxylamine (50% in water, 4.7 ml, 154.5 mmol) in 50 ml was added and the reaction mixture was heated at reflux for 90 min. The suspended solid was filtered off and washed with water and ether. The organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 102d as a brown solid.

1H NMR (DMSO-d6, 400 MHz) δ 3.86 (s, 3H), 6.98 (d, J = 8.07 Hz, 1H), 7.31 (t, J = 8.07 Hz, 1H ), 7.61 (d, J = 8.07 25 Hz, 1H), 7.66 (s, 1H), 9.43 (s, 1H), 12.43 (s, 1H).

Scheme 20

Stage B: Preparation of 7-chloro-6-methoxy-1H-indole-2,3-dione 103d. Compound 102d (10.46 g, 45.74 mmol) was added portionwise to BF3 · Et2O at 40 ° C. Then, the mixture was heated at 90 ° C for 3 h. After cooling to room temperature, the reaction mixture was poured into crushed ice and extracted with EtOAc. The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (petroleum ether / EtOAc). The compound obtained was recrystallized from EtOH to give compound 103d as a brown solid in 63% yield.

1H NMR (DMSO-d6, 400 MHz) δ 3.96 (s, 3H), 6.79 (d, J = 9.10 Hz, 1H), 7.52 (d, J = 9.10 Hz, 1H ), 11.40 (s, 1 H).

Step C: Preparation of 2-amino-3-chloro-4-methoxy benzoic acid 104d. A suspension of compound 103d (6.03 g, 28.52 mmol), NaOH (1.25 g, 31.37 mmol) and NaCl (3.49 g, 59.89 mmol) in water (60 ml) was stirred at room temperature for 30 min and then cooled on ice. H2O2 was added dropwise. The mixture was stirred at 0 ° C for 20 min and at room temperature for 3 h. The reaction mixture was quenched with glacial AcOH, filtered and washed with water. The solid obtained was dissolved in DCM, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (DCM / MeOH) to give compound 104d as an orange solid in 36% yield.

1H NMR (DMSO-d6, 400 MHz) δ 3.85 (s, 3H), 6.41 (d, J = 9.05 Hz, 1H), 6.77 (wide s, 2H), 7.74 ( d, J = 9.05 Hz, 1H), 12.7 (wide s, 1H).

Stage D: Preparation of 2-amino-3-chloro-4-methoxybenzoic acid methyl ester 105d. To a stirred solution of compound 104d (1.9 g, 9.6 mmol) in dry DMF (25 ml) was added K2CO3 (1.32 g, 9.6 mmol) at room temperature. The reaction mixture was stirred for 30 min and methyl iodide (0.77 ml, 12.4 mmol) was added. After 2 h at room temperature, 5% aqueous citric acid was added. The mixture was extracted with EtOAc. The organic extracts were washed with water, dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (petroleum ether / EtOAc) to give compound 105d as a beige solid with 50% yield

1H NMR (CDCl3, 400 MHz) δ (ppm) 3.79 (s, 3H), 3.86 (s, 3H), 6.23 (d, J = 9.03 Hz, 1H), 7.75 ( d, J = 9.03 Hz, 1H).

Step E: Preparation of methyl 3-chloro-2- (4-isopropylthiazol-2-carboxamido) -4-methoxybenzoate 106d. To a stirred solution of compound 37 (758 mg, 4.28 mmol) in dry DCM, oxalyl chloride (720 µL, 8.56 mmol) and a few drops of DMF were added at 0 ° C. The reaction mixture was stirred at 0 ° C for 30 min and at room temperature for 2 h. The mixture was filtered, concentrated under reduced pressure and dissolved in dioxane (3 ml). Compound 105d (770 mg, 3.56 mmol) in dioxane (6 ml) was then added. The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated. Water was added to the mixture. The reaction mixture was extracted with EtOAc. The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (petroleum ether / EtOAc) to give compound 106d as a pale yellow solid in 92% yield. .

1H NMR (CDCl3, 400 MHz) δ 1.19 (d, J = 6.63 Hz, 6H), 3.09-3.16 (m, 1H), 3.79 (s, 3H), 3.91 (s, 3H), 6.82 (d, J = 9.02 Hz, 1H), 7.19 (s, 1H), 7.82 (d, J = 9.02 Hz, 1H), 9.97 (s, 1H).

Step F: Preparation of 8-chloro-2- (4-isopropyl-thiazol-2-yl) -7-methoxy-quinazolin-4-ol 107d. To a stirred solution of compound 106d (1.32 g, 3.58 mmol) in EtOH / H2O (1/1, 10 ml) was added LiOH (10.3 mg, 4.29 mmol). The reaction mixture was stirred at 60 ° C for 2 h. An aqueous solution of citric acid (5%) was added and the mixture was extracted with EtOAc. The organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was stirred with formamidine (26 ml) at 150 ° C for 4 h, and the mixture was allowed to cool to room temperature overnight. The mixture was poured into water and extracted with DCM. The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (petroleum ether / EtOAc) to give compound 107d as a beige solid in 58% yield.

1H NMR (DMSO-d6, 400 MHz) δ 1.32 (d, J = 6.71 Hz, 6H), 3.09-3.15 (m, 1H), 4.01 (s, 3H), 7 , 42 (d, J = 9.03 Hz, 1H), 7.67 (s, 1H), 8.11 (d, J = 9.03 Hz, 1H), 12.42 (s, 1H).

Stage G: Preparation of (Z) - (4R, 6S, 15S, 17S) ethyl ester -17- [8-chloro-7-methoxy-2- (4-isopropylthiazol-2-yl) quinazolin-4-yloxy] - 13-N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic 108d. Compound 108d was synthesized from compounds 53 and 107d in the form of a yellow oil in 16% yield, following the procedure described for compound 54c.

MS (ESI, EI +) mlz = 697 (MH +).

Step H: Preparation of (Z) - (4R, 6S, 15S, 17S) -17- [8-chloro-7-methoxy-2- (4-isopropylthiazol-2-yl) quinazolin-4-yloxy] 13- N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic acid 109d. Compound 109d was synthesized from compound 108d as a white solid in 16% yield, following the procedure described for compound 55c.

MS (ESI, EI +) m / z = 669 (MH +).

Stage I: Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [8-chloro-7-methoxy-2- (4-isopropylthiazol-2-yl) quinazolin-4-yloxy] -13 -Nmethyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-yl] carbonyl (1-methylcyclopropyl) sulfonamide 110d. Compound 110d was synthesized from compound 109d as a white solid in 16% yield, following the procedure described for compound 56c.

MS (ESI, EI +) m / z = 786 (MH +).

Scheme 21

Example 19 Preparation of macrocyclic compound 91e

The synthesis of macrocyclic compound 91e is illustrated in scheme 22

Stage A: Preparation of (2S, 4S) -4- (8-chloro-7-methoxy-2- (3- (trifluoromethyl) -1H-pyrazol-1-yl) quinolin-4-yloxy) pyrrolidine-1,2-dicarboxylate of 1-tert-butyl and 2-methyl 112. Compound 112 was synthesized from the methyl ester of N-Boc5 trans-4-hydroxy-L-proline 111 and compound 88a in the form of a 90% beige foam yield, following the procedure described for compound 54c.

Stage B: Preparation of (2S, 4S) -1- (tert-butoxycarbonyl) -4- (8-chloro-7-methoxy-2- (3- (trifluoromethyl) -1H-pyrazol-1-yl) quinolin-4- iloxy) pyrrolidine-2-carboxylic acid 113. To a stirred solution of compound 112 (650 mg, 1.13 mmol) in THF (12 mL) was added LiOH (82 mg, 3.41 mmol) and water. The reaction mixture was stirred at room temperature.

10 for 16 h and acidified with 1 N HCl at pH 5-6. The aqueous layer was extracted with EtOAc. The organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 113 as a pink solid in 95% yield.

MS (ESI, EI +) m / z = 558 (MH +).

Stage C: Preparation of (2S, 4S) -4- (8-chloro-7-methoxy-2- (3- (trifluoromethyl) -1H-pyrazol-1-yl) quinolin-4-yloxy) -2- (hex -5

fifteen tert-butyl enyl (methyl) carbamoyl) pyrrolidine-1-carboxylate 114. Compound 114 was synthesized from compounds 32a and 113 as a white foam in 87% yield, following the procedure described for compound 48.

MS (ESI, EI +) m / z = 653 (MH +).

Scheme 22

Stage D: Preparation of (2S, 4S) -4- (8-chloro-7-methoxy-2- (3- (trifluoromethyl) -1H-pyrazol-1-yl) quinolin-4-yloxy) -N- (hex -5enyl) -N-methyl pyrrolidine-2-carboxamide 115. Compound 115 was synthesized from compound 114 as a white solid with quantitative yield, following the procedure described for compound 82.

MS (ESI, EI +) m / z = 553 (MH +).

Stage E: Preparation of (1R, 2S) -1 - ((2S, 4S) -4- (8-chloro-7-methoxy-2- (3- (trifluoromethyl) -1H-pyrazol-1-yl) quinolin- Ethyl 4-yloxy) -2 (hex-5-enyl (methyl) carbamoyl) pyrrolidine-1-carboxamido) -2-vinylcyclopropanecarboxylate 116. Compound 116 was synthesized from compounds 33 and 115 as a white solid with 75% yield, following the

10 procedure described for compound 50.

MS (ESI, EI +) m / z = 734 (MH +).

Step F: Preparation of (1R, 2S) -1 - ((2S, 4S) -4- (8-chloro-7-methoxy-2- (3- (trifluoromethyl) -1H-pyrazol-1-yl) quinolin acid -4yloxy) -2- (hex-5-enyl (methyl) carbamoyl) pyrrolidine-1-carboxamido) -2-vinylcyclopropanecarboxylic 117. Compound 117 was synthesized from compound 116 as a white solid in 60% yield , following the

fifteen procedure described for compound 55c.

MS (ESI, EI +) m / z = 706 (MH +).

Stage G: Preparation of (2S, 4S) -4- (8-chloro-7-methoxy-2- (3- (trifluoromethyl) -1H-pyrazol-1-yl) quinolin-4-yloxy) -N1 - (( 1R, 2S) 1- (cyclopropylsulfonylcarbamoyl) -2-vinylcyclopropyl) -N2- (hex-5-enyl) -N2-methylpyrrolidine-1,2-dicarboxamide 118. Compound 118 was synthesized from compound 117 and cyclopropylamine in the form of a white solid with 40% of

5 yield, following the procedure described for compound 56c.

MS (ESI, EI +) m / z = 809 (MH +).

Step H: Preparation of (Z) - (4R, 6S, 15S, 17S) - [17- [8-chloro-7-methoxy-2- (3-trifluoromethyl-1H-pyrazol-1-yl) quinolin-4- yloxy] 13-N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-yl] carbonyl (cyclopropyl) sulfonamide 91e. To a stirred solution of compound 118 (55 mg, 0.07 mmol) in degassed DCE (68 ml) at 40 ° C was added

10 Zhan IB catalyst (1 mg, 2% mol). After the reaction mixture was stirred for 1 h at 40 ° C, a second batch of Zhan IB catalyst (0.5 mg) was added. After the reaction mixture was stirred for 1 h at 60 ° C, a third batch of Zhan IB catalyst (0.5 mg) was added. The reaction mixture was stirred at 60 ° C for 16 h. The mixture was concentrated under reduced pressure and purified by silica gel chromatography (petroleum ether / EtOAc) to give compound 91e as a beige solid in 40% yield.

fifteen MS (ESI, EI +) m / z = 780 (MH +)

Example 20

Preparation of substituted quinolines 88

The syntheses of the substituted quinoline are illustrated in scheme 23, where R8 'and A in compound 119 are the same as those defined in compound 88.

Scheme 23 Stage A: Synthesis of 4,8-dichloro-7-methoxy-2- (3- (trifluoromethyl) -1H-pyrazol-1-yl) quinoline 119b. A mixture of compound 45d (5 g, 19 mmol) and 3-trifluoromethylpyrazole 86a (7.76 g, 57 mmol) was heated at 120 ° C for 4-6 h and the reaction was followed by LCMS and TLC. The reaction mixture was purified by silica gel column (mono and dipyrazole separated) using DCM and heptane as the mobile phase to give compound 119b (3.5 g) with 51% of

5 performance.

Stage B: Synthesis of 8-chloro-7-methoxy-2- (3- (trifluoromethyl) -1H-pyrazol-1-yl) quinolin-4-ol 88b. To a solution of compound 119b (250 mg) in DMSO (2.5 ml) was added CH3COOK (3 eq.), Water (2 eq.). The reaction mixture was heated at 140 ° C for 4 h. After cooling to rt, water (1 ml) was slowly added to the reaction mixture with stirring. The solid was filtered and washed with water to give compound 88b in&gt; 80% yield. In a

10 separate reaction, when 5 eq. of CH3COOK the reaction was completed in 1 h.

Example 21

Preparation of macrocyclic compound 68b

The synthesis of macrocyclic compound 68b is illustrated in schemes 24 and 25.

fifteen Stage A: Synthesis of (1R, 2S) -1- (tert-butoxycarbonylamino) -2-vinylcyclopropanecarboxylic acid 121. Compound 120 (51 g) was dissolved in THF (170 ml) at room temperature. Sodium hydroxide in water (1.47 eq. In 170 ml) was added. The reaction mixture was stirred at room temperature for 15 h, heated at 50 ° C for 1.5 h, and then cooled before neutralizing with 5M HCl. After neutralizing with 5M HCl, the reaction mixture was extracted with DCM. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated to

twenty vacuum to give compound 121 (47.7 g) as a thick yellow oil with 99% yield.

Scheme 24

Stage B: Synthesis of (1R, 2S) -1- (1-methylcyclopropylsulfonyl-carbamoyl) -2-vinylcyclopropylcarbamate 122. Compound 121 (104.6 g) was dissolved in THF (1.0 L) at ambient temperature in argon atmosphere. CDI 5 (1.5 eq.) Was added and the reaction mixture was heated at reflux for 20 min. After cooling the reaction mixture to 4-6 ° C, sulfonamide (1.5 eq.) Was added, followed by the addition of DBU (2 eq.). After stirring at room temperature for 64 h, the reaction mixture was diluted with DCM, neutralized with 1M HCl, and washed with brine saturated at pH 7. The organic extracts were dried over sodium sulfate and concentrated to give a off-white solid, 106.4 g. Crystallization from methanol / water gave compound 122 (91 g) as a white solid.

10 with 77% yield.

Stage C: Synthesis of (1R, 2S) -1-amino-N- (1-methylcyclopropylsulfonyl) -2-vinylcyclopropanecarboxamide hydrochloride

123 Compound 122 (51.5 g) was suspended in methanol (150 ml). A solution of acetyl chloride (3 eq.) In methanol was added to the suspension. The reaction mixture was heated at 50 ° C for 3 h. The reaction mixture was concentrated at 45-50 ° C and coevaporated with DCM to give compound 123 (42.4 g) as a white powder with

fifteen 102% yield due to DCM.

Scheme 25

Stage D: Synthesis of (2S, 4S) -4- (7-methoxy-8-methyl-2- (4- (trifluoromethyl) thiazol-2-yl) quinolin-4-yloxy) pyrrolidine-1,2-dicarboxylate 1- tert-butyl and 2-methyl 124. Triphenylphosphine (1.5 eq.) was dissolved in 180 ml of tetrahydrofuran in

5 argon atmosphere. The solution was cooled to 0-5 ° C. DIAD (1.5 eq.) Was added slowly over a period of 15-20 min. Compound B (20 g, 1 eq.) Was added over 5-10 min at the temperature of 0-5 ° C. Compound 111 (17.6 g, 1.2 eq.) Was added and the reaction mixture was heated to room temperature. One hour later, the reaction mixture was concentrated in vacuo at 40-45 ° C and the crude product was triturated with MeOH, TBME and heptane to give compound 124 (22.24 g) as a white powder with 67% of yield and 98.7% purity.

10 MS: m / z (ESI +) = 568.27 [M + H] +, 100%; m / z (ESI-) = 626.50 [M + OAc] -, 100%.

Stage E. Synthesis of (2S, 4S) -1- (tert-butoxycarbonyl) -4- (7-methoxy-8-methyl-2- (4- (trifluoromethyl) thiazol-2-yl) quinolin-4-yloxy) pyrrolidine -2-carboxylic 125. Compound 124 (22.24 g) was dissolved in THF (66 ml) at room temperature. Water (66 ml) was added followed by lithium hydroxide (5 eq.) In one portion. The reaction mixture was heated at 40 ° C for 3 h, cooled, acidified with 5M HCl and extracted with DCM. The organic phase was dried over Na2SO4 and was

fifteen concentrated in vacuo to give 125 (21.33 g) as an off-white powder with 92% yield (7.5% by weight THF) and 99% purity.

Stage F: Synthesis of (2S, 4S) -2- (hex-5-enyl (methyl) carbamoyl) -4- (7-methoxy-8-methyl-2- (4- (trifluoromethyl) thiazol-2-yl) tert-butyl quinoline 4-yloxy) pyrrolidine-1-carboxylate 126. Compound 125 (21.33 g) was dissolved in anhydrous DMF (48 ml) at room temperature. O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate (1.25 eq.) Was added at room temperature and the reaction mixture was stirred for 10 min. Compound 32b (1.1 eq.) Was added and the reaction mixture was stirred for an additional 10-15 min. After cooling to 5 ° C, diisopropylethylamine (3 eq.) Was added. After heating at room temperature for 1 h, the reaction mixture was diluted with ethyl acetate, washed with brine and ammonium chloride, dried over Na2SO4, and concentrated in vacuo to give crude product 126 (22.09 g ) in the form of an orange foam. The crude product was crystallized from ethyl acetate and heptane to give compound 126 (20.8 g) as an off-white powder with 90% yield and 99% purity. MS: mlz (ESI +) = 649.43 [M + H] +, 100%; m / z (ESI-) = 707.57 [M + OAc] -, 100%.

Stage G: Synthesis of (2S, 4S) -N- (hex-5-enyl) -4- (7-methoxy-8-methyl-2- (4- (trifluoromethyl) thiazol-2-yl) quinolin-4- yloxy) -N-methyl pyrrolidine-2-carboxamide 127. Compound 126 (19.92 g) was suspended in anhydrous methanol (120 ml) under argon at room temperature. Separately, acetyl chloride (3 eq.) Was added to anhydrous methanol (60 ml) at 1020 ° C. This solution was added to the solution of compound 126 at 5 ° C. The reaction mixture was heated at 40 ° C for 3-4 h. After completion of the reaction, the reaction mixture was concentrated in vacuo and then coevaporated with 200 ml of anhydrous dichloromethane. Then, the product was dried in a vacuum oven at 40-45 ° C. Compound 127 (18.35 g) was recovered as a yellow foam with quantitative yield and 100% purity (HPLC).

MS: m / z (ESI +) = 549.31 [M + H] +, 100%; m / z (ESI-) = 607.50 [M + OAc] -, 100%.

Stage H: Synthesis of (2S, 4S) -N- (hex-5-enyl) -1- (1H-imidazol-1-carbonyl) -4- (7-methoxy-8-methyl-2- (4- ( trifluoromethyl) thiazol-2-yl-quinolin-4-yloxy) -N-methyl-pyrrolidine-2-carboxamide 128. Compound 127 (18.35 g) was dissolved in anhydrous dichloromethane (37 ml) under argon. 1,1'-carbonyldiimidazole (2 eq.) Was added at room temperature. The reaction mixture was stirred for 40 min. The mixture was diluted with DCM, washed with water, dried over Na2SO4, and concentrated in vacuo. Compound 128 (19.39 g) was recovered in the form of a pale yellow foam with 99% yield along stages and with 98% purity (HPLC).

MS: m / z (ESI-): 701.63 [M + OAc] -, 100%.

Stage I: Synthesis of (2S, 4S) -N2- (hex-5-enyl) -4- (7-methoxy-8-methyl-2- (4- (trifluoromethyl) thiazol-2-yl) quinolin-4- yloxy) -N2-methylN1 - ((1R, 2S) -1- (1-methylcyclopropylsulfonylcarbamoyl) -2-vinylcyclopropyl) pyrrolidine-1,2-dicarboxamide 129. Compounds 128 (18.89 g) and 123 were mixed at temperature ambient in anhydrous acetonitrile (76 ml) and heated at 65 ° C until the reaction is complete. The reaction mixture was then concentrated in vacuo to give a first orange foam (36.21 g). The first orange foam was dissolved in DCM and washed repeatedly with brine, dried over Na2SO4, and concentrated in vacuo to give a second orange foam (25.08 g). Compound 129 (12.2 g) was crystallized from the second orange foam in DCM, ethyl acetate and heptane as a white solid with 50.8% yield and 98% purity.

MS: m / z (ESI +) = 819.54 [M + H] +, 100%; m / z (ESI-) = 817.60 [MH] -, 100%.

Step J: Synthesis of {(Z) - (4R, 6S, 15S, 17S) -17- [7-methoxy-8-methyl-2- (4-trifluoromethyl-thiazol-2-yl) -quinolin-4- 1- 13-yl-] -13-methyl-2,14-dioxo-1,3,13-triaza-tricyclo [13,3,0,0 * 4,6 *] octadec-7-ene-4-carbonyl} -amide methylcyclopropanesulfonic acid 68b. Compound 129 (3.91 g) was dissolved in dichloroethane (980 ml) under Ar atmosphere at room temperature. The solution was degassed with argon and then heated to 73-77 ° C. Zhan 1B catalyst (1%) in dichloroethane was slowly added to the reaction solution. At 25 min, another 1% of the catalyst in DCE was added. In total, 8% of the catalyst was added over 4 h and 20 min. The reaction mixture was treated with 2-mercaptonicotinic acid ("MNA") (1 g). The reaction mixture was cooled to room temperature, concentrated in vacuo to ~ 100 ml, and then washed with 0.5 M NaHCO3 aqueous solution. To the separated organic phase was added MNA (1 g) and the mixture was stirred at room temperature for 55-65 min. The mixture was washed twice with 0.5 M NaHCO3 aqueous solution, dried over Na2SO4, and filtered. Carbon (11 g) was added to the organic solution and the mixture was stirred at room temperature for 15 h. The mixture was concentrated in vacuo to ~ 10-15 ml and filtered through a silica plug. The crude product was triturated in hot methanol to give compound 68b (1.1 g) as an off-white solid with 30% yield and 98% purity.

MS: m / z (ESI +) = 791.47 [M + H] +, 100%; m / z (ESI-) = 789.57 [MH] -, 100%.

Example 22

Preparation of macrocyclic compound 62d The synthesis of macrocyclic compound 62d is illustrated in Schemes 26 and 27.

Stage A: Synthesis of (1R, 2S) -1- (cyclopropylsulfonylcarbamoyl) -2-vinylcyclopropylcarbamate 130. Compound 121 (47.75 g) was dissolved in THF (480 ml) at room temperature. CDI (1.3 eq.) Was added and the reaction mixture was heated at reflux for 30 min. Then, the reaction mixture was cooled to 20 ° C, sulfonamide (1.5 eq.) Was added followed by the addition of DBU (2 eq.). After stirring at room temperature for 15 h, the reaction mixture was diluted with DCM, neutralized with 5M HCl, and washed with saturated brine to pH 7. The organic extracts were dried over sodium sulfate and concentrated to give a off-white solid, 65 g. Crystallization from methanol / water gave compound 130 (60.17 g) as a white solid with 87% of

10 performance.

Step B: Synthesis of (1R, 2S) -1-amino-N- (cyclopropylsulfonyl) -2-vinylcyclopropanecarboxamide hydrochloride 131. Compound 130 (1 g) was suspended in methanol (2.5 ml). A solution of acetyl chloride (3 eq.) In methanol was added to the suspension. The reaction mixture was heated at 50 ° C for 3 h. The reaction mixture was concentrated at 45-50 ° C and coevaporated with DCM to give compound 131 (833 mg) as a white foam with 103%.

fifteen of performance due to DCM.

Scheme 26

Stage C: Synthesis of (2S, 4S) -4- (8-chloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy) pyrrolidine-1,2-dicarboxylate of 1-tert- butyl and 2-methyl 132. Triphenylphosphine (1.5 eq.) was dissolved in 250 ml of tetrahydrofuran under an atmosphere of

twenty argon. The solution was cooled to 0-5 ° C. DIAD (1.5 eq.) Was added slowly over a period of 15-20 min. Compound 56d (25 g, 1 eq.) Was added over 5-10 min at the temperature of 0-5 ° C. Compound 111 (22.48 g, 1.2 eq.) Was added, and the reaction mixture was heated to room temperature. Three hours later, the reaction mixture was concentrated in vacuo at 40-45 ° C and the crude product was triturated with MeOH, TBME and heptane to give compound 132 (30 g) as a white powder with 70% yield and 98.7% purity.

25 MS: m / z (ESI +) = 562.35 [M + H] +, 100%, 564.31, [M + H] +, 35%; mlz (ESI-) = 620.55 [M + OAc] -, 100%, 622.55 [M + OAc] -, 35%.

Stage D. Synthesis of (2S, 4S) -1- (tert-butoxycarbonyl) -4- (8-chloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy) pyrrolidine-2 -carboxylic 133. Compound 132 (20 g) was dissolved in THF (66 ml) at room temperature. Water (66 ml) was added, followed by lithium hydroxide (5 eq.) In one portion. The reaction mixture was heated at 40 ° C for 3 h, cooled, acidified with 5M HCl and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated in vacuo to give compound 133 (20.57 g) as a yellow foam with 99% yield and 96-97% purity.

MS: m / z (ESI +) = 548.37 [M + H] +, 100%, 550.33, [M + H] +, 35%; mlz (ESI-) = 546.49 [MH] -, 100%, 548.52 [MH] -, 35%.

Scheme 27

Stage E: Synthesis of (2S, 4S) -4- (8-chloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy) -2- (hex-5

tert-butyl enyl (methyl) carbamoyl) pyrrolidine-1-carboxylate 134. Compound 133 (20.5 g) was dissolved in DMF

anhydrous (48 ml) at room temperature. O- (benzotriazol-1-yl) -N, N, N ', N'10 tetramethyluronium tetrafluoroborate (1.25 eq.) Was added at room temperature and the reaction mixture was stirred for 10 min. The

compound 32b (1.1 eq.) and the reaction mixture was stirred for an additional 10-15 min. After cooling to 5 ° C,

diisopropylethylamine (3 eq.) was added. After heating at room temperature for 1 h, the mixture of

The reaction was diluted with ethyl acetate, washed with brine and ammonium chloride, dried over Na2SO4, and dried.

concentrated in vacuo to give crude product 134 (22.09 g) as an orange foam. The crude product was crystallized from ethyl acetate and heptane to give compound 134 (20.55 g) as a white powder with 92% of

yield and 98% purity.

MS: m / z (ESI +) = 643.48 [M + H] +, 100%, 645.48, [M + H] +, 35%; mlz (ESI-) = 701.74 [M + OAc] -, 100%, 703.71 [M + OAc] -, 35%.

Stage F: Synthesis of (2S, 4S) -4- (8-chloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinoline-4-yloxy) -N- (hex-5enyl) -N hydrochloride -methyl-pyrrolidine-2-carboxamide 135. Compound 134 (20.37 g) was suspended in anhydrous methanol (120 ml) under an argon atmosphere at room temperature. Separately, acetyl chloride (3 eq.) Was added to anhydrous methanol (70 ml) at 10-20 ° C. This solution was added to the solution of compound 134 at 5 ° C. The reaction mixture was heated at 40 ° C for 3-4 h. After completion of the reaction, the reaction mixture was concentrated in vacuo and then coevaporated with 100 ml of anhydrous dichloromethane. Then, the product was dried in a vacuum oven at 40-45 ° C. Compound 135 (19.81 g) was recovered as a yellow foam with quantitative yield and 100% purity (HPLC).

MS: m / z (ESI +) = 543.36 [M + H] +, 100%, 545.33, [M + H] +, 35%; m / z (ESI-) = 601.59 [M + OAc] -, 100%, 603.57 [M + OAc] -, 35%.

Stage G: Synthesis of (2S, 4S) -4- (8-chloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy) -N- (hex-5-enyl) -1 - (1Himidazol-1-carbonyl) -N-methyl-pyrrolidine-2-carboxamide 136. Compound 135 (10 g) was dissolved in anhydrous dichloromethane (20 ml) under an argon atmosphere. 1,1'-carbonyldiimidazole (2 eq.) Was added at room temperature. The reaction mixture was stirred for 45 min. The mixture was diluted with DCM, washed with water, dried over Na2SO4, and concentrated in vacuo. Compound 136 (9.9 g) was recovered as an off-white foam with 99% yield and 98% purity (HPLC).

MS: m / z (ESI +) = 637.54 [M + H] +, 100%, 639.56, [M + H] +, 35%.

Stage H: Synthesis of (2S, 4S) -4- (8-chloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy) -N1 - ((1R, 2S) -1 ( cyclopropylsulfonylcarbamoyl) -2-vinylcyclopropyl) -N2- (hex-5-enyl) -N2-methyl-pyrrolidine-1,2-dicarboxamide 137. Compounds 136 (7.2 g) and 131 were mixed at room temperature in anhydrous acetonitrile (29 ml) and heated at 65 ° C until the reaction is complete. The reaction mixture was then concentrated in vacuo to give a first orange foam (14.0 g). The first foam was dissolved in DCM and washed repeatedly with brine, dried over Na2SO4, and concentrated in vacuo to give a second orange foam (9.63 g). Compound 137 (4.48 g) was crystallized from a solution of the second orange foam in acetone and TBME in the form of a white solid with 49% yield and 98% purity. A second crop gave an additional 554 mg of compound 137, therefore, the total yield was 55%.

MS: mlz (ESI +) = 799.61 [M + H] +, 100%, 801.57, [M + H] +, 35%; m / z (ESI-) = 797.72 [M + OAc] -, 100%, 799.71 [M + OAc] -, 35%.

Stage I: Synthesis of {(Z) - (4R, 6S, 15S, 17S) -17- [8-chloro-2- (4-isopropyl-thiazol-2-yl) -7-methoxy-quinolin-4-yloxy ] -13-methyl2,14-dioxo-1,3,13-triaza-tricycle [13,3,0,0 * 4,6 *] octadec-7-eno-4-carbonyl} -amide 62d cyclopropanesulfonic acid. Compound 137 (5.5 g) was dissolved in dichloroethane (1.375 ml) under Ar atmosphere at room temperature. The solution was degassed with argon and then heated to 73-77 ° C. Zhan 1B catalyst (1%) in dichloroethane was slowly added to the reaction solution. At 25 min, another 1% catalyst in DCE was added. At 45 min, 2-mercaptonicotinic acid (0.5 eq.) Was added. The reaction mixture was cooled to room temperature, concentrated in vacuo to ~ 130 ml, and then washed with 0.5 M NaHCO3 aqueous solution. To the separated organic phase was added MNA (0.5 eq.) And the The mixture was stirred at room temperature for 55-65 min. The mixture was washed twice with 0.5 M NaHCO3 aqueous solution, dried over Na2SO4, and filtered. Carbon (5.5 g) was added to the organic solution and the reaction mixture was stirred at room temperature for 15 h. The mixture was concentrated in vacuo to ~ 10-15 ml and filtered through a silica plug. The crude solid was crystallized from hot methanol and DCE to give compound 62d (2.87 g) as a white solid with 54% yield and 98% purity. More product was obtained similarly from the filtrate to give 487 mg of a white solid. Therefore, the total yield was 63%.

MS: m / z (ESI +) = 771.54 [M + H] +, 100%, 773.79, [M + H] +, 35%; m / z (ESI-) = 769.54 [M + OAc] -, 100%, 771.61 [M + OAc] -, 35%.

Example 23

Preparation of macrocyclic compounds G1, G2, G3 and G4

The synthesis of the macrocyclic compounds G1, G2, G3 and G4 is shown in Schemes 28 and 29.

Stage A: Synthesis of N- (6-acetyl-2-chloro-3-methoxyphenyl) -4-bromothiazol-2-carboxamide A1. Oxalyl chloride (6.77 g, 1.4 eq.) Was added dropwise under a nitrogen atmosphere at 0 ° C, to a suspension of 4-bromothiazol-25 carboxylic acid (9.52 g, 1.2 eq.) in DCM (310 ml) and DMF (315 μl). The reaction mixture was stirred at 0 ° C for 30 min and then at room temperature for an additional 90 min. The solvent was then removed under reduced pressure to give the acid chloride that was used directly in the next step without further purification. Under a nitrogen atmosphere, a solution of 6-acetyl-2-chloro-3-methoxy-aniline (7.6 g, 1 eq.) In 1,4-dioxane (310 ml) was added at 0 ° C, to a solution of the acid chloride in 1,4-dioxane. The reaction mixture was stirred at room temperature.

10 for 2.5 h and the solvent was removed under reduced pressure. The residue was triturated in ether and then in isopropyl acetate to give compound A1 in 14% yield.

1H NMR (CDCl3, 400 MHz): δ (ppm) 2.59 (s, 3H), 4 (s, 3H), 6.91 (d, J = 8.78Hz, 1H), 7.54 (s, 1H), 7.72 (d, J = 8.78 Hz, 1H), 10.28 (s, 1H).

Scheme 28

Stage B: Synthesis of N- (6-acetyl-2-chloro-3-methoxyphenyl) -4- (2-trimethylsilyl) ethynyl) thiazol-2-carboxamide B1. Compound A1 (3 g, 1eq.), Ethynyltrimethylsilane (1.6 ml, 1.5 eq.), Diisopropylamine (12 ml), triphenylphosphine (0.081 were mixed together

5 g, 4%), copper (I) iodide (0.059 mg, 4%), Cl2Pd (PPh3) 2 (0.113 g, 2%) and stirred at 90 overnight. After cooling to room temperature, diisopropyl ether was added. The precipitate was collected by filtration, washed with diisopropyl ether and pentane. The solid was solubilized in dichloromethane and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give compound B1 as a brown solid in 93% yield.

10 1H NMR (CDCl3, 400 MHz) δ 0.29 (s, 9H), 2.57 (s, 3H), 4 (s, 3H), 6.91 (d, J = 8.91 Hz, 1H), (d, J = 8.65 Hz, 1H), 7.73 (s, 1H); MS (ESI, EI +) m / z = 407 (MH +).

Scheme 29

Stage C: Synthesis of 8-chloro-7-methoxy-2- (4-ethynylthiazol-2-yl) quinolin-4-ol C1. To a solution of compound B1 (2.94 g, 1 eq.) In tert-butanol (15 ml) was added potassium tert-butoxide (1.7 g, 2.1 eq.) And the mixture was stirred at 90 ° C for two

5 h. The tert-butanol was evaporated in vacuo and water was added before acidification to pH 5 by the addition of 1 N HCl. The product was extracted with dichloromethane. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated in diisopropyl ether and filtered off. The filtrate was purified by silica gel column chromatography (methanol / dichloromethane) to give compound B1 as an orange solid in 48% yield.

10 1H NMR (CDCl3, 400 MHz) δ 3.26 (s, 1H), 4.06 (s, 3H), 6.75 (s, 1H), 7.07 (d, J = 9.15Hz, 1H) , 7.72 (s, 1H), 8.27 (d, J = 9.15Hz, 1H), 9.84 (wide s, 1H); MS (ESI, EI +) m / z = 316.92 (MH +).

Stage D: Synthesis of (Z) - methyl ester - (4R, 6S, 15S, 17R) -2,14-dioxo-17-hydroxy-13-N-methyl-1,3,13triazatricyclo [13.3.0.0] octadec -7-eno-4-carboxylic D. Compound D (beige powder) was synthesized following the procedure described for compound 53.

fifteen 1H NMR (CDCl3, 400 MHz) δ 1.23 (t, J = 7.02 Hz, 1H), 1.29-1.38 (m, 1H), 1.49-1.56 (m, 2H) , 1.64 (dd, J = 8.81 and 5.02 Hz, 1H), 1.69-1.77 (m, 1H), 1.85-1.97 (m, 2H), 2.14 -2.20 (m, 1H), 2.34-2.42 (m, 1H), 2.51-2.56 (m, 1H), 2.73-2.84 (m, 1H), 3 , 01 (s, 3H), 3.54 (s, 2H), 3.71 (s, 3H), 4.10 (wide s, 1H), 4.51-4.61 (m, 2H), 4 , 97 (t, J = 7.49 Hz, 1H), 5.45 (t, J = 10.69 Hz, 1H), 5.63 (td, J = 10. 76 and 5.64 Hz, 1H) , 6.32 (s, 1 H).

Stage E: Synthesis of (Z) - methyl ester (4R, 6S, 15S, 17S) -17 [8-chloro-7-methoxy-2- (4-ethynylthiazol-2-yl) quinolin-4-yloxy] -13 -N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic E1. Compound E1, a mixture of diastereoisomers (brown oil), was synthesized from compound C1 (740 mg, 1 eq.) And compound D (850 mg, 1 eq.) Following the procedure described for compound 54c. MS (ESI, EI +) m / z = 664.13 (MH +).

Stage F: Synthesis of (Z) - (4R, 6S, 15S, 17S) -17 [8-chloro-7-methoxy-2- (4-ethynylthiazol-2-yl) quinolin-4-yloxy] -13- N-methyl2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic F1. Compound F1 (white solid) was synthesized from crude compound E1 in 16% yield along stages, following the procedure described for compound 55c (HPLC purification).

1H NMR (CDCl3, 400MHz) δ 1.26-1.33 (m, 2H), 1.43-1.47 (m, 2H), 1.54-1.56 (m, 2H), 1.79 -1.83 (m, 1H), 1.87-1.93 (m, 1H), 2.2-2.32 (m, 2H), 2.62 (d, J = 13.64 Hz, 1H ), 2.79-2.87 (m, 1H), 2.99-3.04 (m, 1H), 3.05 (s, 3H), 3.23 (s, 1H), 3.81- 3.85 (m, 1H), 4.05-4.08 (m, 1H), 4.09 (s, 3H), 4.60 (td, J = 13.56 Hz and J = 2.38Hz, 1H), 4.91 (t, J = 10.69 Hz, 1H), 4.94-4.98 (m, 1H), 5.39-5.45 (m, 1H), 5.46 (s , 1H), 5.64 (td, J = 10.77 Hz and J = 4.68Hz, 1H), 7.29 (d, J = 9.30 Hz, 1H), 7.55 (s, 1H) , 7.68 (s, 1H), 8.05 (d, J = 9.30 Hz, 1H).

Stage G: Synthesis of (Z) - (4R, 6S, 15S, 17S) - [17- [8-chloro-7-methoxy-2- (4-ethynylthiazol-2-yl) quinolin-4-yloxy] -13 -N-methyl-2.14 dioxo-1,3,13-triazatricyclo- [13.3.0.0] octadec-7-en-4-yl] carbonyl (1-methyl-cyclopropyl) sulfonamide G2. Under a nitrogen atmosphere, a solution of compound F1 (140 mg, 1 eq.) And EDCI (82 mg, 2 eq.) In dry dichloromethane (5 ml) was stirred at room temperature for 2 h. Then, 1-methyl-cyclopropylsulfonamide (116 mg, 4 eq.) And DBU (130 mg, 2 eq.) Were added under a nitrogen atmosphere and the reaction mixture was stirred for an additional 20 h. Dichloromethane and water were added and the two layers were separated. The organic layer was washed with water (3 times) and brine, then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound G2 as a beige solid in 33% yield.

1H NMR (CDCl3, 400 MHz): δ 0.80-0.84 (m, 2H), 0.86-0.90 (m, 1H), 1.24-1.33 (m, 1H), 1.37-1.42 (m, 2H), 1.50-1.55 (m, 5H), 1.79-1.84 (m, 1H), 1.90-1.94 (m, 2H), 2.15-2.22 ( m, 1H), 2.40-2.46 (m, 1H), 2.57-2.63 (m, 1H), 2.82-2.92 (m, 1H), 2.99-3, 06 (m, 1H), 3.05 (s, 3H), 3.24 (s, 1H), 3.80-3.84 (m, 1H), 4.03-4.07 (m, 1H) , 4.08 (s, 3H), 4.61 (td, J = 13.77 and 2.56 Hz, 1H), 4.89-4.97 (m, 2H), 5.19 (s, 1H ), 5.43-5.49 (m, 1H), 5.64 (td, J = 10.73 and 5.78 Hz, 1H), 7.29 (dd, J = 9.24 Hz, 1H) , 7.60 (s, 1H), 7.69 (s, 1H), 8.05 (dd, J = 9.24 Hz, 1H), 11.14 (wide s, 1H); MS (ESI, EI +): m / z = 766.97 (MH +).

Step H: Synthesis of N- (6-acetyl-3-methoxy-2-methylphenyl) -4-bromothiazol-2-carboxamide A2. Compound A2 (beige solid) was synthesized from 4-bromothiazol-2-carboxylic acid (5 g, 1 eq.) And 6-acetyl-3-methoxy-2-methyl-aniline (3.58 g, 1 eq .) with 61% yield, following the procedure described for compound A1.

1H NMR (CDCl3, 400 MHz): δ 2.13 (s, 3H), 2.59 (s, 3H), 3.93 (s, 3H), 6.81 (d, J = 8.73 Hz, 1H), 7.50 (s, 1H), 7.77 (d, J = 8.73 Hz, 1H), 11.18 (wide s, 1H); MS (ESI, EI +): m / z = 392 (MNa +).

Stage I: Synthesis of N- (6-acetyl-3-methoxy-2-methylphenyl) -4- (2-trimethylsilyl) ethynyl) thiazol-2-carboxamide B2. Compound B2 (yellow solid) was synthesized from compound A2 (3.9 g, 1 eq.) And ethynyltrimethylsilane (2.2 ml, 1.5 eq.) In 98% yield, following the procedure described for compound B1.

1H NMR (CDCl3, 400 MHz): δ 0.29 (s, 9H), 2.13 (s, 3H), 2.58 (s, 3H), 3.93 (s, 3H), 6.81 ( d, J = 8.73 Hz, 1H), 7.69 (s, 1H), 7.76 (d, J = 8.73 Hz, 1H), 11.05 (wide s, 1H); MS (ESI, EI +): m / z = 409 (MNa +).

Step J: Synthesis of 7-methoxy-8-methyl-2- (4-ethynylthiazol-2-yl) quinolin-4-ol C2. Compound C2 (white solid) was synthesized from compound B2 (3.81 g, 1 eq.) In 21% yield, following the procedure described for compound C1.

1H NMR (CDCl3, 400 MHz): δ 2.44 (s, 3H), 3.25 (s, 1H), 3.98 (s, 3H), 6.77 (s, 1H), 7.03 ( d, J = 9.05 Hz, 1H), 7.70 (s, 1H), 8.25 (d, J = 9.05 Hz, 1H), 9.39 (wide s, 1H); MS (ESI, EI +): mlz = 297 (MH +).

Step K: Synthesis of (Z) - methyl ester - (4R, 6S, 15S, 17S) -17 [7-methoxy-8-methyl-2- (4-ethynylthiazol-2-yl) quinolin-4-yloxy] -13 -N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic E2. Compound E2, mixture of diastereoisomers (yellow foam), was synthesized from compound C2 (600 mg, 1 eq.) And compound D (768 mg, 1 eq.) Following the procedure described for compound 54c.

MS (ESI, EI +): m / z = 644 (MH +).

Stage L: Synthesis of (Z) - (4R, 6S, 15S, 17S) -17 [7-methoxy-8-methyl-2- (4-ethynylthiazol-2-yl) quinolin-4-yloxy] -13- N-methyl2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic F2. Compound F2 (white solid) was synthesized from compound E2 (2.08 g, 1 eq.) Following the procedure described for compound 55c.

1H NMR (CDCl3, 400 MHz): δ 1.27-1.92 (m, 8H), 2.19-2.25 (m, 1H), 2.28-2.35 (m, 1H), 2 , 54-2.64 (m, 2H), 2.68 (s, 3H), 2.83-2.89 (m, 1 H), 2.94-3.04 (m, 1 H), 3 , 05 (s, 1H), 3.79-3.83 (m, 1H), 3.99 (s, 3H), 4-4.09 (m, 1H), 4.57-4.65 (m , 1H), 4.89-4.98 (m, 2H), 5.21 (s, 1H), 5.39-5.46 (m, 1H), 5.62-5.69 (m, 1H ), 6.99 (s, 1H), 7.25 (d, J = Hz, 1H), 7.50 (s, 1H), 7.66 (s, 1H), 7.98 (d, J = 9.25 Hz, 1H); MS (ESI, EI +): m / z = 630 (MH +).

Stage M: Synthesis of (Z) - (4R, 6S, 15S, 17S) - [17- [8-chloro-7-methoxy-2- (4-ethynylthiazol-2-yl) quinolin-4-yloxy] -13 -N-methyl-2,14 dioxo-1,3,13-triazatricyclo- [13.3.0.0] octadec-7-en-4-yl] carbonyl (cyclopropyl) sulfonamide G1. Compound G1 (cream colored solid) was synthesized from compound F2 (63 mg, 1 eq.) And cyclopropylsulfonamide (47 mg, 4 eq.) In 75% yield, following the procedure described for compound G2 (purification of the desired compound by HPLC).

1H NMR (CDCl3, 400 MHz): δ 0.90-0.97 (m, 1H), 1.06-1.20 (m, 2H), 1.21-1.35 (m, 1H), 1.37-1.43 (m, 1H), 1.46-1.53 ​​(m, 1H), 1.53-1.73 (m, 4H), 1.86-1.93 (m, 1H), 1.94 (dd, J = 8.48 and 6.05 Hz, 1H), 2.15-2.21 (m, 1H), 2.37-2.45 (m, 1H), 2.57-2.62 (m, 1H) , 2.90-2.97 (m, 1H), 3-3.03 (m, 1H), 3.04 (s, 3H), 3.23 (s, 1H), 3.78-3.82 (m, 1H), 4.02-4.06 (m, 1H), 4.08 (s, 3H), 4.60 (td, J = 13.68 and 2.60 Hz, 1H), 4, 89-4.94 (m, 2H), 5.22 (s, 1H), 5.40-5.47 (m, 1H), 5.64 (td, J = 10.79 and 5.70 Hz, 1H), 7.28 (dd, J i = 9.25 Hz, 1H), 7.57 (s, 1H), 7.70 (s, 1H), 8.05 (dd, J = 9.25 Hz, 1H), 11.21 (wide s, 1H); MS (ESI, EI +): mlz = 753 (MH +).

Stage N: Synthesis of (Z) - (4R, 6S, 15S, 17S) - [17- [7-methoxy-8-methyl-2- (4-ethynylthiazol-2-yl) quinolin-4-yloxy] -13 -N-methyl-2.14 dioxo-1,3,13-triazatricyclo- [13.3.0.0] octadec-7-en-4-yl] carbonyl- (cyclopropyl) sulfonamide G3. Compound G3 (beige solid) was synthesized from compound F2 (120 mg, 1 eq.) And cyclopropylsulfonamide (91 mg, 4 eq.) In 35% yield, following the procedure described for compound G2.

1H NMR (CDCl3, 400 MHz): δ 0.76-1.72 (m, 10H), 1.94 (dd, J = 8.45 and 6.04 Hz, 2H), 2.15-2.22 (m, 1H), 2.39-2.46 (m, 1H), 2.57-2.63 (m, 1H), 2.68 (s, 3H), 2.84-3.04 (m , 2H), 3.05 (s, 3H), 3.22 (s, 1H), 3.76-3.80 (m, 1H), 3.99 (s, 3H), 3.99-4, 04 (m, 1H), 4.61 (td, J = 13.45 and 2.65 Hz, 1H), 4.89-4.94 (m, 2H), 5.06 (s, 1H), 5 , 39-5.46 (m, 1H), 5.64 (td, J = 10.78 and 5.77 Hz, 1H), 7.24 (d, J = 9.25 Hz, 1H), 7, 51 (s, 1H), 7.66 (s, 1H), 7.98 (d, J = 9.25 Hz, 1H), 11.17 (wide s, 1H); MS (ESI, EI +): m / z = 733 (MH +).

Stage O: Synthesis of (Z) - (4R, 6S, 15S, 17S) - [17- [7-methoxy-8-methyl-2- (4-ethynylthiazol-2-yl) quinolin-4-yloxy] -13 -N-methyl-2.14 dioxo-1,3,13-triazatricyclo- [13.3.0.0] octadec-7-en-4-yl] carbonyl (1-methylcyclopropyl) sulfonamide G4. Compound G4 (white solid) was synthesized from compound F2 (150 mg, 1 eq.) And 1-methylcyclopropyl sulfonamide (138 mg, 4 eq.) In 8% yield, following the procedure described for compound G2 .

1H NMR (CDCl3, 400 MHz): δ 0.82-1.38 (m, 4H), 1.53 (s, 3H), 1.55-1.84 (m, 5H), 1.90-1 , 95 (m, 2H), 2.15-2.21 (m, 1H), 2.41-2.48 (m, 1H), 2.57-2.63 (m, 1H), 2.68 (s, 3H), 2.83-2.93 (m, 1H), 2.99-3.04 (m, 1H), 3.05 (s, 3H), 3.22 (s, 1H), 3.77-3.81 (m, 1H), 3.99 (s, 3H), 4-4.04 (m, 1H), 4.58-4.65 (m, 1H), 4.89- 4.96 (m, 2H), 5.07 (s, 1H), 5.39-5.46 (m, 1H), 5.61-5.68 (m, 1H), 7.24 (d, J = 9.17 Hz, 1H), 7.52 (s, 1H), 7.66 (s, 1H), 7.99 (d, J = 9.17 Hz, 1H), 11.12 (wide s , 1 HOUR); MS (ESI, EI +): m / z = 747.21 (MH +).

Example 24

Preparation of macrocyclic compounds O1, O2, O3 and O4 The synthesis of macrocyclic compounds O1, O2, O3 and O4 is shown in Schemes 30 and 31.

Stage A: Synthesis of 2- (trifluoromethylthiazole) -4-carboxylic acid ethyl ester. A solution of 2,2,2-trifluoroacetamide (14,24 g, 1 eq.) And Lawesson's reagent (30,6 g, 0, 6 eq.) In THF (120 ml) was stirred by heating at reflux for 18 h. The mixture was cooled, ethyl bromopyruvate (16 ml, 1 eq.) Was added and the reaction was heated to

5 reflux over the weekend. The reaction was cooled, evaporated in vacuo and the resulting crude material was extracted with dichloromethane and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated to give an orange oil. The oil was purified by silica gel chromatography (petroleum ether / dichloromethane) to give compound H in 40% yield.

1H NMR (DMSO-d6, 400 MHz): δ 1.32 (t, J = 7.10 Hz, 3H), 4.34 (q, J = 7.10 Hz, 2H), 8.9 (s, 1 HOUR); 19F NMR (DMSO10 d6, 376 MHz): δ -60.29 (s, 3F); MS (ESI, EI +): m / z = 225.9 (MH +).

Stage B: Synthesis of lithium 2- (trifluoromethyl) thiazol-4-carboxylate I. Compound I (pink solid) was synthesized from compound H (12.14 g, 1 eq.) In 75% yield, following the procedure described for compound 37.

MS (ESI, EI +): m / z = 198 (MH +).

Scheme 30

Stage C: Synthesis of N- (6-acetyl-2-chloro-3-methoxyphenyl) -2- (trifluoromethyl) thiazol-4-carboxamide K1. Oxalyl chloride (1.9 ml, 1.4 eq.) Was added dropwise under a nitrogen atmosphere at 0 ° C to a suspension of compound I (4 g, 1.2 eq.) In DCM (120 ml) and DMF (some drops). The reaction mixture was stirred at 0 ° C for 30 min and then at room temperature for an additional 3 h. The solid was filtered off under a nitrogen atmosphere and the filtrate was evaporated to give a yellow oil. This oil was solubilized in dioxane (30 ml) and added in atmosphere

of nitrogen to a solution of 6-acetyl-2-chloro-3-methoxy-aniline (3.26 g, 1 eq.) in 1,4-dioxane (60 ml). The reaction mixture was stirred at room temperature for 3 days. The solvent was removed under reduced pressure, the residue was solubilized in dichloromethane, washed with water, dried over Na2SO4 and concentrated in vacuo. The crude oil was triturated in a MeOH / Et2O mixture to give compound K1 as a white solid in 69% yield.

1H NMR (CDCl3, 400 MHz): δ 2.59 (s, 3H), 4 (s, 3H), 6.90 (d, J = 8.75 Hz, 1H), 7.70 (d, J = 8.75 Hz, 1H), 8.44 (s, 1H), 10.28 (s, 1H); 19 F NMR (CDCl 3, 376 MHz): δ -61.08 (s, 3F).

Scheme 31

Stage D: Synthesis of 8-chloro-2- (2- (trifluoromethyl) thiazol-4-yl) -7-methoxyquinolin-4-ol L1. Compound L1 (white solid) 10 was synthesized from compound K1 (1 g, 1 eq.) In 26% yield, following the procedure described for compound C1.

1H NMR (CDCl3, 400 MHz): δ (ppm) 4.07 (s, 3H), 6.78 (s, 1H), 7.09 (d, J = 9.13 Hz, 1H), 8.14 (s, 1H), 8.30 (d, J = 9.13 Hz, 1H), 9.93 (s, 1H); 19 F NMR (CDCl 3, 376 MHz): δ -61.14 (s, 3F); MS (ESI, EI +): m / z = 360.91 (MH +).

Stage E: Synthesis of ethyl ester of (Z) - (4R, 6S, 15S, 17S) -17 [8-chloro-7-methoxy-2- (2-trifluoromethylthiazol-415 yl) quinolin-4-yloxy] - 13-N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic M1 Compound M1, a mixture of diastereoisomers, was synthesized from compound L1 (570 mg, 1 eq.) And compound 53 (600 mg, 1 eq.), Following the procedure described for compound 54c.

MS (ESI, EI +): m / z = 722.04 (MH +).

Step F: Synthesis of (Z) - (4R, 6S, 15S, 17S) -17 [8-chloro-7-methoxy-2- (2-trifluoromethylthiazol-4-yl) quinolin-4-yloxy] -13- Nmethyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic N1. Compound N1 was synthesized from compound M1 (1 eq.), Following the procedure described for compound 55c.

1H NMR (CDCl3, 400 MHz): δ 1.27-1.60 (m, 6H), 1.81-1.93 (m, 1H), 2.21-2.26 (m, 1H), 2 , 28-2.35 (m, 1H), 2.59-2.64 (m, 1H), 2.81-2.88 (m, 1H), 3-3.07 (m, 1H), 3 , 05 (s, 3H), 3.83-3.87 (m, 1H), 4.02-4.07 (m, 1H), 4.09 (s, 3H), 4.57-4.64 (m, 1H), 4.89-4.94 (m, 1H), 4.99-5.02 (m, 1H), 5.22 (s, 1H), 5.50-5.57 (m , 1H), 5.65 (td, J = 10.75 and 4.70 Hz, 1H), 7.29 (d, J = 9.25 Hz, 1H), 7.60 (wide s, 1H), 8.09 (d, J = 9.25 Hz, 1H), 8.73 (broad s, 1H); 19F NMR (CDCl3, 376 MHz): δ -60.90 (s, 3F); MS (ESI, EI +): m / z = 693.98 (MH +).

Stage G: Synthesis of (Z) - (4R, 6S, 15S, 17S) - [17- [8-chloro-7-methoxy-2- (2-trifluoromethylthiazol-4-yl) quinolin-4-yloxy] -13 -Nmethyl-2,14-dioxo-1,3,13-triazatricyclo- [13.3.0.0] octadec-7-en-4-yl] carbonyl- (cyclopropyl) sulfonamide O1. Compound O1 (white solid) was synthesized from compound N1 (115 mg, 1 eq.) In 21% yield, following the procedure described for compound G2.

1H NMR (CDCl3, 400 MHz): δ 0.89-0.96 (m, 1H), 1.06-1.17 (m, 1H), 1.22-1.29 (m, 2H), 1 , 38-1.43 (m, 2H), 1.45-1.52 (m, 1H), 1.55-1.69 (m, 1H), 1.88-1.96 (m, 2H) , two. 17-2.23 (m, 1H), 2.39-2.46 (m, 1H), 2.57-2.63 (m, 1H), 2.80-2.89 (m, 1H), 2.89-2.95 (m, 1H), 2.97-3.03 (m, 1H), 3.05 (s, 3H), 3.60-3.69 (m, 1H), 3, 80-3.84 (m, 1H), 4-4.04 (m, 1H), 4.08 (s, 3H), 4.58-4.64 (m, 1H), 4.91 (t, J = 10.69 Hz, 1H), 4.96 (dd, J = 8.75 and 5.10 Hz, 1H), 5.15 (s, 1H), 5.49-5.55 (m, 1H ), 5.64 (td, J = 10.71 and 5.65 Hz, 1H), 7.28 (d, J = 9.20 Hz, 1H), 7.59 (s, 1H), 8.08 (d, J = 9.20 Hz, 1H), 8.72 (s, 1H), 11.18 (wide s, 1H); 19F NMR (CDCl3, 376 MHz): δ -60.89 (s, 3F); MS (ESI, EI +): mlz = 797.02 (MH +).

Stage H: Synthesis of (Z) - (4R, 6S, 15S, 17S) - [17- [8-chloro-7-methoxy-2- (2-trifluoromethylthiazol-4-yl) quinolin-4-yloxy] -13 -Nmethyl-2,14-dioxo-1,3,13-triazatricyclo- [13.3.0.0] octadec-7-en-4-yl] carbonyl- (1-methylcyclopropyl) sulfonamide O2. Compound O2 (white solid) was synthesized from compound N1 (80 mg, 1 eq.) In 19% yield, following the procedure described for compound G2.

1H NMR (CDCl3, 400 MHz): δ 0.77-0.84 (m, 2H), 1.18-1.26 (m, 2H), 1.33-1.43 (m, 2H), 1 , 49-1.56 (m, 1H), 1.52 (s, 3H), 1.64-1.74 (m, 1H), 1.79-1.83 (m, 1H), 1.86 -1.94 (m, 2H), 2. 17-2.24 (m, 1H), 2.41-2.48 (m, 1H), 2.58-2.63 (m, 1H), 2.83-2.92 (m, 1H), 2.96-3.04 (m, 1H), 3.05 (s, 3H), 3.80-3.84 (m, 1H), 4-4.04 (m, 1H), 4.08 ( s, 3H), 4.58-4.65 (m, 1H), 4.91 (t, J = 10.71 Hz, 1H), 4.98 (dd, J = 8.86 and 5.07 Hz , 1H), 5.10 (s, 1H), 5.50-5.56 (m, 1H), 5.64 (td, J = 10.77 and 5.68 Hz, 1H), 7.28 ( d, J = 9.20 Hz, 1H), 7.60 (s, 1H), 8.09 (d, J = 9.20 Hz, 1H), 8.72 (s, 1H), 11.16 ( s wide, 1H); MS (ESI, EI +): m / z = 811.03 (MH +).

Stage I: Synthesis of N- (6-acetyl-3-methoxy-2-methylphenyl) -4- (2-trifluoromethyl) thiazol-4-carboxamide K2. Compound K2 (white solid) was synthesized from compound J (5.2 g, 1.2 eq.) And 6-acetyl-3-methoxy-2-methyl-aniline (3.6 g, 1 eq.) in 52% yield, following the procedure described for compound K1.

1H NMR (DMSO-d6, 400 MHz): δ 2.01 (s, 3H), 3.90 (s, 3H), 7.02 (d, J = 8.81 Hz, 1H), 7.81 ( d, J = 8.81 Hz, 1H), 8.82 (s, 1H); MS (ESI, EI +): mlz = 381 (MNa +).

Step J: Synthesis of 7-methoxy-8-methyl -2- (2-trifluoromethyl-thiazol-4-yl) quinolin-4-ol L2. Compound L2 (brown solid) was synthesized from compound K2 (3.76 g, 1 eq.) In 52% yield, following the procedure described for compound C1 (80 ° C overnight).

1H NMR (CDCl3, 400 MHz): δ 2.42 (s, 3H), 3.98 (s, 3H), 6.72 (s, 1H), 7.04 (d, J = 9.02 Hz, 1H), 8.10 (s, 1H), 8.25 (d, J = 9.02 Hz, 1H), 9.45 (broad s, 1H); MS (ESI, EI +): m / z = 341.06 (MH +).

Step K: Synthesis of (Z) - methyl ester (4R, 6S, 15S, 17S) -17 [7-methoxy-8-methyl-2- (2-trifluoromethylthiazol-4-yl) quinolin-4-yloxy] -13 -N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic M2. Compound M2, a mixture of diastereoisomers, was synthesized from compound L2 (359 mg, 1 eq.) And compound D (400 mg, 1 eq.) In 64% yield, following the procedure described for compound 54c. MS (ESI, EI +): m / z = 688 (MH +).

Stage L: Synthesis of (Z) - (4R, 6S, 15S, 17S) -17 [7-methoxy-8-methyl-2- (2-trifluoromethylthiazol-4-yl) quinolin-4-yloxy] -13- Nmethyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic N2. Compound N2 was synthesized from compound M2 (460 mg, 1 eq.) In 40% yield, following the procedure described for compound 55c (purification by silica gel chromatography).

1H NMR (CDCl3, 400 MHz): δ 1.26-1.34 (m, 1H), 1.38-1.43 (m, 2H), 1.52-1.69 (m, 2H), 1 , 82 (dd, J = 8.12 and 6.26 Hz, 1H), 1.84-1.94 (m, 1H), 2.23 (td, J = 13.52 and 5.65 Hz, 1H ), 2.29-2.36 (m, 1H), 2.61 (td, J = 13.52 and 3.32 Hz, 1H), 2.70 (s, 3H), 2.82-2, 89 (m, 1H), 2.97-3.04 (m, 1H), 3.04 (s, 3H), 3.80-3.84 (m, 1H), 3.98-4.02 ( m, 1H), 3.99 (s, 3H), 4.61 (td, J = 13.63 and 2.73 Hz, 1H), 4.91 (t, J = 10.70 Hz, 1H), 4.98 (dd, J = 8.97 and 5.22 Hz, 1H), 5.14 (s, 1H), 5.47-5.53 (m,

1H), 5.65 (td, J = 10.85 and 4.81 Hz, 1H), 7.24 (d, J = 9.25 Hz, 1H), 7.52 (s, 1H), 8 ( d, J = 9.25 Hz, 1H), 8.59 (s, 1H); MS (ESI, EI +): m / z = 674 (MH +).

Stage M: Synthesis of (Z) - (4R, 6S, 15S, 17S) - [17- [7-methoxy-8-methyl-2- (2-trifluoromethylthiazol-4-yl) quinolin-4-yloxy] -13 -Nmethyl-2,14-dioxo-1,3,13-triazatricyclo- [13.3.0.0] octadec-7-en-4-yl] carbonyl- (cyclopropyl) sulfonamide O3. Compound O3 (white solid) was synthesized from compound N2 (100 mg, 1 eq.) And cyclopropylsulfonamide (72 mg, 4 eq.) In 27% yield, following the procedure described for compound G2.

1H NMR (CDCl3, 400 MHz): δ 0.88-0.94 (m, 1H), 1.07-1.15 (m, 2H), 1.21-1.29 (m, 2H), 1 , 33-1.41 (m, 2H), 1.44-1.51 (m, 1H), 1.53-1.72 (m, 2H), 1.87-1.95 (m, 2H) , 2.15-2.20 (m, 1H), 2.38-2.46 (m, 1H), 2.56-2.62 (m, 1H), 2.69 (s, 3H), 2 , 82-3.03 (m, 2H), 2.97 (s, 3H), 3.74-3.81 (m, 1H), 3.95-4.02 (m, 4H), 4.58 -4.64 (m, 1H), 4.88-4.95 (m, 2H), 5.10-5.13 (m, 1H), 5.44-5.52 (m, 1H), 5 , 59-5.67 (m, 1H), 7.20-7.24 (m, 1H), 7.49-7.54 (m, 1H), 7.98-8.02 (m, 1H) , 8.55-8.59 (m, 1H), 11.16 (broad s, 1H); 19F NMR (CDCl3, 376 MHz): δ -60.88 (s, 3F); MS (ESI, EI +): m / z = 777 (MH +).

Stage N: Synthesis of (Z) - (4R, 6S, 15S, 17S) - [17- [7-methoxy-8-methyl-2- (2-trifluoromethylthiazol-4-yl) quinolin-4-yloxy] -13 -Nmethyl-2,14-dioxo-1,3,13-triazatricyclo- [13.3.0.0] octadec-7-en-4-yl] carbonyl- (1-methylcyclopropyl) sulfonamide O4. Compound O4 (white solid) was synthesized from compound N2 (80 mg, 1 eq.) And (1-methylcyclopro pil) -sulfonamide (64 mg, 4 eq.) In 24% yield, following the procedure described for the compound G2.

1H NMR (CDCl3, 400 MHz): δ 0.79-0.84 (m, 1H), 0.86-0.90 (m, 1H), 1.20-1.43 (m, 4H), 1.52 (s, 3H), 1 , 65-1.73 (m, 2H), 1.78-1.83 (m, 1H), 1.90-1.93 (m, 2H), 2.17-2.22 (m, 1H) , 2.40-2.48 (m, 1H), 2.57-2.62 (m, 1H), 2.70 (s, 3H), 2.84-2.94 (m, 1H), 2 , 95-3.02 (m, 1H), 3.05 (s, 3H), 3.77-3.81 (m, 1H), 3.99 (s, 3H), 3.98-4.01 (m, 1H), 4.58-4.66 (m, 1H), 4.91 (t, J = 10.82 Hz, 1H), 4.96 (dd, J = 8.86 and 5.44 Hz, 1H), 5.07 (s, 1H), 5.47-5.54 (m, 1H), 5.63 (td, J = 10.67 and 5.85 Hz, 1H), 7.23 (d, J = 9.24 Hz, 1H), 7.53 (s, 1H), 8.01 (d, J = 9.24 Hz, 1H), 8.59 (s, 1H), 11.16 (wide s, 1H); 19F NMR (CDCl3, 376 MHz): δ -60.88 (s, 3F); MS (ESI, EI +): m / z = 791 (MH +).

Example 25

Preparation of macrocyclic compounds T1 and T2

The synthesis of macrocyclic compounds T1 and T2 is as shown in scheme 32.

Stage A: Synthesis of 2- (4-bromothiazol-2-yl) -8-chloro-7-methoxy-quinolin-4-ol P. Compound P (yellow solid) was synthesized from compound A1 (2 g, 1 eq.) In 92% yield, following the procedure described for compound AE (80 ° C overnight).

1H NMR (CDCl3, 400 MHz) δ 4.06 (s, 3H), 6.73 (s, 1H), 7.07 (d, J = 9.10 Hz, 1H), 7.46 (s, 1H ), 8.27 (d, J = 9.10 Hz, 1H), 9.74 (wide s, 1H); MS (ESI, EI +): mlz = 372.90 (MH +).

Stage B: Synthesis of 8-chloro-2- (4-cyanothiazol-2-yl) -7-methoxy-quinolin-4-ol Q. Compound P (286 mg, 1 eq.) In degassed dimethylacetamide (10 ml) , and Zn (4.5 mg, 0.09 eq.), Zn (CN) 2 (84 mg, 0.6 eq.), Pd2dba3 (21 mg, 0.03 eq.), and dppf (26 mg, 0.06 eq.) Were heated at 110 ° C with microwave for 30 min. Then, water was added, the precipitate was filtered and dissolved in ethyl acetate, dried and concentrated in vacuo. The residue was purified by silica gel chromatography to give compound Q as a yellow solid in 81% yield.

1H NMR (CDCl3, 400 MHz) δ 4.07 (s, 3H), 6.79 (wide s, 1H), 7.08 (d, J = 9.11 Hz, 1H), 8.19 (s, 1H), 8.28 (d, J = 9.11 Hz, 1H), 9.74 (wide s, 1H); MS (ESI, EI +): m / z = 318.15 (MH +).

5 Stage C: Synthesis of (Z) - methyl ester - (4R, 6S, 15S, 17S) -17 [8-chloro-7-methoxy-2- (4-cyanothiazol-2-yl) quinolin-4-yloxy] -13 -N-methyl-2,14-dioxo-1,3,13-triazatricyclo- [13.3.0.0] octadec-7-eno-4-carboxylic R. Compound R, a mixture of diastereoisomers (beige solid), was synthesized from compound Q (250 mg, 1 eq.) and compound D (299 mg, 1 eq.), following the procedure described for compound 54c.

MS (ESI, EI +): mlz = 665 (MH +).

10 Scheme 32

Stage D: Synthesis of (Z) - (4R, 6S, 15S, 17S) -17 [8-chloro-7-methoxy-2- (4-cyanothiazol-2-yl) quinolin-4-yloxy] -13- N-methyl2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic S. Compound S (white solid) was synthesized from the crude compound R following the procedure described for compound 55c.

fifteen 1H NMR (CDCl3, 400 MHz) δ 0.83-1.60 (m, 8H), 2.21-2.27 (m, 1H), 2.29-2.36 (m, 1H), 2, 58-2.64 (m, 1H), 2.80-2.88 (m, 1H), 3.02-3.10 (m, 1H), 3.06 (s, 3H), 3.87- 3.91 (m, 1H), 4.02-4.09 (m, 1H), 4.09 (s, 3H), 4.56-4.64 (m, 1H), 4.92 (t, J = 10.80 Hz, 1H), 5.02 (dd, J = 8.95 and 4.79 Hz, 1H), 5.17 (s, 1H), 5.46-5.52 (m, 1H ), 5.66 (td, J = 10.81 and 4.38 Hz, 1H), 7.33 (d, J = 9.26 Hz, 1H), 7.53 (s, 1H), 8.09 (d, J = 9.26 Hz, 1H), 8.14 (s, 1H); MS (ESI, EI +): m / z = 651.29 (MH +).

Stage E: Synthesis of (Z) - (4R, 6S, 15S, 17S) - [17- [8-chloro-7-methoxy-2- (2-cyanothiazol-4-yl) quinolin-4-yloxy] -13 -N-methyl-2.14 dioxo-1,3,13-triazatricyclo- [13.3.0.0] octadec-7-en-4-yl] carbonyl- (cyclopropyl) sulfonamide T1. Compound T1 (yellow solid) was synthesized from compound S (80 mg, 1 eq.) In 17% yield, following the procedure described for compound G2.

5 1H NMR (Acetone-d6, 400 MHz) δ 0.83-1.74 (m, 16H), 2.59-2.66 (m, 2H), 3.13 (s, 3H), 3.13- 3.24 (m, 2H), 3.84-3.94 (m, 1H), 4.15 (s, 3H), 4.20-4.30 (m, 1H), 4.61-4, 69 (m, 1H), 5.03-5.09 (m, 1H), 5.51-5.62 (m, 1H), 5.73-5.83 (m, 1H), 7.65 ( d, J = 9.35 Hz, 1H), 7.74 (s, 1H), 8.27 (d, J = 9.35 Hz, 1H), 8.80 (s, 1H); MS (ESI, EI +): mlz = 754.39 (MH +).

Stage F: Synthesis of (Z) - (4R, 6S, 15S, 17S) - [17- [8-chloro-7-methoxy-2- (2-cyanothiazol-4-yl) quinolin-4-yloxy] -13 -N-methyl-2,14 dioxo-1,3,13-triazatricyclo- [13.3.0.0] octadec-7-en-4-yl] carbonyl- (1-methylcyclopropyl) sulfonamide T2. The compound T2

10 (white solid) was synthesized from compound S (40 mg, 1 eq.) in 11% yield, following the procedure described for compound G2.

1H NMR (CDCl3, 400 MHz) δ 0.81-1.96 (m, 9H), 2.17-2.24 (m, 3H), 2.41-2.48 (m, 2H), 2, 57-2.63 (m, 2H), 2.85-2.90 (m, 1H), 3.01-3.09 (m, 2H), 3.06 (s, 3H), 3.85- 3.89 (m, 1H), 4-4.04 (m, 1H), 4.09 (s, 3H), 4.57-4.65 (m, 1H), 4.90-4.95 ( m, 1H), 4.98-5.02 (m, 1H), 5.03 (s, 1H), 5.46-5.53 (m, 1H), 5.61-5.68 (m, 1H), 7.33 (d, J = 9.27 Hz, 1H), 7.55 (s, 1H),

fifteen 8.10 (d, J = 9.27 Hz, 1H), 8.14 (s, 1H), 11.05 (wide s, 1H); MS (ESI, EI +): m / z = 768.06 (MH +).

Example 26

Preparation of macrocyclic compounds AC1, AC2 and AC3

The synthesis of the macrocyclic compounds AC1, AC2 and AC3 is shown in scheme 33.

twenty Stage A: Synthesis of 2-bromo-1-cyclopropyletanone U1. To a stirred and chilled solution of cyclopropylmethyl ketone ice (21 g, 1 eq.) With methanol (150 ml) bromine (12.9 ml, 1 eq.) Was added dropwise. The reaction was allowed to advance (discoloration) below 10 ° C. Stirring was continued at room temperature for 1 h before adding water (75 ml). After an additional 15 min, the mixture was diluted with water (225 ml) and extracted with ethyl ether (2 times). The ether layers were washed with 10% Na2CO3 solution and brine. Organic layers

25 dried, evaporated in vacuo to give a crude orange oil, purified by distillation to give compound U1 as a colorless oil with 52% yield.

1H NMR (CDCl3, 400 MHz): δ 0.98-1.02 (m, 2H), 1.09-1.13 (m, 2H), 2.15-2.22 (m, 1H), 4 (s, 2H).

Stage B: Synthesis of 4-cyclopropylthiazol-2-carboxylic acid ethyl ester V1. Compound V1 (brown oil) was synthesized from compound U1 (10 g, 1.25 eq.) In 73% yield, following the procedure described for

30 compound 36.

1H NMR (DMSO-d6, 400 MHz): δ 0.80-0.84 (m, 2H), 0.92-0.97 (m, 2H), 1.30 (t, J = 7.10 Hz , 3H), 2.13-2.20 (m, 1H), 4.34 (q, J = 7.10 Hz, 2H), 7.70 (s, 1H); MS (ESI, EI +): m / z = 198 (MH +).

Scheme 33

Stage C: Synthesis of lithium 4-cyclopropylthiazol-2-carboxylate W1. Compound W1 (brown solid) was synthesized from compound V1 (6 g, 1 eq.) In 91% yield, following the procedure described for compound 37.

1H NMR (DMSO-d6, 400 MHz): δ 0.780-0.80 (m, 2H), 0.81-0.84 (m, 2H), 1.95-2.01 (m, 1H), 7 , 11 (s, 1H).

Stage D: Synthesis of 4-cyclopropylthiazol-2-carbonyl chloride X1. Compound X1 (brown solid) was synthesized from compound W1 (3 g, 1 eq.) In quantitative yield, following the procedure described for compound 38.

MS (ESI, EI +): m / z = 170 (MH +).

Stage E: Synthesis of N- (6-acetyl-2-chloro-3-methoxyphenyl) -4-cyclopropylthiazol-2-carboxamide Y1. To a solution of compound X1 (3.4 g, 1.2 eq.) With dioxane (60 ml) was added 6-acetyl-2-chloro-3-methoxy-aniline (3.01 g, 1 eq.) With dioxane The mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give compound Y1 as a brown solid in 66% yield.

1H NMR (CDCl3, 400 MHz): δ 1-1.06 (m, 4H), 2.08-2.15 (m, 1H), 2.58 (s, 3H), 3.99 (s, 3H ), 6.87 (d, J = 8.78 Hz, 1H), 7.16 (s, 1H), 7.67 (d, J = 8.78 Hz, 1H), 10.27 (wide s, 1 HOUR); MS (ESI, EI +): m / z = 351 (MH +).

Stage F: Synthesis of 8-chloro-7-methoxy-2- (4-cyclopropylthiazol-2-yl) quinolin-4-ol Z1. Compound Z1 (orange solid) was synthesized from compound Y1 (3.50 g, 1 eq) in 84% yield, following the procedure described for compound AE (80 ° C overnight).

1H NMR (CDCl3, 400 MHz): δ 1.04-1.07 (m, 4H), 2.13-2.18 (m, 1H), 4.06 (s, 3H), 6.75 (s , 1H), 7.06 (d, J = 9.10 Hz, 1H), 7.09 (s, 1H), 8.27 (d, J = 9.10 Hz, 1H), 9.92 (s width, 1H); MS (ESI, EI +): m / z = 333.13 (MH +).

Stage G: Synthesis of ethyl ester of (Z) - (4R, 6S, 15S, 17S) -17 [8-chloro-7-methoxy-2- (4-cyclopropylthiazol-2-yl) quinolin-4-yloxy] -13 -N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic AA1. Compound AA1, a mixture of diastereoisomers (cream-colored solid), was synthesized from compound 53 (342 mg, 1 eq.), Compound Z1 (300 mg, 1 eq.) And supported triphenylphosphine (1.08 g, 2 , 2 eq.) In 95% yield, following the procedure described for compound 54c.

MS (ESI, EI +): m / z = 694 (MH +).

Step H: Synthesis of (Z) - (4R, 6S, 15S, 17S) -17 [8-chloro-7-methoxy-2- (4-cyclopropylthiazol-2-yl) quinolin-4-yloxy] -13- Nmethyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic AB1. Compound AB1 (white solid) was synthesized from compound AA1 (599 mg, 1 eq.) In 15% yield, following the procedure described for compound 55c. In this case, the diastereoisomer was purified by chromatography (DCM / MeOH).

MS (ESI, EI +): m / z = 666 (MH +).

Stage I: Synthesis of (Z) - (4R, 6S, 15S, 17S) - [17- [8-chloro-7-methoxy-2- (4-cyclopropylthiazol-2-yl) quinolin-4-yloxy] -13 -N-methyl2,14-dioxo-1,3,13-triazatricyclo- [13.3.0.0] octadec-7-en-4-yl] carbonyl- (cyclopropyl) sulfonamide AC1. Compound AC1 (yellow solid) was synthesized from compound AB1 (88 mg, 1 eq.) And cyclopropylsulfonamide (64 mg, 4 eq.) In 51% yield, following the procedure described for compound G2 (HPLC purification ).

1H NMR (CDCl3, 400 MHz): δ 0.93-0.97 (m, 2H), 1-1.04 (m, 2H), 1.08-1.17 (m, 2H), 1.37-1.41 (m, 2H) , 1.46-1.53 ​​(m, 1H), 1.55-1.69 (m, 4H), 1.87-1.96 (m, 2H), 2.14-2.59 (m, 2H), 2.38-2.45 (m, 1H), 2.58-2.63 (m, 1H), 2.90-3.01 (m, 2H), 3.04 (s, 3H) , 3.78 (dd, J = 8.26 and 7.03 Hz, 1H), 4.01-4.05 (m, 2H), 4.07 (s, 3H), 4.61 (td, J = 13.74 and 2.79 Hz, 1H), 4.88-4.95 (m, 2H), 5.14 (s, 1H), 5.45-5.51 (m, 1H), 5, 64 (td, J = 10.78 and 5.78 Hz, 1H), 7 (s, 1H), 7.25 (d, J = 9.30 Hz, 1H), 7.53 (s, 1H), 8.04 (d, J = 9.30 Hz, 1H), 11.22 (broad s, 1H); MS (ESI, EI +): m / z = 769 (MH +).

Stage J: Synthesis of 2-bromo-1-cyclobutyl ethyltanone U2. Compound U2 (yellow oil) was synthesized from cyclobutylmethyl ketone (22 g, 1 eq.) And bromine (11.5 ml, 1 eq.) In 60% yield, following the procedure described for compound U1.

1H NMR (CDCl3, 400 MHz): δ 1.75-1.84 (m, 1H), 1.89-2 (m, 1H), 2.10-2.27 (m, 4H), 3.49 -3.57 (m, 1H), 3.82 (s, 2H).

Stage K: Synthesis of ethyl ester of 4-cyclobutyltiazol-2-carboxylic acid V2. Compound V2 (yellow oil) was synthesized from compound U2 (23.87 g, 1 eq.) And ethyl thiooxamate (21.41 g, 1 eq.) In 64% yield, following the procedure described for compound 36.

1H NMR (DMSO-d6, 400 MHz): δ 1.32 (t, J = 7.12 Hz, 3H), 1.82-1.89 (m, 1H), 1.92-2.02 (m , 1H), 2.15-2.33 (m, 4H), 3.65-3.74 (m, 1H), 4.36 (q, J = 7.12 Hz, 2H), 7.76 ( d, J = 0.64 Hz, 1H); MS (ESI, EI +): m / z = 212 (MH +).

Stage L: Synthesis of lithium 4-cyclobutylthiazol-2-carboxylate W2. Compound W2 (beige solid) was synthesized from compound V2 (17.5 g, 1 eq.) In 97% yield, following the procedure described for compound 37.

1H NMR (DMSO-d6, 400 MHz): δ 1.73-1.85 (m, 1H), 1.88-2 (m, 1H), 2.18-2.24 (m, 4H), 3 , 50-3.61 (m, 1H), 7.14 (s, 1H); MS (ESI, EI +): m / z = 184 (MH +).

Stage M: Synthesis of 4-cyclobutylthiazol-2-carbonyl chloride X2. Compound X2 was synthesized from compound W2 (5 g, 1 eq.), Following the procedure described for compound 38.

MS (ESI, EI +): m / z = 198 (MH +).

Stage N: Synthesis of N- (6-acetyl-2-chloro-3-methoxyphenyl) -4-cyclobutylthiazol-2-carboxamide Y2. Compound Y2 (white solid) was synthesized from compound X2 (5.48 g, 1.2 eq.) In 70% yield, following the procedure described for compound Y1.

1H NMR (CDCl3, 400 MHz): δ 1.96-2.12 (m, 2H), 2.34-2.44 (m, 4H), 2.59 (s, 3H), 3.70-3 , 78 (m, 1H), 3.99 (s, 3H), 6.88 (d, J = 8.82 Hz, 1H), 7.20 (s, 1H), 7.68 (d, J = 8.76 Hz, 1H), 10.33 (broad s, 1H); MS (ESI, EI +): mlz = 365 (MH +).

Stage O: Synthesis of 8-chloro-7-methoxy-2- (4-cyclobutylthiazol-2-yl) quinolin-4-ol Z2. Compound Z2 (beige solid) was synthesized from compound Y2 (5.68 g, 1 eq.) In 84% yield, following the procedure described for compound AE (80 ° C overnight).

1H NMR (DMSO-d6, 400 MHz): δ 1.87-1.95 (m, 1H), 1.96-2.07 (m, 1H), 2.23-2.35 (m, 4H) , 3.67-3.76 (m, 1H), 4.02 (s, 3H), 7.51 (s, 1H), 7.53 (d, J = 9.30 Hz, 1H), 7, 63 (s, 1H), 8.11 (d, J = 9.30 Hz, 1H), 11.89 (wide s, 1H); MS (ESI, EI +): mlz = 347 (MH +).

Step P: Synthesis of (Z) - (4R, 6S, 15S, 17S) ethyl ester -17 [8-chloro-7-methoxy-2- (4-cyclobutyltiazol-2-yl) quinolin4-yloxy] -13 -N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic AA2. Compound AA2, a mixture of diastereoisomers, was synthesized from compound Z (365 mg, 1 eq.) And compound 53 (400 mg, 1 eq.) In 34% yield, following the procedure described for compound 54c.

MS (ESI, EI +): mlz = 708 (MH +).

Stage Q: Synthesis of (Z) - (4R, 6S, 15S, 17S) -17 [8-chloro-7-methoxy-2- (4-cyclobutylthiazol-2-yl) quinolin-4-yloxy] -13- Nmethyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic AB2. Compound AB2 (off-white solid) was synthesized from compound AA2 in 35% yield, following the procedure described for compound 55c.

1H NMR (CDCl3, 400 MHz): δ 1.22-1.33 (m, 2H), 1.38-1.42 (m, 2H), 1.52-1.63 (m, 2H), 1.81-1.84 (m, 1H), 1.88-2 (m, 2H), 2.03-2.14 (m, 1H), 2.22-2.36 (m, 4H), 2.40-2.48 (m, 2H), 2.59-2.64 (m, 1H), 2.80-2.88 (m, 1H), 2.97-3.04 (m, 1H), 3.04 (s, 3H) , 3.72-3.83 (m, 2H), 4.03-4.07 (m, 1H), 4.07 (s, 3H), 4.61 (td, J = 13.46 and 2, 20 Hz, 1H), 4.91 (t, J = 10.65 Hz, 1H), 4.98 (dd, J = 8.96 and 4.96 Hz, 1H), 5.19 (s, 1H) , 5.49-5.55 (m, 1H), 5.65 (td, J = 10.65 and 4.55 Hz, 1H), 7.14 (s, 1H), 7.26 (d, J = 9.25 Hz, 1H), 7.58 (s, 1H), 8.05 (d, J = 9.25 Hz, 1H); MS (ESI, EI +): m / z = 680.23 (MH +).

Stage R: Synthesis of (Z) - (4R, 6S, 15S, 17S) - [17- [8-chloro-7-methoxy-2- (4-cyclobutylthiazol-2-yl) quinolin-4-yloxy] -13 -N-methyl2,14-dioxo-1,3,13-triazatricyclo- [13.3.0.0] octadec-7-en-4-yl] carbonyl- (cyclopropyl) sulfonamide AC2. Compound AC2 (off-white solid) was synthesized from compound AB2 (120 mg, 1 eq.) In 24% yield, following the procedure described for compound G2.

1H NMR (CDCl3, 400 MHz): δ 0.86-0.90 (m, 2H), 0.91-0.97 (m, 1H), 1.06-1.19 (m, 2H), 1.22-1.43 (m, 3H), 1.46-1.69 (m, 3H), 1.88-2 (m, 2H), 2.03-2.15 (m, 1H), 2.19-2.25 (m, 1H), 2.29-2.35 (m, 2H), 2.41-2.46 (m, 3H), 2.58-2.64 (m, 1 H), 2.80-2.90 (m, 1H), 2.91-3.02 (m, 1H), 3.05 (s, 3H), 3.74-3.82 (m, 2H), 4.02-4.07 (m , 1 H), 4.07 (s, 3H), 4.58-4.65 (m, 1H), 4.91 (t, J = 10.79 Hz, 1H), 4.94 (dd, J = 8.95 and 5.40 Hz, 1H), 5.08 (s, 1H), 5.48-5.55 (m, 1H), 5.64 (td, J = 10.74 and 5.66 Hz, 1H), 7.14 (s, 1H), 7.26 (d, J = 9.24 Hz, 1H), 7.59 (s, 1H), 8.05 (d, J = 9.24 Hz, 1H), 11.19 (wide s, 1H); MS (ESI, EI +): m / z = 783.24 (MH +).

Step S: Synthesis of (Z) - (4R, 6S, 15S, 17S) - [17- [8-chloro-7-methoxy-2- (4-cyclobutylthiazol-2-yl) quinolin-4-yloxy] -13 -N-methyl2,14-dioxo-1,3,13-triazatricyclo- [13.3.0.0] octadec-7-en-4-yl] carbonyl- (1-methylcyclopropyl) sulfonamide AC3. Compound AC3 (off-white solid) was synthesized from compound AB2 (95 mg, 1 eq.) In 27% yield, following the procedure described for compound G2.

1H NMR (CDCl3, 400 MHz): δ 0.79-0.84 (m, 2H), 0.86-0.90 (m, 1H), 1.22-1.41 (m, 3H), 1.52 (s, 3H), 1 , 49-1.75 (m, 3H), 1.80-1.83 (m, 1H), 1.89-2.01 (m, 2H), 2.05-2.15 (m, 1H) , 2.17-2.24 (m, 1H), 2.29-2.34 (m, 2H), 2.39-2.48 (m, 3H), 2.58-2.63 (m, 1H), 2.82-2.92 (m, 1H), 2.95-3.04 (m, 1H), 3.05 (s, 3H), 3.73-3.82 (m, 2H) , 4.03-4.06 (m, 1H), 4.07 (s, 3H), 4.61 (td, J = 13.71 and 2.41 Hz, 1H), 4.91 (t, J = 10.72 Hz, 1H), 4.96 (dd, J = 8.85 and 5.24 Hz, 1H), 5.14 (s, 1H), 5.47-5.54 (m, 1H) , 5.64 (td, J = 10.80 and 5.79 Hz, 1H), 7.14 (s, 1H), 7.25 (d, J = 9.25 Hz, 1H), 7.59 (s, 1H), 8.05 (d, J = 9.25 Hz, 1H), 11.16 (broad s, 1H); MS (ESI, EI +): m / z = 797.48 (MH +).

Example 27

Preparation of the macrocyclic compound AH The synthesis of the macrocyclic compound AH is shown in scheme 34.

Stage A: Synthesis of N- (6-acetyl-2-chloro-3-methoxyphenyl) -4-vinylthiazol-2-carboxamide AD. A solution of compound A1 (2.10 g, 1 eq.) And tributyl vinyl tin (2.06 g, 1.2 eq.) In toluene (55 ml) was degassed by bubbling

5 nitrogen for 15 min. Then, triphenylphosphine (250 mg, 4%) was added under a nitrogen atmosphere and the reaction mixture was heated at 100 ° C overnight. After cooling, the solvent was concentrated under reduced pressure and the residue was triturated with diethyl ether to give compound G as a beige powder in 88% yield.

1H NMR (CDCl3, 400 MHz): δ 2.60 (s, 3H), 4 (s, 3H), 5.5 (dd, J = 10.85 and 1.24 Hz, 1H), 6.24 ( dd, J = 17.26 and 1.24 Hz, 1H), 6.79 (dd, J = 17.34 and 10.78 Hz, 1H), 6.90 (d, J = 8.74 Hz, 1H ), 7.40 (s, 1H), 7.71 (d, J = 8.74 Hz, 1H), 10.45 (s

10 wide, 1H).

Stage B: Synthesis of 8-chloro-7-methoxy-2- (4-vinylthiazol-2-yl) quinolin-4-ol AE. Potassium tert-butoxide (2.13 g, 2.2 eq.) Was added to a suspension of compound AD (2.91 g, 1 eq.) With tert-butanol (30 ml). The reaction mixture was heated at 100 ° C for 5 h. After overnight at room temperature, the mixture was diluted with diethyl ether and the precipitate was filtered, washed with diethyl ether and solubilized with water. The pH was adjusted to 6-7 by the addition of 1 N HCl

fifteen and the precipitate was filtered, washed with water and triturated with diethyl ether to give compound AE in 73% yield.

1H NMR (CDCl3, 400 MHz): δ 4.06 (s, 3H), 5.54 (d, J = 10.82 Hz, 1H), 6.25 (d, J = 17.31 Hz, 1H) , 6.74 (s, 1H), 6.79 (dd, J = 17.31 and 10.82 Hz, 1H), 7.06 (d, J = 9.10 Hz, 1H), 7.32 ( s, 1H), 8.28 (d, J = 9.10 Hz, 1H), 9.97 (wide s, 1H).

Scheme 34 5 (2 g, 1 eq.) In 43% yield, following the procedure described for compound 54c.

MS (ESI, EI +): m / z = 666.37 (MH +).

Stage D: Synthesis of (Z) - (4R, 6S, 15S, 17S) -17 [8-chloro-7-methoxy-2- (4-vinylthiazol-2-yl) quinolin-4-yloxy] -13- N-methyl2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic AG. Compound AG was synthesized from compound AF (1.62 g, 1 eq.) In 45% yield, following the procedure described for compound 55c.

10 1H NMR (CDCl3, 400 MHz): δ 1.24-1.32 (m, 2H), 1.40-1.44 (m, 2H), 1.51-1.58 (m, 2H), 1.80 (dd, J = 8, 16 and 6.33 Hz, 1H), 1.83-1.91 (m, 1H), 2.2-2.32 (m, 2H), 2.58-2.63 (m, 1H), 2 , 95-3.01 (m, 1H), 3.03 (s, 3H), 3.81 (dd, J = 8.53 and 6.88 Hz, 1H), 4.02-4.06 (m , 1H), 4.07 (s, 3H), 4.59 (td, J = 13.50 and 2.70 Hz, 1H), 4.89-4.96 (m, 2H), 5.33 ( s, 1H), 5.44 (dd, J = 10.82 and 1.44 Hz, 1H), 5.45-5.51 (m, 1H), 5.63 (td, J = 10.82 and 4.72 Hz, 1H), 6.16 (dd, J = 17.34 and 1.31 Hz, 1H), 6.81 (dd, J = 17.34 and 10.90 Hz, 1H), 7, 26 (d, J = 9.29 Hz, 1H), 7.33 (s, 1H), 7.61 (s, 1H), 8.04 (d, J = 9.29 Hz, 1H); MS

fifteen (ESI, EI +): m / z = 652.14 (MH +).

Stage E: Synthesis of (Z) - (4R, 6S, 15S, 17S) - [17- [8-chloro-7-methoxy-2- (4-vinylthiazol-2-yl) quinolin-4-yloxy] -13 -N-methyl-2,14-dioxo-1,3,13-triazatricyclo- [13.3.0.0] octadec-7-en-4-yl] carbonyl (1-methyl-cyclopropyl) sulfonamide AH. Compound AH (white powder) was synthesized from compound AG (160 mg, 1 eq.) And 1-methyl-cyclopropylsulfonamide (133 mg, 4 eq.) In 13% yield, following the procedure described for compound G2 .

1H NMR (CDCl3, 400 MHz): δ 0.79-0.85 (m, 2H), 1.19-1.26 (m, 1H), 1.33-1.41 (m, 2H), 1.53-1.60 (m, 5H), 1.62-1.72 (m, 2H), 1.81-1.85 (m, 1H), 1.92-1.95 (m, 1H), 2.19-2.25 ( m, 1H), 2.40-2.47 (m, 1H), 2.58-2.63 (m, 1H), 2.82-2.93 (m, 1H), 2.96-3, 04 (m, 1H), 3.05 (s, 3H), 3.79-3.83 (m, 1H), 4.01-4.05 (m, 1H), 4.08 (s, 3H) , 4.58-4.65 (m, 1H), 4.92 (t, J = 10.77 Hz, 1H), 4.97 (dd, J = 8.93 and 5.12 Hz, 1H), 5.06 (s, 1H), 5.46 (dd, J = 10.80 and 1.21 Hz, 1H), 5.47-5.54 (m, 1H), 5.61-5.68 ( m, 1H), 6.19 (dd, J = 17.36 and 1.24 Hz, 1H), 6.83 (dd, J = 17.36 and 10.87 Hz, 1H), 7.28 (d, J = 9 Hz, 1H), 7.34 (s, 1H), 7.64 (s, 1H ), 8.06 (d, J = 9.25 Hz, 1H), 11.12 (wide s, 1H); MS (ESI, EI +): m / z = 769.26 (MH +).

Example 28

Preparation of macrocyclic compound AN

10 The synthesis of macrocyclic compound AN is shown in scheme 35.

Scheme 35

Stage A: Synthesis of 4- (4-methoxybenzyloxy) -2,8-dichloro-7-methoxyquinoline AI. Sodium hydride (2.74 g, 1.2 eq.) Was added portionwise to a solution of p-methoxybenzyl alcohol (8.55 ml, 1.2 eq.) And 15-crown-5 (13.6 ml, 1.2 eq.) With 35 ml of DMF. The mixture was allowed to stir at room temperature for 30 min, and then was added to a solution of 2,4,8-trichloro-7-methoxyquinoline (15 g, 1 eq.) With DMF (75 ml) by a cannula. After stirring for 18 h at room temperature, the mixture was poured onto 500 ml of water and aqueous NH4Cl. Ethyl acetate (200 ml) was added and the precipitate was filtered. The filtrate was purified by silica gel chromatography to give compound AI in 56% yield.

1H NMR (CDCl3, 400 MHz) δ 3.85 (s, 3H), 4.05 (s, 3H), 5.19 (s, 2H), 6.77 (s, 1H), 6.97 (d , J = 8.64 Hz, 2H), 7.23 (d, J = 9.25 Hz, 1H), 7.41 (d, J = 8.64 Hz, 2H), 8.08 (d, J = 9.25 Hz, 1H); MS (ESI, EI +): m / z = 386.1 (MNa +).

Stage B: Synthesis of 4- (4-methoxybenzyloxy) -8-chloro-7-methoxy-2- (4-methylthiazol-2-yl) quinoline AJ. To a solution of compound AI (1 g, 1 eq.) And 2- (tributilestannil) -4-methylthiazole (1.28 g, 1.2 eq.) With DMF (14 ml) were added PdCl2 (PPh3) 2 ( 193 mg, 10%) and potassium carbonate (455 mg, 1.2 eq.) And the resulting mixture was stirred at 90 overnight. The DMF was concentrated in vacuo and water and dichloromethane were added. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give compound AJ as a white solid in 65% yield.

1H NMR (CDCl3, 400 MHz) δ 2.57 (s, 3H), 3.86 (s, 3H), 4.06 (s, 3H), 5.33 (s, 2H), 6.98 (d , J = 8.64 Hz, 2H), 7.08 (s, 1H), 7.25 (d, J = 9.25 Hz, 1H), 7.46 (d, J = 8.64 Hz, 2H ), 7.74 (s, 1H), 8.12 (d, J = 9.25 Hz, 1H); MS (ESI, EI +): m / z = 427.1 (MH +).

Stage C: Synthesis of 8-chloro-7-methoxy-2- (4-methylthiazol-2-yl) quinolin-4-ol AK. Compound AJ (750 mg, 1 eq.) With trifluoroacetic acid (5 ml) was stirred at room temperature for 10 min. Then, the acid was evaporated, ethyl acetate was added and concentrated again under reduced pressure. The residue was triturated with diethyl ether to give compound AK as a white solid with quantitative yield.

1H NMR (CDCl3, 400 MHz) δ 2.59 (d, J = 0.81 Hz, 3H), 4.10 (s, 3H), 7.19 (d, J = 9.25 Hz, 1H), 7.22 (d, J = 0.81 Hz, 1H), 7.25 (s, 1H), 8.36 (d, J = 9.25 Hz, 1H), 10.51 (wide s, 1H) ; MS (ESI, EI +): m / z = 306.93 (MH +).

Stage D: Synthesis of (Z) - (4R, 6S, 15S, 17S) ethyl ester -17 [8-chloro-7-methoxy-2- (4-methylthiazol-2-yl) quinolin-4-yloxy] -13 -N-methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic AL. Compound Al, a mixture of diastereoisomers, was synthesized from compound AK (365 mg, 1 eq.) And compound 53 (450 mg, 1 eq.) In 40% yield, following the procedure described for compound 54c.

5 MS (ESI, EI +): m / z = 668.08 (MH +).

Stage E: Synthesis of (Z) - (4R, 6S, 15S, 17S) -17 [8-chloro-7-methoxy-2- (4-methylthiazol-2-yl) quinolin-4-yloxy] -13- N-methyl2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-eno-4-carboxylic AM. Compound AM was synthesized from compound AL (320 mg, 1 eq.) In 11% yield, following the procedure described for compound 55c. 1H NMR (CDCl3, 400 MHz) δ 1.20-1.55 (m, 6H), 1.75-1.79 (m, 1H), 1.84-1.91 (m, 1H), 2, 17-2.28 (m, 2H), 2.53 (s, 3

10 H), 2.56-2.63 (m, 1H), 2.76-2.84 (m, 1H), 2.97-3.05 (m, 1H), 3.02 (s, 3H) , 3.76-3.80 (m, 1H), 4.06 (s, 3H), 4.08-4.11 (m, 1H), 4.54-4.62 (m, 1H), 4 , 91-4.98 (m, 2H), 5.41-5.47 (m, 1H), 5.56-5.62 (m, 1H), 7.08 (s, 1H), 7.25 (d, J = 9.25 Hz, 1H), 7.55 (s, 1H), 8.05 (d, J = 9.25 Hz, 1H); MS (ESI, EI +): m / z = 640.06 (MH +).

Stage F: Synthesis of (Z) - (4R, 6S, 15S, 17S) - [17- [8-chloro-7-methoxy-2- (4-methylthiazol-4-yl) quinolin-4-yloxy] -13 -N-methyl-2,14 dioxo-1,3,13-triazatricyclo- [13.3.0.0] octadec-7-en-4-yl] carbonyl- (cyclopropyl) sulfonamide AN. The compound AN (solid

fifteen blank) was synthesized from compound AM (34 mg, 1 eq.) and cyclopropylsulfonamide (26 mg, 4 eq.) in 9% yield, following the procedure described for compound G2.

1H NMR (CDCl3, 400 MHz) δ 0.85-0.96 (m, 1H), 1.07-1.17 (m, 2H), 1.2-1.79 (m, 6H), 1, 87-1.95 (m, 2H), 2.17-2.24 (m, 1H), 2.36-2.44 (m, 1H), 2.53-2.57 (m, 3H), 2.57-2.62 (m, 1H), 2.81-3 (m, 3H), 3.02-3.05 (m, 3H), 3.75-3.80 (m, 1H), 4.05-4.12 (m, 4H), 4.56-4.64 (m, 1H), 4.87-4.94 (m, 2H), 5.27 (wide s, 1H), 5 , 43-5.50 (m, 1H), 5.59-5.67 (m,

twenty 1H), 7.08-7.09 (m, 1H), 7.24-7.28 (m, 1H), 7.61 (s, 1H), 8.03-8.06 (m, 1H) , 11.24 (broad s, 1H); MS (ESI, EI +): m / z = 743.12 (MH +).

Example 29

Synthesis of DArPhin catalysts

DArPhin catalysts, such as AP, AQ, AR and AT, were prepared following the methods described herein, as shown in scheme 36.

Scheme 36

Stage A: Synthesis of 5-bromo-2-isopropoxybenzaldehyde AX. To a suspension of potassium carbonate (34.4 g, 249

mmol) and cesium carbonate (16.2 g, 50 mmol) with dimethylformamide were added 5-bromosalicaldehyde (25.0 g, 124 mmol) and 2-iodopropane (25.0 ml, 249 mmol). The suspension was stirred at room temperature overnight, then at 70 ° C for 4 h. Volatile components were separated and the residue was partitioned between methyl ether and t-butyl and water. The aqueous layer was extracted with methyl ether and t-butyl and the combined organic phases were washed with water, sodium hydroxide and brine, and then dried over magnesium sulfate. Concentration to dryness gave compound AX (30.0 g) as a pale yellow oil with 99% yield.

1H NMR (CDCl3, 400 MHz) δ 1.40 (d, J = 6.3 Hz, 6H), 4.65 (Sept., J = 6.0 Hz, 1H), 6.89 (d, J = 9.0 Hz, 1H), 7.59 (dd, J = 9.0 and 2.7 Hz, 1H), 7.91 (d, J = 2.7 Hz, 1H), 10.39 (s, 1 HOUR).

Stage B: Synthesis of 4-bromo-1-isopropoxy-2-vinylbenzene AY. To a suspension of methyltriphenylphosphonium bromide (41.1 g, 115 mmol) in THF (1.2 L) cooled to -70 ° C, n-butyllithium (123 mmol, 2.5 M in hexanes) was added. The mixture was stirred for an additional 10 min, and then allowed to warm to 0 ° C and stirred at this temperature for 10 min. The reaction mixture was then cooled again to -50 ° C, and 5-bromo-2-isopropoxybenzaldehyde (20.0 g, 82.2 mmol) in solution in THF (5 ml) was added. The mixture was stirred for 10 min, then allowed to warm to room temperature. An ammonium chloride solution was added and the reaction mixture was diluted with a mixture of methyl ether and t-butyl / hexane, filtered through celite, and then dried over magnesium sulfate. The solvent was removed in vacuo to give compound AY (18.9 g) as a pale yellow oil in 95% yield.

1H NMR (CDCl3, 400 MHz): δ 1.34 (d, J = 6.0 Hz, 6H), 4.50 (Sept., J = 6.0 Hz, 1H), 5.27 (dd, J = 11.0 and 1.1 Hz, 1H), 5.71 (dd, J = 17.9 and 1.2 Hz, 1H), 6.75 (d, J = 8.7 Hz, 1H), 6 , 97 (dd, J = 17.7 and 11.2 Hz, 1H), 7.28 (dd, J = 8.7 and 2.5 Hz, 1H), 7.57 (d, J = 2.5 Hz, 1H).

Stage C: Synthesis of ethyl 4- (trifluoromethyl) phenylphosphinate AZ1. At a degassed solution of 4-iodobenzotrifluoride (4.70 g, 17.2 mmol), anilinium hypophosphite (3.51 g, 22.1 mmol), and 3-aminopropyltriethoxysilane (4.88 g, 22.1 mmol) with acetonitrile Anhydrous (110 ml) was added palladium acetate (82.5 mg, 0.367 mmol, 2 mol%) and 1,3-bis (diphenylphosphino) propane (167 mg, 0.404 mol, 2.2 mol%). The mixture was heated at reflux for 32 h, then cooled to room temperature, diluted with ethyl acetate and hydrochloric acid (1 M) and partitioned. The aqueous layer was further extracted with ethyl acetate and the combined extracts were washed with aqueous sodium hydrogen carbonate solution and brine and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography using 25 to 100% ethyl acetate in petroleum ether. Further purification gave compound AZ1 (1.14 g) in 28% yield.

1H NMR (CDCl3, 400 MHz): δ 1.35-1.43 (m, 3H), 4.12-4.27 (m, 2H), 7.63 (d, J = 570.8 Hz, 1H ), 7.75-7.80 (m, 2H), 7.90-7.94 (m, 2H).

31P NMR (CDCl3, 161.8 MHz): δ 22.6.

Stage D: Synthesis of ethyl [4- (trifluoromethyl) phenyl] - {4- (isopropoxy) -3-vinylphenyl} phosphonate BA1. To a degassed solution of ethyl 4- (trifluoromethyl) -phenylphosphinate (1.00 g, 4.20 mmol) and 4-bromo-1-isopropoxy-2-vinylbenzene (921 mg, 3.81 mmol) with DMF (40 ml) triethylamine (1.1 ml, 7.62 mmol) and tris (dibenzylidenacetone) dipaladium (698 mg, 0.762 mmol) were added. The mixture was heated at 70 overnight. Volatile components were removed in vacuo and the residue was purified by column chromatography using ethyl acetate in petroleum ether of 5 to 100% to give compound BA1 (130 mg) as a dark green oil with 8.6%. of performance.

1H NMR (CDCl3, 400 MHz): δ 1.37 (d, J = 6.0 Hz, 6H), 1.38 (t, J = 7.1 Hz, 3H), 4.07-4.17 ( m, 2H), 4.63 (Sept., J = 6.1 Hz, 1H), 5.31 (dd, J = 11.2 and 1.1 Hz, 1H), 5.79 (dd, J = 17.7 and 1.1 Hz, 1H), 6.92 (dd, J = 8.6 and 3.1 Hz, 1H), 6.99 (dd, J = 17.3 and 10.8 Hz, 1H ), 7.59-7.66 (m, 1H), 7.67-7.72 (m, 2H), 7.87-7.96 (m, 3H).

31P NMR (CDCl3, 161.8 MHz): δ 30.7.

Stage E: Synthesis of 1,3-bis (2,4,6-trimethylphenyl) -4,5-dihydroimidazol-2-ylidene [2- (i-propoxy-5- (4-trifluoromethylphenylethylphosphite)) phenyl] methylenenorutenium (II ) AP. 2nd generation Grubbs catalyst (277 mg, 0.326 mmol) and copper (I) chloride were loaded into a Schlenk tube and degassed. A degassed solution of [4- (trifluoromethyl) phenyl] - {4- (isopropoxy) -3-vinylphenyl} ethyl phosphinate (130 mg, 0.326 mmol) in anhydrous dichloromethane (17 ml) was transferred through a cannula to the solids, and the mixture was heated at 30 ° C for 70 min. The solvent was removed in vacuo and the residue was purified by column chromatography using ethyl acetate in petroleum ether of 20 to 66% to give compound AP (115 mg) as a green powder in 41% yield.

1H NMR (CDCl3, 400 MHz): δ 1.26 (d, J = 6.0 Hz, 6H), 1.39 (t, J = 7.0 Hz, 3H), 2.38 (wide s) and 2.45 (wide s) (18H), 4.07-4.16 (m, 2H), 4.19 (wide s, 4H), 4.93 (sept., J = 6.0 Hz, 1H) , 6.88 (broad dd, J = 8.5 and 2.0 Hz, 1H), 7.05 (wide s, 4H), 7.27-7.47 (m, 3H), 7.86-7 , 99 (m, 3H), 16.4 (wide s, 1H).

31P NMR (CDCl3, 161.8 MHz): δ 29.0.

Stage F: Synthesis of ethyl phenyl- {4- (isopropoxy) -3-vinylphenyl} phosphonate BA4. To a degassed mixture of ethyl phenylphosphinate (1.87 g, 11.0 mmol) and 4-bromo-1-isopropoxy-2-vinylbenzene (2.43 g, 10.0 mmol) in acetonitrile (66 ml) were added triethylamine (3.1 ml, 22.0 mmol), palladium acetate (112 mg, 0.5 mmol) and 1,1'bis (diphenylphosphino) ferrocene (277 mg, 0.5 mmol). The mixture was further degassed and heated at 68 ° C for 24 h. Volatile components were removed in vacuo, and the crude product was purified by column chromatography using 50 to 80% ethyl acetate in petroleum ether to give compound BA4 (3.74 g) in 87% yield.

1H NMR (CDCl3, 400 MHz): δ 1.36 (d, J = 5.7 Hz, 6H), 1.37 (t, J = 6.9 Hz, 3H), 4.15-4.05 ( m, 2H), 4.62 (Sept., J = 6.0 Hz, 1H), 5.28 (dd, J = 11.2 and 1.4 Hz, 1H), 5.78 (dd, J = 17.7 and 1.4 Hz, 1H), 6.91 (dd, J = 8.45 and 3.0 Hz, 1H), 6.99 (dd, J = 17.9 and 11.4 Hz, 1H ), 7.41-7.47 (m, 2H), 7.47-7.55 (m, 1H), 7.63 (ddd, J = 11.7, 8.5 and 2.0 Hz, 1H ), 7.79 (dd, J = 12.3 and 1.4 Hz, 1H), 7.81 (dt, J = 12.3 and 1.4 Hz, 1H), 7.90 (dd, J = 12.4 and 2.0 Hz, 1H).

31P NMR (CDCl3, 161.8 MHz): δ 32.61.

Stage G: Synthesis of 1,3-bis (2,4,6-trimethylphenyl) -4,5-dihydroimidazol-2-ylidene [2- (i-propoxy-5- (phenyl ethylphosphite)) phenyl] methylenenorutenium ( II) AQ. 2nd generation Grubbs catalyst (2.00 g, 2.36 mmol) and copper (I) chloride (233 mg, 2.36 mmol) were loaded into a Schlenk tube and degassed. A degassed solution of ethyl phenyl- {4- (isopropoxy) -3-vinylphenyl} phosphinate (778 mg, 2.36 mmol) in anhydrous dichloromethane (120 ml) was transferred through a cannula to the solids, and the mixture was heated at 30 ° C for 60 min. The solvent was removed in vacuo and the residue was purified by column chromatography using 40 to 100% ethyl acetate in petroleum ether to give compound AQ (775 mg) in 41% yield.

1H NMR (CDCl3, 400 MHz): δ 1.27 (d, J = 6.1 Hz, 6H), 1.37 (t, J = 7.0 Hz, 3H), 2.39 (wide s) and 2.47 (wide s) (18H), 3.98-4.17 (m, 2H), 4.18 (wide s, 4H), 4.93 (sept., J = 6.0 Hz, 1H) , 6.87 (d, J = 7.2 Hz, 1H), 7.05 (s, 4H), 7.32 (d, J = 11.9 Hz, 1H), 7.42-7.57 ( m, 3H), 7.77 (dd, J = 12.3 and 7.2 Hz, 2H), 7.94-8.08 (m, 1H), 16.43 (s, 1H).

31P NMR (CDCl3, 161.8 MHz): δ 30.79.

Stage H: Synthesis of ethyl 4-fluorophenylphosphinate AZ2. To a degassed mixture of 4-fluoro-1-iodo-benzene (25.0 g, 112.6 mmol), anilinium hypophosphite (21.5 g, 135.1 mmol) and 3-aminopropyltriethoxysilane (24.9 g, 135.1 mmol) in anhydrous acetonitrile (750 ml) were added palladium acetate (560 mg, 2.48 mmol) and 1,3-bis (diphenylphosphino) propane (1.02 g, 2.48 mmol). The mixture was refluxed overnight, then cooled to room temperature, and volatile components were removed in vacuo. The residue was diluted with ethyl acetate and hydrochloric acid (1 M) and partitioned. The aqueous layer was reextracted with ethyl acetate and the combined extracts were washed with aqueous sodium hydrogen carbonate solution and brine. Volatiles were removed in vacuo, then the residue was purified by column chromatography using 50 to 100% ethyl acetate in petroleum ether, to give compound AZ2 (10.1 g) as a dark orange oil with 48 % yield

1H NMR (CDCl3, 400 MHz): δ 1.84 (t, J = 7.1 Hz, 3H), 4.08-4.24 (m, 2H), 7.20 (td, J = 8.7 and 2.5 Hz, 2H), 7.58 (d, J = 566.6 Hz, 1H), 7.74-7.85 (m, 2H).

31P NMR (CDCl3, 161.8 MHz): δ 23.62 (J = 566.8 Hz).

Stage I: Synthesis of ethyl (4-fluorophenyl) - [4- {isopropoxy} -3-vinylphenyl] -phosphinate BA2. To a degassed mixture of 4-fluoro-phenylphosphinate (2.07 g, 11.0 mmol) and 4-bromo-1-isopropoxy-2-vinylbenzene (2.43 g, 10.0 mmol) in acetonitrile (66 ml) triethylamine (3.1 ml, 22.0 mmol), palladium acetate (112 mg, 0.5 mmol), and 1.1'bis (diphenylphosphino) ferrocene (277 mg, 0.5 mmol) were added. The mixture was heated at 68 ° C for 24 h. Volatile components were removed in vacuo, and the residue was purified by column chromatography using ethyl acetate in petroleum ether of 40 to 80% to give 2.84 g of compound BA2 in 82% yield.

1H NMR (CDCl3, 400 MHz): δ 1.36 (d, J = 6.0 Hz, 6H), 1.38 (t, J = 7.1 Hz, 3H), 4.02-4.15 ( m, 2H), 4.62 (Sept., J = 6.0 Hz, 1H), 5.29 (dd, J = 11.2 and 1.1 Hz, 1H), 5.78 (dd, J = 17.7 and 1.4 Hz, 1H), 6.91 (dd, J = 8.7 and 3.0 Hz, 1H), 6.99 (dd, J = 17.4 and 10.9 Hz, 1H ), 7.12 (td, J = 8.8 and 2.5 Hz, 2H), 7.61 (ddd, J = 11.7, 8.6 and 1.9 Hz, 1H), 7.75- 7.84 (m, 2H), 7.88 (dd, J = 12.5 and 1.9 Hz, 1H).

31P NMR (CDCl3, 161.8MHz): δ 30.71.

Step J: Synthesis of 1,3-bis (2,4,6-trimethylphenyl) -4,5-dihydroimidazol-2-ylidene [2- (i-propoxy-5 - ({4-fluorophenyl} ethylphosphite)) phenyl] methylenenorutenium (II) AR. 2nd generation Grubbs catalyst (2.00 g, 2.36 mmol) and copper (I) chloride (233 mg, 2.36 mmol) were loaded into a Schlenk tube and degassed. A degassed solution of ethyl phenyl- {4- (isopropoxy) -3-vinylphenyl} phosphinate (822 mg, 2.36 mmol) in anhydrous dichloromethane (120 ml) was transferred through a cannula to the solids and the mixture was heated to 30 ° C for 60 min. The solvent was removed in vacuo and the residue was purified by column chromatography using 30% to 60% ethyl acetate in petroleum ether to give the compound AR (552 mg) in 29% yield.

1H NMR (CDCl3, 400 MHz): δ 1.27 (d, J = 6.1 Hz, 6H), 1.37 (t, J = 7.0 Hz, 3H), 2.39 (wide s) and 2.45 (wide s) (18H), 3.98-4.15 (m, 2H), 4.19 (wide s, 4H), 4.93 (sept., J = 6.0 Hz, 1H) , 6.87 (d, J = 8.2 Hz, 1H), 7.05 (wide s, 4H), 7.15 (dt, J = 8.6 and 2.2 Hz, 2H), 7.29 (d, J = 11.9 Hz, 1H), 7.72-7.81 (m, 2H), 7.91-7.99 (m, 1H), 16.44 (s, 1H).

31P NMR (CDCl3, 161.8 MHz): δ 29.94.

Step K: Synthesis of ethyl 3,5-bis (trifluoromethyl) phenylphosphinate AZ3. To a degassed solution of 1-iodo-3,5bistrifluoromethylbenzene (10.0 g, 29.4 mmol), anilinium hypophosphite (5.62 g, 35.3 mmol) and 3-aminopropyltriethoxysilane (7.81 g, 35, 3 mmol) in anhydrous acetonitrile (200 ml) palladium acetate (132 mg, 0.588 mmol, 2 mol%) and 1,3-bis (diphenylphosphino) propane (267 mg, 0.647 mol, 2.2 mol%) were added ). The mixture was heated at reflux overnight, then cooled to room temperature, diluted with ethyl acetate and hydrochloric acid (1 M), and partitioned. The aqueous layer was further extracted with ethyl acetate and the combined extracts were washed with aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. Volatile components were removed in vacuo, and the residue was purified by column chromatography using ethyl acetate in petroleum ether of 30 to 70% to give compound AZ3 (4.65 g) as a cloudy oil with 52% of performance.

1H NMR (CDCl3, 400 MHz): δ 1.45 (t, J = 7.1 Hz, 3H), 4.18-4.35 (m, 2H), 7.69 (d, J = 579.6 Hz, 1H), 8.10 (s, 1H), 8.23 ​​(s, 1H), 8.27 (s, 1H).

31P NMR (CDCl3, 161.8 MHz): δ 19.59 (J = 580.6 Hz).

Stage L: Synthesis of [3,5-bis (trifluoromethyl) phenyl] - {4- (isopropoxy) -3-vinylphenyl} ethyl phosphonate BA3. To a degassed solution of ethyl 3,5-bis (trifluoromethyl) -phenylphosphinate (3.33 g, 15.24 mmol) and 4-bromo-1-isopropoxy-2-vinylbenzene (3.33 mg, 13.8 mmol) in DMF (25 ml) triethylamine (3.85 ml, 27.6 mmol) and tris (dibenzylidenacetone) dipaladium (2.53 g, 2.76 mmol) were added. The mixture was heated in an oil bath at 70 ° C overnight. Volatiles were removed in vacuo and the mixture was purified by column chromatography with ethyl acetate in petroleum ether from 20 to 70% to give compound BA3 (185 mg) as an oil with 2.8% yield. .

1H NMR (CDCl3, 400 MHz): δ 1.38 (dd, J = 6.1 and 1.4 Hz, 6H) that overlaps 1.41 (t, J = 7.1 Hz, 3H), 4 , 11-4.21 (m, 2H), 4.65 (Sept., J = 6.1 Hz, 1H), 5.33 (dd, J = 11.2 Hz and 1.4 Hz, 1H), 5.80 (dd, J = 17.9 and 1.2 Hz, 1H), 6.96 (dd, J = 8.6 and 3.0 Hz, 1H) that overlaps with 7.00 (dd, J = 18.0 and 11.4 Hz, 1H), 7.63 (ddd, J = 11.9, 11.9 and 2.0 Hz, 1H), 7.90 (dd, J = 12.7 and 2 , 1 Hz, 1H), 7.99 (s, 1H), 8.22 (s, 1H), 8.25 (s, 1H).

31P NMR (CDCl3, 161.8 MHz): δ 28.59.

Stage M: Synthesis of 1,3-bis (2,4,6-trimethylphenyl) -4,5-dihydroimidazol-2-ylidene [2- (i-propoxy-5- (3,5bis (trifluoromethyl) phenylethyl phosphite)) dichloride ) phenyl] methylene-ruthenium (II) AT. 2nd generation Grubbs catalyst (326 mg, 0.384 mmol), and copper (I) chloride (38 mg, 0.384 mmol) were loaded into a Schlenk tube and degassed. A degassed solution of [3,5-bis (trifluoromethyl) phenyl] - {4- (isopropoxy) -3-vinylphenyl} -phosphinate ethyl ester (179 mg, 0.384 mmol) in anhydrous dichloromethane (20 ml) was transferred by a cannula to the solids and the mixture was heated at 30 ° C for 70 min. The solvent was removed in vacuo and the residue was purified by column chromatography with ethyl acetate in petroleum ether of 20 to 80% to give compound AT (185 mg) as a green powder in 52% yield.

1H NMR (CDCl3, 400 MHz): δ 1.26 (dd, J = 6.0 and 4.0 Hz, 6H), 1.43 (t, J = 7.0 Hz, 3H), 2.41 ( s wide) and 2.44 (wide s) (18 H), 4.07-4.25 (m, 2H) that overlaps with 4.20 (wide s, 4H), 4.94 (sept., J = 6.1 Hz, 1H), 6.91 (dd, J = 8.5 and 2.4 Hz, 1H), 7.06 (wide s, 4H), 7.29 (dd, J = 11.9 and 1. 7 Hz, 1H), 8.02 (s wide, 1H), 8.03 (m, 1H), 8.20 (s, 1H), 8.23 ​​(s, 1H), 16.40 ( s, 1H).

31P NMR (CDCl3, 161.8 MHz): δ 26.33.

Example 30

Ring closure metathesis

The catalytic activity of AP, AQ, AR and AT was evaluated, together with AO and AS, as shown in scheme 37, using olefinic substrates as shown in scheme 38.

Scheme 37

Substrate Synthesis

Synthesis of compounds BH and BI Compound BI was synthesized according to scheme 39. Scheme 39

Preparation of (3R, 5S) -1-((1R, 2S) -1- (ethoxycarbonyl) -2-vinylcyclopropyl-carbamoyl) -5- (hex-5enyl (methyl) carbamoyl) pyrrolidine-3-yl 4-nitrobenzoate BI. To a solution of 4-nitrobenzoic acid (3.1 g, 1.5 eq) in CH2Cl2 (61 ml) was added dropwise 3.1 ml of oxalyl chloride (3 eq), followed by 60 μl of DMF. The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo. A solution of the resulting solid in CH2Cl2 (30 ml) was added dropwise to a solution of compound 50 (5.0 g, 1 eq) and triethylamine (3.4 ml, 2 eq) in CH2Cl2 (30 ml). The reaction mixture was stirred at room temperature for 2 h, and then washed with water and a saturated aqueous solution of sodium carbonate. The aqueous layer was extracted with CH2Cl2. The combined organic phases were dried over sodium sulfate, filtered and concentrated to dryness. Recrystallization from TBME gave the BI compound as a yellow powder, and the filtrate was subjected to flash chromatography using CH2Cl2 / MeOH as eluent, giving a total of 6.42 g of BI compound in 93% yield.

1H NMR (CDCl3, 400 MHz) δ 1.23 (m, 3H), 1.36-1.61 (m, 5H), 1.69 (m, 1H), 1.86 (td, J = 5, 1 and 7.8 Hz, 1H), 2.05-2.19 (m, 3H), 2.35-2.50 (m, 2H), 2.95 and 3.15 (2s, rotamers, 3H) , 3.21 and 3.80 (2m, rotamers, 1H), 3.38 (m, 1H), 3.61 (m, 1H), 4.09 (m, 2H), 4.21 (m, 1H ), 4.94-5.00 (m, 1H), 5.05 (broad d, J = 10.3 Hz, 2H), 5.10 (dd, J = 1.30 and 10.2 Hz, 1 H), 5.27 (d, J = 17.0 Hz, 1H), 5.68-5.84 (m, 3H), 8.20 (d, J = 8.8 Hz, 2H), 8, 31 (d, J = 8.8 Hz, 2H).

Compound BH (white powder) was synthesized using the same procedure as for compound 50.

1H NMR (CDCl3, 400 MHz) δ 1.34-1.46 (m, 2H), 1.49-1.57 (m, 3H), 1.70 (s, 2H), 1.86 (td, J = 8.0 and 5.4 Hz, 1H), 2,032.28 (m, 6H), 2.92 and 3.11 (2s, rotamers, 3H), 3.27-3.44 (m, 2H) , 3.69 (s, 3H), 3.79 (m, J = 5.1 and 4.5 Hz, 1H), 4.71 (broad s, 1H), 4.90-4.97 (m, 1H), 4.97-5.05 (m, 1H), 5.09 (dd, J = 10.3 and 1.5 Hz, 1H), 5.20 (wide s, 1H), 5.27 ( dd, J = 17.1 and 1.0 Hz, 1H), 5.67-5.85 (m, 2H).

Synthesis of compounds BK and BM

Compounds BK and BM were prepared according to scheme 40.

Scheme 40

Stage A: Preparation of (1R, 2S) -1 - ((2S, 4S) -2- (hex-5-enyl (methyl) carbamoyl) -4- (7-methoxy-8-methyl-2- (4 ( methyl trifluoromethyl) thiazol-2-yl) quinolin-4-yloxy) pyrrolidine-1-carboxamido) -2-vinylcyclopropanecarboxylate BK. Compound BK (yellow solid) was synthesized using the same procedure as for compound 116, starting from compounds 111 and 65b.

1H NMR (CDCl3, 400 MHz) δ 1.18-1.45 (m, 4H), 1.48-1.58 (m, 1H), 1.81-1.90 (m, 2H), 2, 05 (m, J = 7.6 Hz, 1H), 2.21 (se, J = 7.3 Hz, 1H), 2.27-2.36 (m, 1H), 2.67 (s, 3H ), 2.88 and 3.00 (2s, rotamers, 3H), 3.06-3.14 and 3.20-3.29 (2m, rotamers, 1H), 3.33-3.42 and 3, 49-3.58 (2m, rotamers, 1H), 3.71 (s, 3 H), 3.92 (td, J = 10.1 and 3.8 Hz, 1H), 3.98 and 3.99 (2s, rotamers, 3H), 4.06-4.13 (m, 1H), 4.83-5.03 (m, 3H), 5.10 (d, J = 10.5 Hz, 1H), 5.14 (dd, J = 10.3 and 1.2 Hz, 1H), 5.21 (s, 1H), 5.26-5.34 (m, 1H), 5.40-5.46 (m, 1H), 5.58-5.80 (m, 2H), 7.24-7.28 (m, 1H), 7.45 (d, J = 7.1 Hz, 1H), 7.86 (s, 1H), 8.05 (t, J = 8.1 Hz, 1H); MS (ESI, EI +) m / z = 716.2 (MH +).

Stage B: Preparation of acid (1R, 2S) -1 - ((2S, 4S) -2- (hex-5-enyl (methyl) carbamoyl) -4- (7-methoxy-8-methyl-2- (4 (trifluoromethyl) thiazol-2-yl) quinolin-4-yloxy) pyrrolidine-1-carboxamido) -2-vinylcyclopropanecarboxylic BN. Compound 5 BN (yellow solid) was synthesized in quantitative yield from compound BK (4.30 g, 1 eq.) And LiOH (290 mg, 2 eq.), Following the procedure described for compound AC.

MS (ESI, EI +) m / z = 702.4 (MH +).

Stage C: Preparation of (2S, 4S) -N2- (hex-5-enyl) -4- (7-methoxy-8-methyl-2- (4- (trifluoromethyl) thiazol-2-yl) quinolin-4- yloxy) -N2methyl-N1 - ((1R, 2S) -1- (1-methylcyclopropylsulfonylcarbamoyl) -2-vinylcyclopropyl) pyrrolidine-1,2-dicarboxamide 129. The

10 Compound 129 (white solid) was synthesized from compound BN (4.22 g, 1 eq.) and methylcyclopropylsulfonamide (3.25 g, 4 eq.) in 31% yield, following the procedure described for compound G2.

1H NMR (CDCl3, 400 MHz) δ 0.74-0.86 (m, 2H), 1.11-1.21 (m, 2H), 1.30-1.40 (m, 3H), 1, 50 (s, 3H), 1.60-1.68 (m, 3H), 1.78 (q, J = 6.0 Hz, 1H), 1.88-1.94 (m, 1H), 2 , 00-2.08 (m, 1H), 2.22 (q, J = 8.7 Hz, 1H), 2.33 (dd, J = 14.0 and 2.1 Hz, 1H), 2, 67 (s, 3H), 2.78-2.82 (m, 1H), 2.87 and 2.97 (2s, rotamers, 3H), 3.15-3.36 (m, 1H), 3, 58-3.68 (m, 1H), 3.90

fifteen 4.01 (m, 5H), 4.82-4.91 (m, 1H), 4.92-5.01 (m, 2H), 5.11 (d, J = 10.2 Hz, 1H) , 5.25-5.35 (m, 2H), 5.46-5.51 (m, 1H), 5.54-5.76 (m, 2H), 7.25-7.30 (m, 1H), 7.46 (d, J = 7.0 Hz, 1H), 7.87 (s, 1H), 8.02 (t, J = 10.1 Hz, 1H); MS (ESI, EI +) m / z = 819.2 (MH +).

Ring closure metathesis

All reactions were carried out in 1,2-dichloroethane in concentration 0.005 M with bubbling of N2 through the

twenty reaction mixture. For the substrates represented in scheme 38, the typical reaction scale was 200250 mg. The catalyst was added in solution in 0.5 ml of DCE, in the previously heated reaction mixture. The conversion of the starting material was followed by TLC and / or HPLC. The products were isolated after flash chromatography (note: compound BJ) was stirred with carbon and filtered on celite before purification).

25 The experimental results of the catalytic activity for the different catalysts are listed in Tables 1 to 4, respectively.

Synthesis of (1aR, 6R, 7aS, 15aS, Z) -6-hydroxy-9-methyl-3,8-dioxo-1a, 2,3,5,6,7,7a, 8,9,10,11, 12,13,15a-tetradecahydro-1Hcyclopropa [m] pyrrolo [1,2-c] [1,3,6] methyl triazacyclotetradecin-1a-carboxylate D.

TABLE 1. Compound D

<dl><dt>Entry </dt><dd>Catalyst Temperature Catalyst charge Isolated performance Time (h) </dd></dl>

<dl><dt>1 </dt><dd>AO 80 ° C 2% + 1% (1.5 h) 51% 2.5 </dd></dl>

<dl><dt>2 </dt><dd>AP 80 ° C 2% + 2% (1.5 h) 44% 3.0 </dd></dl>

<dl><dt>3 </dt><dd>Aq 80 ° C 2% + 1% (1.5 h) 56% 2.5 </dd></dl>

<dl><dt>4 </dt><dd>AR 80 ° C 2% + 1% (1.5 h) 47% 2.5 </dd></dl>

<dl><dt>5 </dt><dd>ACE 80 ° C 2% + 1% (1.5 h) fifty% 2.5 </dd></dl>

<dl><dt>6 </dt><dd>AT 80 ° C 2% + 2% (1.5 h) 53% 3.0 </dd></dl>

30 Synthesis of (1aR, 6R, 7aS, 15aS, Z) -9-methyl-6- (4-nitrobenzoyloxy) -3,8-dioxo-1a, 2,3,5,6,7,7a, 8,9, 10,11,12,13,15 ethetradecahydro-1H-cyclopropa [m] pyrrolo [1,2-c] [1,3,6] methyl triazacyclotetradecin-1a-carboxylate BJ.

1H NMR (CDCl3, 400 MHz): δ 1.24 (t, J = 7.1 Hz, 3H), 1.27-1.35 (m, 1H), 1.37-1.47 (m, 1H ), 1.49-1.62 (m, 1H), 1,661.79 (m, 3H), 1.87 (wide t, J = 13.2 Hz, 1H), 2.26-2.47 (m , 2H), 2.60 (broad d, J = 13.5 Hz, 1H), 3.05 (s, 3H), 3.51 (d, J = 9.3 Hz, 1H), 3.94 ( dd, J = 9.8 and 5.3 Hz, 1H), 4.06-4.16 (m, 1H), 4.18-4.27 (m, 1H), 4.57 (td, J = 13.2 and 3.0 Hz,

35 1H), 5.00 (s, 3H), 5.00-5.05 (m, 1H), 5.48 (t, J = 10.3 Hz, 1H), 5.60-5.68 (m , 1H), 5.72 (wide s, 1H), 8.20 (d, J = 8.8 Hz, 2H), 8.31 (d, J = 8.8 Hz, 2H).

TABLE 2. Compound BJ

<dl><dt>Entry </dt><dd>Catalyst Temperature Catalyst charge Isolated performance Time (h) </dd></dl>

<dl><dt>1 </dt><dd>AO 80 ° C 2% + 2% (20 min) 65% 0.67 </dd></dl>

<dl><dt>2 </dt><dd>AP 80 ° C 2% + 2% (20 min) + 1% (40 min) 78% 1.0 </dd></dl>

<dl><dt>3 </dt><dd>AT 80 ° C 2% + 2% (20 min) 75% 0.67 </dd></dl>

Synthesis of (1aR, 6S, 7aS, 15aS, Z) -6- (7-methoxy-8-methyl-2- (4- (trifluoromethyl) thiazol-2-yl) quinolin-4-yloxy) -9-methyl- 3,8-dioxo1a, 2,3,5,6,7,7a, 8,9,10,11,12,13,15a-tetradecahydro-1H-cyclopropa [m] pyrrolo [1,2-c] [1 , 3,6] methyl triazacyclotetradecin-1acarboxylate BL.

5 1H NMR (CDCl3, 400 MHz): δ 1.29-1.44 (m, 2H), 1.50-1.62 (m, 2H), 1.66 (s, 1H), 1.68-1.78 (m, 2H), 1 , 88 (td, J = 13.5 and 2.5 Hz, 1H), 2.15-2.23 (m, 1H), 2.40 (dd, J = 9.9 and 9.5 Hz, 1H ), 2.58 (td, J = 13.7 and 3.5 Hz, 1H), 2.68 (s, 3H), 2.97 (td, J = 13.3 and 8.4 Hz, 1H) , 3.04 (s, 3H), 3.74 (s, 3H), 3.74-3.80 (m, 1H), 3.99 (s, 3H), 4.07 (t, J = 7 , 5 Hz, 1H), 4.62 (td, J = 13.4 and 2.9 Hz, 1H), 4.95 (broad t, J = 6.7 Hz, 1H), 5.07 (s, 1H), 5.41-5.53 (m, 2H), 5.65 (s, J = 5.4 Hz, 1H), 7.25 (d, J = 9.1 Hz, 1H), 7, 51 (s, 1H), 7.87 (s, 1H), 8.02 (d, J = 9.1 Hz, 1H). MS (ESI, EI +): m / z = 687.98 (MH +).

10 TABLE 3. BL compound

<dl><dt>Entry </dt><dd>Catalyst Temperature Catalyst charge Isolated performance Time (h) </dd></dl>

<dl><dt>1 </dt><dd>AO 80 ° C 2% + 2% (1 h) + 2% (2 h) 51% 3.5 </dd></dl>

<dl><dt>2 </dt><dd>AP 80 ° C 2% + 2% (1 h) + 2% (2 h) 49% 3.5 </dd></dl>

<dl><dt>3 </dt><dd>Aq 80 ° C 2% + 2% (1 h) + 2% (2 h) 49% 3.5 </dd></dl>

<dl><dt>4 </dt><dd>AR 80 ° C 2% + 2% (1 h) + 2% (2 h) 48% 3.5 </dd></dl>

<dl><dt>5 </dt><dd>ACE 80 ° C 2% + 2% (1 h) + 2% (2 h) 49% 3.5 </dd></dl>

<dl><dt>6 </dt><dd>AT 80 ° C 2% + 2% (1 h) + 2% (2 h) 49% 3.5 </dd></dl>

Synthesis of (Z) - (4R, 6S, 15S, 17S) - [17- [7-methoxy-8-methyl-2- (4-trifluoromethylthiazol-2-yl) quinolin-4-yloxy] -13-N- methyl-2,14-dioxo-1,3,13-triazatricyclo [13.3.0.0] octadec-7-en-4-yl] carbonyl (1-methylcyclopropyl) sulfonamide 68b.

TABLE 4. Compound 68b

<dl><dt>Entry </dt><dd>Catalyst Temperature Catalyst charge Isolated performance Time (h) </dd></dl>

<dl><dt>1 </dt><dd>AO 60 ° C 2% + 2% (45m) + 2% (2 h) 79% 4.0 </dd></dl>

<dl><dt>2 </dt><dd>AP 60 ° C 2% + 2% (45m) + 2% (2 h) + 2% (3 h) Four. Five% 24.0 </dd></dl>

<dl><dt>3 </dt><dd>Aq 60 ° C 2% + 2% (45m) + 2% (2 h) + 2% (3 h) 63% 24.0 </dd></dl>

<dl><dt>4 </dt><dd>AR 60 ° C 2% + 2% (45m) + 2% (2 h) + 2% (3 h) 30% 24.0 </dd></dl>

<dl><dt>5 </dt><dd>ACE 60 ° C 2% + 2% (45m) + 2% (2 h) + 2% (3 h) 60% 24.0 </dd></dl>

<dl><dt>6 </dt><dd>AT 60 ° C 2% + 2% (45m) + 2% (2 h) + 2% (3 h) 53% 24.0 </dd></dl>

Example 31

fifteen HCV protease assay

General procedure: Measurement of the inhibitory effect of the compounds on HCV protease activity was carried out with the HCV protease assay kit SensoLyte ™ 620 from AnaSpec, Inc. (San Jose, CA) under the conditions described by the supplier, using 1.2 nM HCV NS3-NS4A protease, which was obtained according to Taremi et al. (Protein Science, 1998, 7, 2143-2149). The compounds were tested in a variety of concentrations in

twenty assay buffer containing a final DMSO concentration of 5%. The reactions were allowed to proceed for 60 min at room temperature and fluorescence measurements were recorded with a Tecan Infinity spectrofluorimeter. IC50 values ​​were determined from the percent inhibition versus concentration data using a 4-parameter sigmoidal nonlinear regression analysis with Tecan Magellan software.

25 Example 32

HCV Replicon Assay

General procedure: Huh-7 cells containing HCV Con1 subgenomic replicon (GS4.1 cells) were grown in Dulbecco-modified Eagle medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 2 mM Lglutamine, sodium pyruvate 110 mg / l, 1X non-essential amino acids, penicillin-streptomycin 100 U / ml and G418 0.5 mg / ml (Invitrogen). For dose-response assays, cells were seeded in 96-well plates with 5 7.5 x 103 cells / well in a volume of 50 µl, and incubated at 37 ° C / 5% CO2. Three hours after plating, 50 µl of 10 serial dilutions of 2 times the compounds (highest concentration, 75 µM) were added, and cell cultures were incubated at 37 ° C / 5% CO2 in the presence of DMSO 0.5% Alternatively, the compounds were tested in a single concentration of 15 µM. In all cases, Huh-7 cells lacking HCV replicon served as a negative control. Cells were incubated in the presence of compounds 10 for 72 h, after which the expression of NS4A protein was monitored by linked enzyme immunosorbent assay (ELISA). For this, the plates were then fixed for 1 min with acetone / methanol (1: 1, v / v), washed twice with phosphate buffered saline (PBS), 0.1% Tween 20, blocked during 1 h at room temperature with TNE buffer containing 10% FBS and then incubated for 2 h at 37 ° C with the anti-NS4A mouse monoclonal antibody A-236 (ViroGen) diluted in the same buffer. After washing three

fifteen times with PBS, 0.1% Tween 20, the cells were incubated 1 h at 37 ° C with anti-mouse peroxidase immunoglobulin G conjugate in TNE, 10% FBS. After washing as described above, the reaction was developed with Ofhenylenediamine (Zymed). The reaction was stopped after 30 min with 2 N H2SO4, and the absorbance at 492 nm was read using the Sunrise Tecan spectrophotometer. The EC50 values ​​were determined from the% inhibition versus concentration data, using a sigmoidal nonlinear regression analysis based on 4 parameters with the

twenty Magellan Tecan software. When screening was done with a single concentration, the results were expressed as% inhibition with 15 µM.

For cytotoxicity assessment, GS4.1 cells were treated with the compounds as described above and cell viability was monitored using the Cell Titer 96 AQueous One Solution cell proliferation assay (Promega). The CC50 values ​​were determined from the% cytotoxicity versus concentration data.

25 with Tecan Magellan software as described before.

The biological results are summarized in Table 5, where A represents a value less than 1! M and B represents a value between 1! M and 10! M, C represents a value between 10! M and 75! M and D represents a value greater than 75 µM.

Table 5

<dl><dt>Compound </dt><dd>IC50 (μM) EC50 (μM) CC50 (μM) </dd></dl>

<dl><dt>56th </dt><dd>TO TO D </dd></dl>

<dl><dt>56b </dt><dd>TO TO D </dd></dl>

<dl><dt>56c </dt><dd>TO TO D </dd></dl>

<dl><dt>56d </dt><dd>TO TO D </dd></dl>

<dl><dt>56e </dt><dd>TO B D </dd></dl>

<dl><dt>56f </dt><dd>TO TO D </dd></dl>

<dl><dt>56g </dt><dd>TO TO D </dd></dl>

<dl><dt>56h </dt><dd>TO TO D </dd></dl>

<dl><dt>62b </dt><dd>TO TO D </dd></dl>

<dl><dt>62d </dt><dd>TO TO D </dd></dl>

<dl><dt>62f </dt><dd>TO TO D </dd></dl>

<dl><dt>63b </dt><dd>TO B D </dd></dl>

<dl><dt>68b </dt><dd>TO TO D </dd></dl>

<dl><dt>68d </dt><dd>TO TO D </dd></dl>

<dl><dt>69b </dt><dd>TO TO D </dd></dl>

<dl><dt>69d </dt><dd>TO TO C </dd></dl>

<dl><dt>76th </dt><dd>B B D </dd></dl>

<dl><dt>76b </dt><dd>TO B D </dd></dl>

<dl><dt>83b </dt><dd>TO TO D </dd></dl>

<dl><dt>91a </dt><dd>TO TO D </dd></dl>

<dl><dt>Compound </dt><dd>IC50 (μM) EC50 (μM) CC50 (μM) </dd></dl>

<dl><dt>91b </dt><dd>TO TO C </dd></dl>

<dl><dt>91c </dt><dd>TO TO D </dd></dl>

<dl><dt>91d </dt><dd>TO TO D </dd></dl>

<dl><dt>91e </dt><dd>TO TO D </dd></dl>

<dl><dt>91f </dt><dd>TO TO D </dd></dl>

<dl><dt>91g </dt><dd>TO TO D </dd></dl>

<dl><dt>96d </dt><dd>TO B D </dd></dl>

<dl><dt>101d </dt><dd>TO TO D </dd></dl>

<dl><dt>110d </dt><dd>TO TO D </dd></dl>

<dl><dt>G1 </dt><dd>TO TO C </dd></dl>

<dl><dt>G2 </dt><dd>TO TO C </dd></dl>

<dl><dt>G3 </dt><dd>TO TO C </dd></dl>

<dl><dt>G4 </dt><dd>TO TO C </dd></dl>

<dl><dt>O1 </dt><dd>TO TO C </dd></dl>

<dl><dt>O2 </dt><dd>TO TO C </dd></dl>

<dl><dt>O3 </dt><dd>TO TO C </dd></dl>

<dl><dt>O4 </dt><dd>TO TO D </dd></dl>

<dl><dt>T1 </dt><dd>TO TO C </dd></dl>

<dl><dt>T2 </dt><dd>TO TO D </dd></dl>

<dl><dt>AC1 </dt><dd>TO TO C </dd></dl>

<dl><dt>AC2 </dt><dd>TO TO C </dd></dl>

<dl><dt>AC3 </dt><dd>TO TO D </dd></dl>

<dl><dt>AH </dt><dd>TO TO C </dd></dl>

<dl><dt>AN </dt><dd>TO TO C </dd></dl>

Example 33 Antiviral activity in a genotype 1b replicon assay The compounds were tested in a genotype 1b replicon assay as described in example 32 and

results are summarized in table 6, where A represents a value less than 1! M and B represents a value between 1

! M and 10! M, C represents a value between 10! M and 75! M and D represents a value greater than 75! M.

Table 6

<dl><dt>Comp. No.</dt><dd>EC50 CC50 </dd></dl>

<dl><dt>56b </dt><dd>TO C </dd></dl>

<dl><dt>56d </dt><dd>TO &gt; C </dd></dl>

<dl><dt>62d </dt><dd>TO C </dd></dl>

<dl><dt>68b </dt><dd>TO C </dd></dl>

<dl><dt>69b </dt><dd>TO D </dd></dl>

<dl><dt>91e </dt><dd>TO C </dd></dl>

Example 34 Antiviral activity in an HCV genotype 2a infectious virus assay

162 The compounds were tested in an HCV genotype 2a infectious virus assay and the results are summarized in Table 7, where A represents a value less than 1 µM and B represents a value between 1 µM and 10 µM, C represents a value between 10! M and 75! M and D represents a value greater than 75! M.

Table 7

<dl><dt>Comp. No.</dt><dd>EC50 </dd></dl>

<dl><dt>56b </dt><dd>B </dd></dl>

<dl><dt>56d </dt><dd>TO </dd></dl>

<dl><dt>62d </dt><dd>TO </dd></dl>

<dl><dt>68b </dt><dd>TO </dd></dl>

<dl><dt>69b </dt><dd>TO </dd></dl>

<dl><dt>91e </dt><dd>TO </dd></dl>

5 Example 35

Resistance profile

The compounds were evaluated against 3 mutant proteases R155Q, A156S and D168A, as summarized in Table 8, where A represents a value less than 1 and B represents a value between 1 and 10, and C represents a value greater than

10. The number of times of change in inhibitory activity was determined by measuring the activity ratio.

10 inhibitor of a compound against a mutant enzyme against the inhibitory activity of the same compound against the non-mutant enzyme. The inhibitory activity was determined using the procedure described in the example

31.

Table 8

<dl><dt>Comp. No.</dt><dd>Number of times of change </dd></dl>

<dl><dt>R155Q </dt><dd>A156S D168A </dd></dl>

<dl><dt>56b </dt><dd>TO TO C </dd></dl>

<dl><dt>56d </dt><dd>TO TO C </dd></dl>

<dl><dt>62d </dt><dd>TO TO C </dd></dl>

<dl><dt>91e </dt><dd>TO TO C </dd></dl>

Example 36

fifteen Generation of recombinant JFH-1 virus strains

The recombinant JFH-1 HCV viruses used in the in vitro HCV infection assay were generated by transfection of HPC cells with JFH-1 RNA produced by in vitro transcription. The JFH-1 DNA template was synthetically obtained using sequence information obtained from NCBI accession number AB047639 (Wakita, et al., Nat. Med. 2005, 11: 791-796). Source: DNA2.0, Menlo Park, CA.

twenty The cDNA for the HCV clone JFH-1 was synthesized by DNA2.0 and contains a T7 promoter to direct transcription of the JFH-1 genomic RNA. This plasmid was amplified using the Hi-Speed ​​Plasmid Midi kit (Qiagen) according to the manufacturer's instructions.

30 µg of purified DNA was digested overnight at 37 ° C with 300 U of XbaI. The digested DNA served as a template for in vitro transcription of the JFH-1 genomic RNA using the MEGAScript T7 kit (Ambion) according to

25 manufacturer's instructions The JFH-1 RNA product was resuspended at 1 μg / μl in RNA storage solution (Ambion). The quality of JFH-1 RNA was verified by agarose gel electrophoresis (1.2% E-gel) before electroporation.

Complete growth medium for Huh-7 and HPC cells (Huh-7 medium) was prepared as follows: DMEM (containing glucose, L-glutamine and sodium pyruvate), 10% FBS, 100 IU / ml penicillin, streptomycin 100 μg / ml,

30 2 mM GlutaMAX, 1% MEM non-essential amino acids. Subconfluent HPC cells were treated with trypsin-EDTA, collected with Huh-7 medium and centrifuged at 1,500 rpm for 5 min at 4 ° C with an Allegra 6R centrifuge (Beckman Coulter) in a 50 ml conical tube. The cells were then washed twice by resuspension of the cells in 50 ml of PBS and centrifugation at 1,500 rpm for 5 min at 4 ° C.

JFH-1 RNA was electroporated into HPC cells using a Thermo Scientific Hybaid OptiBuffer kit (containing buffer A, solution B and compounds C and D). After washing, the HPC cells were resuspended in OptiBuffer A buffer with 1x107 cells / ml, and 400 µl (4x106 cells) were transferred to a 1.5 ml RNase-free microfuge tube and gently centrifuged at 2,000 rpm in a Microfuge 18 centrifuge (Beckman Coulter) at room temperature for 5 min. During this centrifugation step, the electroporation medium was prepared by mixing 2.5 ml of OptiBuffer B solution with 1 vial of OptiBuffer C compound (5.5 mg ATP), 1 vial of OptiBuffer D compound (7.7 mg glutathione ) and 2.5 ml of water treated in autoclave. After aspirating the supernatant liquid, the cell pellet was resuspended in 400 µl of electroporation medium. JFH-1 RNA (8 μg) was added to the resuspended cells, after which they were transferred to a 0.4 cm cuvette and electroporated in a Bio-Rad GenePulser XCell electroporation module with a single pulse of 960 μf , 270 V and maximum resistance. A simulated transfection, without RNA, was electroplated as a negative control. Growth medium (600 µl) was immediately added to the cuvette. The cells were then transferred to a 15 ml conical tube containing 3.4 ml of Huh-7 medium. Approximately 1.2x105 cells were seeded in each well of a 6-well Corning Costar plate and incubated at 37 ° C with 5% CO2.

When they reached confluence, the transfected HPC cells were trypsinized and divided 1: 5 into 6-well plates. On days 5 and 14 after transfection, the conditioned medium was collected from the cultures, the cell debris was separated by centrifugation at 2,000 rpm for 10 min in a tabletop centrifuge (Beckman Coulter Allegra 6R with GH3.8 rotor) and the medium was filtered through a 0.2 µm top syringe filter. Transfected cells were also fixed for immunohistochemical analysis and lysed for immunoblot analysis.

The recombinant JFH-1 HCV virus was amplified in a manner described by (Zhong, et al., Proc. Nat. Acad. Sci. USA. 2005, 102: 9294-9299). The HPC cells were divided at 10% confluence into 225 cm2 flasks and infected with 1 ml of the transfected cell culture medium (described above) at 5 h after seeding. 5 days after infection (pi), the cultures were divided 1: 2 into new 225 cm2 flasks. One half of the initial culture medium was taken to the divided cultures to facilitate virus amplification. On day 10 pi, the conditioned medium was collected from the 225 cm2 flasks, centrifuged at 2,000 rpm for 10 min in a tabletop centrifuge and filtered through a bottle unit with upper MF75 sterilization filter (0.45 ! m). 2 ml aliquots of this virus stock solution were stored at -80 ° C for future use.

Example 37

In vitro HCV infection core ELISA assay

The in vitro HCV infection core ELISA assay measures the ability of a test compound to inhibit the replication of an infectious HCV (strain JFH-1; genotype 2a) in cell culture. Recently, it was found that an in vitro infection model identified by Wakita et al. (Nat. Med. 2005, 11: 791-796) was replicated in Huh-7 hepatoma cell lines positive for differentiation clusters (CD) -81 or retinoic acid-inducible gene I (RIG-I). The inventors have developed this model to determine the efficacy of antiviral compounds against an infectious virus in vitro, using HCV-producing cells (HPC), a proprietary Huh-7 derived sublineage capable of spreading JFH-1 HCV. The test reading is the quantification of the HCV core protein by ELISA 5 days after infection with the JFH-1 virus and treatment with a test compound.

96-well Corning Costar plates were seeded with HPC cells with a density of 3.0x103 cells per well in 50 µl of Huh-7 medium. Stock solutions of the compounds were recently prepared in Huh-7 medium (DMEM (containing glucose, L-glutamine and sodium pyruvate), 10% FBS, 100 IU / ml penicillin, 100 μg / ml streptomycin, 2 mM GlutaMAX, amino acids non-essential 1% MEM) as 2X stock solutions. 7 additional dilutions of drug were prepared 3 times from the 2X stock solutions in Huh-7 medium. At least 4 h after the HPC cells were seeded, the medium in the 96-well plates was aspirated and 50 µl of each drug dilution and 50 µl of JFH-1 HCV were added to each well.

At 16 h after treatment and infection, the virus inoculum was removed by aspiration. The cultures were treated with the same final concentrations of the diluted 1X drug in Huh-7 medium to a final volume of 200 µl. The cells were incubated in the presence of drug for an additional 4 days at 37 ° C / 5% CO2.

The medium was removed from the plates by aspiration. The cells were fixed with 250 µl of acetone: methanol 1: 1 for 90 s, washed once in PBS and then 3 times with 1X KPL wash solution. The test plates were then blocked with 150 µl / well of 10% FBS -TNE (50 mM Tris-HCl (pH 7.5; Sigma), 100 mM NaCl, 1 mM EDTA with 10% FBS) for 1 It has room temperature. The cells were washed 3 times with 1X KPL wash solution and incubated with 100 µl / well of hepatitis C anti-core mAB (1 mg / mL stock solution diluted 1: 500 with 10% FBS -TNE) for 2 at 37 ° C. The cells were washed 3 times with 1X KPL wash solution and incubated with 100 µl / well of goat anti-mouse-HRP antibody (diluted 1: 2,500 with 10% FBS -TNE) for 1 h at 37 ° C.

OPD solution was prepared using 1 OPD tablet + 12 ml citrate / phosphate buffer (16 mM citric acid, 27 mM Na2HPO4) plus 5 µl of 30% H2O2 per plate. The cells were washed 3 times with 1X KPL wash solution and developed with 100 µl / well of OPD solution for 30 min in the dark at room temperature. The reaction was stopped with 100 µl / well of 2 N H2SO4, and absorbance at A490 nm was measured on a Victor3 V 1420 multilabel counter (Perkin Elmer). The EC50 values ​​for each compound were calculated from the dose-response curves from the resulting best fit equations determined by the Microsoft Excel and XLfit 4.1 software. The negative control for inhibition of virus replication was untreated HPC cells infected with the HCV strain JFH-1. The negative control of ELISA were uninfected and untreated HPC cells. The positive control of ELISA were untreated HPC cells infected with the HCV strain JFH-1.

Example 38

MTS cytotoxicity test

The cytotoxicity assay measures the viability of the cells after treatment with a test compound for 5 days. The test reading is the bioreduction of the yellow MTS tetrazolium compound to a purple formazan product. This conversion is mediated by NADPH or NADH and is directly proportional to the number of living cells in a culture.

96-well Corning Costar plates were seeded with HPC cells with a density of 3.0x103 cells per well in 50 µl of Huh-7 medium. Stock solutions of the compounds were recently prepared in Huh-7 medium

as 2X stock solutions. 7 additional dilutions of drug were prepared 3 times from the 2X stock solutions in Huh-7 medium, for a total of 8 dilutions.

At least 4 hours later, HPC cells were seeded, and 50 µl of each drug dilution was added to the cultures. At 16 h after treatment, the existing medium was removed by aspiration. The cultures were treated with the same final concentrations of the diluted 1X drug in Huh-7 medium to a final volume of 100 µl. The cells were incubated for an additional 4 days at 37 ° C / 5% CO2 in the presence of drug.

After 5 days of treatment, the CellTiter 96® Aqueous One Solution cell proliferation assay was carried out by adding 20 µl of MTS solution to each well. Then, the plates were incubated at 37 ° C / 5% CO2 for 3 h. Plates were read at A490 nm on a Victor3 V 1420 multilabel counter (Perkin Elmer) and CC50 concentrations were determined using Microsoft Excel and XLfit 4.1 software. Positive control for cell death: culture wells containing only Huh-7 medium . Negative control for cell death: culture wells containing untreated and uninfected HPC cells.

Example 39

Western blot test for in vitro HCV infection

This assay measures the ability of a test compound to inhibit replication of the HCV JFH-1 strain in cell culture. The test reading is quantification of HCV core or NS3 protein by Western blotting 5 days after infection with JFH-1 virus and drug treatment.

Negative controls: uninfected and untreated HPC cells. Positive controls: HPC cells infected with the HCV JFH-1 strain and untreated.

24-well Corning Costar plates were seeded with HPC cells with a density of 1.5x104 cells per well in 0.8 ml of Huh-7 medium (DMEM (containing glucose, L-glutamine and sodium pyruvate), 10% FBS , penicillin 100 IU / ml, streptomycin 100 μg / ml, GlutaMAX 2 mM, non-essential amino acids MEM 1%). The stock solutions of the compounds were recently prepared in Huh-7 medium as 10X stock solutions. 4 additional dilutions of drug 5 times were prepared from the 10X stock solutions in Huh-7 medium for a total of 5 dilutions.

At least 3 h later, HPC cells were seeded, 100 µl of each drug dilution and 100 µl of HCV JFH-1 were added to each well. At 16 h after treatment and infection, the virus inoculum was removed by aspiration. The cultures were treated with the same final concentrations of the diluted 1X drug in Huh-7 medium to a final volume of 1 ml. The cells were incubated in the presence of drug for an additional 4 days at 37 ° C / 5% CO2.

The medium was removed from the plates by aspiration and the cells were washed with 1 ml of PBS. After separating the PBS, 100 µl / well of SDS sample buffer (50 mM Tris-HCl, pH 7.5, 2% ultrapure SDS, 10% glycerol, 0.01% bromophenol blue were added , 0.1 M DTT). Samples were collected in RNase-free microfuge tubes, incubated at 95 ° C for 5-10 min and centrifuged at maximum speed for 2 min in an Eppendorf 5415D centrifuge.

To prepare the Western blot, 15 µl of each sample was loaded into each band of a 4-20% Tris-glycine polyacrylamide gel in an XCell II Blot Module (Invitrogen) module; 6 µl of the SeeBluePlus2 target protein reference was also loaded in a band. Each gel was developed at 125 V for 1.5 h with

Novex SDS development buffer (1X Tris / glycine / SDS) (Invitrogen). Each gel was transferred onto an iBlot nitrocellulose membrane using the iBlot (Invitrogen) apparatus according to the manufacturer's protocol. The membrane was washed with PBST (Sigma) and then blocked with 6 ml of blocking buffer (5% skim milk (w / v) in PBST solution) at room temperature for 1 h with tilting. Each transfer was incubated in 6 ml of 5-block buffer containing HCV NS3 murine mAb (1: 500; ViroGen Corp.) and murine anti-GAPDH Ab IgG (1: 1,000,000; Calbiotech) or anti-core mAb ( 1: 500; Affinity BioReagents) overnight at 4 ° C with tilting. After 3 10 min washes in PBST at room temperature with tilting, each transfer was incubated with 6 ml of blocking buffer (5% skim milk (w / v) in PBST solution) containing Donkey Ab mouse conjugated with HRP (1: 5,000) for 1 h at room temperature with tilting. Each transfer was washed

10 as described before and after it was exposed to 5 ml of substrate from the SuperSignal West Dura (Pierce) substrate kit according to the manufacturer's protocol. The transfers were then exposed using the Florochem 5,500 imager (Alpha Innotech).

Viral replication was quantified by determining the densities in the NS3 and core protein bands using ImageQuant 5.2 software. The background was subtracted (the density determined in NS3 or core region with

fifteen simulated transfected cells) of the densities of the NS3, nucleus and GAPDH bands. Each corrected value of NS3 or core was then normalized to the corresponding corrected value of GAPDH for each sample. The EC50 value, which is the concentration of a test compound that reduced the production of NS3 protein or core by 50%, was determined for each compound using Microsoft Excel and XLfit 4.1 software. Each determination of the EC50 value was carried out in duplicate.