ES2365650T3 - N-PHENYL-DIOXO-HYDROXYPYRIMIDINES USEFUL AS INHIBITORS OF THE HEPATITIS C VIRUS (HCV). - Google Patents

Abstract

A compound or salt thereof, in which: the compound corresponds in structure to formula I: it is selected from the group consisting of carbon-carbon single bond and carbon-carbon double bond; R1 is selected from the group consisting of hydrogen and methyl; R2 is selected from the group consisting of hydrogen, halo, hydroxy, methyl, cyclopropyl and cyclobutyl; R3 is selected from the group consisting of hydrogen, halo, oxo and methyl; R4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl and heterocyclyl, in which: (a) the amino , aminocarbonyl and aminosulfonyl are optionally substituted with: (1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl and alkylsulfonyl, or (2) two substituents which, together with the amino nitrogen, form a heterocyclyl single ring, and (b) alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy and alkylsulfonyl, are optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, nitro, cyano, azido, hydroxy , amino, alkyloxy, trimethylsilyl, carbocyclyl and heterocyclyl, wherein: the amino is optionally substituted with: (1) one or two substituents selected indepe Among the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, or (2) two substituents which, together with amino nitrogen, form a single ring heterocyclyl, and (c) the carbocyclyl and heterocyclyl are optionally substituted with up to three substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl and heterocyclyl, wherein: the amino is optionally substituted with: (1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclyl alkyl and heterocyclylalkyl, or (2) two substituents that, together with amino nitrogen, form a heterocyclyl of a simple nillo; R5 is selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylsulfunyloxy, carbocyclylsulfonyloxy, haloalkylsulfonyloxy and halo; L is selected from the group consisting of C (RA) = C (RB), ethylene and cyclopropyl-1,2-ene; RA and RB are independently selected from the group consisting of hydrogen, C1-C6 alkyl-alkyl, C1-C6 alkyloxy, C3-C5 cycloalkyl and halo, wherein: C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of carboxy, halo, hydroxy, nitro, oxo, amino, cyano, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl and heterocyclyl; R6 is selected from the group consisting of C5-C6 carbocyclyl and 5-6 membered heterocyclyl, in which each of said substituents is optionally substituted with one or more substituents independently selected from the group consisting of RE, RF, RG, RH, R1, RJ and RK; each RE is independently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, cyano, amino, imino, azido and aldehyde, in which: the amino is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl; each RF is independently selected from the group consisting of alkyl, alkenyl and alkynyl, in which: each of said substituents is optionally substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alquinilcarboniloxi, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein: the amino, imino, aminosulfonyl, aminocarbonyl , carbocyclyl and heterocyclyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl, alkylsulfonyl, alkylsulfonylamino, hydroxy and alkyloxy, wherein: an alkylsulfonylamino moiety is optionally substituted with a substituent selected from the group consisting of alkyl, alkenyl and alkynyl; each RG is independently selected from the group consisting of carbocyclyl and heterocyclyl, in which: each of said substituents is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, amino to aminocarbonyl, amino to aminocarbonyl substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl and alkynylsulfonyl; each RH is independently selected from the group consisting of alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, alkenylsulfunyloxy and alkynylsulfonyloxy, in which: each of said substituents is optionally substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclylcarbonyl amino, alkyloxycarbonyl, amino they are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl and alkynylsulfonyl; each RI is independently selected from the group consisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aminocarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl and heterocyclylcarbonyl, wherein: (a) the alkylcarbonyl, alkenylcarbonyl and alkynylcarbonyl are independently substituted with one or more independently substituted with one group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, heterocyclyl, carbocyclyl, bicyclyl, carbocyclyl, bicyclyl, cyclyl, carbonyl the aminocarbonyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxyalkyl, carbocyclyl, heterocyclyl, alkylsulfonyl and alkylsulfonylamino, wherein: the carbocyclyl and heterocyclyl is n optionally substituted with one or two substituents independently selected from the group consisting of halo, alkyl and oxo; each RJ is independently selected from the group consisting carbociclilsulfonilamino, heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, alquinilcarbonilamino, alkyloxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, alquinilsulfonilamino, aminocarbonylamino, alquiloxicarbonilaminoimino, alquilsulfonilaminoimino, alquenilsulfonilaminoimino and alquinilsulfonilaminoimino, wherein: (a) the amino portion of said substituents is optionally substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkenyl, alkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl that: (1) the carbocyclyl portion of the carbocyclyl alkyl and the heterocyclyl portion of the hetero Cyclylalkyl are optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido, oxo and amino, and (2) the amino portion of the aminocarbonylalkyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl, (b) the alkyl, alkenyl and alkyl portion of said substituents is optionally substituted with one or more substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl and cyano, in which: the amino is optionally substituted with one or two substituents independently selected from the group consisting of alkyl , alkenyl, alkynyl, alkyloxy, alkenyloxy and alkynyloxy, in which: the alkyl is optionally substituted with one or more hydroxy; (c) the carbocyclyl and heterocyclyl portions of said substituents are optionally substituted with one or more substituents independently selected from the g

Description

Cross reference to related patent applications

This patent application claims priority in relation to U.S. Provisional Patent Application No. 60 / 972,887 (filed September 17, 2007) and U.S. Provisional Patent Application No. 61 / 096,794 (filed September 13, 2008 ). The full text of these applications is incorporated by reference in this application.

Field of the Invention

This invention relates to: (a) compounds and salts thereof which, among others, are useful as hepatitis C virus (HCV) inhibitors; (b) intermediates useful for the preparation of said compounds and salts; (c) compositions comprising said compounds and salts; (d) methods for preparing said intermediates, compounds, salts and compositions; (e) methods of using said compounds, salts and compositions; and (f) kits comprising said compounds, salts and compositions.

Background of the invention

Hepatitis C is an infectious viral disease in the blood caused by a hepatotropic virus called HCV. So far at least six different HCV genotypes are known (with various subtypes within each genotype). In North America, HCV of genotype 1a predominates, followed by genotypes 1b, 2a, 2b and 3a of HCV. In the United States, HCV genotypes 1, 2 and 3 are the most common, with HCV genotype 1 presenting approximately 80% of patients with hepatitis C. In Europe, HCV genotype 1b is predominant, followed by HCV genotypes 2a, 2b, 2c and 3a. HCV genotypes 4 and 5 are found almost exclusively in Africa. As described below, the HCV genotype of patients is clinically important in determining a possible response of patients to therapy and the necessary duration of such therapy.

An HCV infection can cause liver inflammation (hepatitis) that is often asymptomatic, but the resulting chronic hepatitis can cause liver cirrhosis (hepatic fibrotic scarring), liver cancer and / or liver dysfunction. The World Health Organization estimates that approximately 170 million people worldwide are chronically infected with HCV and approximately three to approximately four million people are recently infected worldwide each year. According to the Centers for Disease Control and Prevention, approximately four million people in the United States are infected with HCV. Co-infection with the human immunodeficiency virus (HIV) is common and the rates of HCV infection are higher among HIV-positive populations.

There is a small chance of eliminating the virus spontaneously, but most patients with chronic hepatitis C will not eliminate it without treatment. Indications for treatment typically include demonstrated trials of HCV infection and persistent abnormal liver function. There are two treatment regimens that are mainly used to treat hepatitis C: monotherapy (using an interferon agent - like a long-acting or "conventional" pegylated interferon) and combination therapies (using an interferon agent and ribavirin). Interferon, which is injected into the bloodstream, acts by strengthening the immune response against HCV; and ribavirin, which is administered orally, is thought to work by preventing HCV replication. Taken alone, ribavirin does not effectively suppress HCV levels, but a combination of interferon / ribavirin is more effective than interferon alone. Typically, hepatitis C is treated with a combination of pegylated interferon alfa and ribavirin for a period of 24 or 48 hours, depending on the HCV genotype.

The goal of treatment is the sustained viral response - which means that HCV is not measurable in the blood after completing therapy. After treatment with a combination of pegylated interferon alfa and ribavirin, sustained cure rates (sustained viral response) of approximately 75% or more occur in people with HCV genotypes 2 and 3 at 24 weeks of treatment, approximately 50% in those with HCV genotype 1 at 48 weeks of treatment and approximately 65% in those with HCV genotype 4 at 48 weeks of treatment.

Treatment can be physically demanding, particularly for those with a previous history of drug or alcohol abuse, since both interferon and ribavirin have numerous side effects. Common side effects associated with interferon include flu-like symptoms, extreme tiredness, nausea, loss of appetite, thyroid problems, high blood sugar, alopecia, and skin reactions at the injection site. Possible serious side effects associated with interferon include psychosis (for example, suicidal behavior), heart problems (for example, heart attack, decreased blood pressure), other injuries to internal organs, blood problems (for example, dangerously low blood counts lower) and new autoimmune diseases or worsening (for example, rheumatoid arthritis). The side effects associated with ribavirin include anemia, tiredness, irritability, rash, lack of nasal ventilation, sinusitis and cough.

Ribavirin can also cause birth defects, so that during treatment and six months after treatment, pregnancy should be avoided in patients and in patients' partners.

Some patients do not complete the treatment due to the serious side effects described above;

5 other patients (non-responders) continue to have measurable HCV levels despite treatment; and yet other patients (repeat offenders) "eliminate" the virus during therapy, but the virus comes back a few times after completing the treatment regimen. Therefore, there remains a need for alternative compounds, compositions and treatment procedures (used in combination with or instead of an interferon and / or ribavirin agent) to relieve the symptoms of hepatitis C, thereby providing a

10 partial or complete relief. The present invention provides compounds (including salts thereof), compositions and treatment methods that generally address said need.

Summary of the Invention

The present invention relates to compounds that correspond to the structure of formula I:

image 1

In formula I:

image 1 is selected from the group consisting of carbon-carbon single bond and carbon20 carbon double bond;

R1 is selected from the group consisting of hydrogen and methyl,

R2 is selected from the group consisting of hydrogen, halo, hydroxy, methyl, cyclopropyl and cyclobutyl;

R3 is selected from the group consisting of hydrogen, halo, oxo and methyl;

R4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl and heterocyclyl, in the

that:

(a) the amino, aminocarbonyl and aminosulfonyl are optionally substituted with:

30 (1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl and alkylsulfonyl, or

(2) two substituents that, together with the amino nitrogen, form a single ring heterocyclyl, and

(b) alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy and alkylsulfonyl, optionally are

Substituted with one or more substituents independently selected from the group consisting of halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl and heterocyclyl, in which: it is optionally substituted with:

(1) one or two substituents independently selected from the group consisting of alkyl,

Alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, or

(2) two substituents that, together with the amino nitrogen, form a single ring heterocyclyl, and

(c) carbocyclyl and heterocyclyl are optionally substituted with up to three substituents selected

Independently from the group consisting of alkyl, alkenyl, alkynyl, halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl and heterocyclyl, in which: the amino is optionally substituted with:

(1) one or two substituents independently selected from the group consisting of alkyl,

Alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, or

(2) two substituents that, together with the amino nitrogen, form a single ring heterocyclyl;

R5 is selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, carbocyclylsulfonyloxy, haloalkylsulfonyloxy and halo;

L is selected from the group consisting of C (RA) = C (RB), ethylene and cyclopropyl-1,2-ene; RA and RB are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1C6 alkyloxy, C3-C8 cycloalkyl and halo, wherein:

C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of carboxy, halo, hydroxy, nitro, oxo, amino, cyano, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl and heterocyclyl;

R6 is selected from the group consisting of carbocyclyl-C5-C6, 5-6 membered heterocyclyl, carbocyclyl condensate of 2 rings and heterocyclic condensate of 2 rings, in each of said substituents is optionally substituted with one or more substituents independently selected from the group that it consists of RE, RF, RG, RH, R1, RJ and RK; each RE is independently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, cyano, amino, imino, azido and aldehyde, in which:

the amino is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl;

each RF is independently selected from the group consisting of alkyl, alkenyl and alkynyl, in which:

each of said substituents is optionally substituted with one or more substituents selected independently among the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl, in which: the amino, imino, aminosulfonyl, aminocarbonyl, carbocyclyl and heterocyclyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl, alkylsulfonyl, alkylsulfonylamino, hydroxy and alkyloxy, wherein:

the amino portion of the alkylsulfonylamino is optionally substituted with a substituent selected from the group consisting of alkyl, alkenyl and alkynyl;

each RG is independently selected from the group consisting of carbocyclyl and heterocyclyl, in which:

each of said substituents is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkyloxycarbonyl, alkylcarbonyloxy , alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl, in which:

the amino, aminosulfonyl and aminocarbonyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl and alkylsulfonyl;

each RH is independently selected from the group consisting of alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, alkenylsulfonyloxy and alkynylsulfonyloxy, in which:

each of said substituents is optionally substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy , alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl, in which:

the amino, aminosulfonyl and aminocarbonyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl and alkylsulfonyl;

each RI is independently selected from the group consisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aminocarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl and heterocyclylcarbonyl, in which:

(to)

the alkylcarbonyl, alkenylcarbonyl and alkynylcarbonyl are optionally substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxycarbonyloxycarbonyloxycarbonylcarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonylcarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxy alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl, and

(b)

the aminocarbonyl is optionally substituted with one or two substituents selected

independently from the group consisting of alkyl, alkenyl, alkynyl, alkyloxyalkyl, carbocyclyl, heterocyclyl, alkylsulfonyl and alkylsulfonylamino, in which:

the carbocyclyl and heterocyclyl are optionally substituted with one or two substituents independently selected from the group consisting of halo, alkyl and oxo;

each RJ is independently selected from the group consisting carbociclilsulfonilamino, heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, alquinilcarbonilamino, alkyloxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, alquinilsulfonilamino, aminocarbonylamino, alquiloxicarbonilaminoimino, alquilsulfonilaminoimino, alquenilsulfonilaminoimino and alquinilsulfonilaminoimino, wherein:

(to)

the amino portion of said substituents is optionally substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkenyl, alkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl that:

(one)

the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl are optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano , azido, oxo and amino, and

(2)

the amino portion of the aminocarbonylalkyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl,

(b)

the alkyl, alkenyl and alkynyl portion of said substituents is optionally substituted with one or more substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl and cyano, in the that:

the amino is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy and alkynyloxy, wherein: the alkyl is optionally substituted with one or more hydroxy;

(C)

the carbocyclyl and heterocyclyl portions of said substituents are optionally substituted with one

or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido and amino, wherein:

the amino is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl; Y

each RK is independently selected from the group consisting of aminosulfonyl, alkylsulfonyl, alkenylsulfonyl and alkylsulfonyl, in which:

(to)

the alkylsulfonyl, alkenylsulfonyl and alkynylsulfonyl are optionally substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylaryloxycarbonyloxy, alkyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxy alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl, in which:

the amino, aminosulfonyl and aminocarbonyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl; Y

(b)

the aminosulfonyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl.

The present invention also relates to the salts (including pharmaceutically acceptable salts) of the compounds of the invention.

The present invention also relates to compositions (including pharmaceutical compositions) comprising one or more compounds and / or salts of the invention and, optionally, one or more additional therapeutic agents.

The present invention also relates to kits comprising one or more compounds and / or salts of the invention and, optionally, one or more additional therapeutic agents.

The present invention also relates to the compounds, salts, compositions and / or kits of the invention for use in, for example, inhibition of the replication of an RNA virus (including HCV), which treats a disease

which can be treated by inhibiting HCV ribonucleic acid (RNA) polymerase (including hepatitis C).

The present invention also relates to a use of one or more compounds and / or salts of the invention to prepare a medicament. The medicament may optionally comprise one more additional therapeutic agents. In some embodiments, the medication is useful for treating hepatitis C.

Additional benefits of the Applicants' invention will be apparent to a person skilled in the art from the

reading of this patent application.

SUMMARY DESCRIPTION OF THE FIGURES

Figure 1 shows an illustrative PXRD pattern for the disodium salt nonahydrate of compound IB-L1-1.1.

Figure 2 shows an illustrative PXRD pattern for the tetrahydrate disodium salt of compound IB-L1-1.1.

Figure 3 shows an illustrative TGA profile of the disodium salt tetrahydrate of compound IB-L1-1.1.

Figure 4 shows an illustrative PXRD pattern for the dipotassium tetrahydrate salt of compound IB-L1-1.1.

Figure 5 shows an illustrative PXRD pattern for the monopotassium salt trihydrate of compound IB-L1-1.1.

Figure 6 shows an illustrative PXRD pattern for the monopotassium salt dihydrate of compound IB-L1-1.1.

Figure 7 shows an illustrative TGA profile of the monopotassium salt dihydrate of compound IB-L1-1.1.

Figure 8 shows an illustrative PXRD pattern for potassium salt 1/7 of compound IB-L1-1.1.

Figure 9 shows an illustrative PXRD pattern for the monodiethylamine tetrahydrate salt of compound IB-L1-1.1.

Figure 10 shows an illustrative TGA profile of the monodiethylamine tetrahydrate salt of compound IB-L1-1.1.

Figure 11 shows an illustrative PXRD pattern for polymorph A pattern of compound IB-L1-1.1.

Figure 12 shows an illustrative DSC profile of polymorph pattern A of compound IB-L1-1.1.

Figure 13 shows an illustrative PXRD pattern for polymorph B pattern of compound IB-L1-1.1.

Figure 14 shows an illustrative PXRD pattern for polymorph C pattern of compound IB-L1-1.1.

Figure 15 shows an illustrative PXRD pattern for polymorph D pattern of compound IB-L1-1.1.

Figure 16 shows an illustrative PXRD pattern for the hydrate A pattern of compound IB-L1-1.1.

Figure 17 shows an illustrative TGA profile of the hydrate A hydrate standard of compound IB-L1-1.1.

Figure 18 shows an illustrative PXRD pattern for the hydrate B hydrate standard of compound IB-L1-1.1.

Figure 19 shows an illustrative TGA profile of the hydrate B hydrate standard of compound IB-L1-1.1.

Figure 20 shows an illustrative PXRD pattern for the hydrate C pattern of compound IB-L1-1.1.

Figure 21 shows an illustrative TGA profile of the hydrate C hydrate standard of compound IB-L1-1.1.

Figure 22 shows an illustrative PXRD pattern for the hydrate D hydrate standard of compound IB-L1-1.1.

Figure 23 shows an illustrative PXRD pattern for the hydrate E hydrate standard of compound IB-L1-1.1.

Detailed description of the invention

The present detailed description is intended only to make known to other experts in the field the invention of the Applicants, their principles and their practical application so that other experts in the field can adapt and apply the invention in its numerous forms, according to the most suitable for a particular use. This description and specific examples are intended for illustrative purposes only. The present invention, therefore, is not limited to the embodiments described in the present patent application and can be modified in various ways.

A. Definitions

The term "alkyl" (alone or together with another or other terms) refers to a saturated linear or branched chain hydrocarbyl substituent typically containing from 1 to about 20 carbon atoms, more typically from 1 to about 8 carbon atoms and even more typically from 1 to about 6 carbon atoms. Examples of such substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl and hexyl. As in this definition, throughout this detailed description the Applicants have provided illustrative examples. The provision of such illustrative examples should not be construed as if the illustrative examples provided were the only options available to a person skilled in the art.

The term "alkenyl" (alone or together with another or other terms) refers to a linear or branched chain hydrocarbyl substituent containing one or more double bonds and typically from 2 to about 20 carbon atoms, more typically from about 2 to about 8 carbon atoms and even more typically from about 2 to about 6 carbon atoms. Examples of such substituents include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl and 3-butenyl.

The term "alkynyl" (alone or together with another or other terms) refers to a linear chain hydrocarbyl substituent

or branched containing one or more triple bonds and typically from 2 to about 20 carbon atoms, more typically from about 2 to about 8 carbon atoms and even more typically from about 2 to about 6 carbon atoms. Examples of such substituents include ethynyl, 2-propynyl, 3-propynyl, 2-butynyl and 3-butynyl.

The term "carbocyclyl" (alone or together with another or other terms) means a saturated cyclic hydrocarbyl substituent (ie, "cycloalkyl"), partially saturated cyclic (ie, "cycloalkenyl") or completely unsaturated (ie, "aryl ") containing from 3 to 14 carbon atoms in the ring (" atoms in the ring "are atoms bonded together to form the ring or rings of a cyclic substituent). A carbocyl can be a single bond, typically containing 3 to 6 ring atoms. Examples of said single bond ring include cyclopropyl (cyclopropanyl), cyclobutyl (cyclobutanyl), cyclopentyl (cyclopentanyl), cyclopentenyl, cyclopentadienyl, cyclohexyl (cyclohexanyl), cyclohexenyl, cyclohexadienyl and phenyl. Alternatively, a carbocyclyl can be 2 or 3 rings fused together, such as naphthalenyl, tetrahydronaphthalenyl (tetralinyl), indenyl, indanyl (dihydroindenyl), anthracenyl, phenanthrenyl and decalinyl.

The term "cycloalkyl" (alone or together with another or other terms) refers to a saturated cyclic hydrocarbyl substituent containing from 3 to 14 ring carbon atoms. A cycloalkyl may be a single carbon ring, which typically contains 3 to 6 carbon atoms in the ring. Examples of such single ring cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Alternatively, a cycloalkyl may be 2 or 3 carbon rings fused together, such as decalinyl.

The term "aryl" (alone or together with another or other terms) refers to an aromatic carbocyclyl containing from 6 to 14 carbon atoms in the ring. Examples of aryls include phenyl, naphthalenyl and indenyl.

In some cases, the number of carbon atoms in a hydrocarbyl substituent (for example, alkyl, alkenyl, alkynyl or cycloalkyl) is indicated by the suffix "-Cx-Cy", in which x is the minimum e and is the maximum number of carbon atoms in the substituent. Therefore, for example, "C1-C6-alkyl" refers to an alkyl substituent containing 1 to 6 carbon atoms. By way of further illustration, C3-C6 cycloalkyl refers to a saturated hydrocarbyl ring containing from 3 to 6 carbon atoms in the ring.

The term "hydrogen" (alone or together with another or other terms) refers to a hydrogen radical and can be represented as -H.

The term "hydroxy" (alone or together with another or other terms) means -OH.

The term "nitro" (alone or together with another or other terms) means -NO2.

The term "cyano" (alone or together with another or other terms) means -CN, which can also be represented as C = N.

The term "keto" (alone or together with another or other terms) refers to an oxo radical and can be represented as = O.

The term "carboxy" (alone or together with another or other terms) means -C (O) -OH.

The term "amino" (alone or together with another or other terms) means -NH2.

The term "imino" (alone or together with another or other terms) means = NH.

The term "aminoimino" (alone or together with another or other terms) means = NNH2,

The term "halogen" or "halo" (alone or together with another or other terms) refers to a fluorine radical (which can be represented as -F), chlorine radical (which can be represented as -CI), bromine radical (which can represented as -Br) or iodine radical (which can be represented as -I).

A substituent is "substitutable" if it comprises at least one carbon or nitrogen atom that is attached to one or more hydrogen atoms. Therefore, for example, hydrogen, halogen and cyano do not fall within this definition. In addition, a sulfur atom in a heterocyclyl containing said atom is substitutable with one or two oxo substituents.

If a substituent is described as being "substituted," a non-hydrogen radical is in place of a hydrogen radical in a carbon or nitrogen of the substituent. Therefore, for example, a substituted alkyl substituent is an alkyl substituent in which at least one non-hydrogen radical is in the place of a hydrogen radical in the alkyl substituent. By way of illustration, monofluoroalkyl is alkyl substituted with a fluorine radical and difluoroalkyl is alkyl substituted with fluorine radicals. It should be recognized that if there is more than one substitution in a substituent, each non-hydrogen radical may be the same or different (unless otherwise indicated).

If a substituent is described as being "optionally substituted", the substituent may be (1) whether to replace or

(2) replaced. If a substituent is described as being optionally substituted with up to a particular number of radicals other than hydrogen, said unsubstituted substituent (1); or (2) substituted with up to that particular number of radicals other than hydrogen or with up to the maximum number of substitutable positions in the substituent, whichever is less. Therefore, for example, said substituent is described as a heteroaryl optionally substituted with up to 3 different radicals of hydrogen, then any heteroaryl with less than 3 suitable positions could be optionally substituted with up to only as many different radicals of hydrogen as suitable positions have the heteroaryl. By way of illustration, tetrazolyl (having only a suitable position) could optionally be substituted with up to a radical other than hydrogen. By way of further illustration, if amino nitrogen is described as being optionally substituted with up to 2 different hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to 2 different hydrogen radicals, while a secondary amino nitrogen will be optionally substituted with up to 1 non-hydrogen radical.

The present patent application uses the terms "substituent" and "radical" interchangeably.

The prefix "halo" indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen radicals. For example, haloalkyl refers to an alkyl substituent in which at least one hydrogen radical is replaced with a halogen radical. Examples of haloalkyl include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl and 1,1,1-trifluoroethyl. It should be recognized that if a substituent is substituted with more than more than one halogen radical, said halogen radicals may be the same.

or different (unless otherwise indicated).

The prefix "perhalo" indicates that all hydrogen radicals in the substituent to which the prefix is attached are replaced with independently selected halogen radicals, that is, each hydrogen radical in the substituent is replaced with a halogen radical. If all halogen radicals are identical, the prefix will typically identify the halogen radical. Therefore, for example, the term "perfluoro" means that all hydrogen radicals in the substituent to which the prefix is attached are substituted with fluorine radicals. By way of illustration, the term "perfluoroalkyl" refers to an alkyl substituent in which a fluorine radical is in place of each of the hydrogen radicals.

The term "carbonyl" (alone or together with another or other terms) means -C (O) -.

The term "aminocarbonyl" (alone or together with another or other terms) means -C (O) -NH2,

The term "oxy" (alone or together with another or other terms) refers to an ether substituent and can be represented as -O-.

The term "alkoxy" (alone or together with another or other terms) refers to an alkyl ether substituent, that is, -O-alkyl. Examples of said substituent include methoxy (-O-CH3), ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, secbutoxy and tert-butoxy.

The term "alkylcarbonyl" (alone or together with another or other terms) means -C (O) -alkyl.

The term "aminoalkylcarbonyl" (alone or together with another or other terms) means -C (O) -alkyl-NH2.

The term "alkoxycarbonyl" (alone or together with another or other terms) means -C (O) -O-alkyl.

The term "carbocyclylcarbonyl" (alone or together with another or other terms) means -C (O) -carbocyclyl.

Similarly, the term "heterocyclylcarbonyl" (alone or together with another or other terms) means -C (O) heterocyclyl.

The term "carbocyclylalkylcarbonyl" (alone or together with another or other terms) means -C (O) -alkylcarbocyclyl.

Similarly, the term "heterocyclylalkylcarbonyl" (alone or together with another or other terms) means -C (O) alkylheterocyclyl.

The term "carbocyclyloxycarbonyl" (alone or together with another or other terms) means -C (O) -O-carbocyclyl.

The term "carbocyclylalkoxycarbonyl" (alone or together with another or other terms) means -C (O) -O-alkyl-carbocyclyl.

The term "uncle" or "aunt" (alone or together with another or other terms) refers to a thiather substituent, that is, an ether substituent, in which the divalent sulfur atom is in the place of the oxygen atom of the ether. Said substituent can be represented as -S-. This, for example, "alkylthio-alkyl" means alkyl-S-alkyl (alkylsulfanyl-alkyl).

The term "thiol" or "sulfhydryl" (alone or together with another or other terms) refers to a sulfhydryl substituent and can be represented as -SH.

The term "(thiocarbonyl)" (alone or together with another or other terms) refers to a carbonyl in which the oxygen atom has been substituted with one of sulfur. Said substituent may be represented as -C (S) -.

The term "sulfonyl" (alone or together with another or other terms) means -S (O) 2-.

The term "aminosulfonyl" (alone or together with another or other terms) means -S (O) 2-NH2-.

The term "sulfinyl" or "sulfoxide" (alone or together with another or other terms) means -S (O) -.

The term "heterocyclyl" (alone or together with another or other terms) refers to a saturated ring structure (ie, "heterocycloalkyl"), partially saturated (ie, "heterocycloalkenyl") or completely unsaturated (ie, " heteroaryl ") containing a total of 3 to 14 ring atoms. At least one of the atoms in the ring is a heteroatom (i.e. oxygen, nitrogen or sulfur), the remaining atoms in the ring being selected from the group consisting of carbon, oxygen, nitrogen and sulfur.

A heterocyclyl can be a single ring, typically containing 3 to 7 ring atoms, more typically 3 to 6 ring atoms and even more typically 5 to 6 ring atoms. Examples of heterocyclyls single ring include furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl (thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, oxazolyl, oxazolidinyl, isoxazolidinyl , isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl (furazanyl) or 1,3 , 4-oxadiazolyl), oxatriazolyl (including 1,2,3,4-oxatriazolyl or 1,2,3,5oxatriazolyl), dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3 , 2-di-oxazolyl or 1,3,4-dioxazolyl), oxathiazolyl, oxatiolyl, oxathiolanyl, pyranyl, dihydropyranyl, thiopyranyl, tetrahydrothiopyranyl, pyridinyl (azinyl), piperidinyl, diazinyl (including pyridazinyl (1,2-diazinyl) (1,3-diazinyl) or pi razinyl (1,4-diazinyl)), piperazinyl, triazinyl (including 1,3,5-triazinyl, 1,2,4-triazinyl and 1,2,3-triazinyl)), oxazinyl (including 1,2-oxazinyl, 1,3-oxazinyl or 1,4-oxazinyl)), oxathiazinyl (including 1,2,3-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,5-oxathiazinyl or 1,2,6oxathiazinyl)), oxadiazinyl (including 1,2,3-oxadiazinyl, 1,2,4-oxadiazinyl, 1,4,2-oxadiazinyl or 1,3,5-oxadiazionyl)), morpholinyl, azepinyl, oxepinyl, tiepinyl and diazepinyl.

Alternatively, a heterocyclyl can have 2 or 3 rings fused together, such as, for example, indolizinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl (including pyrido [3,4-b] -pyridinyl, pyrido [3 , 2-b] pyridinyl or pyrido [4,3-b] -pyridinyl) and pteridinyl. Other examples of condensed ring heterocyclyls include benzo fused heterocyclyls, such as indolyl, isoindolyl (isobenzazolyl, pseudoisoindolyl), indoleninyl (pseudoindole), isoindazolyl (benzapyrazyl), benzazinyl (including quinolinyl (1-benzazinyl) or isobenzinyl) phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (1,2-benzodiazinyl) or quinazolinyl (1,3-benzodiazinyl)), benzopyranyl (including chromanyl or iso-chromanyl), benzoxazinyl (including 1,3,2-benzoxazinyl, , 4,2-benzoxazinyl, 2,3,1-benzoxazinyl or 3,1,4-benzoxazinyl) and bencisoxazinyl (including 1,2-bencisoxazinyl or 1,4-bencisoxazinyl).

The term "2-condensed ring" heterocyclyl (alone or together with another or other terms) refers to a saturated, partially saturated or aryl heterocyclyl containing 2 condensed rings. Examples of heterocyclyls-fused two ring include indolizinyl, quinolizinyl, purinyl, naphthyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl and tetrahydroisoquinolinyl.

The term "heteroaryl" (alone or together with another or other terms) refers to an aromatic heterocyclyl containing from 5 to 14 ring atoms. A heteroaryl can be a single ring or 2 or 3 condensed rings. Examples of heteroaryl substituents include 6-membered ring substituents, such as pyridyl, pyrazyl, pyrimidinyl, pyridazinyl and 1,3,5-, 1,2,4- or 1,2,3-triazinyl; 5-membered ring substituents, such as imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4- oxadiazolyl and isothiazolyl; 6/5-membered condensed ring substituents, such as benzothiofuranyl, bencisoxazolyl, benzoxazolyl, purinyl and anthranilyl; and 6/6 fused condensed rings, such as benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl and benzoxazinyl.

A suffix attached to a multi-component substituent only applies to the first component. By way of illustration, the term "alkylcycloalkyl" contains two components: alkyl and cycloalkyl. Therefore, the suffix -C1-C6 in C1-C6 alkylcycloalkyl means that the alkyl component of the alkylcycloalkyl contains from1 to 6 carbon atoms; The suffix -C1-C6 does not describe the cycloalkyl component. By way of further illustration, the prefix "halo" in haloalkoxyalkyl indicates that only the alkoxy component of the alkoxyalkyl substituent is substituted with one or more halogen radicals. If the halogen substitution may appear alternatively or additionally in the alkyl component, the substituent may instead be described as "halogen substituted alkoxyalkyl" as opposed to "haloalkoxyalkyl". And finally, if the halogen substitution can only appear in the alkyl component, the substituent could instead be described as "alkoxyhaloalkyl".

If substituents are described as being "independently selected" from one group, each substituent is independently selected from the others. Each substituent may, therefore, be identical or different from the other or other substituents.

When words are used to describe a substituent, the component described more to the right of the substituent is the component that has free valence.

When a chemical formula is used to describe a substituent, the hyphen on the left side of the formula indicates the portion of the substituent that has free valence.

When a chemical formula is used to describe a link element between two distinct elements of a represented chemical structure, the leftmost dash of the substituent indicates the portion of the substituent that is attached to the element on the left in the represented structure. The rightmost dash, on the other hand, indicates the portion of the substituent that is attached to the element on the right in the structure represented. By way of illustration, if the chemical structure represented is X-L-Y and L is described as -C (O) -N (H) -, the chemical compound could be X-C (O) -N (H) -Y.

With reference to the use of the words "comprise" or "comprises" or "comprising" in the present patent application (including claims), Applicants indicate that unless the context requires otherwise, the words are used in the base and clear knowledge that they must be interpreted in an inclusive manner, rather than exclusively and said Applicants claim that each of said words must be interpreted in this way to construct the present patent application, including subsequent claims.

ChemDraw software has been used to generate the names of the compounds in the present patent application.

The term "amorphous" as applied to a compound refers to the solid state in which the molecules of the compound are present in a disordered arrangement and do not form crystalline networks or distinguishable unit cells. When subjected to powder X-ray diffraction, an amorphous compound does not produce any of the characteristic crystalline peaks.

The term "crystalline form" as applied to a compound refers to a solid state in which the molecules of the compound are arranged to form a distinguishable crystalline network (i) comprising distinguishable unit cells and (ii) that produce pattern peaks diffraction when subjected to x-ray radiation.

The term "purity", unless otherwise classified, refers to the chemical purity of a compound according to a conventional HPLC assay.

The term "phase purity" refers to the solid state purity of a compound with respect to a particular amorphous or crystalline form of the compound as determined by analytical methods of powder X-ray diffraction.

The term "phase purity" refers to purity with respect to other solid state forms of the compound, and not

It necessarily implies a high degree of chemical purity with respect to other compounds. The term "PXRD" means powder X-ray diffraction. 5 The term "TGA" means thermogravimetric analysis. The term "DSC" means differential scanning calorimetry.

B. Compounds

The present invention relates, in part, to compounds that are derivatives of phenyl uracil that correspond to the structure of formula I:

image 1

15 In these compounds,

image 1 it is selected from the group consisting of carbon-carbon single bond and carbon-carbon double bond.

In some embodiments,

image 1 It is a simple carbon-carbon bond. In these embodiments, the compounds of the formula I correspond in the structure with the following formula (ie, formula IA): image 1

20 In other embodiments,

image 1 It is a double carbon-carbon bond. In these embodiments, the compounds of the formula I correspond in structure to the following formula (ie, the formula IB): image 1

25 B1. R1 substituent.

R1 is selected from the group consisting of hydrogen and methyl.

In some embodiments, R1 is hydrogen. In some embodiments, R1 is methyl.

In some embodiments, R1 is selected from the group consisting of hydrogen and methyl.

B2. R2 substituent.

R2 is selected from the group consisting of hydrogen, halo, hydroxy, methyl, cyclopropyl and cyclobutyl.

In some embodiments, R2 is hydrogen.

In some embodiments, R1 is halo. In some of said embodiments, R2 is selected from the group consisting of fluorine and chlorine. In other such embodiments, R2 is fluorine. In other such embodiments, R2 is chlorine. In other such embodiments, R2 is bromine. In said additional embodiments, R2 is iodine.

In some embodiments, R2 is hydroxy.

In some embodiments, R2 is methyl.

In some embodiments, R2 is cyclopropyl.

In some embodiments, R2 is cyclobutyl.

In some embodiments, R2 is selected from the group consisting of hydrogen, methyl, hydroxy and halo. In some of said embodiments, R2 is selected from the group consisting of hydrogen, methyl, hydroxy, fluorine and chlorine. In other such embodiments, R2 is selected from the group consisting of hydrogen, methyl, hydroxy, and fluorine. In other such embodiments, R2 is selected from the group consisting of hydrogen, methyl, hydroxy and chlorine. In other such embodiments, R2 is selected from the group consisting of hydrogen, methyl, hydroxy and bromine. In said additional embodiments, R2 is selected from the group consisting of hydrogen, methyl, hydroxy and iodine.

In some embodiments, R2 is selected from the group consisting of hydrogen, methyl and halo. In some of said embodiments, R2 is selected from the group consisting of hydrogen, methyl, fluorine and chlorine. In other such embodiments, R2 is selected from the group consisting of hydrogen, methyl and fluorine. In other such embodiments, R2 is selected from the group consisting of hydrogen, methyl and chlorine. In other such embodiments, R2 is selected from the group consisting of hydrogen, methyl and bromine. In said additional embodiments, R2 is selected from the group consisting of hydrogen, methyl and iodine.

In some embodiments, R2 is selected from the group consisting of hydrogen and halo. In some of said embodiments, R2 is selected from the group consisting of hydrogen, fluorine and chlorine. In other such embodiments, R2 is selected from the group consisting of hydrogen and fluorine. In other such embodiments, R2 is selected from the group consisting of hydrogen and chlorine. In other such embodiments, R2 is selected from the group consisting of hydrogen and bromine. In said additional embodiments, R2 is selected from the group consisting of hydrogen and iodine.

B3 R3 substituent.

R3 is selected from the group consisting of hydrogen, halo, oxo and methyl. In some of said embodiments, R3 is selected from the group consisting of hydrogen, fluoro, oxo and methyl. In other such embodiments, R3 is selected from the group consisting of hydrogen, chlorine, oxo and methyl. In other such embodiments, R3 is selected from the group consisting of hydrogen, bromine, oxo and methyl. In other such embodiments, R3 is selected from the group consisting of hydrogen, iodine, oxo and methyl.

In some embodiments, R3 is selected from the group consisting of hydrogen, halo and oxo. In some of said embodiments, R3 is selected from the group consisting of hydrogen, fluoro and oxo. In other such embodiments, R3 is selected from the group consisting of hydrogen, chlorine and oxo. In other such embodiments, R3 is selected from the group consisting of hydrogen, bromine and oxo. In other such embodiments, R3 is selected from the group consisting of hydrogen, iodine and oxo.

In some embodiments, R3 is selected from the group consisting of hydrogen and methyl.

In some embodiments, R3 is hydrogen.

In some embodiments, R3 is methyl.

In some embodiments, R3 is oxo.

In some embodiments, R3 is halo. In some of said embodiments, R3 is fluoro. In other such embodiments, R3 is chlorine. In other such embodiments, R3 is bromine. In said additional embodiments, R3 is iodine.

B4 R4 substituent.

R4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl and heterocyclyl, in which:

(to)

the amino, aminocarbonyl and aminosulfonyl are optionally substituted with:

(one)

one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl and alkylsulfonyl, or

(2)

two substituents that, together with amino nitrogen, form a single ring heterocyclyl,

(b)

alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy and alkylsulfonyl, are optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl and heterocyclyl, in which: the amino is optionally substituted with:

(one)

one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, or

(2)

two substituents that, together with the amino nitrogen, form a single ring heterocyclyl, and

(C)

the carbocyclyl and heterocyclyl are optionally substituted with up to three substituents selected independently among the group consisting of alkyl, alkenyl, alkynyl, halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl and heterocyclyl, in which: The amino is optionally substituted with:

(one)

one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, or

(2)

two substituents that, together with amino nitrogen, form a single ring heterocyclyl.

In some embodiments, R4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl and heterocyclyl, in which: the amino, aminocarbonyl and aminosulfonyl are optionally substituted with:

(one)

one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl and alkylsulfonyl, or

(2)

two substituents that, together with amino nitrogen, form a single ring heterocyclyl.

In some embodiments, R4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl and heterocyclyl, in which: alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy and alkylsulfonyl, are optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl and heterocyclyl, in which: The amino is optionally substituted with:

(one)

one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl or

(2)

two substituents that, together with amino nitrogen, form a single ring heterocyclyl.

In some embodiments, R4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl and heterocyclyl, in which:

the carbocyclyl and heterocyclyl are optionally substituted with up to three substituents selected independently among the group consisting of alkyl, alkenyl, alkynyl, halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl and heterocyclyl, in which: The amino is optionally substituted with:

(one)

 one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl or

(2)

two substituents that, together with amino nitrogen, form a single ring heterocyclyl.

In some embodiments, R4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl and heterocyclyl, in which:

(to)

the amino, aminocarbonyl and aminosulfonyl are optionally substituted with:

(one)

one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl or,

(2)

two substituents that, together with amino nitrogen, form a single ring heterocyclyl; Y

(b)

alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyl, carbocyclyl and heterocyclyl are optionally substituted with up to three substituents independently selected from the group consisting of halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, carbocyclyl and heterocyclyl, in which the amino is optionally substituted with:

(one)

one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl or,

(2)

two substituents that, together with amino nitrogen, form a single ring heterocyclyl.

In some embodiments, R4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl and heterocyclyl, in which: the amino, aminocarbonyl and aminosulfonyl are optionally substituted with:

(one)

one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl or,

(2)

two substituents that, together with amino nitrogen, form a single ring heterocyclyl.

In some embodiments, R4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl and heterocyclyl, in which:

alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyl, carbocyclyl and heterocyclyl are optionally substituted with up to three substituents independently selected from the group consisting of halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, carbocyclyl and heterocyclyl, in which the amino is optionally substituted with:

(one)

one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl or,

(2)

two substituents that, together with amino nitrogen, form a single ring heterocyclyl.

In some embodiments, R4 is selected from the group consisting of halo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, C1-C4 alkylsulfonyl, C3-C6 carbocyclyl and 5-heterocyclyl -6 members, in which:

(to)

the amino is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl and alkylsulfonyl,

(b)

C1-C4 alkyl, C2-C4 alkenyl and C2-C4 alkynyl are optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy and trimethylsilyl and

(C)

the 5-6 membered carbocyclyl-C3-C6 and heterocyclyl are optionally substituted with up to three substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, and amino, in which:

the amino is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl and alkylsulfonyl.

In some embodiments, R4 is selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, C1-C4 alkylsulfonyl, C3-C6 carbocyclyl and 5-6 membered heterocyclyl, in which:

(to)

the amino is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl and alkylsulfonyl,

(b)

C1-C4 alkyl, C2-C4 alkenyl, and C2-C4 alkynyl are optionally substituted with one or more

substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy and trimethylsilyl and

(C)

the 5-6 membered carbocyclyl-C3-C6 and heterocyclyl are optionally substituted with up to three substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, and amino, in which:

the amino is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl and alkylsulfonyl.

In some embodiments, R4 is selected from the group consisting of halo, C1-C4 alkyl, C3-C6 carbocyclyl and 5-6 membered heterocyclyl, in which:

(to)

C1-C4 alkyl is optionally substituted with up to three substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy and trimethylsilyl, and

(b)

the 5-6 membered carbocyclyl-C3-C6 and heterocyclyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo and alkylsulfonylamino.

In some embodiments, R4 is selected from the group consisting of halo, C1-C4 alkyl, C3-C6 carbocyclyl and 5-6 membered heterocyclyl, in which:

(to)

C1-C4 alkyl is optionally substituted with one or two substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy and trimethylsilyl, and

(b)

the 5-6 membered carbocyclyl-C3-C6 and heterocyclyl are optionally substituted with a substituent selected from the group consisting of alkyl, halo and alkylsulfonylamino.

In some embodiments, R4 is selected from the group consisting of C1-C4 alkyl, C3-C6 carbocyclyl and 5-6 membered heterocyclyl, in which:

(to)

C1-C4 alkyl is optionally substituted with up to three substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy and trimethylsilyl, and

(b)

the 5-6 membered carbocyclyl-C3-C6 and heterocyclyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo and alkylsulfonylamino.

In some embodiments, R4 is selected from the group consisting of halo, tert-butyl, C3-C6 carbocyclyl and 5-6 membered heterocyclyl, in which:

the 5-6 membered carbocyclyl-C3-C6 and heterocyclyl are optionally substituted with a substituent selected from the group consisting of alkyl, halo and alkylsulfonylamino.

In some embodiments, R4 is selected from the group consisting of tert-butyl, carbocyclyl-C3-C6 and

5-6-membered heterocyclyl, in which:

the 5-6 membered carbocyclyl-C3-C6 and heterocyclyl are optionally substituted with a substituent

selected from the group consisting of alkyl, halo and alkylsulfonylamino.

In some embodiments, R4 is selected from the group consisting of halo, alkyl, haloalkyl, carboxyalkyl, hydroxyalkyl, alkyloxyalkyl, trimethylsilylalkyl, alkylcarbocyclyl, carbocyclyl, alkylheterocyclyl, heterocyclyl, halocarbocyclyl, alkylsulfonylamino.

In some embodiments, R4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl and heterocyclyl.

In some embodiments, R4 is selected from the group consisting of halo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, C1-C4 alkylsulfonyl, C3-C6 carbocyclyl and 5-heterocyclyl -6 members. In some of said embodiments, R4 is selected from the group consisting of halo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, C1-C4 alkylsulfonyl, C6 carbocyclyl and 5-heterocyclyl -6 members. In other such embodiments, R4 is selected from the group consisting of halo, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, C1-C4 alkylsulfonyl, 5-6 membered phenyl and heteroaryl.

In some embodiments, R4 is selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, C1-C4 alkylsulfonyl, C3-C6 carbocyclyl and 5-6 membered heterocyclyl. In some of said embodiments, R4 is selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, C1-C4 alkylsulfonyl, C6 carbocyclyl and 5-6 heterocyclyl members. In other such embodiments, R4 is selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, C1-C4 alkylsulfonyl, 5-6 membered phenyl and heteroaryl.

In some embodiments, R4 is selected from the group consisting of halo, C1-C4 alkyl, C3-C6 carbocyclyl and 5-6 membered heterocyclyl. In some of said embodiments, R4 is selected from the group consisting of halo, C1-C4 alkyl, carbocyclyl-C6 and 5-6 membered heterocyclyl. In other such embodiments, R4 is selected from the group consisting of halo, C1-C4 alkyl, phenyl and 5-6 membered heteroaryl.

In some embodiments, R4 is selected from the group consisting of C1-C4 alkyl, C3-C6 carbocyclyl and 5-6 membered heterocyclyl. In some of said embodiments, R4 is selected from the group consisting of C1-C4 alkyl, C6 carbocyclyl and 5-6 membered heterocyclyl. In other such embodiments, R4 is selected from the group consisting of C1-C4 alkyl, 5-6 membered phenyl and heteroaryl.

In some embodiments, R4 is selected from the group consisting of halo, tert-butyl, carbocyclyl-C3-C6 and 5-6 membered heterocyclyl. In some of said embodiments, R4 is selected from the group consisting of halo, tert-butyl, carbocyclyl-C6 and 5-6 membered heterocyclyl. In other such embodiments, R4 is selected from the group consisting of 5-6 membered halo, tert-butyl, phenyl and heteroaryl.

In some embodiments, R4 is selected from the group consisting of tert-butyl, carbocyclyl-C3-C6 and 5-6 membered heterocyclyl. In some of said embodiments, R4 is selected from the group consisting of tert-butyl, carbocyclyl-C6 and 5-6 membered heterocyclyl. In other such embodiments, R4 is selected from the group consisting of 5-6 membered tert-butyl, phenyl and heteroaryl.

In some embodiments, R4 is selected from the group consisting of carbocyclyl-C3-C6 and 5-6 membered heterocyclyl. In some of said embodiments, R4 is selected from the group consisting of C6 carbocyclyl and 5-6 membered heterocyclyl. In other such embodiments, R4 is selected from the group consisting of 5-6 membered phenyl and heteroaryl.

Suitable carbocyclyls for the above embodiments include, for example, cyclopropyl and phenyl.

Suitable heterocyclyls for the above reactions include, for example, furanyl, thienyl and pyridinyl.

In some embodiments, R4 is selected from the group consisting of halo, alkyl and alkyloxy.

In some embodiments, R4 is alkyl.

In some embodiments, R4 is tert-butyl.

B5 R5 substituents.

R5 is selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, carbocyclylsulfonyloxy, haloalkylsulfonyloxy and halo.

In some embodiments, R5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy and halo. In some of said embodiments, R5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy, and fluorine. In other such embodiments, R5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy, and fluoro. In other such embodiments, R5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy and chlorine. In other such embodiments, R5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy and bromine. In said further additional embodiments, R5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy and iodine.

In some embodiments, R5 is selected from the group consisting of hydrogen, hydroxy, methoxy and halo. In some of said embodiments, R5 is selected from the group consisting of hydrogen, hydroxy, methoxy and fluoro. In other such embodiments, R5 is selected from the group consisting of hydrogen, hydroxy, methoxy and chlorine. In other such embodiments, R5 is selected from the group consisting of hydrogen, hydroxy, methoxy and bromine. In said additional embodiments, R5 is selected from the group consisting of hydrogen, hydroxy, methoxy and iodine.

In some embodiments, R5 is selected from the group consisting of hydrogen, hydroxy and alkyloxy. In some of said embodiments, R5 is selected from the group consisting of hydrogen, hydroxy, methoxy and ethoxy.

In some embodiments, R5 is hydrogen.

In some embodiments, R5 is hydroxy.

In some embodiments, R5 is alkyloxy.

In some embodiments, R5 is methoxy.

In some embodiments, R5 is ethoxy.

B6 Substitute L.

5 L is selected from the group consisting of C (RA) = C (RB), ethylene and cyclopropyl-1,2-ene, in which RA and RB are as described below.

In some embodiments, L is C (RA) = C (RB), in which RA and RB are as described below. In these 10 embodiments, the compounds of the formula I correspond in structure to the formula I-L1:

image 1

In some of said embodiments, the compounds correspond in structure to the formula IA-L1:

image 1

In other such embodiments, the compounds correspond in structure to the formula IB-L1:

image 1

Typically, the compounds of the formula I-L1 are more potent if R6 and the phenyl-uracil are on opposite sides of the double bond (ie, in trans configuration relative to the double bond).

In some embodiments, L is ethylene. In these embodiments, the compounds of the formula I correspond in structure with I-L5-2:

image 1

In some of said embodiments, the compounds correspond in structure with the formula IA-L5-2:

image 1

In other such embodiments, the compounds correspond in structure to the formula IB-L5-2:

image 1

In some embodiments, L is cyclopropyl-1,2-ene. In these embodiments, the compounds of the formula I correspond in structure to the formula I-L8:

10

image 1

In some of said embodiments, the compounds correspond in structure to the formula IA-L8:

image 1

In other such embodiments, the compounds correspond in structure to the formula IB-L8:

image 1

B7 Substituents R4 and R8.

RA and RB are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkyloxy, C3-C8 cycloalkyl and halo, wherein:

C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of carboxy, halo, hydroxy, nitro, oxo, amino, cyano, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl and heterocyclyl.

In some embodiments, one of RA and RB is hydrogen and the other is selected from the group consisting of C1-C6 alkyl, C1-C6 alkyloxy, C3-C8 cycloalkyl and halo, wherein:

C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of carboxy, halo, hydroxy, nitro, oxo, amino, cyano, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl and heterocyclyl.

In some embodiments, RA and RB are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkyloxy, C3-C8 cycloalkyl and halo.

In some of the above embodiments, RA is hydrogen. In another of the above embodiments, RB is hydrogen.

In some embodiment, one of RA and RB is hydrogen and the other is selected from the group consisting of hydrogen, methyl, methoxy and halo.

In some embodiments, RA is hydrogen and RB is selected from the group consisting of methyl, methoxy, and halo. In some of said embodiments, RB is selected from the group consisting of methyl, methoxy and fluorine. In other such embodiments, RB is selected from the group consisting of methyl, methoxy and chlorine. In other such embodiments, RB is selected from the group consisting of methyl, methoxy and bromine. In said additional embodiments, RB is selected from the group consisting of methyl, methoxy and iodine. In said further additional embodiments, RB is selected from the group consisting of methyl, methoxy, chlorine and fluoro.

In some embodiments, RB is hydrogen and RA is selected from the group consisting of methyl, methoxy, and halo. In some of said embodiments, RA is selected from the group consisting of methyl, methoxy and fluorine. In other such embodiments, RA is selected from the group consisting of methyl, methoxy and chlorine. In other such embodiments, RA is selected from the group consisting of methyl, methoxy and bromine. In said additional embodiments, RA is selected from the group consisting of methyl, methoxy and iodine. In said further additional embodiments, RA is selected from the group consisting of methyl, methoxy, fluorine chlorine.

In some embodiments, RA is hydrogen and RB is hydrogen.

B8 R6 substituent.

R6 is selected from the group consisting of C5-C6 carbocyclyl, 5-6 membered heterocyclyl, 2 ring fused carbocyclyl and 2 ring fused heterocyclic, in each of said substituents is optionally substituted with one or more selected substituents independently between the group consisting of RE, RF, RG, RH, RI, RJ and RK, in which RE, RF, RG, RH, RI, RJ and RK are as described below. In some of said embodiments, the C5-C6 carbocyclyl, 5-6 membered heterocyclyl, 2 ring condensed carbocyclyl and 2 ring condensed heterocyclyl are not substituted. In other such embodiments, the carbocyclyl-C5-C6, 5-6 membered heterocyclyl, 2 ring fused carbocyclyl and 2 ring fused heterocyclyl are substituted with a substituent selected from the group consisting of RE, RF, RG, RH , RI, RJ and RK. In other such embodiments, the carbocyclyl-C5-C6, 5-6 membered heterocyclyl, 2 ring condensed carbocyclyl and 2 ring condensed heterocyclyl is optionally substituted with a substituent selected from the group consisting of RE, RF, RI, RJ and RK. In other such embodiments, the carbocyclyl-C5-C6, 5-6 membered heterocyclyl, 2 ring fused carbocyclyl and 2 ring fused heterocyclyl are substituted with a substituent selected from the group consisting of RE, RF and RJ. In other such embodiments, the C5-C6 carbocyclyl, 5-6 membered heterocyclyl, 2 ring fused carbocyclyl and 2 ring fused heterocyclyl are substituted with substituent selected from the group consisting of RF and RJ. In other such embodiments, the carbocyclyl-C5-C6, 5-6 membered heterocyclyl, 2 ring fused carbocyclyl and 2 ring fused heterocyclyl are substituted with RJ. In other such embodiments, the C5-C6 carbocycle, 5-6 membered heterocyclyl, 2 ring fused carbocyclyl and 2 ring fused heterocyclyl are substituted with two substituents independently selected from the group consisting of RE, RF, RG , RH, R1, RJ and RK. In other such embodiments, the carbocyclyl-C5-C6, 5-6 membered heterocyclyl, 2 ring fused carbocyclyl and 2 ring fused heterocyclyl are substituted with two substituents independently selected from the group consisting of RE, RF, R1 , RJ and RK. In other such embodiments, the carbocyclyl-C5-C6, 5-6 membered heterocyclyl, 2 ring fused carbocyclyl and 2 ring fused heterocyclyl are substituted with two substituents independently selected from the group consisting of RE, RF and RJ . In other such embodiments, the C5-C6 carbocyclyl, 5-6 membered heterocyclyl, 2 ring fused carbocyclyl and 2 ring fused heterocyclyl are substituted with two substituents independently selected from the group consisting of RF and RJ. In said further embodiments, the carbocyclyl-C5-C6, 5-6 membered heterocyclyl, 2 ring fused carbocyclyl and 2 ring fused heterocyclyl are substituted with three substituents independently selected from the group consisting of RE, RF, RG, RH , R1, RJ and RK. In said further embodiments, the C5-C6 carbocycle, 5-6 membered heterocyclyl, 2 ring fused carbocyclyl and 2 ring fused heterocyclyl are substituted with three substituents independently selected from the group consisting of RE, RF, RI, RJ and RK. In said further embodiments, the C5-C6 carbocyclyl, 5-6 membered heterocyclyl, 2 ring condensed carbocyclyl and 2 ring condensed heterocyclyl are substituted with three substituents independently selected from the group consisting of RE, RF and RJ. In said further embodiments, the C5-C6 carbocyclyl, 5-6 membered heterocyclyl, 2 ring condensed carbocyclyl and 2 ring condensed heterocyclyl are substituted with three substituents independently selected from the group consisting of RF and RJ. In said further embodiments, the C5-C6 carbocyclyl, 5-6 membered heterocyclyl, 2 ring fused carbocyclyl and 2 ring fused heterocyclyl are substituted with one, two or three substituents independently selected from the group consisting of RE, RF , RG, RH, RI, RJ and RK. In said further embodiments, the C5-C6 carbocyclyl, 5-6 membered heterocyclyl, 2 ring fused carbocyclyl and 2 ring fused heterocyclyl are substituted with one, two or three substituents independently selected from the group consisting of RE, RF , R1, RJ and RK. In said further embodiments, the C5-C6 carbocyclyl, 5-6 membered heterocyclyl, 2 ring fused carbocyclyl and 2 ring fused heterocyclyl are substituted with one, two or three substituents independently selected from the group consisting of RE, RF and RJ. In said further embodiments, the C5-C6 carbocycle, 5-6 membered heterocyclyl, 2 ring fused carbocyclyl and 2 ring fused heterocyclyl is substituted with one, two or three substituents independently selected from the group consisting of RF and RJ .

In some embodiments, R6 is selected from the group consisting of C5-C6 carbocyclyl and 5-6 membered heterocyclyl, wherein each of said substituents is optionally substituted with one or more substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK. In some of these embodiments, the 5-6 membered C5-C6 carbocycle and heterocyclyl are not substituted. In other such embodiments, the 5-6 membered carbocyclyl-C5-C6 and heterocyclyl are substituted with a substituent selected from the group consisting of RE, RF, RG, RHR ', RJ and RK. In another such embodiment, the 5-6 membered carbocyclyl-C5-C6 and heterocyclyl are substituted with two substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK. In said further embodiments, the 5-6 membered carbocyclyl-C5-C6 and heterocyclyl are substituted with three substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK. In said further embodiments, the 5-6 membered carbocyclyl-C5-C6 and heterocyclyl are substituted with one, two or three substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK

In some embodiments, R6 is carbocyclyl-C5-C6 optionally substituted with one or more substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK. In some of said embodiments, the carbocyclyl-C5-C6 is not substituted. In other such embodiments, the carbocyclyl-C5-C6 is substituted with a substituent selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK. In other such embodiments, the C5-C6 carbocyclyl is substituted with two substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK. In said additional embodiments, the carbocyclyl-C5-C6 is substituted with three substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK. In said additional embodiments, the carbocyclyl-C5-C6 is substituted with one, two or three substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK.

In some embodiments, R6 is 5-6 membered heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK. In some of said embodiments, the 5-6 membered heterocyclyl is not substituted. In other such embodiments, the 5-6 membered heterocyclyl is substituted with a substituent selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK. In other such embodiments, the 5-6 membered heterocyclyl is substituted with two substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK. In said additional embodiments, the 5-6 membered heterocyclyl is substituted with three substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK. In said further embodiments, the 5-6 membered heterocyclyl is substituted with one, two or three substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK.

In some embodiments, R6 is selected from the group consisting of condensed ring 2 carbocyclyl and condensed ring 2 heterocyclyl, in each of said substituents it is optionally substituted with one or more substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK. In some of said embodiments, the condensed ring 2 carbocyclyl and 2-condensed ring heterocyclyl are substituted. In other such embodiments, the condensed ring 2 carbocyclyl and condensed ring 2 heterocyclyl are substituted with a substituent selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK. In other such embodiments, the condensed ring 2 carbocyclyl and condensed ring 2 heterocyclyl are substituted with two substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK. In said further embodiments, the condensed ring 2 carbocyclyl and 2-condensed ring heterocyclyl are substituted with three substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK. In said further embodiments, the condensed ring 2 carbocyclyl and 2-condensed ring heterocyclyl are substituted with one, two or three substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK.

In some embodiments, R 6 is condensed ring 2 carbocyclyl optionally substituted with one or more substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK. In some of said embodiments, the ring carbocyclyl 2 condensate is not substituted. In other such embodiments, the 2-condensed ring carbocyclyl is substituted with a substituent selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK. In other such embodiments, the condensed ring carbocyclyl 2 is substituted with two substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK. In said additional embodiments, the 2-condensed ring carbocyclyl is substituted with three substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK. In said additional embodiments, the 2-condensed ring carbocyclyl is substituted with one, two or three substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK.

In some embodiments, R6 is a 2-condensed ring heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK. In some of said embodiments, the heterocyclyl of 2-condensate ring is not substituted. In other such embodiments, the 2-condensed ring heterocyclyl is substituted with a substituent selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK. In other such embodiments, the condensed ring heterocyclyl 2 is substituted with two substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK. In said additional embodiments, the 2-condensed ring heterocyclyl is substituted with three substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK. In said further embodiments, the 2-condensed ring heterocyclyl is substituted with one, two

or three substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJ and RK.

In some of the above embodiments, the optionally substituted carbocyclyl-C5-C6 is selected from the group consisting of cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and phenyl. In some of said embodiments, the optionally substituted carbocyclyl-C5-C6 is phenyl.

In some of the above embodiments, the optionally substituted carbocyclyl-C5-C6 is carbocyclyl-C5. Examples of C5 carbocyclyls include cyclopentyl, cyclopentenyl and cyclopentadienyl.

In another of the above embodiments, the optionally substituted carbocyclyl-C5-C6 is carbocyclyl-C6. Examples of C6 carbocyclyls include cyclohexyl, cyclohexenyl, cyclohexadienyl and phenyl.

In some of the above embodiments, the optionally substituted 5-6 substituted heterocyclyl is selected from the group consisting of furanyl, dihydrofuranyl, tetrahydrofuranoyl, thiophenyl (thiopheuranyl), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, dioxazolyl, oxazolyl , dihydroisoxazolyl, oxazolidinyl, isoxazolidinyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxathiolyl, oxathiolanyl, triazolyl, oxadiazolyl, furazanyl, tetrazolyl, oxatriazolyl, dioxazolyl, oxathiazolyl, oxathiazolidinyl, dihydrooxadiazolyl , dioxazolidinilo, pyranyl, dihydropyranyl, tetrahydropyranyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl, diazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, dihydropyrazinyl, tetrahydropyrazinyl, piperazinyl, triazinyl, dihydrotriazinyl, tetrahidrotriazinilo, triazinanyl, oxazinyl, dihydrooxazinyl, morpholinyl, oxathiazinyl, dihydrooxathiazinyl, oxathiazinanyl, oxadiazinyl, dihydrooxadiazinyl, oxadiazinanyl, thiopyranyl, dihydrothiopyranyl and tetrahydrothiopyranyl.

In some of the above embodiments, the 5-6 membered heterocyclyl is optionally substituted 5-membered heterocyclyl. Examples of such heterocyclyl of 5 members include furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl (thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, dihydrooxazolyl, isoxazolyl, dihydroisoxazolyl, oxazolidinyl, isoxazolidinyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxatiolyl, oxathiolanyl, triazolyl, oxadiazolyl, furazanyl, tetrazolyl, oxatriazolyl, dioxazolyl, oxathiazolyl, oxathiazolidinyl

5 dihydrooxadiazolyl and dioxazolidinyl.

In another of the above embodiments, the optionally substituted 5-6 membered heterocyclyl is 6 membered heterocyclyl. Examples of 6-membered heterocyclyl include piranyl, dihydropyranyl, tetrahydropyranyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl, diazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, dihydropyrazinyl,

10 tetrahydropyrazinyl, piperazinyl, triazinyl, dihydrotriazinyl, tetrahidrotriazinilo, triazinanyl, oxazinyl, dihydrooxazinyl, morpholinyl, oxathiazinyl, dihidrooxatiazinilo, oxatiazinanilo, oxadiazinyl, dihidrooxadiazinilo, oxadiazinanilo, thiopyranyl, dihydrothiopyranyl, and tetrahydrothiopyranyl.

In some of the above embodiments, the optionally substituted 2-condensed ring carbocyclyl is

15 selects from the group consisting of naphthalenyl, dihydronaphthalenyl, tetrahydronaphthalenyl, hexahydronaphthalenyl, octahydronaphthalenyl, decahydronaphthalenyl, indenyl, dihydroindenyl, hexahydroindenyl, octahydroindenyl, pentalenyl, octahydropentalenyl and hexahydropentalenyl. In some of said embodiments, the optionally substituted condensed ring carbocyclyl 2 is selected from the group consisting of naphthalenyl and dihydroindenyl. In some of said embodiments, the optionally substituted 2-condensed ring carbocyclyl is naphthalenyl. In

In other such embodiments, the optionally substituted 2-condensed ring carbocyclyl is dihydroindenyl. In said further embodiments, the optionally substituted 2-condensed ring carbocyclyl is indenyl.

In some of the above embodiments, the optionally substituted 2-condensed ring heterocyclyl is selected from the group consisting of

image 1

image 1

Y

X1, X2 and X3 are independently selected from the group consisting of N and C (H); image 1 X4 is selected from the group consisting of N (H), O and S; X5, X6 and X7 are independently selected from the group consisting of N and C (H); X8 is selected from the group consisting of N (H), O and S; X9 is selected from the group consisting of N (H), O and S;

X10

, X11, X12 and X13 are independently selected from the group consisting of N and C (H); X14 is selected from the group consisting of N (H), O and S;

X15

, X16, X17 and X18 are independently selected from the group consisting of N and C (H); one or more of X19, X10 and X21 is N and the remaining one or more are C (H); one or more of X22, X23, X14 and X25 is N and the remaining one or more are C (H); one or more of X26, X27 and X28 is N, and the remaining one or more are C (H); one or more of X19, X30, X31 and X32 is N, and the remaining one or more are C (H); one or more of X33, X34 and X35 is N, and the remaining one or more are C (H); one or more of X36, X37, X38, and X39 is N and the remaining one or more are C (H);

X40

, X41, and X42 are independently selected from the group consisting of N and C (H); one of X43, X44 and X45 is selected from the group consisting of N (H), O and S, and the remaining two are C (H) 2; one of X46 and X47 is selected from the group consisting of N (H), O and S, and the other is C (H) 2;

X48, X49, X50

and X51 are independently selected from the group consisting of N and C (H);

X52

, X53 and X54 are independently selected from the group consisting of N and C (H); X55 is selected from the group consisting of N (H), O and S;

X56

, X57 and X58 are independently selected from the group consisting of N and C (H); X59 is selected from the group consisting of N (H), O and S; X60 is selected from the group consisting of N (H), O and S;

X61, X61, X63

and X64 are independently selected from the group consisting of N and C (H); X65 is selected from the group consisting of N (H), O and S;

X66, X67, X68

and X69 are independently selected from the group consisting of N and C (H); one or more of X70, X71 and X72 is N and the remaining one or more are C (H); one or more of X73, X74, X75 and X76 is N and the remaining one or more are C (H); and one of X77 and X78 is N (H) and the remainder is C (H) 2.

In some of the above embodiments, the optionally substituted 2-condensed ring heterocyclyl is selected from the group consisting of In any of the above embodiments, the optionally substituted 2-condensed ring heterocyclyl is selected from the group consisting in:

image 1

image 1

In some of the above embodiments, X1, X2 and X3 are C (H). 5 In some of the above embodiments, X5, X6 and X7 are C (H). , X11X12

In some of the above embodiments, X10 and X13 are C (H). In some of the above embodiments, X15, X16, X17 and X18 are C (H).

10

In some of the above embodiments, one of X19, X20 and X21 is N. In some of the above embodiments, one of X22, X23, X24 and X25 is N.

In one of the previous embodiments, one of X26, X27 and X28 is N, and one of X29, X30, X31 and X32 is N. In some of the previous embodiments, X40, X41 and X42 are C (H). In some of the above embodiments, X48, X49, X50 and X51 are C (H).

twenty

In some of the above embodiments, X52, X53 and X54 are C (H). In some of the above embodiments, X56, X57 and X58 are C (H).

In one of the previous embodiments, X61, X62, X63 and X64 are C (H). In some of the previous embodiments, X88, X87, X88 and X89 are C (H). In any of the above embodiments, one or more of X70, X71 and X72 is N and the remaining one or more are C (H).

, X74X75

In any of the above embodiments, one or more of X73 and X76 is N, and the remaining one or more are C (H).

B9 RE substituent.

Each RE is independently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, cyano, amino, imino, azido and aldehyde, in which the amino is optionally substituted with one or two substituents independently selected from the group that It consists of alkyl, alkenyl and alkynyl.

In some embodiment, each RE is independently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, amino, imino and aldehyde, wherein the amino is optionally substituted with one or two independently selected alkyls.

In some embodiment, each RE is independently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, amino, imino, aldehyde and alkylamino.

In some embodiment, each RE is independently selected from the group consisting of chlorine, fluorine, nitro, hydroxy, oxo, carboxy, amino, imino, aldehyde and alkylamino.

In some embodiment, each RE is independently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, cyano, amino, imino and azido. In some of these embodiments, each RE is halo. In other such embodiments, each RE is nitro. In other such embodiments, each RE is hydroxy. In other such embodiments, each RE is oxo. In other such embodiments, each RE is carboxy. In other such embodiments, each RE is cyano. In another of these embodiments, each RE is amino. In another of these embodiments each RE is imino. In said further additional embodiments, each RE is azido.

In some embodiments, each RE is independently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, cyano, amino and imino.

B10 RF substituent.

Each RF is independently selected from the group consisting of alkyl, alkenyl and alkynyl, in which:

each of said substituents is optionally substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyl , alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl, in which:

the amino, imino, aminosulfonyl, aminocarbonyl, carbocyclyl and heterocyclyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl, alkylsulfonyl, alkylsulfonylamino, hydroxy and alkyloxy,

in which:

the amino portion of the alkylsulfonylamino is optionally substituted with a substituent selected from the group consisting of alkyl, alkenyl and alkynyl.

In some embodiment, each RF is independently selected from the group consisting of alkyl, alkenyl and alkynyl, in which:

each of said substituents is optionally substituted with one or more substituents independently selected from the group consisting of 0 in carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyl , alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl, in which:

The amino, imino, aminosulfonyl and aminocarbonyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl, alkylsulfonyl and alkylsulfonylamino, wherein:

the amino portion of the alkylsulfonylamino is optionally substituted with a substituent selected from the group consisting of alkyl, alkenyl and alkynyl.

In some of the above embodiments, each RF is independently selected from the group consisting of alkyl, alkynyl and alkynyl, in which said substituents are not substituted.

In some embodiments, each RF is independently selected from the group consisting of alkyl, alkenyl and alkynyl, in which:

each of said substituents is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl, in which:

the amino, imino, aminosulfonyl and aminocarbonyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkylsulfonyl and alkylsulfonylamino, in which:

the amino portion of the alkylsulfonylamino is optionally substituted with alkyl.

In some embodiments, each RF is an independently selected alkyl, optionally substituted with a substituent selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl, in which:

the amino, imino, aminosulfonyl and aminocarbonyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkylsulfonyl and alkylsulfonylamino, in which:

the amino portion of the alkylsulfonylamino is optionally substituted with alkyl.

In some embodiments, each RF is an independently selected alkyl, optionally substituted with a substituent selected from the group consisting of carboxy, halo, amino, imino and aminosulfonyl, in which:

the amino, imino and aminosulfonyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkylsulfonyl and alkylsulfonylamino.

In some embodiments, each RF is an independently selected alkyl, optionally substituted with amino, wherein the amino is optionally substituted with alkylsulfonyl.

In some embodiments, each RF is an independently selected alkyl substituted with amino, wherein the amino is substituted with alkylsulfonyl. In some of said embodiments, each RF is methylsulfonylaminomethyl.

In some embodiments, each RF is independently selected from the group consisting of alkyl, alkenyl and alkynyl, in which:

each of said Substituents is optionally substituted with one, two or three substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkyloxycarbonyl, alkylcarbonyloxy , alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl.

In some embodiments, each RF is independently selected alkyl substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl.

B11 RG substituent.

Each RG is independently selected from the group consisting of carbocyclyl and heterocyclyl, in which:

each of said substituents is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkyloxycarbonyl, alkylcarbonyloxy , alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl, in which:

the amino, aminosulfonyl and aminocarbonyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl and alkylsulfonyl.

In some of the above embodiments, each RG is independently selected from the group consisting of carbocyclyl and heterocyclyl, in which said substituents are not substituted.

In some embodiments, each RG is independently selected from the group consisting of carbocyclyl and heterocyclyl, in which:

each of said substituents is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl , in which:

the amino, aminosulfonyl and aminocarbonyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl and alkylsulfonyl.

In some of the above embodiments, the carbocyclyl is carbocyclyl-C3-C6.

In some of the above embodiments, the heterocyclyl is 5-6 membered heterocyclyl.

B12 RH substituent.

Each RH is independently selected from the group consisting of alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, alkenylsulfonyloxy and alkynylsulfonyloxy, in which:

each of said substituents is optionally substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy , alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl, in which:

the amino, aminosulfonyl and aminocarbonyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl and alkylsulfonyl.

In some of the above embodiments, each RH is independently selected from the group consisting of alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, alkenylsulfonyloxy and alkylsulfonyloxy, in which said substituents are not substituted.

In some embodiments, each RH is independently selected from the group consisting of alkyloxy and alkylsulfonyloxy, in which:

each of said substituents is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl, in the one who:

the amino, aminosulfonyl and aminocarbonyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl and alkylsulfonyl.

In some embodiments, each RH is independently selected from the group consisting of alkyloxy and alkylsulfonyloxy, in which:

each of said substituents is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, cyano and aminocarbonyl, in which:

the amino, aminosulfonyl and aminocarbonyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl and alkylsulfonyl.

In some embodiments, each RH is independently selected from the group consisting of alkyloxy and alkylsulfonyloxy, in which:

each of said substituents is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, cyano and aminocarbonyl.

In some embodiments, each RH is independently selected alkyloxy.

In some embodiments, each RH is independently selected alkylsulfonyloxy.

B13 RI substituent.

Each RI is independently selected from the group consisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aminocarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl and heterocyclylcarbonyl, in which:

(to)

the alkylcarbonyl, alkenylcarbonyl and alkynylcarbonyl are optionally substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxycarbonyloxycarbonyloxycarbonylcarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonylcarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxy alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl, and

(b)

The aminocarbonyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxyalkyl, carbocyclyl, heterocyclyl, alkylsulfonyl, and alkylsulfonylamino, wherein:

the carbocyclyl and heterocyclyl are optionally substituted with one or two substituents independently selected from the group consisting of halo, alkyl and oxo.

In some embodiments, each RI is independently selected from the group consisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aminocarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl and heterocyclylcarbonyl, wherein said substituents are not substituted.

In some embodiments, each RI is independently selected from the group consisting of alkylcarbonyl, aminocarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl and heterocyclylcarbonyl, in which:

(to)

the alkylcarbonyl is optionally substituted with a substituent selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy and aminocarbonyl, and

(b)

The aminocarbonyl is optionally substituted with a substituent selected from the group consisting of alkyl, alkyloxyalkyl, alkylsulfonyl and alkylsulfonylamino.

In some embodiments, each RI is independently selected from the group consisting of alkylcarbonyl and aminocarbonyl, in which: the aminocarbonyl is optionally substituted with a substituent selected from the group consisting of alkyl, alkyloxyalkyl, alkylsulfonyl and alkylsulfonylamino.

In some embodiment, each RI is independently selected from the group consisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl and aminocarbonyl, in which:

(to)

the alkylcarbonyl, alkenylcarbonyl and alkynylcarbonyl are optionally substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxycarbonyloxycarbonyloxycarbonylcarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonylcarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxy alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl, and

(b)

The aminocarbonyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl and alkylsulfonylamino.

In some of the above embodiments, each RI is independently selected from the group consisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl and aminocarbonyl, wherein said substituents are not substituted.

In some embodiments, each RI is independently selected from the group consisting of alkylcarbonyl and aminocarbonyl, in which:

(to)

the alkylcarbonyl is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl, and

(b)

The aminocarbonyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl and alkylsulfonylamino.

In some embodiments, each RI is independently selected from the group consisting of alkylcarbonyl and aminocarbonyl, in which:

(to)

the alkylcarbonyl is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, cyano and aminocarbonyl, and

(b)

the aminocarbonyl is optionally substituted with one or two substituents selected

independently between the group consisting of alkyl and alkylsulfonylamino.

In some embodiments, each RI is independently selected from the group consisting of alkylcarbonyl and aminocarbonyl, in which:

The alkylcarbonyl is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl.

In some embodiments, each RI is independently selected alkylcarbonyl.

In some embodiments, each RI is independently selected aminocarbonyl.

B14 RJ substituents.

Each RJ is independently selected from the group consisting carbociclilsulfonilamino, heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, alquinilcarbonilamino, alkyloxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, alquinilsulfonilamino, aminocarbonylamino, alquiloxicarbonilaminoimino, alquilsulfonilaminoimino, alquenilsulfonilaminoimino and alquinilsulfonilaminoimino, wherein:

(to)

the amino portion of said substituents is optionally substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkenyl, alkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl that:

(one)

the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl are optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido , oxo and amino, and

(2)

the amino portion of the aminocarbonylalkyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl,

(b)

the alkyl, alkenyl and alkynyl portion of said substituents is optionally substituted with one or more substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl and cyano, in which: the amino is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy and alkynyloxy, in which:

the alkyl is optionally substituted with one or more hydroxy;

(C)

the carbocyclyl and heterocyclyl portions of said substituents are optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido and amino, in which:

the amino is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl.

In some embodiment, each RJ is independently selected from the group consisting carbociclilsulfonilamino, heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, alquinilcarbonilamino, alkyloxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, alquinilsulfonilamino, aminocarbonylamino, alquilsulfonilaminoimino, alquenilsulfonilaminoimino and alquinilsulfonilaminoimino, wherein:

(to)

the amino portion of said substituents is optionally substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkenyl, alkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl that:

(one)

the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl are optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido , oxo and amino, and

(2)

the amino portion of the aminocarbonylalkyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl,

(b)

the alkyl, alkenyl and alkynyl portion of said substituents is optionally substituted with one or more substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl and cyano, in the that:

The amino is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy and alkynyloxy, in which:

the alkyl is optionally substituted with one or more hydroxy;

(c) the carbocyclyl and heterocyclyl portions of said substituents are optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido and amino, in which:

the amino is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl; Y

In any of the above embodiments, each RJ is independently selected from the group consisting carbociclilsulfonilamino, heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, alquinilcarbonilamino, alkyloxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, alquinilsulfonilamino, aminocarbonylamino, alquilsulfonilaminoimino, alquenilsulfonilaminoimino and alquinilsulfonilaminoimino in which said substituents are not substituted.

In some embodiments, each RJ is independently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino, alkyloxycarbonylamino, alkylsulfonylamino, aminocarbonylamino and alkylsulfonylaminoimino, in which:

(to)

the amino portion of said substituents is optionally substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl and alkylsulfonyl:

(one)

the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo and amino, and

(2)

the amino portion of the aminocarbonylalkyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl,

(b)

the alkyl portion of said substituents is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl and cyano, in which:

the amino is optionally substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, in which:

the alkyl is optionally substituted with one or more hydroxy;

(c) the carbocyclyl and heterocyclyl portions of said substituents are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano and amino, in which:

the amino is optionally substituted with one or two independently selected alkyl substituents.

In some embodiments, each RJ is independently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylsulfonylamino and alkylsulfonylaminoimino, in which:

(to)

the amino portion of said substituents is optionally substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl and alkylsulfonyl:

(one)

the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo and amino, and

(2)

the amino portion of the aminocarbonylalkyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl,

(b)

the alkyl portion of said substituents is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl and cyano, in which:

the amino is optionally substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, in which:

the alkyl is optionally substituted with one or more hydroxy;

(c) the carbocyclyl and heterocyclyl portions of said substituents are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano and amino, in which:

the amino is optionally substituted with one or two independently selected alkyl substituents

In some embodiments, each RJ is independently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylsulfonylamino and alkylsulfonylaminoimino, in which:

the amino portion of said substituents is optionally substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl and alkylsulfonyl:

(one)

the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo and amino, and

(2)

the amino portion of the aminocarbonylalkyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl.

In some embodiments, each RJ is independently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylsulfonylamino and alkylsulfonylaminoimino, in which:

the alkyl portion of the alkylsulfonylamino and alkylsulfonylaminoimino is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl and cyano, in which:

the amino is optionally substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, in which:

the alkyl is optionally substituted with one or more hydroxy.

In some embodiments, each RJ is independently selected from the group consisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylsulfonylamino and alkylsulfonylaminoimino, in which:

the carbocyclyl and heterocyclyl portions of said substituents are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano and amino.

In some embodiments, each RJ is independently selected from the group consisting of carbocyclylsulfonylamino and heterocyclylsulfonylamino, in which:

the carbocyclyl and heterocyclyl portions of said substituents are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano and amino.

In some embodiments, each RJ is independently selected from the group consisting of alkylsulfonylamino, alkenylsulfonylamino, alkylsulfonylamino and alkylsulfonylaminoimino, in which:

(to)

the amino portion of said substituents is optionally substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl and alkylsulfonyl:

(one)

the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl are optionally substituted with one or two substituents independently selected from the group that

it consists of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo and amino, and

(2)

the amino portion of the aminocarbonylalkyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl,

(b)

the alkyl, alkenyl and alkyl portion of said substituents is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl and cyano, in the that:

the amino is optionally substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, in which:

the alkyl is optionally substituted with one or more hydroxy.

In some embodiments, each RJ is an independently selected alkylsulfonylamino, in which:

(to)

the amino portion of the alkylsulfonylamino is optionally substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulf

(one)

the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo and amino, and

(2)

the amino portion of the aminocarbonylalkyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl,

(b)

the alkyl portion of the alkylsulfonylamino is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl and cyano, in which:

the amino is optionally substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, in which:

the alkyl is optionally substituted with one or more hydroxy.

In some embodiments, each RJ is an independently selected alkylsulfonylamino, in which:

the amino portion of the alkylsulfonylamino is optionally substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulf

(one)

the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo and amino, and

(2)

the amino portion of the aminocarbonylalkyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl.

In some embodiments, each RJ is an independently selected alkylsulfonylamino, in which: the amino portion of the alkylsulfonylamino is optionally substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyloxy, , alkylcarbonyloxyalkyl and alkylsulfonyl.

In some embodiments, each RJ is an independently selected alkylsulfonylamino, in which:

the alkyl portion of the alkylsulfonylamino is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl and cyano, in which:

the amino is optionally substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, in which: the alkyl is optionally substituted with one or more hydroxy.

In some embodiments, each RJ is an independently selected alkylsulfonylamino, wherein: the alkyl portion of the alkylsulfonylamino is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy , alkyloxy, carbocyclyl, heterocyclyl and cyano.

In some embodiments, each RJ is an independently selected alkylsulfonylamino. In some of said embodiments, each RJ is methylsulfonylamino.

In some embodiments, each RJ is an independently selected alkylsulfonylaminoimino, in which:

(to)

the amino portion of the alkylsulfonylaminoimino is optionally substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl:

(one)

the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo and amino, and

(2)

the amino portion of the aminocarbonylalkyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl,

(b)

the alkyl portion of the alkylsulfonylaminoimino is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl and cyano, in which:

the amino is optionally substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, in which:

the alkyl is optionally substituted with one or more hydroxy.

In some embodiments, each RJ is an independently selected alkylsulfonylaminoimino, in which:

the amino portion of the alkylsulfonylaminoimino is optionally substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl:

(one)

the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo and amino, and

(2)

the amino portion of the aminocarbonylalkyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl.

In some embodiments, each RJ is an independently selected alkylsulfonylaminoimino, in which:

the amino portion of the alkylsulfonylaminoimino is optionally substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl.

In some embodiments, each RJ is an independently selected alkylsulfonylaminoimino, in which:

the alkyl portion of the alkylsulfonylaminoimino is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl and cyano, in which:

the amino is optionally substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, in which:

the alkyl is optionally substituted with one or more hydroxy.

In some embodiments, each RJ is an independently selected alkylsulfonylaminoimino, in which:

the alkyl portion of the alkylsulfonylaminoimino is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl and cyano.

In some embodiments, each RJ is an independently selected alkylsulfonylaminoimino. In some of said embodiments, each RJ is methylsulfonylaminoimino.

In some embodiments, each RJ is independently selected from the group consisting of alkylcarbonylamino and alkyloxycarbonylamino, in which:

the alkyl portion of said substituents is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl and cyano.

B15 RK substituent.

Each RK is independently selected from the group consisting of aminosulfonyl, alkylsulfonyl, alkenylsulfonyl and alkylsulfonyl, in which:

(to)

the alkylsulfonyl, alkenylsulfonyl and alkynylsulfonyl are optionally substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylaryloxycarbonyloxy, alkyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxy alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl, in which:

the amino, aminosulfonyl and aminocarbonyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl; Y

(b)

the aminosulfonyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl.

In some of the above embodiments, each RK is independently selected from the group consisting of aminosulfonyl, alkylsulfonyl, alkenylsulfonyl and alkylsulfonyl, wherein said substituents are not substituted.

In some embodiments, each RK is independently selected from the group consisting of aminosulfonyl and alkylsulfonyl, in which:

(to)

the alkylsulfonyl is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl; Y

(b)

the aminosulfonyl is optionally substituted with one or two independently selected alkyl substituents.

In some embodiments, each RK is independently selected from the group consisting of aminosulfonyl and alkylsulfonyl.

C. Completions of Compounds of Formula I.

Various embodiments of substituents R1, R2, R3, R4, R5, L, RA, RB, RC, RD, R6, RE, RF, RG, RH, RI, RJ and RK have been described above. These substituent embodiments may be combined to form various embodiments of the compounds of the formula I. All embodiments of the Compounds of the formula I formed by combining the substituent embodiments described above are within the scope of the Applicants' invention, and some embodiments Illustrative of the compounds of formula I are provided below.

In some embodiments, in the compounds of the formula I:

image 1 is selected from the group consisting of carbon-carbon single bond and carbon-carbon double bond; R1 is selected from the group consisting of hydrogen and methyl; R2 is selected from the group consisting of hydrogen and halo; R3 is selected from the group consisting of hydrogen and halo; R4 is selected from the group consisting of C1-C4 alkyl, C3-C6 carbocyclyl and 5-6 membered heterocyclyl, in which:

(to)

C1-C4 alkyl is optionally substituted with up to three substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy and trimethylsilyl, and

(b)

the 5-6 membered carbocyclyl-C3-C6 and heterocyclyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo and alkylsulfonylamino;

R5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy and halo; L is selected from the group consisting of C (RA) = C (RB), ethylene and cyclopropyl-1,2-ene; one of RA and RB is hydrogen and the other is selected from the group consisting of hydrogen, methyl, methoxy and halo; R6 is selected from the group consisting of carbocyclyl-C5-C6 and 5-6 membered heterocyclyl, in which each of said substituents is substituted with one, two or three substituents selected independently between the group consisting of RE, RF and RJ; each RE is independently selected from the group consisting of chlorine, fluorine, nitro, hydroxy, oxo, carboxy, amino, imino, aldehyde and alkylamino; each RF is an independently selected alkyl, optionally substituted with a substituent selected from the group consisting of carboxy, halo, amino, imino and aminosulfonyl, in which:

the amino, imino and aminosulfonyl are optionally substituted with one or two substituents selected

independently from the group consisting of alkyl, alkylsulfonyl and alkylsulfonylamino; each RI is independently selected from the group consisting of alkylcarbonyl and aminocarbonyl, in which:

the aminocarbonyl is optionally substituted with a substituent selected from the group consisting

in alkyl, alkyloxyalkyl, alkylsulfonyl and alkylsulfonylamino; and each RJ is independently selected from the group consisting of alkylsulfonylamino, alkenylsulfonylamino, alkylsulfonylamino and alkylsulfonylaminoimino, in which:

(to)

the amino portion of said substituents is optionally substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl and alkylsulfonyl:

(one)

the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo and amino, and

(2)

the amino portion of the aminocarbonylalkyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl,

(b)

the alkyl, alkenyl and alkyl portion of said substituents is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl and cyano, in the that:

the amino is optionally substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, in which the alkyl is optionally substituted with one or more hydroxy.

Examples of the compounds of the formula I (and salts thereof) are shown below in Tables 1-7. The subsequent synthesis examples provide step-by-step preparation instructions for any of these compounds. The remaining compounds were prepared using the description of the general preparation method, subsequent specific synthesis examples and / or the description throughout the present application.

TABLE 1

compound

R5 RB Substitute (s)

IA-L1-1.3

-OCH3 -CI -4-N (H) S (O) 2CH3 [Z]

IA-L1-1.4

-OCH3 -F -4-N (H) S (O) 2CH3 [Z]

IA-L1-1.5

-OCH3 -F -4-N (H) S (O) 2CH3 [E]

IA-L1-1.6

-OCH3 -CH3 -4-N (H) S (O) 2CH3 [E]

IA-L1-1.9

-OCH3 -H -4-N (H) S (O) 2CH3 [E]

IA-L1-1.10

-OCH3 -H -4-N (H) S (O) 2CH3 [Z]

IA-L1-1.11

-OCH3 -H -4-N [C (O) CH3] S (O) 2CH3 [E]

IA-L1-1.12

-OCH3 -H -4-F [E]

IA-L1-1.13

-OCH3 -H -4-NH2 [E]

IA-L1-1.14

-OCH3 -H -4-OCH3 [E]

IA-L1-1.16

-H -H -4-N (H) S (O) 2CH3 [E]

IA-L1-1.17

-OCH3 -OCH3 -4-N (H) S (O) 2CH3 [Z]

IA-L1-1.18

-OCH3 -H -[AND]

IA-L1-1.20

-OCH3 -H -4-N (H) S (O) 2CH3 [Z]

IA-L1-1.21

-OCH3 -F -4-N (H) S (O) 2CH3 [Z]: [E] (1: 1)

IA-L1-1.22

-OCH3 -H -4-NO2 [E]

IA-L1-1.23

-OCH3 -Cl -4-NO2 [Z]

IA-L1-1.24

-OCH3 -CH3 -4-NO2 [E]

IA-L1-1.25

-H -H -4-NO2 [E]

IA-L1-1.26

-OCH3 -H -3-F and -4-N (H) S (O) 2CH3 [E]

IA-L1-1.27

-OCH3 -H -2-OCH3 and -4-N (H) S (O) 2CH3 [E]

TABLE 2

Compound

Substitute (s)

IB-L1-1.1

-4-N (H) S (O) 2CH3 [E]

IB-L1-1.4

-2-C (O) OH and -4-N (H) S (O) 2CH3 [E]

IB-L1-1.5

-3-F and -4-N (H) S (O) 2CH3 [E]

IB-L1-1.6

-2-C (O) H and -4-N (H) S (O) 2CH3 [E]

IB-L1-1.7

-2-C (O) OCH3 and -4-N (H) S (O) 2CH3 [E]

IB-L1-1.8

-2-C (H) = N (OH) and -4-N (H) S (O) 2CH3 [E]

IB-L1-1.9

-2-C (O) N (H) CH2CH2OCH3 and -4-N (H) S (O) 2CH3 [E]

IB-L1-1.10

-2-CH2OH and -4-N (H) S (O) 2CH3 [E]

IB-L1-1.11

-2-C (O) OC (H) 2CH3 and 4-N (H) S (O) 2CH3 [E]

IB-L1-1.13

-2-C (H) 2OCH3 and -4-N (H) S (O) 2CH3 [E]

IB-L1-1.14

-2-C (O) N (CH3) 2 and -4-N (H) S (O) 2CH3 [E]

IB-L1-1.15

-2-CH3 and -4-N (H) S (O) 2CH3 and -5-F [E]

IB-L1-1.16

imidazol-2-yl and -4-N (H) S (O) 2CH3 [E]

IB-L1-1.17

-2-C (O) N (H) CH3 and -4-N (H) S (O) 2CH3 [E]

(Cont.)

Compound

Substitute (s)

IB-L1-1.18

-2 and -4-N (H) S (O) 2CH3 [E]

IB-L1-1.19

-2-C (H) = NOCH3 and -4-N (H) S (O) 2CH3 [E]

IB-L1-1.21

-2-C (O) NH2 and -4-N (H) S (O) 2CH3 [E]

IB-L1-1.22

-2 and -4-N (H) S (O) 2CH3 [E]

IB-L1-1.23

-2 and 4-N (H) S (O) 2CH3 [E]

IB-L1-1.14

-2-C (O) N (CH3) C (H) 2C (H) 2OCH3 and-4N (H) S (O) 2CH3 [E]

IB-L1-1.25

-2-C (H) 2OC (H) (CH3) 2 and 4-N (H) S (O) 2CH3 [E]

IB-L1-1.26

-2 and -4-N (H) S (O) 2CH3 [E]

IB-L1-1.27

-2 and 4-N (MS (O) 2CH3 [E]

IB-L1-1.28

-2-NH2 and -4-N (H) S (O) 2CH3 [E]

IB-L1-1.29

-2 and -4-N (H) S (O) 2CH3 [E]

IB-L1-1.31

-2-C (H) 2N (H) C (H) 2C (H) C (H) (CH3) 2 and-4N (H) S (O) 2CH3 [E]

IB-L1-1.32

-2-N (H) C (O) OC (CH) 3 and -4-N (H) S (O) 2CH3 [E]

IB-L1-1.33

-2 and 4-N (H) S (O) 2CH3 [E]

IB-L1-1.34

-4-N (H) S (O) 2CH3 [Z]

TABLE 3

Compound

R4

IB-L1-1.45

-C (CH3) 2C (H) 2OH [E]

IB-L1-1.46

furan-2-yl [E]

IB-L1-1.47

[AND]

IB-L1-1.48

[AND]

IB-L1-1.49

-S (O) 2CH3 [E]

IB-L1-1.50

furan-3-ilo [E]

IB-L1-1.51

-l [E]

IB-L1-1.52

-Br [E]

IB-L1-1.53

pyridin-3-yl [E]

IB-L1-1.55

pyridin-4-yl [E]

TABLE 4

Compound

R2 R5

IB-L1-1.2

-F -OCH3 [E]

IB-L1-1.12

-H -CI [E]

IB-L1-1.20

-CI -OCH3 [E]

IB-L1-1.30

-H -OCH2CH3 [E]

TABLE 5 TABLE 6

compound

R5

IA-L5-2-1.1

-OCH3

IA-L5-2-1.2

-H

Compound

Substitute (s)

IB-L5-2-1.1

-2-C (O) OCH3 and -4-N (H) S (O) 2CH3

IB-L5-2-1.2

-4-N (H) S (O) 2CH3

TABLE 7

image 1

D. Isomers.

The present invention also relates, in part, to all stereoisomers of the compounds of the formula I (and salts thereof). Stereoisomers include E / Z isomers (i.e., isomers with respect to one or more double bonds), enantiomers (i.e., stereoisomers having opposite configurations at all stereogenic centers) and diastereoisomers (i.e., stereoisomers having the same configuration in one or more stereogenic centers, but they differ in other stereogenic centers).

fifteen

E. Sales.

The present also refers, in part, to all salts of the compound of the formula I. A salt of a compound may be advantageous due to one or more of the properties of the salt, such as, for example, pharmaceutical stability. improved at different temperatures and humidity or a desirable solubility in water or other solvents. When a patient intends to administer a salt (as opposed to, for example, being used in an in vitro context), the salt is preferably pharmaceutically acceptable and / or physiologically compatible. The term "pharmaceutically acceptable" is used as an adjective in the present patent application to indicate that the indicated name is suitable for use as a pharmaceutical product or as part of a product

25 pharmacist Pharmaceutically acceptable salts include salts that are commonly used to form alkali metal salts and to form free acid addition salts or free bases. In general, these salts can typically be prepared by conventional means by reacting, for example, the suitable acid or base with a compound of the invention.

The pharmaceutically acceptable acid addition salts of the compounds of the formula I can be prepared from an inorganic or organic acid. Examples of suitable suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acids. Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids. Specific examples of suitable suitable organic acids include

35 acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, stearate, stearate , p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), ethanesulfonate, benzenesulfonate, pantothenate, 2-hydroxyethanesulfonate, sulfanylate, cyclohexylaminosulfonate, alginic acid, beta-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, bisrate, alginate, bisrate, alginate, bisrate, alginate, bisrate, alginate, biscate

40 camphorsulfonate, cyclopentanepropionate, dodecyl sulfate, glycoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate, oxalate, palmoate, pectinate, 2-naphthanesulfonate, 3-phenylpropionate, picrate, pivalate, thiocyanate, cough and undecanoate.

The base addition salts of the compounds of the formula I include, for example, metal salts and organic salts. Preferred metal salts include alkali metal salts (group la), alkaline earth metal salts (group Ila) and other physiologically acceptable metal salts. Said salts can be manufactured from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Preferred organic salts can be made from amines, such as tromethamine, diethylamine, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. The basic groups containing nitrogen can be quaternized with agents, such as lower alkyl (C1-C6) halides (for example, chlorides, bromides and iodides of methyl, ethyl, propyl and butyl), dialkyl sulfates (for example, sulfates of dimethyl, diethyl, dibutyl and diamyl), long chain halides (for example, chlorides, bromides and iodides of decyl, lauryl, myristyl and stearyl), arylalkyl halides (for example, benzyl and phenethyl bromides) and others.

In some embodiments, the salt is sodium salt of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxycyryl ) phenyl) methanesulfonamide.

In some embodiments, the salt is potassium salt of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxycyryl ) phenyl) methanesulfonamide.

In some embodiments, the salt is potassium salt of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin- (2H) -yl) -2-methoxistiryl) phenyl) methanesulfonamide.

In some embodiments, the salt is monopotassium salt of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) yl) -2- methoxystyryl) phenyl) methanesulfonamide.

F. Purity.

Compounds of the formula I (and salts thereof) with any level of purity (including pure and substantially pure) are within the scope of the Applicants' invention. The term "substantially pure" in reference to compound / salt / isomer, means that the preparation / composition containing the compound / salt / isomer contains more than about 85% by weight of the compound / salt / isomer, preferably more than about 90% by weight of the compound / salt / isomer, preferably more than about 95% by weight of the compound / salt / isomer, preferably more than about 97% by weight of the compound / salt / isomer and preferably more than about 99% by weight of the compound / salt / isomer.

G. Crystalline Forms of Some Specific Compounds and Salts of the Invention.

G1. Crystalline Forms of Disodium Salt of (E) -N- (4- (3-tert-Butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) phenyl) methanesulfonamide .

The present invention also relates, in part, to crystalline forms of disodium salt of (E) -N- (4- (3-tert-butyl-5 (2,4-dioxo-3,4-dihydropyrimidin-1 (2H ) -yl) 2-methoxystyryl) phenyl) methanesulfonamide, specifically the crystalline forms nonahydrate and tetrahydrate are described below.

The present invention relates, in part, to a crystalline disodium salt nonahydrate. The crystallographic parameters of the unit cell of the crystalline disodium salt nonahydrate were determined to be as follows: a is 8.9 Å, b is 9.4 Å and c is 20.7 Å (more precisely, a is 8.926 ( 2) Å, b is 9,415 (2) Å and c is 20,674 (5) Å); The cell angles are: α -94.8 °, β -93.3 ° and γ -107.0 ° (more precisely, α is 94.796 (4) °, β is 93.345 (4) ° and γ is 107,013 (4) °); and the cell volume is 1649 Å3 (more precisely, 1649.3 (7) Å3. The salt crystallizes in the spatial group P-1.

In some embodiments, the disodium salt nonahydrate has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 4.3 ± 0.2, 10.4 ± 0.2, 10.9 ± 0.2, 11.6 ± 0.2, 12.9 ± 0.2, 14.7 ± 0.2, 16.4 ± 0.2, 17.8 ± 0.2, 19.4 ± 0 , 2, 19.8 ± 0.2, 20.8 ± 0.2, 21.9 ± 0.2 and 23.5 ± 0.2 degrees 2θ. In some of said embodiments, the disodium salt nonahydrate has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 4.3 ± 0.2, 10.4 ± 0.2, 10 , 9 ± 0.2, 11.6 ± 0.2, 12.9 ± 0.2, 14.7 ± 0.2, 16.4 ± 0.2, 17.8 ± 0.2, 19.4 ± 0.2, 19.9 ± 0.2, 20.8 ± 0.2, 21.9 ± 0.2 and 23.5 ± 0.2 degrees 2θ. In other such embodiments, the disodium salt nonahydrate has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 4.3 ± 0.2, 10.4 ± 0.2, 10 , 9 ± 0.2, 11.6 ± 0.2, 12.9 ± 0.2, 14.7 ± 0.2, 16.4 ± 0.2, 17.9 ± 0.2, 19.4 ± 0.2, 19.8 ± 0.2, 20.8 ± 0.2, 21.9 ± 0.2 and 23.5 ± 0.2 degrees 2θ.

In some embodiments, the disodium salt nonahydrate has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 4.3 ± 0.2, 10.4 ± 0.2, 10.9 ± 0.2, 11.6 ± 0.2, 12.9 ± 0.2, 14.7 ± 0.2, 14.9 ± 0.2, 16.4 ± 0.2, 17.8 ± 0 , 2, 19.4 ± 0.2, 19.7 ± 0.2, 19.8 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.9 ± 0.2 , 22.1 ± 0.2 and 23.5 ± 0.2 degrees 2θ. In some of said embodiments, the disodium salt nonahydrate has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 4.3 ± 0.2, 10.4 ± 0.2, 10 , 9 ± 0.2, 11.6 ± 0.2, 12.9 ± 0.2, 14.7 ± 0.2, 14.9 ± 0.2, 16.4 ± 0.2, 17.8 ± 0.2, 19.4 ± 0.2, 19.7 ± 0.2, 19.8 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.9 ± 0 , 2, 22.1 ± 0.2 and 23.5 ± 0.2 degrees 2θ. In other such embodiments, the disodium salt nonahydrate has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 4.3 ± 0.2, 10.4 ± 0.2, 10 , 9 ± 0.2, 11.6 ± 10.2, 12.9 ± 0.2, 14.7 ± 0.2, 14.9 ± 0.2, 16.4 ± 0.2, 17.8 ± 0.2, 19.4 ± 0.2, 19.7 ± 0.2, 19.8 ± 0.2, 20.8 ± 0.2, 20.9 ± 0.2, 21.9 ± 0 , 2, 22.1 ± 0.2 and 23.5 ± 0.2 degrees 2θ.

In some embodiments, the disodium salt nonahydrate has a powder X-ray diffraction pattern substantially as shown in Figure 1. The 2θ values for the peaks in Figure 1 (and their intensities) are as follows: 4.31 (100), 10.36 (12), 10.91 (23), 11.61 (52), 12.93 (24), 14.73 (65), 14.89 (20), 16 , 44 (41), 17.80 (38), 19.44 (26), 19.67 (37), 19.83 (59), 20.75 (69), 20.89 (21), 21, 92 (43), 22.13

(40) and 22.42 (24).

The present invention also relates, in part, to a process for preparing the disodium salt nonahydrate. This was prepared in an aqueous medium. Aqueous NaOH (1 M, 1.18 ml) was added to (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl)) -2-methoxystyryl) phenyl) methanesulfonamide (compound IB-L1-1.1) (27.82 mg) (acidic molar ratio: base 1:20). The resulting suspension was equilibrated at ambient conditions. The disodium salt nonahydrate was formed seven days later through a solution-mediated process. Alternatively, the disodium salt nonahydrate was prepared by suspending 278.8 mg of compound IB-L1-1.1 in 1.25 ml of THF while heating at 50 ° C. Aqueous NaOH (1 N, 1.5 ml, 2.2 molar equivalents) was added. The solid was completely redissolved to produce a clear solution, which cooled naturally to room temperature. The salt crystallized spontaneously. The molecular structure was determined by simple crystalline diffractometry.

The present invention relates, in part, to a crystalline disodium salt tetrahydrate.

In some embodiments, the tetrahydrate disodium salt has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 4.8 ± 0.2, 12.1 ± 0.2, 14.0 ± 0.2, 17.0 ± 0.2, 17.5 ± 0.2, 20.9 ± 0.2, 21.6 ± 0.2, 25.0 ± 0.2 and 29.5 ± 0 , 2 degrees 2θ. In some of said embodiments, the tetrahydrate disodium salt has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 4.8 ± 0.2, 12.1 ± 0.2, 14 , 0 ± 0.2, 17.0 ± 0.2, 17.5 ± 0.2, 20.9 ± 0.2, 21.6 ± 0.2, 25.0 ± 0.2 and 29.5 ± 0.2 degrees 2θ. In other such embodiments, the tetrahydrate disodium salt has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 4.8 ± 0.2, 12.1 ± 0.2, 14 , 0 ± 0.2, 17.0 ± 0.2, 17.5 ±: 0.2, 20.9 ± 0.2, 21.6 ± 0.2, 25.0 ± 0.2 and 29, 5 ± 0.2 degrees 2θ.

In some embodiments, the tetrahydrate disodium salt has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 4.8 ± 0.2, 12.1 ± 0.2, 14.0 ± 0.2, 14.4 ± 0.2, 17.0 ± 0.2, 17.5 ± 0.2, 20.9 ± 0.2, 21.6 ± 0.2, 25.0 ± 0 , 2, 29.5 ± 0.2 and 34.2 ± 0.2 degrees 2θ. In some of said embodiments, the tetrahydrate disodium salt has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 4.8 ± 0.2, 12.1 ± 0.2, 14 , 0 ± 0.2, 14.4 ± 0.2, 17.0 ± 0.2, 17.5 ± 0.2, 20.9 ± 0.2, 21.6 ± 0.2, 25.0 ± 0.2, 29.5 ± 0.2 and 34.2 ± 0.2 degrees 2θ. In other such embodiments, the tetrahydrate disodium salt has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 4.8 ± 0.2, 12, ± 0.2, 14, 0 ± 0.2, 14.4 ± 0.2, 17.0 ± 0.2, 17.5 ± 0.2, 20.9 ± 0.2, 21.6 ± 0.2, 25.0 ± 0.2, 29.5 ± 0.2 and 34.2 ± 0.2 degrees 2θ. In some embodiments, the tetrahydrate disodium salt has a powder X-ray diffraction pattern substantially as shown in Figure 2. The 2θ values for the peaks in Figure 2 (and their intensities) are as follows: 4.81 (100), 12.07 (7), 14.01 (27), 14.41 (8), 16.96 (18), 17.53 (11), 20.87 (18), 21 , 58 (22), 24.99 (11), 29.47 (9) and 34.20 (9).

The present invention also relates, in part, to a process for preparing the disodium salt tetrahydrate by suspending the disodium salt nonahydrate in an organic solvent (for example, ethanol, 1-propanol or 2-propanol).

G2 Crystalline Form of Dipotassium Salt of (E) -N- (4- (3-tert-Butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) phenyl) methanesulfonamide .

The present invention also relates, in part, to a crystalline dipotassium salt tetrahydrate of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1- (2H ) -yl) -2-methoxystyryl) phenyl) methanesulfonamide.

The crystallographic parameters of the unit cell dipotassium salt tetrahydrate were determined to be as follows: a is 14.5 Å, b is 10.8 Å and c is 35.8 Å (more precisely, a is 14.454 ( 14) Å, b is 10,763 (14) Å and c is 35.75 (4) Å); the angle of the cell is β 98.8 ° (more precisely, β is 98.82 (3) °); and the cell volume is 5499 Å3 (more precisely, 5499 (11) Å3). Salt crystallizes in the C2 / c space group.

In some embodiments, the dipotassium salt tetrahydrate has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 5.0 ± 0.2, 11.9 ± 0.2, 12.4 ± 0.2, 13.7 ± 0.2, 15.0 ± 0.2, 16.5 ± 0.2, 17.1 ± 0.2, 20.8 ± 0.2, 21.3 ± 0 , 2, 22.2 ± 0.2, 24.0 ± 0.2, 26.4 ± 0.2 and 29.3 ± 0.2 degrees 2θ. In some of said embodiments, the dipotassium tetrahydrate salt has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 5.0 ± 0.2, 11.9 ± 0.2, 12 , 4 ± 0.2, 13.7 ± 0.2, 15.0 ± 0.2, 16.5 ± 0.2, 17.1 ± 0.2, 20.8 ± 0.2, 21.3 ± 0.2, 22.2 ± 0.2, 24.0 ± 0.2, 26.4 ± 0.2 and 29.3 ± 0.2 degrees 2θ. In other such embodiments, the dipotassium tetrahydrate salt has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 5.0 ± 0.2, 11.9 ± 0.2, 12 , 4 ± 0.2, 13.7 ± 0.2, 15.0 ± 0.2, 16.5 ± 0.2, 17.1 ± 0.2, 20.8 ± 0.2, 21.3 ± 0.2, 22.2 ± 0.2, 24.0 ± 0.2, 26.4 ± 0.2 and 29.3 ± 0.2 degrees 2θ.

In some embodiments, the dipotassium salt tetrahydrate has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 5.0 ± 0.2, 11.9 ± 0.2, 12.4 ± 0.2, 12.6 ± 0.2, 13.7 ± 0.2, 15.0 ± 0.2, 16.5 ± 0.2, 16.7 ± 0.2, 17.1 ± 0 , 2, 20.7 ± 0.2, 20.8 ± 0.2, 21.3 ± 0.2, 22.2 ± 0.2, 22.4 ± 0.2, 24.0 ± 0.2 , 26.4 ± 0.2 and 29.3 ± 0.2 degrees 20. In some of these embodiments, the dipotassium salt tetrahydrate has a powder X-ray diffraction pattern comprising three or more peaks selected from the group that consists of 5.0 ± 0.2, 11.9 ± 0.2, 12.4 ± 0.2, 12.6 ± 0.2, 13.7 ± 0.2, 15.0 ± 0.2, 16.5 ± 0.2, 16.7 ± 0.2, 17.1 ± 0.2, 20.7 ± 0.2, 20.8 ± 0.2, 21.3 ± 0.2, 22, 2 ± 0.2, 22.4 ± 0.2, 24.0 ± 0.2, 26.4 ± 0.2 and 29.3 ± 0.2 degrees 2θ. In other such embodiments, the dipotassium tetrahydrate salt has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 5.0 ± 0.2, 11.9 ± 0.2, 12 , 4 ± 0.2, 12.6 ± 0.2, 13.7 ± 0.2, 15.0 ± 0.2, 16.5 ± 0.2, 16.7 ± 0.2, 17.1 ± 0.2, 20.7 ± 0.2, 20.8 ± 0.2, 21.3 ± 0.2, 22.2 ± 0.2, 22.4 ± 0.2, 24.0 ± 0 , 2, 26.4 ± 0.2 and 29.3 ± 0.2 degrees 2θ.

In some embodiments, the dipotassium tetrahydrate salt has a powder X-ray diffraction pattern substantially as shown in Figure 4. The 2θ values for the peaks in Figure 4 (and their intensities) are as follows: 5.00 (100), 11.86 (34), 12.39 (32), 12.64 (19), 13.70 (23), 15.03 (21), 16.47 (24), 16 , 66 (24), 17.12 (28), 20.75 (29), 20.81 (33), 21.34 (22), 22.15 (46), 22.38 (31), 24, 02 (24), 26.44

(24) and 29.32 (21).

The present invention also relates, in part, to a process for preparing the dipotassium salt tetrahydrate by suspending the compound D3-L1-1.1 (261.13 mg) in THF for 1.25 min while heating at 50 ° C. Aqueous KOH (1 N, 1.3 ml, 2.2 molar equivalents) was added. The solid dissolved completely to produce a clear suspension, which cooled naturally to room temperature. Crystallization occurred during the slow evaporation process.

G3 Crystalline form of Monopotassium Salt of (E) -N- (4- (3-tert-Butyl-5- (2,4-diaro-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) phenyl) methanesulfonamide .

The present invention also relates, in part, to crystalline forms of monopotassium salt of (E) -N- (4- (3-tert-butyl5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) phenyl) methanesulfonamide, specifically the crystalline trihydrate and dihydrate forms described below.

The present invention relates, in part, to a monopotassium salt trihydrate. The crystallographic parameters of the unit cell of the crystalline monopotassium salt trihydrate were determined to be as follows: a is 9.0 Å, b is 8.3 Å and c is 18.6 Å (more precisely, a is 9, 0393 (16) Å, b is 8.3332 (15) Å and c is 18,582 (3) Å); the angles of the cell are α -80.5 °, β -85.1 ° and γ -80.5 ° (more precisely, α is 80.511 (2) °, β is 85.134 (3) °, and γ is 80,531 (2) °); and the cell volume is 1359 Å3 (more precisely, 1359.3 (4) Å3). Salt crystallizes in the space group P-1.

In some embodiments, the monopotassium salt trihydrate has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 4.8 ± 0.2, 10.8 ± 0.2, 11.3 ± 0.2, 13.4 ± 0.2, 15.3 ± 0.2, 16.9 ± 0.2, 21.2 ± 0.2, 21.7 ± 0.2, 22.1 ± 0 , 2, 22.5 ± 0.2 and 23.0 ± 0.2 degrees 2θ. In some of said embodiments, the monopotassium salt trihydrate has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 4.8 ± 0.2, 10.8 ± 0.2, 11 , 3 ± 0.2, 13.4 ± 0.2, 15.3 ± 0.2, 16.9 ± 0.2, 21.2 ± 0.2, 21.7 ± 0.2, 22.1 ± 0.2, 22.5 ± 0.2 and 23.0 ± 0.2 degrees 2θ. In other such embodiments, the monopotassium salt trihydrate has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 4.8 ± 0.2, 10.8 ± 0.2, 11 , 3 ± 0.2, 13.4 ± 0.2, 15.3 ± 0.2, 16.9 ± 0.2, 21.2 ± 0.2, 21.7 ± 0.2, 22.1 ± 0.2, 22.5 ± 0.2 and 23.0 ± 0.2 degrees 2θ.

In some embodiments, the monopotassium salt trihydrate has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 4.8 ± 0.2, 10.8 ± 0.2, 11.3 ± 0.2, 13.4 ± 0.2, 13.6 ± 0.2, 15.3 ± 0.2, 16.9 ± 0.2, 21.2 ± 0.2, 21.7 ± 0 , 2, 21.7 ± 0.2, 22.1 ± 0.2, 22.5 ± 0.2, 22.6 ± 0.2 and 23.0 ± 0.2 degrees 2θ. In some of these embodiments , the monopotassium salt trihydrate has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 4.8 ± 0.2, 10.8 ± 0.2, 11.3 ± 0, 2, 13.4 ± 0.2, 13.6 ± 0.2, 15.3 ± 0.2, 16.9 ± 0.2, 21.2 ± 0.2, 21.7 ± 0.2, 21.7 ± 0.2, 22.1 ± 0.2, 22.5 ± 0.2, 22.6 ± 0.2 and 23.0 ± 0.2 degrees 2θ. In other such embodiments, the monopotassium salt trihydrate has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 4.9 ± 0.2, 10.8 ± 0.2, 11 , 3 ± 0.2, 13.4 ± 0.2, 13.6 ± 0.2, 15.3 ± 0.2, 16.9 ± 0.2, 21.2 ± 0.2, 21.7 ± 0.2, 21.7 ± 0.2, 22.1 ± 0.2, 22.5 ± 0.2, 22.6 ± 0.2 and 23.0 ± 0.2 degrees 2θ.

In some embodiments, the monopotassium salt trihydrate has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 4.8 ± 0.2, 10.8 ± 0.2, 11.3 ± 0.2, 13.4 ± 0.2, 13.6 ± 0.2, 15.3 ± 0.2, 16.9 ± 0.2, 21.2 ± 0.2, 21.7 ± 0 , 2, 21.7 ± 0.2, 22.1 ± 0.2, 22.5 ± 0.2, 22.6 ± 0.2 and 23.0 ± 0.2 degrees 2θ. In some of these embodiments , the monopotassium salt trihydrate has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 4.8 ± 0.2, 10.8 ± 0.2, 11.3 ± 0, 2, 13.4 ± 0.2, 15.3 ± 0.2, 16.9 ± 0.2, 21.2 ± 0.2, 21.7 ± 0.2, 22.1 ± 0.2, 22.5 ± 0.2 and 23.0 ± 0.2 degrees 2θ. In other such embodiments, the monopotassium salt trihydrate has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 4.8 ± 0.2, 10.8 ± 0.2, 11 , 3 ± 0.2, 13.4 ± 0.2, 15.3 ± 0.2, 16.9 ± 0.2, 21.2 ± 0.2, 21.7 ± 0.2, 22.1 ± 0.2, 22.5 ± 0.2 and 23.0 ± 0.2 degrees 2θ.

In some embodiments, the monopotassium salt trihydrate has a powder X-ray diffraction pattern substantially as shown in Figure 5. The 2θ values for the peaks in Figure 5 (and their intensities) are as follows: 4.83 (60), 10.79 (100), 11.31 (22), 13.42 (41), 13.59 (18), 15.32 (21), 16.90 (38), 21 , 24 (22), 21.68 (20), 21.68 (21), 22.15 (22), 22.55 (29), 22.63 (23) and 23.02 (27).

The present invention also relates, in part, to a process for preparing the monopotassium salt trihydrate. This was prepared by suspending compound IB-L11.1 (108.81 mg) in 0.4 ml of THF while heating at approximately 50 ° C. An aqueous solution of KOH (1 N, 0.278 ml, 1.2 molar equivalents) was added. The solid dissolved completely to produce a clear solution. An additional 1.6 ml of THF was added to the solution, which was then cooled naturally to room temperature and crystallization was observed. Alternatively, the monopotassium salt trihydrate was prepared by suspending compound IB-L11.1 (343.89 mg) in 1.0 ml of THF while heating 50 ° C. Aqueous KOH (1 N, 0.878 ml, 1.2 molar equivalents) was added. The solid dissolved completely to produce a clear solution. Ethanol was added dropwise to the solution at a total volume of 4.0 ml. Then, the solution was cooled naturally to room temperature and crystallization was observed.

The present invention relates, in part, to a monopotassium salt dihydrate.

In some embodiments, the monopotassium salt dihydrate has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 7.7 ± 0.2, 8.8 ± 0.2, 16.1 ± 0.2 and 19.7 ± 0.2 degrees 2θ. In some of said embodiments, the monopotassium salt dihydrate has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 2θ degrees.

In some embodiments, the monopotassium salt dihydrate has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 7.7 ± 0.2, 8.8 ± 0.2, 12.4 ± 0.2, 14.0 ± 0.2, 16.1 ± 0.2, 17.7 ± 0.2, 19.2 ± 0.2, 19.7 ± 0.2, 23.1 ± 0 , 2 and 29.2 ± 0.2 degrees 2θ. In some of said embodiments, the monopotassium salt dihydrate has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 7.7 ± 0.2, 8.8 ± 0.2, 12 , 4 ± 0.2, 14.0 ± 0.2, 16.1 ± 0.2, 17.7 ± 0.2, 19.2 ± 0.2, 19.7 ± 0.2, 23.1 ± 0.2 and 29.2 ± 0.2 degrees 2θ. In other such embodiments, the monopotassium salt dihydrate has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 7.7 ± 0.2, 8.8 ± 0.2, 12 , 4 ± 0.2, 14.0 ± 0.2, 16.1 ± 0.2, 17.7 ± 0.2, 19.2 ± 0.2, 19.7 ± 0.2, 23.1 ± 0.2 and 29.2 ± 0.2 degrees 2θ.

In some embodiments, the monopotassium salt dihydrate has a powder X-ray diffraction pattern substantially as shown in Figure 6. The 2θ values for the peaks in Figure 6 (and their intensities) are as follows: 7.68 (19), 8.83 (100), 12.40 (7), 13.97 (10), 16.12 (25), 17.75 (9), 19.22 (12), 19 , 73 (40), 23.05 (9) and 29.21 (7).

The present invention also relates, in part, to a process for preparing the monopotassium salt dihydrate. This was prepared by suspending the monopotassium salt trihydrate in low aqueous activity media, such as an ethanol / H2O mixture (50/1 v / v). Alternatively, the monopotassium salt dihydrate was prepared by dissolving solid potassium trihydrate (1.8 g) in 36 ml of IPA and 4 ml of water at 80 ° C. The resulting solution was cooled at 55 ° C for 1 h. Then, the solution was seeded with 7.5 mg of dihydrate crystals at 55 ° C and maintained at 55 ° C for 1 h. Then, heptane (36 ml) was added for 3 h. The reaction mixture was cooled to 0 ° C and filtration produced a material containing both di- and trihydrate crystals. Then, the solid was resuspended in 20 ml of 10: 1 v / v EtOH / H2O at 50 ° C for 3 h and then at 25 ° C for 5 h. Then, the suspension was mixed at 25 ° C for an additional 3 days, cooled to 0 ° C for 3 h and maintained at this temperature for 2 h. The resulting crystals were filtered and air dried in a filtration funnel for 1 h to give a dihydrate. The monopotassium salt dihydrate was also prepared by suspending a mixture of dihydrate and trihydrate crystals in EtOH / H2O 10: 1 v / v at 80 ° C for 2 days. Potassium content was confirmed by ion chromatography.

G4 Crystalline Form of Potassium Salt 1/7 of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2methoxystyryl ) phenyl) methanesulfonamide.

The present invention also relates, in part, to a crystalline form of the potassium salt 1/7 of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin) -1- (2H) -yl) -2-methoxystyryl) phenyl) methanesulfonamide.

In some embodiments, the 1/7 potassium salt has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 7.7 ± 0.2, 8.3 ± 0.2, 10 , 1 ± 0.2, 10.6 ± 0.2, 11.4 ± 0.2, 12.0 ± 0.2, 13.4 ± 0.2, 15.6 ± 0.2, 16.3 ± 0.2, 16.7 ± 0.2, 17.2 ± 0.2, 18.3 ± 0.2, 18.8 ± 0.2, 19.4 ± 0.2, 19.9 ± 0 , 2, 20.2 ± 0.2, 20.5 ± 0.2, 21.2 ± 0.2, 22.1 ± 0.2 and 22.9 ± 0.2 degrees 2θ. In some of said embodiments, the 1/7 potassium salt has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 7.7 ± 0.2, 8.3 ± 0.2 , 10.1 ± 0.2, 10.6 ± 0.2, 11.4 ± 0.2, 12.0 ± 0.2, 13.4 ± 0.2, 15.6 ± 0.2, 16 , 3 ± 0.2, 16.7 ± 0.2, 17.2 ± 0.2, 18.3 ± 0.2, 18.8 ± 0.2, 19.4 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 20.5 ± 0.2, 21.2 ± 0.2, 22.1 ± 0.2 and 22.9 ± 0.2 degrees 2θ. In other such embodiments, the 1/7 potassium salt has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 7.7 ± 0.2, 8.3 ± 0.2 , 10.1 ± 0.2, 10.6 ± 0.2, 11.4 ± 0.2, 12.0 ± 0.2, 13.4 ± 0.2, 15.6 ± 0.2, 16 , 3 ± 0.2, 16.7 ± 0.2, 17.2 ± 0.2, 18.3 ± 0.2, 18.8 ± 0.2, 19.4 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 20.5 ± 0.2, 21.2 ± 0.2, 22.1 ± 0.2 and 22.9 ± 0.2 degrees 2θ.

In some embodiments, the 1/7 potassium salt has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 7.7 ± 0.2, 8.3 ± 0.2, 10 , 1 ± 0.2, 10.6 ± 0.2, 11.4 ± 0.2, 12.0 ± 0.2, 13.4 ± 0.2, 15.6 ± 0.2, 16.3 ± 0.2, 16.7 ± 0.2, 17.2 ± 0.2, 18.3 ± 0.2, 18.8 ± 0.2, 19.4 ± 0.2, 19.9 ± 0 , 2, 20.2 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 21.2 ± 0.2, 22.1 ± 0.2, 22.9 ± 0.2 , 24.3 ± 0.2, 24.9 ± 0.2 and 25.1 ± 0.2 degrees 2θ. In some of said embodiments, the 1/7 potassium salt has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 7.7 ± 0.2, 8.3 ± 0.2 , 10.1 ± 0.2, 10.6 ± 0.2, 11.4 ± 0.2, 12.0 ± 0.2, 13.4 ± 0.2, 15.6 ± 0.2, 16 , 3 ± 0.2, 16.7 ± 0.2, 17.2 ± 0.2, 18.3 ± 0.2, 18.8 ± 0.2, 19.4 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 21.2 ± 0.2, 22.1 ± 0.2, 22.9 ± 0 , 2, 24.3 ± 0.2, 24.9 ± 0.2 and 25.1 ± 0.2 degrees 2θ. In other such embodiments, the 1/7 potassium salt has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 7.7 ± 0.2, 8.3 ± 0.2 , 10.1 ± 0.2, 10.6 ± 0.2, 11.4 ± 0.2, 12.0 ± 0.2, 13.4 ± 0.2, 15.6 ± 0.2, 16 , 3 ± 0.2, 16.7 ± 0.2, 17.2 ± 0.2, 18.3 ± 0.2, 18.8 ± 0.2, 19.4 ± 0.2, 19.9 ± 0.2, 20.2 ± 0.2, 20.5 ± 0.2, 20.8 ± 0.2, 21.2 ± 0.2, 22.1 ± 0.2, 22.9 ± 0 , 2, 24.3 ± 0.2, 24.9 ± 0.2 and 25.1 ± 0.2 degrees 2θ.

In some embodiments, the 1/7 potassium salt has a powder X-ray diffraction pattern substantially as shown in Figure 8. The 2θ values for the peaks in Figure 8 (and their intensities) are as indicated by continued: 7.71 (19), 8.33 (34), 10.10 (100), 10.66 (29), 11.39 (27), 12.04 (22), 13.39 (39) , 15.56 (41), 16.27 (62), 16.69 (70), 17.22 (59), 18.31 (18), 18.78 (47), 19.44 (36), 19.89 (28), 20.19 (33), 20.54 (87), 20.80 (33), 21.15 (47), 22.05 (24), 22.82 (67), 24 , 32 (22), 24.87 (22) and 25.07 (33).

The present invention also relates, in part, to a process for preparing 1/7 potassium salt. This was prepared by suspending compound IB-L1-1.1 (2 g) in 6 ml of THF at 50 ° C. A molar equivalent of KOH dissolved in 4.3 ml of water was added and the reaction mixture was heated to 65 ° C to dissolve all solids. Then, the solution was cooled at room temperature for 2 h and spontaneous crystallization took place. Then, the suspension was cooled to 5 ° C and maintained at that temperature for 2 h. The pale yellow crystals were filtered and air dried for 24 h under ambient conditions. Potassium content was determined by ion chromatography.

G5 Crystalline Form of the Salt Tetrahydrate Monodiethylamine of (E) -N- (4- (3-tert-Butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) phenyl ) methanesutfonamide.

The present invention also relates, in part, to crystalline monodyethylamine tetrahydrate (E) -N- (4- (3-tert-butyl5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) salt ) -2-methoxystyryl) phenyl) methanesulfonamide.

In some embodiments, the modiethylamine tetrahydrate salt has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 9.5 ± 0.2, 10.0 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 14.4 ± 0.2, 16.8 ± 0.2, 17.6 ± 0.2, 19.8 ± 0.2, 20.8 ± 0 , 2, 21.4 ± 0.2, 21.8 ± 0.2 and 29.8 ± 0.2 degrees 2θ. In some of said embodiments, the modiethylamine tetrahydrate salt has a powder X-ray diffraction pattern comprising three

or more peaks selected from the group consisting of 9.5 ± 0.2, 10.0 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 14.4 ± 0.2, 16.8 ± 0.2, 17.6 ± 0.2, 19.8 ± 0.2, 20.8 ± 0.2, 21.4 ± 0.2, 21.8 ± 0.2 and 29, 8 ± 0.2 degrees 2θ. In other such embodiments, the modiethylamine tetrahydrate salt has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 9.5 ± 0.2, 10.0 ± 0.2, 11 , 8 ± 0.2, 12.1 ± 0.2, 14.4 ± 0.2, 16.8 ± 0.2, 17.6 ± 0.2, 19.8 ± 0.2, 20.8 ± 0.2, 21.4 ± 0.2, 21.8 ± 0.2 and 29.8 ± 0.2 degrees 2θ.

In some embodiments, the modiethylamine tetrahydrate salt has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 9.5 ± 0.2, 10.0 ± 0.2, 11.8 ± 0.2, 12.1 ± 0.2, 14.4 ± 0.2, 16.8 ± 0.2, 17.6 ± 0.2, 19.4 ± 0.2, 19.8 ± 0 , 2, 20.8 ± 0.2, 21.4 ± 0.2, 21.8 ± 0.2, 21.9 ± 0.2 and 29.8 ± 0.2 degrees 2θ. In some of these embodiments , the modiethylamine tetrahydrate salt has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 9.5 ± 0.2, 10.0 ± 0.2, 11.8 ± 0, 2, 12.1 ± 0.2, 14.4 ± 0.2, 16.8 ± 0.2, 17.6 ± 0.2, 19.4 ± 0.2, 19.8 ± 0.2, 20.8 ± 0.2, 21.4 ± 0.2, 21.8 ± 0.2, 21.9 ± 0.2 and 29.8 ± 0.2 degrees 2θ. In other such embodiments, the modiethylamine tetrahydrate salt has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 9.5 ± 0.2, 10.0 ± 0.2, 11 , 8 ± 0.2, 12.1 ± 0.2, 14.4 ± 0.2, 16.8 ± 0.2, 17.6 ± 0.2, 19.4 ± 0.2, 19.8 ± 0.2, 20.8 ± 0.2, 21.4 ± 0.2, 21.8 ± 0.2, 21.9 ± 0.2 and 29.8 ± 0.2 degrees 2θ.

In some embodiments, the modiethylamine tetrahydrate salt has a powder X-ray diffraction pattern substantially as shown in Figure 9. The 2θ values for the peaks in Figure 9 (and their intensities) are as follows: 9.45 (100), 9.97 (31), 11.85 (67), 12.09 (16), 14.38 (22), 16.80 (9), 17.59 (10), 19 , 39 (8), 19.83 (21), 20.85 (25), 21.37 (12), 21.75 (34), 21.87 (8) and 29.78 (7).

The present invention also relates, in part, to a process for preparing the modiethylamine tetrahydrate salt. This was prepared in an aqueous medium. Compound IB-L1-1.1 was added slowly to 500 µl of 1 M diethylamine until no more solid could dissolve in the solution. Then, the solution was evaporated slowly at room temperature and the salt crystallized 2 days later. Alternatively, the modiethylamine tetrahydrate salt was prepared by suspending 64.15 mg of compound IB-L1-1.1 in 400 µl of 1 M diethylamine while heating at 50 ° C. Approximately 5 drops of THF (-20 μl) were added. The solid dissolved completely after the addition to produce a clear solution. Then, the solution was evaporated at room temperature and the salt crystallized 4 days later. Stoichiometry of the salt per 1 H NMR solution.

G6 Crystalline Forms of (E) -N- (4- (3-tert-Butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxistyryl) phenyl) methanesulfonamide (compound IB -L1-1.1).

The present invention also relates, in part, to crystalline forms of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1- (2H) -yl) ) -2-methoxystyryl) phenyl) methanesulfonamide (compound IB-L1-1.1), specifically true polymorphs (standard A, standard B, standard C and standard D) and hydrate (standard AH, standard BH, standard CH and standard DH) crystalline forms described below.

G6A. True Polymorphs of IB-L1-1.1.

The present invention relates, in part, to (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxistiryl ) phenyl) crystalline standard methanesulfonamide A.

In some embodiments, polymorph pattern A has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 5.8 ± 0.2, 9.9 ± 0.2, 11.8 ± 0.2, 12.4 ± 0.2, 14.5 ± 0.2, 18.8 ± 0.2, 22.7 ± 0.2 and 29.2 ± 0.2 degrees 2θ. In some of said embodiments, polymorph pattern A has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 5.8 ± 0.2, 9.9 ± 0.2, 11 , 8 ± 0.2, 12.4 ± 0.2, 14.5 ± 0.2, 18.8 ± 0.2, 22.7 ± 0.2 and 29.2 ± 0.2 degrees 2θ. In other such embodiments, the polymorphic pattern A diffraction pattern of ayos X powder comprising five or more peaks selected from the group consisting of 5.8 ± 0.2, 9.9 ± 0.2, 11.8 ± 0.2, 12.4 ± 0.2, 14.5 ± 0.2, 18.8 ± 0.2, 22.7 ± 0.2 and 29.2 ± 0.2 degrees 2θ.

In some embodiments, polymorph pattern A has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 5.8 ± 0.2, 9.9 ± 0.2, 11.8 ± 0.2, 12.4 ± 0.2, 14.0 ± 0.2, 14.5 ± 0.2, 15.3 ± 0.2, 18.5 ± 0.2, 18.8 ± 0 , 2, 22.2 ± 0.2, 22.7 ± 0.2, 23.8 ± 0.2, 26.0 ± 0.2 and 29.2 ± 0.2 degrees 2θ. In some of said embodiments, polymorph pattern A has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 5.8 ± 0.2, 9.9 ± 0, 2, 11.8 ± 0.2, 12.4 ± 0.2, 14.0 ± 0.2, 14.5 ± 0.2, 15.3 ± 0.2, 18.5 ± 0.2, 18.8 ± 0.2, 22.2 ± 0.2, 22.7 ± 0.2, 23.8 ± 0.2, 26.0 ± 0.2 and 29.2 ± 0.2 degrees 2θ. In other such embodiments, polymorph pattern A has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 5.8 ± 0.2, 9.9 ± 0.2, 11 , 8 ± 0.2, 12.4 ± 0.2, 14.0 ± 0.2, 14.5 ± 0.2, 15.3 ± 0.2, 18.5 ± 0.2, 18.8 ± 0.2, 22.2 ± 0.2, 22.7 ± 0.2, 23.8 ± 0.2, 26.0 ± 0.2 and 29.2 ± 0.2 degrees 2θ.

In some embodiments, polymorph pattern A has a powder X-ray diffraction pattern substantially as shown in Figure 11. The 2θ values for the peaks in Figure 11 (and their intensities) are as follows: 5.85 (28), 9.88 (51), 11.79 (73), 12.38 (56), 14.03 (38), 14.45 (100), 15.27 (29), 18 , 52 (39), 18.80 (47), 22.24 (40), 22.72 (77), 23.76 (39), 25.98 (22) and 29.21 (64).

The present invention also relates, in part, to a process for preparing polymorph pattern A. Polymorph pattern A was prepared as described in Example E below.

The present invention relates, in part, to (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxistiryl ) phenyl) crystalline standard methanesulfonamide B.

In some embodiments, the polymorph B pattern has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 11.5 ± 0.2, 13.3 ± 0.2, 15.4 ± 0.2, 16.4 ± 0.2, 17.1 ± 0.2, 18.6 ± 0.2, 19.4 ± 0.2, 20.4 ± 0.2, 21.6 ± 0 , 2, 22.4 ± 0.2, 24.0 ± 0.2, 26.8 ± 0.2 and 29.0 ± 0.2 degrees 2θ. In some of said embodiments, polymorph B pattern has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 11.5 ± 0.2, 13.3 ± 0.2, 15 , 4 ± 0.2, 16.4 ± 0.2, 17.1 ± 0.2, 18.6 ± 0.2, 19.4 ± 0.2, 20.4 ± 0.2, 21.6 ± 0.2, 22.4 ± 0.2, 24.0 ± 0.2, 26.8 ± 0.2 and 29.0 ± 0.2 degrees 2θ. In other such embodiments, polymorph B pattern has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 11.5 ± 0.2, 13.3 ± 0.2, 15 , 4 ± 0.2, 16.4 ± 0.2, 17.1 ± 0.2, 18.6 ± 0.2, 19.4 ± 0.2, 20.4 ± 0.2, 21.6 ± 0.2, 22.4 ± 0.2, 24.0 ± 0.2, 26.8 ± 0.2 and 29.0 ± 0.2 degrees 2θ.

In some embodiments, polymorph B pattern has a powder X-ray diffraction pattern substantially as shown in Figure 13. The 2θ values for the peaks in Figure 13 (and their intensities) are as follows: 11 , 52 (71), 13.30 (87), 15.37 (100), 16.42 (60), 17.13 (69), 18.60 (97), 19.37 (56), 20, 40 (62), 21.55 (55), 22.41 (39), 23.99 (33), 26.81 (31) and 28.98 (50).

The present invention relates, in part, to (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxistiryl ) phenyl) crystalline standard methanesulfonamide C.

In some embodiments, polymorphic pattern C has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 7.7 ± 0.2, 10.1 ± 0.2, 10.0 ± 0.2, 12.0 ± 0.2, 13.4 ± 0.2, 16.2 ± 0.2, 19.4 ± 0.2, 20.5 ± 0.2, 21.4 ± 0 , 2, 22.0 ± 0.2, 22.6 ± 0.2, 24.3 ± 0.2 and 27.6 ± 0.2 degrees 2θ. In some of said embodiments, polymorphic pattern C has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 7.7 ± 0.2, 10.1 ± 0.2, 10 , 6 ± 0.2, 12.0 ± 0.2, 13.4 ± 0.2, 16.2 ± 0.2, 19.4 ± 0.2, 20.5 ± 0.2, 21.4 ± 0.2, 22.0 ± 0.2, 22.6 ± 0.2, 24.3 ± 0.2 and 27.6 ± 0.2 degrees 2θ. In other such embodiments, the polymorph C pattern has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 7.7 ± -0.2, 10.1 ± 0.2, 10.6 ± 0.2, 12.0 ± 0.2, 13.4 ± 0.2, 16.2 ± 0.2, 19.4 ± 0.2, 20.5 ± 0.2, 21, 4 ± 0.2, 22.0 ± 0.2, 22.6 ± 0.2, 24.3 ± 0.2 and 27.6 ± 0.2 degrees 2θ.

In some embodiments, the polymorph C pattern has a powder X-ray diffraction pattern substantially as shown in Figure 14. The 2θ values for the peaks in Figure 14 (and their intensities) are as follows: 7.69 (27), 10.13 (27), 10.64 (49), 12.01 (31), 13.39 (33), 16.25 (91), 19.44 (46), 20 , 49 (100), 21.40 (35), 22.03 (37), 22.60 (30), 24.32 (23) and 27.55 (27).

The present invention relates, in part, to (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxistiryl ) phenyl) crystalline standard methanesulfonamide D.

In some embodiments, the polymorph D pattern has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 5.8 ± 0.2, 10.7 ± 0.2, 11.2 ± 0.2, 15.2 ± 0.2, 16.1 ± 0.2, 16.9 ± 0.2, 19.9 ± 0.2, 22.1 ± 0.2, 24.7 ± 0 , 2 and 26.0 ± 0.2 degrees 2θ. In some of said embodiments, the polymorph D pattern has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 5.8 ± 0.2, 10.7 ± 0.2, 11 , 2 ± 0.2, 15.2 ± 0.2, 16.1 ± 0.2, 16.9 ± 0.2, 19.9 ± 0.2, 22.1 ± 0.2, 24.7 ± 0.2 and 26.0 ± 0.2 degrees 2θ. In another such embodiment, the polymorph D pattern has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 5.8 ± 0.2, 10.7 ± 0.2, 11 , 2 ± 0.2, 15.2 ± 0.2, 16.1 ± 0.2, 16.9 ± 0.2, 19.9 ± 0.2, 22.1 ± 0.2, 24.7 ± 0.2 and 26.0 ± 0.2 degrees 2θ.

In some embodiments, the polymorph D pattern has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 5.8 ± 0.2, 10.7 ± 0.2, 11.2 ± 0.2, 15.2 ± 0.2, 16.1 ± 0.2, 16.9 ± 0.2, 17.1 ± 0.2, 19.9 ± 0.2, 20.1 ± 0 , 2, 22.1 ± 0.2, 24.7 ± 0.2 and 26.0 ± 0.2 degrees 2θ. In some of said embodiments, the polymorph D pattern has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 5.9 ± 0.2, 10.7 ± 0.2, 11 , 2 ± 0.2, 15.2 ± 0.2, 16.1 ± 0.2, 16.9 ± 0.2, 17.1 ± 0.2, 19.9 ± 0.2, 20.1 ± 0.2, 22.1 ± 0.2, 24.7 ± 0.2 and 26.0 ± 0.2 degrees 2θ. In other such embodiments, the polymorph D pattern has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 5.8 ± 0.2, 10.7 ± 0.2, 11 , 2 ± 0.2, 15.2 ± 0.2, 16.1 ± 0.2, 16.9 ± 0.2, 17.1 ± 0.2, 19.9 ± 0.2, 20.1 ± 0.2, 22.1 ± 0.2, 24.7 ± 0.2 and 26.0 ± 0.2 degrees 2θ.

In some embodiments, the polymorph D pattern has a powder X-ray diffraction pattern substantially as shown in Figure 15. The 2θ values for the peaks in Figure 15 (and their intensities) are as follows: 5.81 (24), 10.70 (91), 11.23 (60), 15.17 (28), 16.10 (48), 16.89 (100), 17.10 (42), 19 , 88 (81), 20.12 (100), 22.12 (59), 24.72 (37) and 25.91 (24).

The present invention also relates, in part, to a process for preparing polymorphic standards B, C, and D by heating polymorphic pattern A to approximately 160, approximately 225 and approximately 268 ° C, respectively, using DSC.

G6B IB-L1-1.1 hydrates.

The present invention also relates, in part, to hydrates of compound IB-L1-1.1, specifically hydrates A, B, C, D and E described below.

The present invention relates, in part, to a hydrate of (E) -N- (4- (3-tert-buti) -5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) - il) -2-methoxystyryl) phenyl) methanesulfonamide of standard A.

In some embodiments, the hydrate pattern A has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 5.1 ± 0.2, 7.9 ± 0.2, 9, 5 ± 0.2, 10.3 ± 0.2, 13.7 ± 0.2, 16.5 ± 0.2, 17.1 ± 0.2, 17.5 ± 0.2, 18.8 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 21.3 ± 0.2, 21.6 ± 0.2, 25.8 ± 0.2, 26.8 ± 0, 2 and 28.4 ± 0.2 degrees 2θ. In some of these embodiments, the hydrate pattern A has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 5.1 ± 0.2, 7.9 ± 0.2, 9.5 ± 0.2, 10.3 ± 0.2, 13.7 ± 0.2, 16.5 ± 0.2, 17.1 ± 0.2, 17.5 ± 0.2, 18, 8 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 21.3 ± 0.2, 21.6 ± 0.2, 25.8 ± 0.2, 26.8 ± 0.2 and 28.4 ± 0.2 degrees 2θ. In another such embodiment, the hydrate pattern A has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 5.1 ± 0.2, 7.9 ± 0.2, 9.5 ± 0.2, 10.3 ± 0.2, 13.7 ± 0.2, 16.5 ± 0.2, 17.1 ± 0.2, 17.5 ± 0.2, 18, 8 ± 0.2, 19.2 ± 0.2, 20.7 ± 0.2, 21.3 ± 0.2, 21.6 ± 0.2, 25.8 ± 0.2, 26.8 ± 0.2 and 28.4 ± 0.2 degrees 2θ.

In some embodiments, the hydrate pattern A has a substantially X-ray powder diffraction pattern as shown in Figure 16. The 2θ values for the peaks in Figure 16 (and their intensities) are as indicated below. : 5.13 (13), 7.87 (80), 9.45 (100), 10.29 (60), 13.7 (28), 16.54 (30), 17.07 (17), 17.51 (40), 18.80 (99), 19.18 (74), 20.69 (21), 21.25 (21), 21.63 (23), 25.85 (32), 26 , 81 (20) and 28.35 (27).

The present invention also relates, in part, to a process for preparing the hydrate standard A by suspending the polymorphic pattern A (described above) in ethyl acetate. The recovered hydrate A standard contained ~ 1 molecule of water per molecule of compound IB-L1-1.1.

The present invention also relates, in part, to a hydrate of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1- (2H) -yl) ) -2-methoxystyryl) phenyl) methanesulfonamide of standard B.

In some embodiments, the standard B hydrate has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 6.3 ± 0.2, 7.7 ± 0.2, 10, 4 ± 0.2, 12.7 ± 0.2, 13.3 ± 0.2, 14.9 ± 0.2, 15.4 ± 0.2, 16.4 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 19.4 ± 0.2, 22.5 ± 0.2, 23.5 ± 0.2, 24.0 ± 0.2, 26.8 ± 0, 2 and 29.0 ± 0.2 degrees 2θ. In some of said embodiments, the standard B hydrate has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 6.3 ± 0.2, 7.7 ± 0.2, 10.4 ± 0.2, 12.7 ± 0.2, 13.3 ± 0.2, 14.9 ± 0.2, 15.4 ± 0.2, 16.4 ± 0.2, 18, 6 ± 0.2, 18.9 ± 0.2, 19.4 ± 0.2, 22.5 ± 0.2, 23.5 ± 0.2, 24.0 ± 0.2, 26.8 ± 0.2 and 29.0 ± 0.2 degrees 2θ. In another of said embodiments, the standard B hydrate has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 6.3 ± 0.2, 7.7 ± 0.2, 10.4 ± 0.2, 12.7 ± 0.2, 13.3 ± 0.2, 14.9 ± 0.2, 15.4 ± 0.2, 16.4 ± 0.2, 18, 6 ± 0.2, 18.9 ± 0.2, 19.4 ± 0.2, 22.5 ± 0.2, 23.5 ± 0.2, 24.0 ± 0.2, 26.8 ± 0.2 and 29.0 ± 0.2 degrees 2θ.

In some embodiments, the standard B hydrate has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 6.3 ± 0.2, 7.7 ± 0.2, 10, 4 ± 0.2, 12.7 ± 0.2, 13.3 ± 0.2, 13.5 ± 0.2, 14.9 ± 0.2, 15.4 ± 0.2, 16.4 ± 0.2, 18.5 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 19.4 ± 0.2, 22.5 ± 0.2, 23.5 ± 0, 2, 24.0 ± 0.2, 26.8 ± 0.2 and 29.0 ± 0.2 degrees 2θ. In some of said embodiments, the standard B hydrate has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 6.3 ± 0.2, 7.7 ± 0.2, 10.4 ± 0.2, 12.7 ± 0.2, 13.3 ± 0.2, 13.5 ± 0.2, 14.9 ± 0.2, 15.4 ± 0.2, 16, 4 ± 0.2, 18.5 ± 0.2, 18.6 ± 0.2, 8.9 ± 0.2, 19.4 ± 0.2, 22.5 ± 0.2, 23.5 ± 0.2, 24.0 ± 0.2, 26.8 ± 0.2 and 29.0 ± 0.2 degrees 2θ. In other such embodiments, the standard B hydrate has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 6.3 ± 0.2, 7.7 ± 0.2, 10.4 ± 0.2, 12.7 ± 0.2, 13.3 ± 0.2, 13.5 ± 0.2, 14.9 ± 0.2, 15.4 ± 0.2, 16, 4 ± 0.2, 18.5 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 19.4 ± 0.2, 22.5 ± 0.2, 23.5 ± 0.2, 24.0 ± 0.2, 26.8 ± 0.2 and 29.0 ± 0.2 degrees 2θ.

In some embodiments, pattern B hydrate has a substantially X-ray powder diffraction pattern as shown in Figure 18. The 2θ values for the peaks in Figure 18 (and their intensities) are as indicated below. : 6.31 (7), 7.72 (14), 10.45 (24), 12.67 (26), 13.30 (88), 13.50 (44), 14.89 (70), 15.40 (100), 16.43 (43), 18.46 (47), 18.63 (86), 18.91 (26), 19.42 (33), 22.52 (47), 23 , 52 (44), 24.02 (20), 26.82 (40) and 28.97 (49).

The present invention also relates, in part, to a process for preparing the standard B hydrate by suspending the polymorphic pattern A (described above) in acetonitrile / water (9/1 v / v). The recovered hydrate of standard B contains ~ 0.7 molecules of water per molecule of compound IB-L1-1.1.

The present invention also relates, in part, to a hydrate of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1- (2H) -yl) ) -2-methoxystyryl) phenyl) methanesulfonamide of standard C.

In some embodiments, the standard C hydrate has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 10.5 ± 0.2, 13.3 ± 0.2, 14, 9 ± 0.2, 15.4 ± 0.2, 16.4 ± 0.2, 18.6 ± 0.2, 19.0 ± 0.2, 19.4 ± 0.2, 22.5 ± 0.2, 23.5 ± 0.2, 26.9 ± 0.2 and 29.0 ± 0.2 degrees 2θ. In some of said embodiments, the standard C hydrate has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 10.5 ± 0.2, 13.3 ± 0.2, 14.9 ± 0.2, 15.4 ± 0.2, 16.4 ± 0.2, 18.6 ± 0.2, 19.0 ± 0.2, 19.4 ± 0.2, 22, 5 ± 0.2, 23.5 ± 0.2, 26.9 ± 0.2, and 29.0 ± 0.2 degrees 2θ. In other such embodiments, the standard C hydrate has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 10.5 ± 0.2, 13.3 ± 0.2, 14.9 ± 0.2, 15.4 ± 0.2, 16.4 ± 0.2, 18.6 ± 0.2, 19.0 ± 0.2, 19.4 ± 0.2, 22, 5 ± 0.2, 23.5 ± 0.2, 26.9 ± 0.2 and 29.0 ± 0.2 degrees 2θ.

In some embodiments, standard C hydrate has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 10.5 ± 0.2, 13.3 ± 0.2, 13, 5 ± 0.2, 14.9 ± 0.2, 15.4 ± 0.2, 16.4 ± 0.2, 18.6 ± 0.2, 19.0 ± 0.2, 19.4 ± 0.2, 22.5 ± 0.2, 23.5 ± 0.2, 26.9 ± 0.2 and 29.0 ± 0.2 degrees 2θ. In some of said embodiments, the standard C hydrate has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 10.5 ± 0.2, 13.3 ± 0.2, 13.5 ± 0.2, 14.9 ± 0.2, 15.4 ± 0.2, 16.4 ± 0.2, 18.6 ± 0.2, 19.0 ± 0.2, 19, 4 ± 0.2, 22.5 ± 0.2, 23.5 ± 0.2, 26.9 ± 0.2 and 29.0 ± 0.2 degrees 2θ. In other such embodiments, the standard C hydrate has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 10.5 ± 0.2, 13.3 ± 0.2, 13.5 ± 0.2, 14.9 ± 0.2, 15.4 ± 0.2, 16.4 ± 0.2, 18.6 ± 0.2, 19.0 ± 0.2, 19, 4 ± 0.2, 22.5 ± 0.2, 23.5 ± 0.2, 26.9 ± 0.2 and 29.0 ± 0.2 degrees 2θ.

In some embodiments, standard C hydrate has a substantially X-ray powder diffraction pattern as shown in Figure 20. The 2θ values for the peaks in Figure 20 (and their intensities) are as indicated below. : 10.47 (21), 13.31 (56), 13.49 (31), 14.91 (28), 15.40 (86), 16.43 (48), 18.61 (100), 18.96 (20), 19.44 (19), 22.55 (26), 23.54 (39), 26.84 (29) and 28.99 (54).

The present invention also relates, in part, to a process for preparing the standard C hydrate by suspending the polymorphic pattern A (described above) in water. The recovered standard C hydrate contains ~ 1 molecule of water per molecule of compound IB-L1-1.1.

The present invention also relates, in part, to a hydrate of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1- (2H) -yl) ) -2-methoxystyryl) phenyl) methanesulfonamide standard D.

The crystallographic parameters of the unit cell of the standard D hydrate salt were determined to be as follows: a is 17.8 Å, b is 9.6 Å and c is 27.0 Å (more precisely, a is 17,783 (2) Å, b is 9,5651 (12) Å and ces 27,014 (4) Å); the angle of the cell is: β -93.3 ° (more precisely, β is 93.256 (2) °); and the cell volume is 4588 Å3 (more precisely, 4587.5 (10) Å3). Salt crystallizes in the C2 / c space group.

In some embodiments, the standard D hydrate has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 6.6 ± 0.2, 10.0 ± 0.2, 10, 5 ± 0.2, 11.1 ± 0.2, 11.6 ± 0.2, 12.2 ± 0.2, 14.2 ± 0.2, 16.6 ± 0.2, 17.1 ± 0.2, 17.7 ± 0.2, 18.5 ± 0.2, 18.8 ± 0.2, 19.3 ± 0.2, 21.4 ± 0.2, 22.7 ± 0, 2, 23.1 ± 0.2, 23.6 ± 0.2, 24.6 ± 0.2, 25.2 ± 0.2, 27.2 ± 0.2, 29.1 ± 0.2 and 31.0 ± 0.2 degrees 2θ. In some of said embodiments, the standard D hydrate has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 6.6 ± 0.2, 10.0 ± 0.2, 10.5 ± 0.2, 11.1 ± 0.2, 11.6 ± 0.2, 12.2 ± 0.2, 14.2 ± 0.2, 16.6 ± 0.2, 17, 1 ± 0.2, 17.7 ± 0.2, 18.5 ± 0.2, 18.8 ± 0.2, 19.3 ± 0.2, 21.4 ± 0.2, 22.7 ± 0.2, 23.1 ± 0.2, 23.6 ± 0.2, 24.6 ± -0.2, 25.2 ± 0.2, 27.2 ± 0.2, 29.1 ± 0 , 2 and 31.0 ± 0.2 degrees 2θ. In other such embodiments, the standard D hydrate has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 6.6 ± 0.2, 10.0 ± 0.2, 10.5 ± 0.2, 11.1 ± 0.2, 11.6 ± 0.2, 12.2 ± 0.2, 14.2 ± 0.2, 16.6 ± 0.2, 17, 1 ± 0.2, 17.7 ± 0.2, 18.5 ± 0.2, 18.8 ± 0.2, 19.3 ± 0.2, 21.4 ± 0.2, 22.7 ± 0.2, 23.1 ± 0.2, 23.6 ± 0.2, 24.6 ± 0.2, 25.2 ± 0.2, 27.2 ± 0.2, 29.1 ± 0, 2 and 31.0 ± 0.2 degrees 2θ.

In some embodiments, the standard D hydrate has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 6.6 ± 0.2, 10.0 ± 0.2, 10, 5 ± 0.2, 11.1 ± 0.2, 11.6 ± 0.2, 12.2 ± 0.2, 12.5 ± 0.2, 14.2 ± 0.2, 16.6 ± 0.2, 17.1 ± 0.2, 17.7 ± 0.2, 18.5 ± 0.2, 18.8 ± 0.2, 19.3 ± 0.2, 21.4 ± 0, 2, 22.7 ± 0.2, 22.8 ± 0.2, 23.1 ± 0.2, 23.6 ± 0.2, 24.6 ± 0.2, 24.9 ± 0.2, 25.2 ± 0.2, 27.2 ± 0.2, 29.1 ± 0.2 and 31.0 ± 0.2 degrees 2θ. In some of said embodiments, the standard D hydrate has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 6.6 ± 0.2, 10.0 ± 0.2, 10.5 ± 0.2, 11.1 ± 0.2, 11.6 ± 0.2, 12.2 ± 0.2, 12.5 ± 0.2, 14.2 ± 0.2, 16, 6 ± 0.2, 17.1 ± 0.2, 17.7 ± 0.2, 18.5 ± 0.2, 18.8 ± 0.2, 19.3 ± 0.2, 21.4 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.1 ± 0.2, 23.6 ± 0.2, 24.6 ± 0.2, 24.9 ± 0, 2, 25.2 ± 0.2, 27.2 ± 0.2, 29.1 ± 0.2 and 31.0 ± 0.2 degrees 2θ. In other such embodiments, the standard D hydrate has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 6.6 ± 0.2, 0.0 ± 0.2, 10.5 ± 0.2, 11.1 ± 0.2, 11.6 ± 0.2, 12.2 ± 0.2, 12.5 ± 0.2, 14.2 ± 0.2, 16, 6 ± 0.2, 17.1 ± 0.2, 1.7 ± 0.2, 18.5 ± 0.2, 18.8 ± 0.2, 19.3 ± 0.2, 21.4 ± 0.2, 22.7 ± 0.2, 22.8 ± 0.2, 23.1 ± 0.2, 23.6 ± 0.2, 24.6 ± 0.2, 24.9 ± 0, 2, 25.2 ± 0.2, 27.2 ± 0.2, 29.1 ± 0.2 and 31.0 ± 0.2 degrees 2θ.

In some embodiments, the standard D hydrate has a substantially X-ray powder diffraction pattern as shown in Figure 22. The 2θ values for the peaks in Figure 22 (and their intensities) are as indicated below. : 6.55 (10), 9.96 (12), 10.51 (37), 11.09 (31), 11.62 (100), 12.24 (44), 12.54 (40), 14.22 (15), 16.62 (68), 17.07 (22), 17.77 (21), 18.52 (82), 18.84 (47), 19.30 (63), 21 , 45 (34), 22.67 (30), 22.80 (34), 23.08 (20), 23.57 (58), 24.63 (73), 24.88 (26), 25, 24 (21), 27.23 (36), 29.06 (41) and 31.04 (21).

The present invention also relates, in part, to a process for preparing the standard D hydrate. This was prepared by suspending the polymorphic pattern A (described above) in ethanol. Alternatively, it was prepared by suspending compound IB-L1-1.1 (103.03 mg) in 400 µl of THF while heating at approximately 55 ° C. Aqueous NaOH (1 M, 264 µl, 1.2 molar equivalents) was added. The solid dissolved completely to produce a clear solution. Ethanol (1.6 ml) was added to the solution. The solution was allowed to cool naturally at room temperature. The crystals were suspended during the slow evaporation process. Although it appeared that the network could accommodate at most 0.5 water molecules per molecule of compound IB-LI-1.1, the recovered standard D hydrate contained ~ 0.2 water molecules per molecule of compound IB-L1-1.1.

The present invention also relates, in part, to a hydrate of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1- (2H) -yl) ) 2-methoxystyryl) phenyl) methanesulfonamide of standard E.

The crystallographic parameters of the unit cell of the crystalline disodium salt hydrate of standard E were determined to be as follows: a is 9.5 Å, b is 14.5 Å and c is 17.3 Å (more precisely, a is 9,462 (2) Å, bes 14,462 (3) Å and c is 17,281 (4) Å); The angles of the cells are: α -84.9 °, β -80.8 ° and γ -81.8 ° (more precisely, α is 84.863 (4) °, β is 80.760 (4) ° and γ is 81,751 (4) °, and the cell volume is 2304 Å3 (more precisely, 2304.4 (9) Å3). The salt crystallizes in the space group P-1.

In some embodiments, the standard E hydrate has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 6.2 ± 0.2, 7.8 ± 0.2, 10, 2 ± 0.2, 10.7 ± 0.2, 12.1 ± 0.2, 16.3 ± 0.2, 19.7 ± 0.2, 20.9 ± 0.2, 21.8 ± 0.2, 24.5 ± 0.2 and 28.0 ± 0.2 degrees 2θ. In some of said embodiments, the standard E hydrate has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 6.2 ± 0.2, 7.8 ± 0.2, 10.2 ± 0.2, 10.7 ± 0.2, 12.1 ± 0.2, 16.3 ± 0.2, 19.7 ± 0.2, 20.9 ± 0.2, 21, 8 ± 0.2, 24.5 ± 0.2 and 28.0 ± 0.2 degrees 2θ. In other such embodiments, the standard E hydrate has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 6.2 ± 0.2, 7.8 ± 0.2, 10.2 ± 0.2, 10.7 ± 0.2, 12.1 ± 0.2, 16.3 ± 0.2, 19.7 ± 0.2, 20.9 ± 0.2, 21, 8 ± 0.2, 24.5 ± 0.2 and 28.0 ± 0.2 degrees 2θ.

In some embodiments, the standard E hydrate has a powder X-ray diffraction pattern comprising one or more peaks selected from the group consisting of 6.2 ± 0.2, 7.8 ± 0.2, 10, 2 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 12.1 ± 0.2, 16.3 ± 0.2, 19.7 ± 0.2, 20.9 ± 0.2, 21.8 ± 0.2, 24.5 ± 0.2 and 28.0 ± 0.2 degrees 2θ. In some of said embodiments, the standard E hydrate has a powder X-ray diffraction pattern comprising three or more peaks selected from the group consisting of 6.2 ± 0.2, 7.8 ± 0.2, 10.2 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 12.1 ± 0.2, 16.3 ± 0.2, 19.7 ± 0.2, 20, 9 ± 0.2, 21.8 ± 0.2, 24.5 ± 0.2 and 28.0 ± 0.2 degrees 2θ. In other such embodiments, the standard E hydrate has a powder X-ray diffraction pattern comprising five or more peaks selected from the group consisting of 6.2 ± 0.2, 7.8 ± 0.2, 10.2 ± 0.2, 10.4 ± 0.2, 10.7 ± 0.2, 12.1 ± 0.2, 16.3 ± 0.2, 19.7 ± 0.2, 20, 9 ± 0.2, 21.8 ± 0.2, 24.5 ± 0.2 and 28.0 ± 0.2 degrees 2θ.

In some embodiments, the standard E hydrate has a substantially X-ray powder diffraction pattern as shown in Figure 23. The 2θ values for the peaks in Figure 23 (and their intensities) are as indicated below. : 6.19 (6), 7.81 (18), 10.17 (13), 10.40 (14), 10.68 (39), 12.06 (20), 16.29 (78), 19.72 (32), 20.88 (100), 21.77 (27), 24.52 (25) and 28.01 (27).

The present invention also relates, in part, to a process for preparing the standard E hydrate. This was prepared by suspending compound IB-L1-1.1 (56.76 mg) in 200 µl THF while heating. Aqueous NaOH (1 M, 146 μl, 1.2 molar equivalents) was added, which produced a clear solution. Ethanol (800 µl) was added to the solution. The solution was allowed to cool naturally at room temperature. The crystals formed during the slow evaporation process. Although it seems that the network could accommodate at most one molecule of water per molecule of compound IB-L1-1.1, the recovered standard D hydrate contained ~ 0.25 water molecules of water per molecule of compound IB-L1-1.1.

H. Compositions

The present invention also relates, in part, to compositions comprising one or more compounds and / or salts of the invention (including crystalline compounds and salts described in section G above). In some embodiments, the compositions comprise one or more substantially pure phase crystalline forms (compounds / salts / solvates / hydrates) described in section G above. The compositions may be pharmaceutical compositions.

In some embodiments, the compositions additionally comprise one or more additional therapeutic agents. Such therapeutic agents may, but not necessarily, be additional HCV inhibitors.

The preferred composition depends on the method of administration and typically comprises one or more pharmaceutically acceptable carriers, adjuvants and / or vehicles (collectively referred to as "excipients"). Drug formulation is generally described, for example, in Hoover, J., Remington's Pharmaceutical Sciences (Mack Formulation of drugs is generally discussed in, for example, Hoover, J., Remington's Pharmaceutical Sciences (Mack Publishing Co., 1975) and Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (Lippincott Williams & Wilkins, 2005).

Solid dosage forms for oral administration include, for example, capsules, tablets, pills, powders and granules. In such solid dosage forms, the compounds or salts are usually combined with one or more excipients. If administered orally, the compounds or salts may be mixed, for example, with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, alkyl cellulose esters, talc, stearic acid, magnesium stearate, magnesium oxide , sodium and calcium salts of phosphoric and sulfuric acids, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone and / or polyvinyl alcohol, and then compressed or encapsulated for convenient administration. Said capsules or tablets may contain a controlled release formulation, since they may be provided, for example, in a dispersion of the compound or salt in hydroxypropylmethyl cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents, such as sodium or carbonate citrate or magnesium or calcium bicarbonate.

The tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions (including both oil-in-water and water-in-oil emulsions), solutions (including both aqueous and non-aqueous solutions), suspensions (including both aqueous and non-aqueous suspensions aqueous), syrups and elixirs containing inert diluents commonly used in the art (eg, water). Such compositions may also comprise, for example, wetting, emulsifying, suspending, flavoring (for example, sweeteners) and / or perfuming agents.

Parenteral administration includes subcutaneous injections, intravenous injections, intramuscular injections, intrasternal injections and infusion. Injectable preparations (for example, sterile injectable aqueous or oleaginous suspensions) may be formulated in accordance with known art using suitable dispersing agents, humectants and / or suspending agents. Acceptable carriers and solvents include, for example, water, 1,3-butanediol, Ringer's solution, isotonic sodium chloride solution, mild non-volatile oils (e.g., synthetic mono- or diglycerides), fatty acids (e.g., oleic acid), dimethyl acetamide, surfactants (for example, ionic and non-ionic detergents) and / or polyethylene glycols.

Formulations for parenteral administration may, for example, be prepared from sterile powders or granules having one or more of the excipients mentioned for use in formulations for oral administration. A compound or salt of the invention can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride and / or various buffers. The pH can be adjusted, if necessary, with a suitable acid, base or buffer. Suppositories for rectal administration can be prepared, for example, by mixing a compound or salt of the invention with a suitable non-irritating excipient that is solid at normal temperatures, but liquid at the rectal temperature and will therefore be fused in the rectum to release the drug Suitable excipients include, for example, cocoa butter; mono-, di- or synthetic triglycerides, fatty acids and / or polyethylene glycols.

Topical administration includes the use of transdermal administration, such as transdermal patches or iontophoresis devices.

Other excipients and modes of administration known in the pharmaceutical art can also be used.

Applicants of the invention have discovered that some I-L1 compounds in which R6 and phenyluracil are in a trans position with respect to the double bond, when in solution, tend to become the corresponding cis isomer after exposure to light; therefore, it may be desirable to store such solutions under conditions that reduce light exposure (for example, in an amber bottle or in a dark place).

The preferred total daily dose of the compound or salt (administered in single or divided doses) is typically from about 0.001 to about 100 mg / kg, more preferably from about 0.001 to about 30 mg / kg, and even more preferably from about 0.01 at about 10 mg / kg (i.e., mg of the compound or salt per kg of body weight). The unit dosage compositions may contain said amounts or submultiples thereof to constitute the daily dose. In many cases, the administration of the compound or salt will be repeated several times. Multiple doses per day can typically be used to increase the total daily dose if desired.

Factors that influence the preferred dosage regimen include the type, age, weight, sex, diet and condition of the patient; the severity of the pathological condition; the route of administration; pharmacological weightings, such as activity, efficacy, pharmacokinetics and toxicological profiles of the particular compound or salt used; whether a drug delivery system is used and whether the compound or salt is administered as part of a drug combination. Therefore, the dosage regimen actually employed can vary widely, and therefore, can be obtained from the preferred dosage regimen set forth above.

I. Kits

This invention also relates, in part, to a kit comprising one or more compounds and / or salts of the invention. The kit may optionally contain one or more additional therapeutic agents and / or instructions for, for example, the use of the kit.

J. Methods of Use

This invention also relates, in part, to a method of inhibiting the replication of an RNA virus comprising exposing the virus to one or more compounds and / or salts of this invention in vitro. RNA virus replication is inhibited in vitro. This invention also relates, in part, to the compounds and / or salts of the invention for use in inhibiting RNA virus replication in vivo. In some embodiments, the RNA virus, whose replication is to be inhibited, is a positive sense single stranded RNA virus. In some of these embodiments, the RNA virus whose replication is to be inhibited is a virus of the Flaviviridae family. In some of these embodiments, the RNA virus whose replication is to be inhibited is HCV.

The present invention also relates, in part, to a method for inhibiting HCV RNA polymerase in vitro. The method comprises exposing the polymerase with one or more compounds and / or salts of this invention.

In some embodiments, HCV RNA polymerase activity is inhibited in vitro. This invention also relates, in part, to the compounds and / or salts of the invention for use by inhibiting the activity of HCV RNA polymerase in vivo.

The term "inhibit" means the reduction of the level of activity of HCV RNA polymerase / RNA virus replication in vivo or in vitro. For example, if a compound / salt of the invention reduces the level of RNA virus replication by at least about 10% compared to the level of RNA virus replication before exposing the virus to the compound / salt, then the compound / salt inhibits RNA virus replication. In some embodiments, the compound / salt can inhibit RNA virus replication by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60% , at least about 70%, at least about 80%, at least about 90% or at least about 95%.

This invention also relates, in part, to the compounds and / or salts of the invention for use in the method for the treatment of a disease that can be treated by inhibiting HCV RNA polymerase. Therefore, this invention also relates, in part, to the compounds and / or salts of the invention for use in a method for the treatment of hepatitis C in an animal in need of such treatment. These methods comprise administering to the animal one or more compounds and / or salts of the invention, and, optionally one or more additional therapeutic agents. In some embodiments, the animal is administered a therapeutically effective amount of the compound (or compounds) and / or salt (or salts). "Treatment" means improvement, suppression, elimination, prevention, risk reduction of, and / or delaying the onset of the disease to be treated. Applicants of the invention specifically wish that the term "treatment" includes the administration of the compounds and / or salts of the invention to an HCV negative patient who is a candidate for an organ transplant. The treatment methods are particularly suitable for use with humans, but can also be used with other animals, particularly mammals. A "therapeutically effective amount" or "effective amount" is an amount that will achieve the goal of treating the target condition.

In some embodiments, the methods comprise a combination therapy, in which the compound (or compounds) and / or salt (or salts) of the invention are co-administered with a second (or even a third, fourth, etc.) compound, such as, for example, another therapeutic agent used to treat hepatitis C (for example, interferon or combination of interferon / ribavirin or an HCV inhibitor such as, for example, an HCV polymerase inhibitor or a protease inhibitor HCV). The compound (or compounds) and / or salt (or salts) of this invention can also be co-administered with therapeutic agents other than the therapeutic agents used to treat hepatitis C (eg, anti-HIV agents). In these co-administration embodiments, the compound (or compounds) and the salt (or salts) of the invention and the second, etc. therapeutic agent (or agents) can be administered in a substantially simultaneous manner (for example, or with a difference of about 5 minutes from each other) in a sequential manner or both. It is contemplated that such combination therapies may include the administration of one therapeutic agent several times between the administrations of the other. The period of time between the administration of each agent may vary from a few seconds (or less) to several hours or days and will depend on, for example, the properties of each composition and the active ingredient (e.g., potency, solubility, bioavailability, half-life and kinetic profile), as well as the patient's condition. The compound (or compounds) and / or salt (or salts) of the invention and the second, etc. Therapeutic agent can also be administered in a single formulation.

This invention also relates, in part, to the use of one or more compounds and / or salts of the invention and optionally to one or more additional therapeutic agents for preparing a medicament. In some embodiments, the medicament is for co-administration with one or more additional therapeutic agents.

In some embodiments, the medicament is to inhibit the replication of an RNA virus.

In some embodiments, the medication is for the treatment of hepatitis C.

This invention also relates, in part, to one or more compounds and / or salts of the invention and optionally to one or more additional therapeutic agents for use as a medicament. In some embodiments, the medicament is to inhibit the replication of an RNA virus. In other embodiments, the medication is for the

5 treatment of hepatitis C.

K. Intermediate Compounds.

Also described are intermediate compounds, which correspond in structure to formula II, which can

10 used to prepare the compounds of the formula I (and their salts) (although some intermediate may also be used, just like the compounds of the formula I, as HCV inhibitors and one skilled in the art can determine said ability of the compounds of formula II using, for example, the methods described below):

image2

In formula II:

X2 is halo. 20 The various embodiments for

R1, R2, R3, R4 and R5 (as well as their combinations) described above apply to the compounds of the formula image 1

II. Comma for X2, in some embodiments, X2 is selected from the group consisting of chlorine, bromine and iodine. In

In other embodiments, X2 is selected from the group consisting of chlorine and bromine. In yet other embodiments, X2 is selected from the group consisting of chlorine and iodine. In yet other embodiments, X2 is selected from the group consisting of iodine and bromine. In other embodiments, X2 is fluorine. In other additional embodiments, X2 is chlorine. In other additional embodiments, X2 is bromine. And in other additional embodiments, X2 is iodine.

30 The various embodiments for

R1, R2, R3, R4, R5 and X2 described above can be combined to form various embodiments of image 1 Compounds of the formula II and all embodiments of the compounds of the formula II formed in this manner are within the scope of the Applicants' invention. Some exemplary embodiments of the compounds (and

Salts thereof) of the formula II are described below.

In some embodiments, the compounds of the formula II correspond in structure to the formula IIA: In other embodiments, the compounds of the formula II correspond in structure to the formula IIB:

image 1

image 1

In some embodiments of the compounds of formula II: R 1 is selected from the group consisting of hydrogen, methyl and nitrogen protecting group; R2 is selected from the group consisting of hydrogen and halo; R3 is selected from the group consisting of hydrogen and halo; R4 is selected from the group consisting of C1-C4 alkyl, C3-C6 carbocyclyl and 5-6 membered heterocyclyl, in which:

(to)

C1-C4 alkyl is optionally substituted with up to three substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy and trimethylsilyl, and

(b)

the 5-6 membered carbocyclyl-C3-C6 and heterocyclyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo and alkylsulfonylamino;

R5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy and halo; Y X2 is selected from the group consisting of chlorine, bromine and iodine.

In some embodiments of the compounds of formula II:

image 1

it is a carbon-carbon double bond; R1 is hydrogen; R2 is selected from the group consisting of hydrogen and halo; R3 is hydrogen; R4 is tert-butyl; R5 is selected from the group consisting of hydrogen, hydroxy and methoxy; Y X2 is selected from the group consisting of bromine and iodine.

In some embodiments of the compounds of formula II:

R1 is selected from the group consisting of hydrogen and methyl; R2 is selected from the group consisting of hydrogen and methyl; R3 is selected from the group consisting of hydrogen and methyl; R4 is tert-butyl; R5 is selected from the group consisting of hydroxy and methoxy; Y X2 is selected from the group consisting of chlorine, bromine and iodine.

In some embodiments of the compounds of formula II:

image 1

it is a double carbon-carbon bond;

R1 is hydrogen;

R2 is hydrogen;

R3 is hydrogen;

R4 is tert-butyl;

R5 is selected from the group consisting of hydroxy and methoxy; Y

X2 is selected from the group consisting of chlorine, bromine and iodine.

In some embodiments, the compound of formula II is selected from the group consisting of

image 1

Next, the description provides instructions for the preparation of intermediate compounds of formula II (and salts thereof). 5

L. Departure Compounds.

The following also describes starting compounds that correspond in structure to formula III that can be used to prepare the compounds of formulas II and I (and their salts): image 1

10

In formula III, image 1 , R1, R2 and R3 image 1 they are as described above for the compounds of the formula I and

II. The various embodiments for, R1, R2 and R3 (as well as their combinations) are described below. image 1

applied to the compounds of the formula III. The various embodiments for, R1, R2 and R3 described

15 above can be combined to form various embodiments of the compounds of formula III and all embodiments of the compounds of formula III formed in this manner are within the scope of the Applicants' invention. Some exemplary embodiments of the embodiments of the compounds (and salts thereof) of the formula III are described below.

In some embodiments of the compounds of formula III:

R1 is selected from the group consisting of hydrogen, methyl and nitrogen protecting group; R2 is selected from the group consisting of hydrogen and halo; Y R3 is selected from the group consisting of hydrogen and halo.

In some embodiments of the compounds of formula III:

image 1 it is a carbon-carbon double bond;

R1 is selected from the group consisting of hydrogen; R2 is selected from the group consisting of hydrogen and halo; Y R3 is selected from the group consisting of hydrogen.

In some embodiments of the compounds of formula III:

R1 is selected from the group consisting of hydrogen and methyl; R2 is selected from the group consisting of hydrogen and methyl; and R3 is selected from the group consisting of hydrogen and methyl.

In some embodiments, the compound of formula III is uracil.

Also described are starting compounds that correspond in structure to formula IV that can be used to prepare the compounds of formulas II and I (and their salts): In formula IV:

image 1

R4, R5 and X2 are as described above for the compounds of formulas I and II; Y X1 is halo.

The various embodiments for R4, R5 and X2 (as well as their combinations) described above apply to the compounds of formula IV. As for X1, in some embodiments, X1 is selected from the group consisting of chlorine, bromine and iodine. In other embodiments, X1 is selected from the group consisting of chlorine and bromine. In yet other embodiments, X1 is selected from the group consisting of chlorine and iodine. In yet other embodiments, X1 is selected from the group consisting of iodine and bromine. In other embodiments, X1 is fluorine. In other additional embodiments, X1 is chlorine. In other additional embodiments, X1 is bromine. And in other additional embodiments, X1 is iodine. As for X1 and X2, in some embodiments, X1 and X2 are identical.

The various embodiments for R4, R5, X1 and X2 described above may be combined to form various embodiments of compounds of the formula IV and all embodiments of the compounds of the formula III formed in this manner are within the scope of the Applicants' invention. . Some exemplary embodiments of the embodiments of the compounds (and salts thereof) of formula IV are described below.

In some embodiments of the compounds of formula IV:

R4 is selected from the group consisting of C1-C4 alkyl, C3-C6 carbocyclyl and 5-6 membered heterocyclyl, in which:

(to)

C1-C4 alkyl is optionally substituted with up to three substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy and trimethylsilyl, and

(b)

e carbocyclyl-C3-C6 and 5-6 membered heterocyclyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo and alkylsulfonylamino;

R5 is selected from the group consisting of hydrogen, hydroxy and alkyloxy; X1 is selected from the group consisting of chlorine, bromine and iodine; Y X2 is selected from the group consisting of chlorine, bromine and iodine.

In some embodiments of the compounds of formula IV:

R4 is selected from the group consisting of tert-butyl; R2 is selected from the group consisting of hydrogen, hydroxy and methoxy; X1 is selected from the group consisting of bromine and iodine; Y X2 is selected from the group consisting of bromine and iodine.

In some embodiments of the compounds of formula IV:

R4 is selected from the group consisting of tert-butyl; R5 is selected from the group consisting of hydroxy and methoxy; X1 is selected from the group consisting of chlorine, bromine and iodine; Y X2 is selected from the group consisting of chlorine, bromine and iodine.

In some embodiments of the compounds of formula IV:

R4 is tert-butyl; R5 is selected from the group consisting of hydroxy and methoxy; X1 is selected from the group consisting of chlorine, bromine and iodine; Y X2 is selected from the group consisting of chlorine, bromine and iodine.

In some embodiments, the compound of formula IV is selected from the group consisting of

image 1

Next, the description provides instructions for the preparation of starting compounds of the formula IV (and salts thereof). 5

L. Preparation Methods.

A process for preparing compounds of the formula II is also described. The process comprises reacting a compound of the formula III with a compound of the formula IV in the presence of (i) copper salt catalyst (I) and

10 (ii) nitrogen heteroaryl ligand:

image 1

In the above processes, R1, R2, R3, R4, R5, X1 and X2 are as described above.

The Applicants have discovered that the processes generally result in the substitution of the hydrogen N1 hydrogen of the compound III derived thereby resulting in the intermediate compound II. When X2 in intermediate II is chlorine, bromine or iodine, then compound II is suitable for subsequent reaction (for example, Suzuki coupling with a boronato ester or boronic acid) to provide compound of the formula I. In other words , when X2 in intermediate II is chlorine, bromine or iodine, the

The above process is suitable for preparing compounds of the formula I as well.

In some embodiments, compound III is uracil and compound IV corresponds in structure to a compound selected from the group consisting of compound IV-I, IV-Br and IV-CI, typically resulting in compounds IV-I and IV-Br better performance than compound IV-CI.

Suitable Cu (l) catalysts include, for example, Cul, CuBr, CuCI, Cu2O and CH3C (O) OCu. In some embodiments, the catalyst is selected from the group consisting of Cul and CuBr. In some of said embodiments, the catalyst is Cul. In another of said embodiments, the catalyst is CuBr.

30 In some embodiments, the process is performed in the presence of a base. In some of said embodiments, the base is an inorganic base. Suitable inorganic bases include, for example, potassium, sodium and cesium salts (for example, K2CO3, K3PO4, Cs2CO3, Na2CO3). In some embodiments, the base is selected from the group consisting of potassium salt and cesium salt. In some of said embodiments, the salt is selected from the group consisting of K3PO4 and Cs2CO3. In some embodiments, the base comprises a potassium salt. In some of

35 said embodiments, the potassium salt is K2CO3. In other such embodiments, the potassium salt is K3PO4. In some embodiments, the base comprises a cesium salt. In some of said embodiments, the potassium salt is Cs2CO3.

Typically, the process is performed in the presence of a solvent. Suitable solvents include, for example,

Dimethylsulfoxide (DMSO), dimethylformamide (DMF) and acetonitrile (MeCN). In some embodiments, the solvent is DMSO.

Typically, the process is performed at a temperature of about 40 to about 130 ° C.

In some embodiments, the nitrogen heteroaryl ligand comprises 8-hydroxyquinoline. In other embodiments, the ligand comprises 2- (2-pyridyl) -benzimidazole. In yet other embodiments, the ligand comprises a compound of

picolina that corresponds in structure to the formula V:

image 1

In the formula V, R11, R12, R13, R14, R15, R16 and R17 are independently selected from the group consisting of hydrogen, perfluoroalkyl-C1-4, alkyloxy-C1-4, haloalkyl-C1-4, chlorine or cyano In some embodiments, R11, R12, R13,

R14

, R15, R16 and R17 are independently selected from the group consisting of hydrogen, methyl, methoxy, trifluoromethyl, chlorine and cyano. In some embodiments, the ligand of the formula V comprises N- (4-cyanophenyl) picolinamide. In other embodiments, the ligand of the formula V comprises N- (2-cyanophenyl) picolinamide.

In some embodiments, the process comprises (a) preparing a compound of the formula IV; and (b) reacting a compound of the formula III with a compound of the formula IV in the presence of (i) copper salt catalyst (I) and

(ii) nitrogenous heteroaryl ligand, optionally in the presence of an inorganic base.

The compound of the formula IV-I can be prepared, for example, by converting 2-tert-butylphenol into 2-tert-butyl-4,6

Diiodophenol (for example, by reacting with NaI and NaOCl) and then converting 2-tert-butyl-4,6-diiodophenol into 1-tert-butyl-3,5-diiodo-2-methoxybenzene (for example, by treating it with CH3I in the presence of a base,

image3

The compound of the formula IV-Br can be prepared, for example, by converting 2-tert-butylphenol into 2,4-dibromo-6-tert-butylphenol (for example, by reacting it with 1,3-dibromo-5,5-dimethylimidazolidine). 2,4-dione), and then converting 2,4-dibromo-6-tert-butylphenol into 1,5-dibromo-3-tert-butyl-2-methoxybenzene (for example, treating it with CH3I in the presence of KOtBu) .

Additional information on the preparation of compounds of formulas I and II (and their salts) is provided in the general description and / or specific synthesis examples below. Next, in the description, R1, R2, R3, R4, R5, L, RA, RB, RC, RD, R6, RE, RF, RG, RH, RI, RJ, RK, X1 and X2 have the meaning described above unless otherwise indicated.

image 1

The compound (1-1), in which R7 is, for example, hydrogen or -CO2Me and R8 is, for example, hydrogen or t-butyl, can be treated with nitric acid in solvents, such as, for example, acetic acid or water in a temperature range of about 0 to about 35 ° C for about 1 to about 5 h to provide the compound (1-2). Then, the compound (1-2) can be reduced using conditions known to those skilled in the art to form the corresponding aniline (1-3). Typical conditions for this reduction include using hydrogen at a pressure of about 1 to about 5 atmospheres in the presence of a catalyst, such as, for example, palladium or platinum on carbon in a solvent, such as, for example, tetrahydrofuran, acetate ethyl, ethanol or hexane at or near room temperature for a period of about 1 to about 12 h. Depending on the functional groups present, an alternative reduction procedure may be more suitable, such as, for example, using iron powder in the presence of a weak acid, such as, for example, ammonium chloride or dilute hydrochloric acid at temperatures of reflux in a solvent mixture containing, for example, methanol, water and / or tetrahydrofuran for about 1 to about 12 h. Another set of reduction conditions includes the use of sodium borohydride in a mixture of solvents, such as, for example, water and tetrahydrofuran. Another set of further reduction conditions includes the use of tin chloride (ll) in the presence of hydrochloric acid in solvents, such as, for example, water and methanol or mixtures thereof.

The compound (1-2) can be modified before reduction. For example, the treatment of compound (1-2), wherein R7 is hydrogen, with iodine monochloride in a mixture of methanol and water at, or near room temperature for a period of about 8 to about 24 h provides the compound (1-4), in which X1 is iodine. Alternatively, the compound (1-2) can be treated with pyridinium hydrobromide perbromide in a solvent, such as, for example, acetic acid at, or near room temperature for a period of about 2 to about 16 h to provide the compound (1-4), in which X1 is bromine. Modifications can be made to the phenol moiety in the compound (1-4). For example, the phenol can be alkylated with alkyl halides (for example, methyl iodide), alkyl sulfates (for example, methyl sulfate), alkenyl halides (for example, allyl bromide), alkynyl halides (for example, propargyl bromide) in the presence of a base, such as, for example, potassium carbonate in acetone, sodium hydride in dimethylformamide or potassium t-butoxide in tetrahydrofuran, at temperatures of about 0 to about 35 ° C for a period of about 1 to about 24 h to provide the compound (1-5), wherein R9 is, for example, alkyl, alkenyl or alkynyl. Alternatively, alkylation can be achieved using a reagent such as (trimethylsilyl) diazomethane in solvents, such as, for example, methanol or t-butyl methyl ether or mixtures thereof in a tightly sealed tube at, or near room temperature. for about 8 to about 24 h. Subsequently, the compound (1-5) can be reduced to give the compound (1-6) using the conditions of iron powder or tin chloride (ll) described above. An alternative reduction process employs hydrogenation at approximately 1 atmosphere pressure with a catalyst such as 5% platinum on sulfurized carbon in a solvent such as methanol. Protection of the resulting aniline of compound (1-6) with, for example, t-butyl carbamate can be achieved by treatment with di-tert-butyl dicarbonate in

A solvent, such as, for example, tetrahydrofuran or dioxane at a temperature of about 50 to about 65 ° C for about 1 to about 8 h provides the compound (1-7).

Modifications may also appear in the phenol moiety in the compound (1-2). A person skilled in the art can rent the phenol of the compound (1-2) using, for example, the conditions described above to obtain the

10 compound (1-8). Compound (1-8) is transformed into compound (1-9) using, for example, one or more of the appropriate reduction conditions described above.

Another modification of the phenol group in the compound (1-2) is sulfonylation to form the compound (1-8), wherein R9 is alkylsulfonyl, carbocyclylsulfonyl or haloalkylsulfonyl. Said compound may be prepared by exposing the compound (1-2) to sulfonyl chlorides, such as, for example, methanesulfonyl chloride, cyclohexanesulfonyl chloride, benzenesulfonyl chloride or 3-chloropropane sulfonyl chloride in the presence of a base, such as, for example, triethylamine, diisopropylethylamine or pyridine in a solvent, such as, for example, dichloromethane at or near room temperature for a period of about 1 to about 24 h. Then, one skilled in the art can transform the compound (1-8) into the compound (1-9) with a set

20 suitable reduction conditions.

image 1

Aniline (2-4) can be prepared by a Curtius rearrangement. To this end, the compound (2-1), in which

R4 is not amino, it can be treated in thionyl chloride at reflux with a catalytic amount of dimethylformamide for about 1 to about 4 h to obtain the acid chloride (2-2). Treatment with thionyl chloride at reflux temperature in solvents, such as, for example, chloroform or toluene also provides the compound (2-2). The compound (2-2) can be reacted with an aqueous solution of sodium azide in a solvent, such as, for example, acetone for about 1 to about 8 h to provide the

30 acyl azide (2-3). Then, the compound (2-3) can be subjected to a reordering of Curtius in reflux solvents, such as dioxane or toluene. The intermediate isocyanate is hydrolyzed with an aqueous acid, such as dilute hydrochloric acid, in a solvent, such as dimethoxyethane to provide the compound (2-4).

image 1

The compound (3-1), in which R10 is, for example, hydrogen, bromine, iodine or -CO2Me, can be treated with an acrylic acid in a pure state at or near room temperature in a solvent, such as, for example toluene and it

5 refluxed for a period of about 15 to about 48 h to provide the compound (3-2). When excess of an acrylic acid is used, compound (3-3) is produced. The compound (3-2) or (3-3) can be treated with urea in a solvent, such as, for example, acetic acid from about 100 to about 120 ° C from about 2 to about 48 h to provide the compound (3- 4).

image4

The compound (4-2) can be prepared from the compound (3-1) dissolved in solvents, such as, for example, dimethylformamide or dimethylacetamide by adding a benzene solution of (E) -3-methoxyacryloyl isocyanate (prepared as described by Santana, L; et al. J. Heterocyclic Chem. 1999, 36, 293-295,) at a temperature of about -40 to about -15 ° C in an inert atmosphere and then heating at room temperature of about 30 min to approximately 4 h. The compound (4-2) can be treated with an acid, such as, for example, sulfuric acid in mixtures of water and ethanol at a temperature range of about 90 to about 110 ° C for about 1 to about 8 h to provide the compound (4-3). Alternatively, compound (4-2) can be cycled to give uracil (4-3) in the

20 basic conditions described by Ueno, Y .; et al. J. Org. Chem. 70: 7925-7935 (2005).

image 1

The compound (9-1) can be treated in thionyl chloride at reflux for about 1 to about 4 h to obtain the acid chloride (9-2). Treatment with thionyl chloride at reflux temperature in solvents, such as, for example, chloroform or toluene also provides the compound (9-2). The compound (2) is converted into the corresponding aldehyde (9-3) by reduction with lithium tri-t-butoxy aluminum hydride in a solvent, such as, for example, tetrahydrofuran at about -78 ° C for about 1 to about 8 h. The reduction can also be achieved by treatment with indium chloride and tributyltin hydride in the presence of triphenylphosphine in a solvent, such as tetrahydrofuran or toluene at temperatures from about -40 to about 0 ° C. The compound (9-3) can be treated with the compound (9-4) in the presence of a base, such as potassium t-butoxide in a solvent, such as dichloromethane a,

or close to room temperature for a period of about 1 to about 8 hours to

image5

The compound (10-1), in which X1 is halo (for example, bromine, iodine) can undergo a reaction of Suzuki reaction with vinyl boronic acid (10-2) to provide the compound (10-3). The reaction typically requires the use of a catalyst base. Examples of bases include, for example, potassium carbonate, potassium phosphate, potassium t-butoxide, sodium carbonate, cesium carbonate and cesium fluoride. Examples of catalysts include, for example, tris (dibenzylinoacetone) dipaladium (0), palladium acetate, chloride

20 bis (triphenylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium, dichloro [1,1'-bis (di-tert-butylphosphino) ferrocene] palladium (II),

or dichloromethane dichloromethane [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) adduct. The reaction can be carried out in a solvent, such as, for example, water, dioxane, dimethoxyethane, dimethylformamide, toluene, ethanol, tetrahydrofuran and the like or mixtures thereof. The reaction can be carried out at room temperature or elevated.

image 1

The compound (11-1) can be converted into the compound (11-2) by treatment with diazomethane in a solvent, such as, for example, tetrahydrofuran in the presence of palladium acetate at, or near room temperature for a period of approximately 30 min to approximately 4 h.

image 1

The compound (11-1) is reduced to provide the compound (14-2). Typical conditions for stopping this reduction include the use of hydrogen at a pressure of about 1 to about 5 atmospheres in the presence of a catalyst, such as, for example, palladium or platinum on carbon in a solvent, such as, for example,

10 tetrahydrofuran, ethyl acetate, ethanol or hexane at or near room temperature for a period of about 1 to about 12 h.

image 1

The compound (15-1) can be converted into a two-stage sequence in the compound (15-2). The initial stage involves the reduction of the aromatic nitro moiety with iron powder in the presence of a weak acid, such as, for example, ammonium chloride or dilute hydrochloric acid at temperatures of about 60 to about 80 ° C in a solvent mixture containing , for example, methanol, water and tetrahydrofuran for about 1 to about 12 h. The second stage consists of the exposure of the aniline, prepared

20 in the first stage, in methanesulfonyl chloride in the presence of a base, such as pyridine in a solvent, such as dichloromethane at, or near room temperature.

image 1

The compound (17-1) can be mesylated to provide the compound (17-2) by treatment with methanesulfonyl chloride in the presence of a base, such as, for example, pyridine in a solvent, such as, for example, dichloromethane. The compound (17-3) can be exposed to dimethyl borane disulfide complex in a solvent, such as, for example, tetrahydrofuran from about 0 to about 10 ° C to provide the compound (17-4). Compounds (17-2) and (17-4) can be combined with acetaldehyde in tetrahydrofuran at reflux. Subsequent treatment with water at room temperature produces the compound (17-5).

image4

The carboxylic acid (18-1) can be reduced with boron tetrahydrofuran complex with heating to provide the alcohol (18-2). Compound (18-2) is converted into the corresponding bromide (18-3) with Nbromosuccinimide and triphenylphosphine in solvents, such as, for example, dichloromethane at room temperature in

15 several hours. Treatment of the compound (18-3) with triethyl phosphite at about 120 ° C for about 1 to about 3 h provides the compound (18-4). The compound (18-4) can be used, for example, to prepare the compound (9-5) as described in Scheme 5.

image 1

The benzaldehyde (19-1) can be treated with diethyl phosphonate in the presence of a base, such as, for example, sodium methoxide in a solvent, such as, for example, methanol at room temperature to provide the compound (19-2 ). The compound (19-2) can be treated with N-chlorosuccinimide and triphenylphosphine in dichloromethane at room temperature to produce the compound (19-3). Compound (19-2) can also be reacted

25 with (diethylamino) sulfur trifluoride (DAST) to provide the compound (19-4).

The compound (19-1) can also be treated with p-toluenesulfonic acid and trimethyl orthoformate in methanol at about 50 ° C to provide the acetal (19-5). Compound (19-5) can be converted to compound (19-6) by exposure to triethylphosphite and boron trifluoride diethyl ether from about -20 ° C to about

30 room temperature

Compounds (19-3), (19-4) and (19-6) can be used, for example, to prepare compound (9-5) as described in Scheme 5.

image6

Phenol (20-1), in which R4 is different from amino, is treated with an electrophilic halide source, such as, for example,

iodine monochloride to provide the dihalogenated compound (20-2), in which X1 and X2 are

independently bromine or iodine. The compound (20-2) is transformed into the compound (20-3) by reaction of an alkylating agent, such as, for example, methyl sulfate with a base such as, for example, carbonate

potassium acetone at reflux. Alternatively, methyl iodide in the presence of a base, such as, for example, t

potassium butoxide in a solvent, such as, for example, tetrahydrofuran or dimethylformamide also provides

the compound (20-3). In yet another alternative embodiment, the compound (20-2) can be methylated with

(trimethylsilyl) diazomethane in a solvent, such as, for example, t-butyl methyl ether. The compound (20-3) can be reacted with uracil, ligand (20-4), copper (I) iodide and potassium phosphate in dimethyl sulfoxide.

about 40 ° C to about 100 ° C to provide the compound (20-5).

For example, when in compound (20-3), R4 is tert-butyl, X1 is iodine and X2 is iodine or bromine, compound (20

3) can be stirred with uracil and the compound (20-4) in the presence of CuI and K2PO4 in DMSO from about 1520 to about 24 h at about 60 ° C to provide the compound (20-5). Alternatives to the ligand The compound (21-1) can be nitrated with nitric acid in acetic acid in a temperature range of about 10 to about 15 ° C to give the compound (21-2). The phenol moiety of the compound (21-2) can be protected as a silyl ether, for example t-butyldimethylsilyl ether, by treatment with a silyl chloride, such as, for example, t-butyl dimethylsilyl chloride and imidazole in a solvent, such as, for example, dimethyl formamide a

image7

5 room temperature to form the compound (21-3). Then, the compound (21-3) can be reduced using conditions known to those skilled in the art to form the corresponding aniline (21-4).

Typical conditions for this reduction include the use of hydrogen at a pressure of about 1 to about 5 atmospheres in the presence of a catalyst, such as, for example, palladium or platinum on carbon in a solvent, such as, for example, tetrahydrofuran. , ethyl acetate, ethanol, methanol or hexane at, or near room temperature for a period of about 1 to about 12 h. Depending on the functional groups present, an alternative reduction process may be more suitable, such as, for example, using iron powder in the presence of a weak acid, such as, for example, ammonium chloride or dilute hydrochloric acid at temperatures of reflux in a solvent mixture that contains, by

For example, methanol, water and tetrahydrofuran for about 1 to about 12 h.

Then, the aniline (21-4) can be sulfonated with methanesulfonyl chloride in the presence of pyridine in a solvent, such as, for example, dichloromethane. The starting material and reagents are combined at about 0 ° C and then allowed to gradually warm to room temperature during the course of the reaction to provide the compound (21-5). The silyl ether protecting group is removed in familiar conditions for those skilled in the art. For example, tetrabutylammonium fluoride in tetrahydrofuran at room temperature transforms the compound (21-5) into the compound (21-6). The phenol group of the compound (21-6) can be sulfonated with trifluoromethanesulfonic anhydride in the presence of a base, such as, for example, pyridine in a solvent, such as, for example, dichloromethane at room temperature to provide the compound (21-7 ). The compound (21-7) can

25 be used as described in Scheme 12 to prepare the compound (12-3).

image 1

The compound (22-1) is converted to the compound (22-2) in a two-step sequence. First, the compound (22-1) can be hydrolyzed with a base, such as, for example, sodium hydroxide, lithium hydroxide or potassium hydroxide in a solvent, such as, for example, methanol, ethanol or tetrahydrofuran, or mixtures thereof. The resulting reaction mixture may be stirred for a period of about 6 to about 48 h at room temperature. Second, the intermediate carboxylic acid is treated in thionyl chloride at reflux with or without a catalytic amount of dimethylformamide for about 1 to about 4 h to release the acid chloride (22-2). The treatment with thionyl chloride at the temperature of

Reflux in solvents, such as, for example, chloroform or toluene also produces the compound (22-2). Treatment of the carboxylic acid with oxalyl chloride in dichloromethane with a catalytic amount of dimethylformamide also produces the compound (22-2).

The compound (22-2) can be treated with an amine or the corresponding salt in a solvent, such as, for example, dioxane, dimethylformamide, dimethylacetamide or dichloromethane, optionally in the presence of a base, such as, for example, pyridine, triethylamine or diisopropylethylamine at temperatures varying from, or near, room temperature at about 100 ° C for between about 1 and about 24 h to provide compound (22-4), wherein R11 and R12 are independently hydrogen or RF, or taken together with the nitrogen

5 to which they are attached form a 5-6 membered heterocyclyl or a condensed 2 ring heterocyclyl.

The compound (22-2) is converted into the corresponding aldehyde (22-3) by reduction with tri-tbutoxyaluminium lithium hydride in a solvent, such as, for example, tetrahydrofuran from about -60 ° C to about -78 ° C.

10

image 1

The compound (22-3) can be converted into the compound (23-2), in which R11 and R12 are independently hydrogen or RF, or taken together with the nitrogen to which they are attached form a 5-6 membered heterocyclyl or a

Condensed 2-ring heterocyclyl by treatment with an amine, N (R11) (R12), in the presence of a reducing agent, such as, for example, sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent, such as, for example, methanol , ethanol, dichloromethane, dimethylacetamide or dimethylformamide for a period of about 1 to about 24 h. Frequently, the reaction proceeds best at an acidic pH that can be maintained by the addition of acetic acid or hydrochloric acid.

The compound (22-3) can also be converted into the compound (23-3) by reduction with tri-tutoxyaluminium lithium hydride in a solvent such as tetrahydrofuran at room temperature.

image 1

The compound (23-3) can be converted into the compound of the formula (24-2) by treatment with thionyl chloride in dichloromethane at room temperature. The compound (24-2) can be treated with a sodium alkoxide, R13ONa, in a heated solution of the corresponding alcohol to provide the compound (24-3), in which R13 is hydrogen or

RF

image 1

The compound (25-1) can be brominated by treatment with, for example, pyridinium hydrobromide perbromide in a solvent, such as, for example, acetic acid at, or near room temperature for a period of about 1 to about 8 h to give the compound (25-2). The amino group of compound (25-2) can be removed by exposing it to t-butyl nitrite in a solvent, such as, for example, dimethylformamide initially at room temperature and then increasing at a range of about 50 to

About 65 ° C to give the compound (25-3). Additional aliquots of t-butyl nitrite may be added at room temperature followed by heating until the transformation is complete. The compound (25-3) can be reduced to give the compound (25-4) by, for example, treatment with ammonium chloride and iron.

Examples

20 The following examples are merely illustrative and not limiting the present disclosure in any way.

Example A. Preparation of (E) -N- (3-tert-butyl-5-iodo4-methoxyphenylcarbamoyl) -3-methoxy acrylamide.

image8

To a vigorous stirring solution of 2-tert-butylphenol (10 g, 66.6 mmol) in heptane (67 ml) a 70% solution of nitric acid (4.25 ml, 66,) was added dropwise 6 mmol) diluted with water (4.25 ml). The resulting dark red / brown mixture was vigorously stirred for 2 h. The suspended solid was collected by filtration, washed with hexane (300 ml), water (200 ml) and again with hexane (200 ml) to give a cocoa powder which was dried at a constant weight (4, 65 g, 35.6%).

10 Part B. Preparation of 2-tert-butyl-6-iodo-4-nitrophenol.

To the product of Part A (4.5 g, 23.05 mmol) dissolved in MeOH (120 ml) and water (30 ml) was added dropwise iodine monochloride (1.155 ml, 23.05 mmol) during a 10 min period The mixture was stirred for 2 h, it was

15 diluted in 1 l of water and allowed to stand overnight. The solid material was collected by filtration, washed 3 x 50 ml with water and dried in vacuo overnight to give a brown solid (7.14 g, 96%).

Part C. Preparation of 1-tert-butyl-3-iodo-2-methoxy-5-nitrobenzene.

To a bath of ice-cold solution of the product of Part B (5.5 g, 17.13 mmol) in MTBE (15 ml) in a 50 ml pressure vessel was added 2.0M TMS diazomethane ( 12.85 ml, 25.7 mmol) followed by the dropwise addition of methanol (1.0 ml), resulting in gentle bubbling. The vessel was tightly closed and stirred at room temperature for 16 h, cooled and the pressure released. The solution was partitioned between EtOAc and water. The organic layer was washed with 1.0 M HCl, saturated potassium carbonate solution and saturated NaCl. The layer

The organic was dried over sodium sulfate, filtered and concentrated to give a red oil that was used without purification (5.4 g, 84%).

Part D. Preparation of 3-tert-butyl-5-iodo-4-methoxyaniline.

A mixture of the product of Part C (5.80 g, 17.31 mmol), ammonium chloride (1.389 g, 26.0 mmol) and iron (4.83 g, 87 mmol) in THF / MeOH / water (200 ml total, 2/2/1) was heated at reflux for 2 h, cooled and filtered through Celite. The filtrate was evaporated and the residue was partitioned between water and EtOAc. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and evaporated to give a brown oil (5.28 g, 100% yield).

35 Part E. Preparation of (E) -N- (3-tert-butyl-5-iodo-4-methoxyphenylcarbamoyl) -3-methoxyacrylamide.

To a solution of the product of Part E (3.05 g, 10 mmol) in DMF (50 ml) at -20 ° C under an atmosphere of N2, a 0.4 M solution in isocyanate benzene of (E) -3-Methoxyacryloyl (50.0 ml, 20.00 mmol, prepared by the method of Santana et al., J. Heterocyclic Chem. 36: 293 (1999). The solution was stirred for 15 min.

40 at -20 ° C, heated at room temperature for 45 min and diluted in EtOAc. The EtOAc layer was washed with 4 x 300 ml of water, 2 x 100 ml of brine, dried (Na2SO4) and concentrated to give a brown solid. The residue was triturated in Et2O / hexane to give a fine powder, collected by filtration and dried to give a brown powder (2.46 g, 57%).

Example B. Preparation of 1- (3-tert-butyl-5-iodo-4-methoxyphenyl) dihydropyrimidin-2,4 (1H, 3H) -dione.

image 1

To a suspension of the product of the product of Example A (2.46 g, 5.69 mmol) in ethanol (50 ml) was added a

solution of 5.5 ml of H2SO4 in 50 ml of water and the mixture was heated at 110 ° C for 2.5 h to give a clear solution. The solution was cooled and diluted with 50 ml of water while stirring to give an off-white solid that was collected by filtration, washed with water and dried (2.06 g, 90%).

Example C. Preparation of 1- (3-tert-butyl-5-iodo-4-methoxyphenyl) pyrimidin-2,4 (1 H, 3H) -dione.

image 1

Part A. Preparation of 2-tert-butyl-4,6-diiodophenol

A solution of 2-tert-butylphenol (20.0 g, 133 mmol) in methanol (266 ml) was treated with granules of sodium hydroxide (6.39 g, 160 mmol). The mixture was stirred until all the sodium hydroxide had dissolved and then cooled in an ice-salt bath at -2 ° C. Sodium iodide (15.0 g, 100 ml) was added and then a 10% solution of sodium hypochlorite (45 ml, 73.3 mmol) was added dropwise at a rate such that the temperature of the solution was not higher at 1.3 ° C. This sequence of events was repeated (3 x) until a total of 60 g (400 mmol) of iodide was

15 had been added and the sodium hypochlorite solution was added until the color of the solution changed from light yellow-green to the color of light iced tea. This required everything except 16 ml of the total measured 180 ml sodium hypochlorite solution. With continuous stirring at about 2 ° C, a solution of sodium thiosulfate pentahydrate (20g) in water (100 ml) was added dropwise over 20 min. After the addition, the solution was acidified to pH 3 by the dropwise addition of concentrated hydrochloric acid (approx., 35 ml of the 40 ml were needed

20 placed in the addition funnel). The precipitate was collected by filtration and washed with> 1 liter of water. The salmon solid was suctioned as dry as possible and dried in a vacuum oven at 50 ° C for 18 h. These procedures provided the product (49.61 g, 93%) as a brown solid.

Part B. Preparation of 1-tert-butyl-3,5-diiodo-2-methoxybenzene.

A solution of the product from Part A (20.0 g, 49.7 mmol) in acetone (140 ml) was treated with methyl iodide (3.9 ml, 8.83 g, 62.2 mmol) and solution 50% (w / w) sodium hydroxide (3.02 ml, 4.58 g, 57.2 mmol) followed by stirring at room temperature for 48 h. The mixture was concentrated in vacuo to a volume of approx. 50-60 ml, followed by dilution with heptane (80 ml) and water (50 ml). The layers were separated and the organic layer was extracted with

30 a saturated solution of sodium chloride. Drying (Na2SO4) and concentration in vacuo provided the product (20.59 g, 99%) as a light yellow oil.

Part C. Preparation of 1 - (3-tert-butyl-5-iodo-4-methoxyphenyl) pyrimidin-2,4 (1 H, 3H) -dione.

A suspension of the product of Part B (12.04 g, 28.9 mmol), uracil (3.89 g, 34.7 mmol), N- (2-cyanophenyl) picolinamide (1.29 g, 5.79 mmol ) and tribasic potassium phosphate (12.9 g, 60.8 mmol) in DMSO (181 ml) was degassed by spraying with nitrogen for 1 h. Then, the mixture was treated with copper (I) iodide (551 mg, 2.89 mmol) and degassing continued for a further 10 min. Then, the mixture was heated at 60 ° C for 18 h. Then, the mixture was poured into water in water (600 ml) and acidified to pH 3 by the addition of a 4 N solution.

40 hydrochloric acid. The mixture was diluted with ethyl acetate and the organic layer was extracted with water (3 x), saturated ammonium chloride solution (1 x) and saturated sodium chloride solution. The solution was dried and treated with (3-mercaptopropyl) silica gel, followed by stirring for 2 h. The mixture was filtered and concentrated in vacuo. The solid obtained was triturated with ether-ethyl acetate (> 10: 1), collected by filtration and washed with ether. After drying in a vacuum oven at 50 ° C for 2 h, these procedures provided the product (2.75 g) in the form of a

45 white solid. The mother liquors were concentrated in vacuo to provide an amber solid. This material was chromatographed on a Flash 65 silica gel cartridge, eluting with 20-100% ethyl acetate in hexanes. These procedures provided a practically white solid, which was triturated with etherhexanes and collected by filtration. After drying in a vacuum oven for 3 h, these procedures provided an additional 4.31 g of the product as a white solid. Total yield: 7.06 g (61%).

Example D. Preparation of 1- (3-tert-butyl-5-iodo-4-methoxyphenyl) pyrimidin-2,4 (1H, 3H) -dione.

image9

2-tert-Butylphenol (99.95 g, 665.36 mmol) was dissolved in 1250 ml of methanol and converted to the corresponding phenoxide with 31.96 g (799.0 mmol, 1.2 equiv.) Of sodium hydroxide by stirring the granules of sodium hydroxide at room temperature and then cooling the reaction mixture in an ice / salt bath. Sodium hydride (299.34 g, 1997.07 mmol, 3.0 equiv.) And 8.3% bleach (1265.83 g, 1411.39 mmol, 2.1 equiv.) Were added in four equal portions to the cold reaction solution, the bleach being added while maintaining the reaction mixture at <0 ° C. 500 ml of 20% (w / w) solution of sodium thiosulfate were added over a period of 18 minutes, increasing the temperature from -0.6 ° C to 2.5 ° C. The pH of the reaction mixture was adjusted to approximately 3 by the addition of 197.5 l conc. HCl. over a period of 97 min, the reaction temperature varying from 1.2 ° C to 4.1 ° C. The resulting suspension was filtered and the wet cake washed with ~ 2 L of water. The wet cake was left in the Buchner funnel under vacuum overnight (approximately 15 h) to produce 289.33 g (potency yield = 254.61 g) of the title product.

Part B. Preparation of 1-tert-butyl-3,5-diiodo-2-methoxybenzene.

The product of Part A (93% assay, 21.6 g, 50 mmol) was dissolved in 140 ml of acetone. Methyl iodide (4.2 ml, 67.5 mmol, 1.35 equiv.) Was added, followed by 50% aqueous sodium hydroxide (5.0 g, 62.5 mmol, 1.25 equiv.). The reaction was stirred overnight and then concentrated to approximately 50-60 ml. 80 ml of heptanes were added followed by 50 ml of water, the layers were stirred and separated, and the aqueous layer was extracted again with 20 ml of heptanes. The organic layers were combined and washed twice each with 50 ml of 10% aqueous NaCl to provide 91.1 grams of a heptane solution, which was subjected to the test to give 19.1 g of the title compound.

Part C. Preparation of 1 - (3-tert-Butyl-5-iodo-4-methoxyphenyl) pyrimidin-2,4 (1 H, 3H) -dione.

Uracil (33.3 g, 297 mmol, 1.2 equiv.), K3PO4 (106 g, 500 mmol, 2.1 equiv.), Cul (4.6 g, 24.2 mmol, 0.1 equiv. .) and N- (2-cyanophenyl) picolinamide (6.4 g, 28.7 mmol, 0.12 equiv.) in a flask and made inert with argon. The 1-tert-butyl-3,5-diiodo-2-methoxybenzene was changed from solvent to MeCN, dissolved in 1 L of DMSO, sprayed with argon and added to the solids. The reaction was heated at 60 ° C for 16 h. After a period of cooling, the reaction was diluted with 2 L of EtOAc and washed with 2.6 L of water (extracted again with 3 x 1 L of EtOAc). The combined organic layers were washed with 2 x 1 L of 2 0.25 M (CuOAc), then 2 x 830 ml of 15% NH4CI and then with 800 ml of brine. Then, the organic layer was concentrated and followed with 1 L of heptane, then triturated with heptane: iPrOAc 85:15 (v / v) at reflux for 4 h. After a period of cooling, the product was collected by filtration and washed with 330 ml more of heptanes: EtOAc 85:15 v / v to produce, after drying, 66.9 g (70% yield) of the product in Shape of a white solid.

Example E. Preparation of (E) -N- (4- (3-tert-Butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1- (2H) -yl) -2-methoxistyryl) phenyl) methanesulfonamide .

image 1

Boronic acid (96% potency) (3.75 g, 15.6 mmol, 1.2 equiv.), The product of Example D (5.0 g, 12.5 mmol), Cytec ligand (175 mg, 5% in mol), Pd2 (dba) 3 (46 mg, 0.4% in mol) and potassium phosphate (5.25 g, 25.0 mmol, 2 equiv.) 5 were loaded into a three-mouth RB flask . The solids were purged with nitrogen for 10 min. 75 ml of THF: 4: 1 water was sprayed for 10 min and loaded into the flask. The mixture was stirred to dissolve the solids followed by heating the mixture at 50 ° C in the dark overnight. HPLC analysis showed that the reaction was not complete after stirring overnight (remaining iodouracil ~ 2%). The reaction mixture was diluted with 375 ml of DCM and 250 ml of 10% citric acid. The mixture was stirred in a separatory funnel and the layers separated. The DCM layer was washed with a solution of 0.6 g of L-cesteine in 250 ml of 5% NaHCO3 for 30 min which changed the DCM layer from orange to yellow. The treatment of 0.6 g of L-cysteine was repeated in 250 ml of 5% NaHCO3 for 30 min, followed by a wash with 250 ml of 5% NaHCO3 and a wash with 250 ml of 10% NaCl. The DCM layer was treated with 2 g of thiourea silica for 30 min. 1 g of carbon was added to bleach, mixed for 5 min and filtered through hy-flo. 15 The wet cake was washed with DCM. Then, the DCM solution separated to give 6.74 g of a light yellow solid. The solids were ~ 92% pure. The solids were heated in a mixture of DCM and 9 ml of MeOH for 192 min. They never dissolved completely. It was cooled with mixing at room temperature. 80 ml of heptane were added and more product began to crystallize. The suspension was stirred over the weekend. 50 ml of heptane were added in portions to a total of 230 ml of heptane. The product was filtered. The filtrate was measured at 1.21 mg / ml at 210 nm and 1.35 at 220 nm, which was equal to 522-582 mg of loss in the mother liquor or 910% loss against the theoretical value. The wet cake was washed with 50 ml of a mixture of 27 ml of heptane: 22 ml of DCM: 1 ml of MeOH. The wash contained 0.5 mg / ml of product or 25 mg (0.4% versus theoretical value). Product yield 5.22 g (88.9%), purity 99.2% PA. Iodouracil was removed on crystallization. The samples were subjected to solid state for analysis and analytical for Pd determination. NMR showed no

25 residual solvent.

Example 1. Preparation of (E) -N- (4- (3-tert-Butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxystyryl) phenyl) methanesulfonamide (compound IA-L1-1.9 ).

image 1

30 Part A. Preparation of methyl 3-tert-butyl-2-hydroxy-5-nitrobenzoate.

Methyl 3,5-di-tert-butyl-2-hydroxybenzoate (28.66 g, 1.08.4 mmol) was dissolved with stirring in 430 ml of glacial acetic acid and the resulting mixture was treated dropwise with nitric acid smoker (90%, 179.26 ml). When

35 the addition was complete, the resulting mixture was stirred for 2.5 h. The reaction mixture was poured into 2.0 L of crushed ice and allowed to stand for 30 min. Then, 1.0 L of water was added and the mixture of ice and water was allowed to melt. The mixture is then filtered, washed with water and dried to provide the title compound (24.57 g, 89%).

Part B. Preparation of methyl 3-tert-butyl-2-methoxy-5-nitrobenzoate.

Methyl 3-tert-butyl-2-hydroxy-5-nitrobenzoate (11.41 g, 45.0 mmol), potassium carbonate (9.34 g, 67.6 mmol), acetone (200 ml) were added together and dimethyl sulfate (6.46 g, 67.6 mmol). Then, the resulting mixture was heated at reflux for 16 h. Then, the mixture was filtered and the solid was washed with ethyl acetate. Then, the resulting organic liquid was concentrated in vacuo to give an oil and again dissolved in ethyl acetate (600 ml). Then, the organic solution was washed with water, dried, filtered and concentrated in vacuo to give an oil that was subjected to purification by column chromatography (5% to 40% gradient of EtOAc / Hexanes) to yield the compound. of the title in the form of an oil (10.42, 87%).

Part C. Preparation of methyl 5-amino-3-tert-butyl-2-methoxybenzoate.

Methyl 3-tert-butyl-2-methoxy-5-nitrobenzoate (10.42 g, 39.0 mmol), iron powder (325 mesh, 10.89 g, 195 mmol), ammonium chloride ( 3.13 g, 58.5 mmol), water (30 ml) and methanol (150 ml). Then, the resulting mixture was heated at reflux for 1 h. Then, the mixture was cooled to room temperature, filtered through Celite, and the Celite was washed with methanol. Then, the filtrate was concentrated in vacuo and dissolved in ethyl acetate (600 ml). Then, the resulting solution was washed with water and brine. Then, the organic extract was dried, filtered and concentrated in vacuo to yield the title compound as an oil (9.25 g, 100%).

Part D. Preparation of 3- (3-tert-butyl-4-methoxy-5- (methoxycarbonyl) phenylamino) propanoic acid.

The product of Part C (16.44 g, 69.3 mmol) was dissolved in toluene (200 ml). This mixture was heated to reflux and acrylic acid was added over a period of time (1 ml of acrylic acid was added every 3 h, total 5.23 ml, 76.2 mmol). Then, the mixture was heated at reflux for 24 h. Then, the mixture was cooled and concentrated to dryness in vacuo to yield an oil as the crude title compound that was used directly in the next reaction.

Part E. Preparation of methyl 3-tert-butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxybenzoate.

The product of Part D (21.43 g, 69.3 mmol), urea (10.4 g, 173 mmol) and acetic acid (glacial, 200 ml) were added together. Then, the mixture was heated at 120 ° C for 18.5 h, followed by concentration in vacuo to give an oil. To this oil was added methanol (13 ml) and ethyl acetate (350 ml). The resulting mixture was allowed to stand for 24-48 h whereby a precipitate formed. The resulting solid was filtered off and washed with a small amount of methanol (10 ml) and then air dried to yield the title compound as a solid (15.26 g, 66%).

Part F. Preparation of 3-tert-butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxybenzoic acid.

The product of Part D (4.52 g, 13.52 mmol), methanol (70 ml) and tetrahydrofuran (70 ml) were added together. Then, the mixture was stirred vigorously until a homogeneous solution was achieved. Once it was homogeneous, an aqueous sodium hydroxide solution (1.0 M, 68 ml) was added. Then, the mixture was stirred for 12 h, then the mixture was concentrated in vacuo to remove the organic solvent, followed by the addition of aqueous hydrochloric acid (1.0 M, 80 ml) which resulted in the formation of a solid. Then, the mixture was concentrated in vacuo. To this material was added hydrochloric acid (12 M, 100 ml) and the resulting material was heated at 100 ° C for 1.5 h. Then, the reaction was cooled and water was added. The resulting solid was filtered, washed with water and dried to yield the title compound as a solid (3.55 g, 82%).

Part G. Preparation of 3-tert-butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxybenzaldehyde.

The product obtained in Part F (4.07 g, 12.71 mmol) and thionyl chloride (40.82 ml, 559 mmol) were combined and the mixture was heated at reflux for 2 h, followed by vacuum concentration to provide a light yellow solid product. The solid was dissolved in tetrahydrofuran (125 ml), the solution was cooled to -78 ° C and LiAIH (OtBu) 3 (1 M, 14 ml) was added slowly for 10 min while maintaining the temperature at -78 ° C. The mixture was stirred at -78 ° C for 2 h and the reaction was quenched with hydrochloric acid (aq., 1 M, 25 ml) at -78 ° C. The mixture was heated to room temperature and ethyl acetate was added. The layers were separated and the aqueous layer was washed with ethyl acetate. The organic extracts were combined and washed with a semi-saturated solution of sodium bicarbonate. The organic layer was dried, filtered and concentrated in vacuo to yield the title compound as a solid (3.73 g, 96%).

Part H. Preparation of 1- (3-tert-butyl-4-methoxy-5- (4-nitrostyryl) phenyl) dihydropyrimidin-2,4 (1H, 3H) -dione.

The product prepared in Part G (1.00 g, 3.29 mmol) and diethyl 4-nitrobenzyl phosphonate (0.853 g, 3.12 mmol) were dissolved in dichloromethane (50 ml). Solid potassium tert-butoxide (0.737 g, 6.57 mmol) was added portionwise at room temperature. The resulting dark red solution was stirred for 1.5 h at room temperature. 1N aqueous HCl (50 ml) was added, the mixture was stirred for 30 min and then diluted with dichloromethane (50 ml). The resulting organic layer was separated and dried. The material was purified by column chromatography on silica gel using 99/1 dichloromethane / methanol as eluent to obtain the title compound as a solid (1.12 g, 80%).

Part I. Preparation of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2

methoxystyryl) phenyl) methanesulfonamide.

The product obtained in Part H (1.1 g, 2.60 mmol), iron (0.725 g, 12.99 mmol) and ammonium chloride (0.208 g, 3.90 mmol) was added to a mixture of tetrahydrofuran (40 ml), ethanol (40 ml) and water (12 ml). The suspension was heated at 90 ° C for 45 min and then cooled to room temperature. The solution was filtered through a layer of Celite (10 g), washed with ethanol (20 ml) and the filtrate was concentrated in vacuo to give a solid. The resulting solid was dissolved in ethyl acetate (100 ml) and the solution was washed with water (50 ml) and dried over Na2SO4. He

The drying agent was filtered off and the solvent was removed in vacuo to give the aniline adduct as a yellow solid (830 mg).

The solid (830 mg, 2.109 mmol) was dissolved in dichloromethane (50 ml), pyridine (0.512 ml, 6.33 mmol) and methanesulfonyl chloride (0.181 ml, 2.32 mmol) were added and the resulting solution was stirred at room temperature for 16-15 h. Dichloromethane (100 ml) was added followed by extraction with a 1 N aqueous solution of HCl (2 x 50 ml). The organic layer was dried, concentrated in vacuo and purified by column chromatography on silica gel using CH2CI2 / MeOH 98/2 to provide the title compound as a solid (480 mg, 39%, two steps), pf = 260-261 ° C (trans isomer). 1H NMR (500 MHz, DMSO-d6): δ ppm 1.37 (s, 9H), 2.71 (t, J = 6.7 Hz, 2H), 3.01 (s, 3H), 3.75 (s, 3H), 3.79 (t, J = 6.6 Hz, 2H), 7.13 (d, J = 16.5 Hz, 1H), 7.15 (d, J = 2.4 Hz , 2H), 7.23 (d, J = 8.5 Hz, 2H),

20 7.25 (d, J = 16.5 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.61 (d, J = 8.6 Hz, 2H), 9 , 80 (sa, 1H), 10.30 (s, 1H). (trans isomer).

Example 2. Preparation of (Z) -N- (4- (2- (3-tert-butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyidenyl) -1-chlorovinyl) phenyl) methanesulfonamide (compound image 1 IA-L1-1.3).

25

Part A. Preparation of diethyl hydroxy (4-nitrophenyl) methylphosphonate.

The title compound was prepared as described in Taylor, WP, et. Al, Bioorg. Med. Chem. 4: 1515-1520 (1996).

30 4-Nitrobenzaldehyde (3.0 g, 19.85 mmol) and diethyl phosphonate (2.74 g, 19.85 mmol) were combined and treated with a 0.5 N solution of sodium methoxide in methanol (0.993 ml , 0.496 mmol). The resulting orange-red solution was stirred for 12 h at room temperature. The reaction mixture was extracted with dichloromethane (20 ml) followed by semi-saturated ammonium chloride (20 ml). The organic layer was separated, dried and concentrated in vacuo to give the title compound as a semi-solid (5.1 g, 89%).

Part B. Preparation of diethyl chloro (4-nitrophenyl) methylphosphonate.

The product prepared in Part A (500 mg, 1,729 mmol) was dissolved in dichloromethane (10 ml) and treated with triphenylphosphine (998 mg, 3.80 mmol), followed by N-chlorosuccinimide (462 mg, 3.46 mmol ). The mixture was stirred at

40 room temperature for 18 h. The solution was concentrated in vacuo and the residue was purified by column chromatography using silica gel, eluting with a 1/1 mixture of hexanes / ethyl acetate to provide the title compound as an oil (262 mg, 49% ).

Part C. Preparation of (Z) -N- (4- (2- (3-tert-butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -145 chlorovinyl) phenyl ) methanesulfonamide.

The product prepared in Example 1, Part G (100 mg, 0.329 mmol) was treated with the product obtained from Part B using the procedures described in Example 1, Part H and Example 1, Part I to provide 39 mg of the compound of the title. 1 H NMR (300 MHz, DMSO-d6): δ ppm 1.36 (s, 9H), 2.71 (t, J = 6.8 Hz, 2H), 3.06 (s, 3H), 3.71

50 (s, 3H), 3.78 (t, J = 6.8 Hz, 2H), 7.23 (d, J = 2.6 Hz, 1H), 7.27 (s, 1H), 7, 28 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 2.6 Hz, 1H), 7.78 d, J = 8.8 Hz, 1H), 10.05 (s , 1H), 10.34 (s, 1H).

Example 3. Preparation of (E) -1- (3-tert-butyl-5- (4-fluorostyryl) -4-methoxyphenyl) dihydropyrimidine-2,4 (1H, 3H) -dione (compound IA-L1-1.12) .

image 1

The title compound was prepared according to the procedures described in Example 1, Part H and Example 1, Part I, using the product obtained in Example 1, Part G (50 mg, 0.164 mmol) and 4-fluorobenzyl phosphonate of diethyl (40.5 mg, 0.164 mmol). The title compound was obtained as a solid (30 mg, 46%). 1 H NMR (300 MHz, DMSO-d6): δ ppm 1.37 (s, 9H), 2.72 (t, J = 6.6 Hz, 2H), 3.76 (s, 3H), 3.79 (t, = 6.6 Hz, 2H), 7.21 (m, 4H), 7.30 (d, J = 16.3 Hz, 1H), 7.53 (d, J = 2.6 Hz, 1H), 7.73 (m, 2H), 10.35 (s, 1H).

Example 4. Preparation of (Z) -N- (4- (2- (3-tert-butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1-fluorovinyl) phenyl ) methanesulfonamide (compound image 1 IA-L1-1.4).

Part A. Preparation of diethyl fluoro (4-nitrophenyl) methylphosphonate.

The title compound was prepared as described in Taylor, WP, et. Al, Bioorg. Med. Chem. 4: 1515-1520 (1996). The product of Example 2, Part A (500 mg, 1,729 mmol) was dissolved in dichloromethane (10 ml) and treated by the dropwise addition of sulfur (diethylamino) sulfur trifluoride (DAST) (2.5 ml, 18, 9 mmol). The mixture was stirred at

20 room temperature for 18 h. A semi-saturated solution of monobasic sodium phosphate (20 ml) was added followed by the addition of dichloromethane (20 ml) and the separation was the resulting organic phase. The organic solution was dried, concentrated in vacuo and then subjected to column chromatography using silica gel, eluting with a 1/1 mixture of hexanes / ethyl acetate to give the title compound as an oil (215 mg , 43%).

Part B. Preparation of (Z) -N- (4- (2- (3-tert-butyl-5- (2,4-dioxotetrahydropyrimidin-1- (2H) -yl) -2-methoxyphenyl) -1-fluorovinyl) phenyl) methanesulfonamide.

The product prepared as described in Part A (100 mg, 0.329 mmol) was treated with the product prepared

30 in Example 1, Part G (96 mg, 0.329 mmol) according to the procedures described in Example 1, Part H and Example 1, Part I to provide 53 mg of the title compound as a 1/1 mixture of cis / trans isomers. Chromatographic separation by reverse phase HPLC using a gradient of 40-100% acetonitrile in 0.1% aqueous trifluoroacetic acid gave the title compound as a solid (20 mg). 1 H NMR (300 MHz, DMSO-d6): δ ppm 1.37 (s, 9H), 2.71 (t, J = 6.8 Hz, 2H), 3.06 (s, 3H), 3.77 (s, 3H), 3.78 (m, 2H), 6.62 (d, J

35 = 40.4 Hz, 1H), 7.18 (d, J = 2.6 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 2.6 Hz, 1H), 7.75 (d, J = 8.8 Hz, 2H), 10.08 (s, 1H), 10.33 (s, 1H).

Example 5. Preparation of (E) -N- (4- (2- (3-tert-butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1-fluorovinyl) phenyl) methanesulfonamide (compound IA-L1-1.5).

image 1

5 Chromatographic separation by reverse phase HPLC of the 1/1 mixture of the cis / trans isomeric material (53 mg) of Example 4, Part A using a gradient of 40-100% acetonitrile in 0.1% aqueous trifluoroacetic acid provided the title compound as a solid (16.5 mg). 1 H NMR (300 MHz, DMSO-d6): δ ppm 1.33 (s, 9H), 2.60 (t, J = 6.6 Hz, 2H), 3.01 (s, 3H), 3.57 (t, J = 6.6 Hz, 2H) 3.79 (s, 3H), 6.46 (d, J = 21.3 Hz, 1H), 6.87 (d, J = 2.2 Hz, 1H), 7.14 (m, 3H), 7.36 (d, J = 8.8 Hz, 2H), 10.02 (s, 1H), 10.24 (s, 1H).

Example 6. Preparation of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxystyryl) -2fluorophenyl) methanesulfonamide (compound IA -L1-1.26)

image 1

15 Part A. Preparation of 4- (bromomethyl) -2-fluoro-1-nitrobenzene.

(3-Fluoro-4-nitrophenol) methanol (1.24 g, 7.25 mmol) was dissolved in dichloromethane (25 ml) and treated with triphenylphosphine (2.28 1 g, 8.70 mmol) followed by N- bromosuccinimide (1,548 g, 8.70 mmol). The mixture was stirred at room temperature for 2 h. Water (50 ml) and dichloromethane (40 ml) were added, and the organic layer was separated and dried.

The solution was concentrated in vacuo and purified by column chromatography using silica gel, eluting with a 5/1 mixture of hexanes / ethyl acetate to give the title compound as a solid (1.27 g, 75 %).

Part B. Preparation of diethyl 3-fluoro-4-nitrobenzylphosphonate.

The product prepared in Part A (1.27 g, 5.43 mmol) was added to triethyl phosphite (8 ml, 54.3 mmol) and the solution was heated at 120 ° C for 1 h. After a period of cooling, excess triethyl phosphite was removed by vacuum heating and the residue was subjected to column chromatography on silica gel using 99/1 dichloromethane / methanol to obtain the crude title compound. in the form of an oil (800 mg).

30 Part C. Preparation of (E) -N- (4- (3-tert-Butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxystyryl) -2fluorophenyl) methanesulfonamide.

The product described in Example 1, Part G (533 mg, 1,751 mmol) was treated with the product described in Part B

35 (510 mg, 1,751 mmol) according to the procedures described in Example 1, Part H and Example 1, Part I to provide 80 mg of the title compound. 1H NMR (300 MHz, DMSO-d6): δ ppm 1.37 (s, 9H), 2.71 (t, J = 6.5 Hz, 2H), 3.05 (s, 3H), 3.76 (s, 3H), 3.79 (t, J = 6.6 Hz, 2H), 7.18 (m, 2H), 7.36 (d, J = 16.5 Hz, 1H), 7.39 (m, 1H), 7.44 (m, 1H), 7.52 (d, J = 2.6 Hz, 1H), 7.63 (m, 1H), 9.65 (s, 1H), 10 , 35 (s, 1 H).

40

Example 7. Preparation of N- (4- (2- (3-tert-butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) cyclopropyl) phenyl) methanesulfonamide (compound IA-L8- 1.1).

image 1

The product obtained as described in Example 1, Part I (30 mg, 0.064 mmol) was dissolved in tetrahydrofuran (2 ml) and treated with 0.95 ml of a 0.67 M ethereal solution of diazomethane ( 0.636 mmol) followed by palladium acetate (0.7 mg, 0.0031 mmol). The mixture was stirred for 30 min at room temperature followed by removal of the solid by filtration and concentration of the filtrate. The filtrate was purified by column chromatography on silica gel using dichloromethane / methanol 98/2 as eluent to obtain the title compound.

10 in the form of a solid (21.6 mg, 70%). m.p. 265-266 ° C. 1H NMR (300 MHz, DMSO-d6): δ ppm 1.33 (s, 9H) 1.50 (m, 2H), 2.13 (m, 1H), 2.27 (m, 1H), 2, 69 (t, J = 6.6 Hz, 2H), 2.94 (s, 3H), 3.63 (s, 3H), 3.74 (t, J = 6.6 Hz, 2H), 6, 84 (d, J = 2.6 Hz, 1H), 7.04 (d, J = 2.6 Hz, 1H), 7.14 (d, J = 8.8 Hz, 2H), 7.20 ( d, J = 8.8 Hz, 2H), 9.60 (s, 1H), 10.29 (s, 1H).

Example 8. Preparation of N- (4- (3-tert-butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -215 methoxyphenethyl) phenyl) methanesulfonamide (compound image 1 IA-L5-2-1.1).

The product obtained as described in Example 1, Part I (415 mg, 0.88 mmol) was dissolved in methanol (30 ml) and treated with 50 mg of 10% palladium on carbon. The suspension was stirred for 48 h at temperature

20 dwarf atmosphere hydrogen atmosphere. The reaction mixture was filtered through Celite and concentrated in vacuo to give the title compound as a solid (230 mg, 55%). m.p. 233-234 ° C. 1H NMR (300 MHz, DMSO-d6): δ ppm 1.34 (s, 9H), 2.68 (t, J = 6.8 Hz, 2H), 2.86 (s, 4H), 2.93 (s, 3H), 3.70 (m, 2H), 3.74 (s, 3H), 7.11 (m, 4H), 7.23 (m, 2H), 9.59 (s, 1H) , 10.29 (s,).

Example 9. Preparation of (E) -N- (4- (3-tert-Butyl-5- (2,4-dioxotetrahydropyrimidin-1- (2H) yl) styryl) phenyl) methanesulfonamide (compound IA-L1-1.16 )

image 1

Part A. Preparation of methyl 3-tert-butyl-5- (chlorocarbonyl) benzoate. A mixture of 3-tert-butyl-5- (methoxycarbonyl) benzoic acid (9.18 g, 38.9 mmol, prepared by the Carter method

et. al., WO2005021500A1), thionyl chloride (75 ml) and 1 drop of DMF in toluene (200 ml) was heated at reflux for 2 h, cooled and concentrated. The residue was azeotropically distilled with toluene (3 x 50 ml) and dried under high vacuum to give the title compound as an off-white waxy solid (9.9 g, quantitative yield).

5 Part B. Preparation of methyl 3- (azidocarbonyl) -5-tert-butylbenzoate.

To the product of Part A (9.9 g, 38.9 mmol) in acetone (200 ml), a solution of sodium azide (10.12 g, 156 mmol) dissolved in water (20 ml) was added dropwise . The mixture was stirred for 2 h and diluted with EtOAc. The

The organic layer was washed with H2O and saturated brine, dried (Na2SO4), filtered and concentrated to give the title compound as a white solid (9.9 g, 97%).

Part C. Preparation of methyl 3-amino-5-tert-butylbenzoate.

The product of Part B (9.9 g, 37.9 mmol) in toluene (100 ml) was heated at reflux for 1 h and concentrated to give the isocyanate intermediate that was dissolved in DME (60 ml), treated with 8% HCl (150 ml) and stirred for 16 h. The mixture was concentrated and the residue was dissolved in water, neutralized with solid sodium bicarbonate and extracted 3 x 100 ml with EtOAc. The organic extracts were combined, washed with saturated NaCl, dried (Na2SO4), filtered and concentrated. The crude product was chromatographed on silica eluting with 2: 1 of

20 hexane / EtOAc to give the title compound as an oil (2.7 g, 35%).

Part D. Preparation of methyl 3-tert-butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxybenzoate.

A mixture of the product of Part C (2.34 g, 11.29 mmol) and acrylic acid (2.32 ml, 33.9 mmol) in toluene (60 ml)

25 was heated under reflux under a nitrogen atmosphere for 24 h, cooled and concentrated. Then, the resulting residue was treated with urea (2.03 g, 33.9 mmol) in acetic acid (35 ml) and heated at 120 ° C for 24 h, cooled and concentrated. The residue was azeotropically distilled 3 x 50 ml with toluene and dissolved in 100 ml of EtOAc. The organic layer was washed with dilute aqueous NaHCO3, H2O and saturated brine, dried (Na2SO4), filtered and concentrated to give the title compound as a white solid (2.1 g, 61%).

30 Part E. Preparation of 3-tert-butyl-5- (2,4-dioxotetrahydropyrimidin-1- (2H) -yl) benzoic acid.

A mixture of the product of Part D (1.8 g, 5.91 mmol) and 1 M NaOH (29.6 ml, 29.6 mmol) in MeOH (15 ml) and THF (15 ml) was stirred for 24 h and concentrated. The residue was treated with 50 ml of 1M HCl and extracted in EtOAc. The

The EtOAc layer was washed with H2O and saturated brine, dried (Na2SO4), filtered and concentrated to give a white solid. This urea intermediate was combined with 20 ml of concentrated HCl and heated at 100 ° C for 1 h, cooled and diluted with 75 ml of ice-cold water to give a white powder that was collected by filtration and dried at a constant mass to give the title compound (1.6 g, 93%).

Part F. Preparation of (E) -N- (4- (3-tert-Butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) styryl) phenyl) methanesulfonamide.

The product described in Part E was treated with thionyl chloride and tri-tert-butoxy aluminum lithium hydride according to the procedures described in Example 1, Part G to produce 3-tert-butyl-5- (2,4- dioxotetrahydropyrimidin1- (2H) -yl) benzaldehyde. The aldehyde was treated with diethyl 4-nitrobenzylphosphonate according to the procedures

45 described in Example 1, Part H and Example 1, Part I to provide the title compound (85 mg). 1 H NMR (300 MHz, DMSO-d6): δ ppm 1.32 (s, 9 H) 2.72 (t, J = 6.43 Hz, 2 H) 3.01 (s, 3 H) 3.82 (t, J = 6.62 Hz, 2 H) 7.18 -7.25 (m, 5 H) 7.39 (s, 1H) 7.46 (s, 1H) 7.58 (d, J = 8.46 Hz, 2 H) 9.84 (s, 1 H) 10.37 (s, 1 H).

Example 10. Preparation of (Z) -N- (4- (2- (3-tert-butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -150 methoxyvinyl) phenyl ) methanesulfonamide (compound IA-L1-1.17).

image 1

Part A. Preparation of 1- (dimethoxymethyl) -4-nitrobenzene.

A flask equipped with a magnetic stir bar and a vigreux column was loaded with 4-nitrobenzaldehyde (5.0 g, 33.1 mmol), pyridinium p-toluenesulfonate (1.66 g, 6.62 mmol), trimethoxyethane ( 3.51 g, 33.1 mmol) and methanol (100 ml). The mixture was heated at 50 ° C for 12 h and concentrated in vacuo. The residue was dissolved again in EtOAc and washed with aq. NaOH. (1 M), H2O and brine. The mixture was dried (Na2SO4), filtered and concentrated at

5 to produce the title compound as a light yellow transparent oily product (6.36 g, 97%).

Part B. Preparation of diethyl methoxy (4-nitrophenyl) methylphosphonate.

The product of Part A (3.0 g, 15.2 mmol) and triethyl phosphite (2.53 g, 15.2 mmol) were dissolved in dichloromethane (30 ml) under a nitrogen atmosphere, cooled to -20 ° C and treated by dropwise addition of boron trifluoride etherate (2.27 g, 16 mmol). The mixture was allowed to slowly warm to room temperature overnight with stirring. Water was added and the resulting mixture was stirred for 5 min, separated and the organic layer dried (Na2SO4), filtered and concentrated in vacuo to give a solid residue. The residue was purified on silica gel

15 (100% EtOAc to 3% CH3OH / EtOAc) to yield the title compound as a light yellow oily product (3.78 g, 82%).

Part C. Preparation of (Z) -N- (4- (2- (3-tert-butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1-methoxyvinyl) phenyl) methanesulfonamide.

The product obtained according to the procedure described in Example 1, Part G (400 mg, 1,314 mmol) was treated with the product obtained in Part B (399 mg, 1,314 mmol) according to the procedures described in Example 1, Part H and Example 1, Part I to provide the title compound (17 mg, 6%). 1 H NMR (300 MHz, DMSO-d6): δ ppm 1.36 (s, 9 H) 2.71 (t, J = 6.62 Hz, 2 H) 3.05 (s, 3 H) 3.58 (s, 3 H) 3.75 (s, 3 H) 3.76 -3.81

25 (m, 2 H) 6.25 (s, 1H) 7.11 (d, J = 2.57 Hz, 1H) 7.27 (d, J = 8.46 Hz, 2 H) 7.60 ( d, J = 8.82 Hz, 2 H) 7.67 (d, J = 2.57 Hz, 1H) 9.96 (s, 1H) 10.32 (s, 1H).

Example 11. Preparation of (E) -1 - (3-tert-butyl-4-methoxy-5-styrylphenyl) dihydropyrimidin-2,4 (1H, 3H) -dione (compound IA-L1-1.18).

30

image 1

The product was obtained according to the procedure described in Example 1, Part G (50 mg, 0.164 mmol) was treated with diethyl benzyl phosphonate (0.034 ml, 0.164 mmol) according to the procedure described in Example 1, Part H to provide the title compound (13 mg, 19%). 1 H NMR (300 MHz, DMSO-d6): δ ppm 1.37 (s, 9

35 H) 2.72 (t, J = 6.62 Hz, 2 H) 3.76 (s, 3 H) 3.80 (t, J = 6.80 Hz, 2 H) 7.16-7, 18 (m, 1H) 7.21 -7.23 (m, 1H) 7.29 -7.33 (m, 2 H) 7.36-7.43 (m, 2 H) 7.54 (d, J = 2.57 Hz, 1H) 7.64 (d, J = 7.35 Hz, 2 H) 10.35 (s, 1H).

Example 12. Preparation of (E) -1- (3-tert-butyl-4-methoxy-5- (4-methoxystyryl) phenyl) dihydro pyrimidin-2,4- (1H, 3H) -dione (compound IA-L1 -1.14).

40

image 1

The product obtained according to the procedure described in Example 1, Part G (50 mg, 0.164 mmol) was treated with diethyl 4-methoxybenzyl phosphonate (0.028 ml, 0.164 mmol) according to the procedure described in Example 1, Part H to provide the title compound (4 mg, 4%). 1 H NMR (300 MHz, DMSO-d6): δ ppm 1.37 45 (s, 9 H) 2.71 (t, J = 6.62 Hz, 2 H) 3.70 -3.81 (m, 8H ) 6.96 (d, J = 8.82 Hz, 2 H) 7.13 (d, J = 2.21 Hz, 1H) 7.15 (d, J =

2.57 Hz, 2 H) 7.50 (d, J = 2.57 Hz, 1H) 7.58 (d, J = 8.46 Hz, 2 H) 10.34 (s, 1H). Example 13A. Preparation of (E) -N- (4- (3-tert-Butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1- (2H) -yl) -2-methoxystyryl) phenyl) methanesulfonamide (compound IB -L1-1.1).

image 1

5 Part A. Preparation of (E) -methyl 3-tert-butyl-2-methoxy-5- (3- (3-methoxyacryloyl) ureido) benzoate.

The product obtained as described in Example 1, Part C (2.0 g, 8.43 mmol) was dissolved in 30 ml of N, N-dimethylacetamide and cooled to -25 ° C. A 0.5 molar solution of E-3-methoxyacryloyl isocyanate in benzene (21.9

10 ml, 10.96 mmol) was added dropwise, the resulting solution was stirred at room temperature for 4 h and then poured into water. The product was extracted into dichloromethane, washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo to give the title compound.

Part B. Preparation of methyl 3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1- (2H) -yl) -2-methoxybenzoate.

The product of Part A (3.1 g, 8.51 mmol) was dissolved in ethanol (60 ml). To this solution was added a mixture of concentrated sulfuric acid (6 ml) and water (60 ml). The heterogeneous mixture was heated at 100 ° C for 3 h. The ethanol was removed in vacuo and then the aqueous solution was extracted with dichloromethane and evaporated to dryness. This residue was purified by column chromatography on silica gel, eluting with 1% methanol / dichloromethane.

20 to produce the title compound (1.23 g, 44%).

Part C. Preparation of 3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1- (2H) -yl) -2-methoxybenzoic acid.

The product of Part B (1.23 g, 3.7 mmol) was taken up in ethanol (5 ml) and a 1 M solution of sodium hydroxide (10

25 ml) and stirred at room temperature for 18 h. The solution was acidified with 1M HCl and the resulting solid was filtered and dried to give the title compound (0.945 g, 80%).

Part D. Preparation of 3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1- (2H-yl) -2-methoxybenzaldehyde.

The product of Part C (0.945 g, 2.97 mmol) was taken up in thionyl chloride (4.5 ml) and the mixture was heated at 80 ° C for 40 min. After evaporation to dryness, the acid chloride was dissolved in dry THF (8 ml) and cooled to -78 ° C. A 1M solution of tri-tert-butoxy aluminum lithium hydride in THF (3.0 mL, 3.0 mmol) was added dropwise. After 45 min the cold reaction was stopped with 1M HCl (5 ml), extracted in ethyl acetate and purified by column chromatography on silica gel, eluting with dichloromethane followed by methanol at

1% / dichloromethane to give the title compound (0.635 g, 71%).

Part E. Preparation of (E) -1- (3-tert-butyl-4-methoxy-5- (4-nitrostyryl) phenyl) pyrimidin-2,4 (1H, 3H) -dione.

The product of Part D (0.634 g, 2.1 mmol) and diethyl 4-nitrobecylphosphonate (0.573 g, 2.1 mmol) were combined in

40 dichloromethane (25 ml) at room temperature. Potassium tert-butoxide (0.494 g, 4.4 mmol) was added portionwise, the resulting heterogeneous red / brown mixture was stirred for 1.5 h. This mixture was quenched with 1M HCl (15 ml), poured into water and extracted into ethyl acetate and the crude product was purified by column chromatography on silica gel, eluting with 1% methanol / dichloromethane to give the title compound (0.735 g, 83%).

45 Part F. Preparation of (E) -1 - (3- (4-aminoestyryl) -5-tert-butyl-4-methoxyphenyl) pyrimidin-2,4 (1H, 3H) -dione

The product of Part E (0.735 g, 1.74 mmol), ammonium chloride (0.14 g, 2.62 mmol) and iron (0.477 g, 8.72 mmol) were combined in an ethanol solution (10 ml), water (5 ml) and THF (10 ml) and heated at 75 ° C for 1 h. The mixture was filtered through diatomaceous earth, rinsing thoroughly with THF and concentrated to give the

50 title compound.

Part G. Preparation of (E) -N- (4- (3-tert-Butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxistyryl) phenyl) methanesulfonamide.

The product of Part F (0.683 g, 1.75 mmol) and pyridine (0.564 ml, 6.98 mmol) were combined in dichloromethane (15 ml) at room temperature. Methane sulfonylchloride (0.163 ml, 2.1 mmol) was added dropwise and the solution was stirred for 18 h. The mixture was poured into 1M HCl and extracted into dichloromethane, concentrated, purified by column chromatography on silica gel, eluting with 1%, 2% methanol / dichloromethane. Trituration in dichloromethane provided a solid that was filtered and dried to give the title compound as a colorless powder (0.465 g, 57%). 1 H NMR (300 MHz, DMSO-D6) δ ppm 1.38 (s, 9 H), 3.01 (s, 3 H), 3.79 (s, 3 H) 5.65 (d, J = 7, 72 Hz, 1H), 7.17-7.28 (m, 5 H), 7.58-7.70 (m, 3 H), 7.75 (d, J = 7.72 Hz, 1H), 9.86 (s, 1 H), 11.42 (s, 1 H).

Example 13B. Preparation of (E) -N- (4- (3-tert-Butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) phenyl) methanesulfonamide (compound IB- L1-1.1).

image 1

10 Part A. Preparation of N- (4-ethynylphenyl) methanesulfonamide.

4etinylaniline (30 g, 256 mmol) and pyridine (42.5 ml, 525 mmol) in dichloromethane (512 ml) was added to a three-neck, 2-l round bottom flask equipped with a stirrer on the top color solution

15 orange The mixture was cooled to 5 ° C and methanesulfonyl chloride (19.96 ml, 256 mmol) was added dropwise over 15 min. The reaction solution was stirred at 5 ° C for 2 h and washed with 1 M aqueous HCl (3 x 250 ml). Then, the dichloromethane layer was washed sequentially with saturated aqueous NaHCO3, water and saturated aqueous NaCl. The dichloromethane layer was dried over sodium sulfate and treated simultaneously with decolorized carbon for 30 min, then the solution was filtered through Celite and the filtrate was concentrated. The solid pink / orange is

20 dissolved in a minimum amount of hot ethyl acetate (50-75 ml) and slowly diluted with hexanes (500-600 ml) for orange crystals that were collected by filtration and dried to provide the title compound (40 , 0 g, 80%).

Part B. Preparation of (E) -4- (methylsulfonamido) styrylboronic acid.

25 (Reference: Org. Prep. Proc. Int., 2004, 36, 573-579) In a flask was added methyl borane-sulfide complex (8.03 ml, 85 mmol) followed by tetrahydrofuran (16 ml) and then The mixture was cooled to 0 ° C. Then, (1R) - (+) - alpha-pinene (26.2 ml, 169 mmol) (for 10 min) was added dropwise to the ice-cold solution. Then, the mixture was stirred at 0 ° C for 1 h followed by stirring for 2 h at room temperature. Thick suspension

The resulting white color was cooled to -40 ° C in a dry ice / acetone bath, followed by the dropwise addition of the product from Part A (15.0 g, 77 mmol) dissolved in 60 ml of THF for 30 min. After the addition was complete, the mixture was stirred for an additional hour at -35 ° C and then 1 h at room temperature. Then, the light yellow solution was cooled to 0 ° C and acetaldehyde (61.4 ml, 1088 mmol) was added, then the mixture was heated at reflux at 50 ° C for 18 h. Then, the solvent was removed in vacuo to provide a syrup of

Orange, to which water (115 ml) was added and the heterogeneous mixture was stirred for 3 h at room temperature. The light yellow solid generated was collected and washed with water (250 ml) and then dried in a vacuum oven overnight. The resulting material was then dissolved in boiling acetone (190 ml), which provided a homogeneous yellow solution, followed by removal of the heating solution and the addition of hexanes (365 ml) for a time of 5 min. A white solid formed in the solution and the

The mixture was stirred until the solution was cooled to room temperature, then the white solid was collected and dried in a vacuum oven for 1 h to provide the title compound (12.1 g, 85%).

Part C. Preparation of 2-tert-butyl-4-nitrophenol.

To a vigorous stirring solution of 2-tert-butylphenol (10 g, 66.6 mmol) in heptane (67 ml) a solution of 70% nitric acid (4.25 ml, 66,) was added dropwise 6 mmol) diluted with water (4.25 ml). The dark red / brown mixture was stirred vigorously for 2 h. The suspended solid was collected by filtration, washed with hexane (300 ml), water (200 ml) and once again with hexane (200 ml) to give a cocoa powder that was dried at constant mass (4.65 g , 35.6%).

50 Part D. Preparation of 2-bromo-6-tert-butyl-4-nitrophenol.

A solution of the product of Part C (1.0 g, 5.12 mmol) in glacial acetic acid (10.25 ml) was treated portionwise with pyridine hydrobromide perbromide (1.80 g, 5.63 mmol) followed stirring at room temperature for 2

55 h. More quantity of pyridine hydrobromide perbromide (3.6 g) was added in two portions and after 3 h more stirring, the reaction was complete. The mixture was poured into ice water and the mixture was treated with a small amount of sodium sulphite. The resulting solid was filtered and dried in vacuo to give the title compound as a brown solid (1.40 g, 100%).

Part E. Preparation of 1-bromo-3-tert-butyl-2-methoxy-5-nitrobenzene.

A solution of the Part D product (1.40 g, 5.11 mmol) in t-butyl methyl ether: 10: 1 methanol (25.5 ml) was treated with 2.0 M trimethylsilyldiazomethane in ether (5.1 ml, 10.21 mmol), followed by stirring at room temperature for 18

h. The mixture was concentrated in vacuo to provide a yellow oil, which was purified by column chromatography on silica gel eluting with EtOAc / hexanes to give the title compound as a yellow oil (1.36 g, 92%).

Part F. Preparation of tert-butyl 3-bromo-5-tert-butyl-4-methoxyphenylcarbamate.

A solution of the product of Part E (960 mg, 3.33 mmol) in methanol (17 ml) was treated with 5% platinum on sulfur carbon (100 mg), followed by hydrogenation under balloon pressure for 3 h and then filtered through Celite and concentrated in vacuo to provide 3-bromo-5-tert-butyl-4-methoxyaniline as a yellow oil (860 mg, 3.33 mmol, 100%). A solution of this material in THF (17 ml) was treated with di-tert-butyl dicarbonate (800 mg, 3.66 mmol) followed by heating under reflux for 2 h. Concentration in vacuo provided a beige solid, which was purified by column chromatography on silica gel eluting with EtOAc / hexanes. The solid was triturated with hexanes, collected by filtration and dried in vacuo to give the title compound as a practically white solid (890 mg, 75%).

Part G. Preparation of (E) -N- (3-Bromo-5-tert-butyl-4-methoxyphenylcarbamoyl) -3-methoxyacrylamide.

The product of Part F (2.0 g, 5.58 mmol) was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (5 ml) was added. The solution was stirred at room temperature for 1 h followed by concentration in vacuo and the addition of 10% aqueous sodium bicarbonate (50 ml), followed by extraction with ethyl acetate (3 x 50 ml). The combined organic extracts were dried and concentrated to provide a residue that was dissolved in 10 ml of N, N-dimethylacetamide and cooled to -25 ° C. A 0.5 molar solution of E-3-methoxyacryloyl isocyanate in benzene (20.3 ml, 11.16 mmol) was added dropwise, the resulting solution was stirred at room temperature for 4 h and then poured into water. The product was extracted into dichloromethane, washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo to give the title compound.

Part H. Preparation of 1- (3-Bromo-5-tert-butyl-4-methoxyphenyl) pyrimidin-2,4 (1H, 3H) -dione.

The product of Part G (2.15 g, 5.58 mmol) was dissolved in ethanol (10 ml). To this solution was added a mixture of concentrated sulfuric acid (1 ml) and water (10 ml). The heterogeneous mixture was heated at 100 ° C for 2 h. The ethanol was removed in vacuo and then the aqueous solution was extracted with dichloromethane and evaporated to dryness. This residue was purified by column chromatography on silica gel, eluting with 1% methanol / dichloromethane to yield the title compound (1.35 g, 69%).

Part I. Preparation of (E) -N- (4- (3-tert-Butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxistyryl) phenyl) methanesulfonamide.

The product of Part H (8.0 g, 22.65 mmol), the product of Part B (5.90 g, 24.46 mmol), 1,1'bis (di-tert-butylphosphino) bichloride Palladium ferrocene (0.738 g, 1,132 mmol) and potassium phosphate (9.62 g, 45.3 mmol) were dissolved in a mixture of tetrahydrofuran (128 ml) and water (32 ml). Nitrogen gas was bubbled through the resulting mixture for 10 min followed by heating the solution at 50 ° C for 5 h in the dark. The reaction was allowed to cool to room temperature followed by the addition of saturated aqueous ammonium chloride (50 ml) and water (200 ml), and the solution was extracted with dichloromethane (600 ml). To the organic extract was added magnesium sulfate and silica gel functionalized with 3-mercaptopropyl (20 g), and the resulting solution was stirred in the dark for 18

h. The solids were then filtered off and the filtrate was concentrated in vacuo and subjected to column chromatography on silica gel using a 99/1 to 99/2 dichloromethane / methanol gradient to provide the title compound (7, 4 g, 70%). 1 H NMR (300 MHz, DMSO-D6) δ ppm 1.38 (s, 9 H), 3.01 (s, 3 H), 3.79 (s, 3 H) 5.65 (d, J = 7 , 72 Hz, 1H), 7.17-7.28 (m, 5 H), 7.58-7.70 (m, 3 H), 7.75 (d, J = 7.72 Hz, 1H) , 9.86 (s, 1 H), 11.42 (s, 1 H).

Example 14. Preparation of (E) -N- (4- (3-tert-butyl-5- (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxistiryl) phenyl) methanesulfonamide (compound IB-L1.1.2).

image 1

5 Part A. Preparation of methyl 3-tert-butyl-5- (5-fluoro-6-methoxy-2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxybenzoate.

The fluorination procedure was performed as described in Lai, GS, et al. J. Org Chem., 60: 7340-7342 (1995). The product of Example 13A, Part B (0.42 g, 1.26 mmol) and Selectfluor ™ (0.672 g, 1.9 mmol) were combined in one

10 mixture of acetonitrile (8 ml) and methanol (1 ml) and heated at 90 ° C under an atmosphere of N2 for 5 h. The solution was diluted with water, extracted into ethyl acetate, washed with a solution of sodium bicarbonate, concentrated and purified by column chromatography on silica gel to give the title compound (0.138 g, 29%).

Part B. Preparation of methyl 3-tert-butyl-5- (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1- (2H) -yl) -2-methoxybenzoate.

The product of Part A (0.134 g, 0.35 mmol) and triethylamine (1 ml) were combined in methanol (4 ml) and stirred at room temperature for 18 h. The solution was then quenched with 1M HCl, extracted into dichloromethane and concentrated to give the title compound (0.113 g, 92%).

Part C. Preparation of 3-tert-butyl-5- (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1- (2H) -yl) -2-methoxybenzoic acid.

The product of Part B (0.113 g, 0.32 mmol) was treated as described in Example 13A, Part C to give the title compound (0.088 g, 81%).

Part D. Preparation of 3-tert-butyl-5- (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxybenzaldehyde.

The product of Part C (0.088 g, 0.26 mmol) was treated as described in Example 13A, Part D to give the title compound (0.075 g, 90%).

30 Part E. Preparation of (E) -1- (3-tert-butyl-4-methoxy-5- (4-nitrostyryl) phenyl) -5-fluoropyrimidin-2,4 (1H, 3H) -dione.

The product of Part D (0.075 g, 0.23 mmol) was treated as described in Example 13A, Part E to give 0.077 g (75%).

35 Part F. Preparation of (E) -1- (3- (4-aminoestyryl) -5-tert-butyl-4-methoxyphenyl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione.

The product of Part E (0.077 g, 0.18 mmol) was treated as described in Example 13A, Part F to give the title compound (0.07 1 g, 94%).

40 Part G. Preparation of (E) -N- (4- (3-tert-Butyl-5- (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxistiril ) phenyl) methanesulfonamide.

The product of Part F (0.071 g, 0.17 mmol) was treated as described in Example 13A, Part G to give the

45 title compound (0.048 g, 57%). 1 H NMR (300 MHz, DMSO-D6): δ ppm 1.38 (s, 9 H), 3.01 (s, 3 H), 3.79 (s, 3 H) 7.19-7.27 ( m, 5 H), 7.62 (d, J = 8.82 Hz, 2 H), 7.66 (d, J = 2.57 Hz, 1H), 8.25 (d, J = 6.99 Hz, 1H).

Example 15, Preparation of (E) -N- (4- (3-Bromo-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) phenyl) methanesulfonamide (compound IB -L1-1.52).

image 1

5 Part A. Preparation of 2-bromo-4,6-diiodophenol.

A 1 liter round bottom flask was charged with 2-bromophenol (8.65 g, 50 mmol) and methanol (100 ml) to give a colorless solution. Sodium hydroxide (2.40 g, 60.0 mmol) was added and stirred until the hydroxide granules dissolved. The solution was cooled in an ice-cold water bath and sodium iodide (5.6 g, 37.4 mmol) was added followed by dropwise addition of sodium hypochlorite (17 mL, 27 mmol) to give a transparent brown / red solution and a gradual precipitation of a thick white solid. The addition of sodium iodide and bleach was repeated 3 times to give an orange mixture that was stirred for 2 h, treated with a solution of sodium thiosulfate in water (20 g in 100 ml), stirred for 15 min and treated dropwise with concentrated HCl at a pH of 1. The mixture was stirred for 15 min and filtered to collect a white solid that was washed.

15 repeatedly with water and dried at constant mass (14.7 g, 69%).

Part B. Preparation of 1-bromo-3,5-diiodo-2-methoxybenzene.

A 500 ml round bottom flask was charged with the product of Part A (14.7 g, 34.6 mmol), iodomethane

20 (2.70 ml, 43.3 mmol) and sodium hydroxide (2.101 ml, 39.8 mmol) in acetone (96 ml) to give a brown solution. The mixture was stirred for 24 h and concentrated. The residue was dissolved in ethyl acetate, washed with water and saturated sodium chloride, dried over sodium sulfate, filtered and concentrated to give a white solid. The solid was recrystallized from hot hexane to give a white solid that was collected by filtration (12.3 g, 81%).

Part C. Preparation of 1- (3-Bromo-5-iodo-4-methoxyphenyl) pyrimidin-2,4 (1H, 3H) -dione.

A 250 ml round bottom flask was charged with the product of Part B (8.09 g, 18.44 mmol), pyrimidin-2,4 (1H, 3H) -dione (2,273 g, 20.28 mmol) , N- (2-cyanophenyl) picolinamide (0.823 g, 3.69 mmol), copper (I) iodide (0.351

30 g, 1,844 mmol) and potassium phosphate (8.22 g, 38.7 mmol) in DMSO (70 ml). The mixture was sealed, sprayed with nitrogen for 15 min and heated at 60 ° C for 16 h. The mixture was partitioned with ethyl acetate and water. The organic layer was washed with 1M HCl, water and brine, dried over sodium sulfate and filtered. The filtrate was treated with 3-mercaptopropyl-functionalized silica gel (Aldrich catalog No. 538086), filtered through Celite and evaporated to give an off-white solid (3.92 g, 50%).

35 Part D. Preparation of (E) -N- (4- (3-Bromo-5- (2,4-dioxo-3,4-dihydropyrimidin-1- (2H) -yl) -2-methoxystyryl) phenyl) methanesulfonamide.

The product of Part C (846 mg, 2.0 mmol), the product was added in a 100 ml round bottom flask

40 of Example 13B, Part B (482 mg, 2,000 mmol), potassium phosphate (892 mg, 4.20 mmol), 1,3,5,7-tetramethyl-6-phenyl2,4,8-trioxa-6-phosphaadamantane (PA-Ph) (CAS 97739-46-3) (17.54 mg, 0.060 mmol) and tris (dibenzylideneacetone) dipaladium (0) (18.31 mg, 0.020 mmol) in THF (12.0 ml) and water (4.0 ml). The flask was tightly closed and the mixture was sprayed with nitrogen for 5 min and stirred at room temperature for 72 h. The mixture was partitioned with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate and

Brine, dried over sodium sulfate and filtered. The filtrate was treated with 3mercaptopropyl run silica gel, filtered and evaporated. The residue was triturated with a minimum amount of methanol / CH2CI2 to give the title compound as a white solid (595 mg, 60%). 1 H NMR (300 MHz, DMSO-d6) δ ppm 3.03 (s, 3 H) 3.82 (s, 3 H) 5.69 (dd, J = 7.72, 1.50 Hz, 1H) 7 , 24 (d, J = 8.46 Hz, 2 H) 7.35 (m, 2H) 7.61 (d, J = 8.46 Hz, 2H) 7.69 (d, J = 2.21 Hz , 1H) 7.78 (d, J = 8.09 Hz, 1H) 7.87 (d, J = 2.21 Hz, 1H) 9.90 (s, 1H) 11.50 (s, 1H). MS (ESI-) m / z

50,490,492 (M-H) +.

Example 16. Preparation of (E) -N- (4- (5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (thiophene-2-yl) styryl ) phenyl) methanesulfonamide (compound IB-L1-1.48).

image 1

In a 5 ml microwave tube the product of Example 15, Part D (40 mg, 0.081 mmol), thiophene-2-ylboronic acid (10.40 mg, 0.081 mmol), 1,1'- bichloride was added bis (di-tert-butylphosphino) ferrocene palladium (2.65 mg, 4.06 μmol) and potassium phosphate (34.5 mg, 0.162 mmol) in THF (3.0 ml) and water (1.0 ml). The vessel was tightly closed, the mixture was sprayed with nitrogen for 5 min and heated at 50 ° C for 3 h. The mixture was partitioned with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate and brine.

10 dried with sodium sulfate and filtered. The filtrate was treated with 3-mercaptopropyl functionalized silica gel, filtered through Celite and evaporated. The residue was purified by reverse phase chromatography to give the title compound as a white solid (20 mg, 50%). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.03 (s, 3H) 3.70 (s, 3H) 5.70 (dd, J = 7.72, 2.21 Hz, 1H) 7.18 (dd, J = 5.43, 4.05 Hz, 1H) 7.25 (d, J = 8.82 Hz, 2H) 7.35 (s, 2H) 7.63 (d, J = 8.82 Hz, 2H) 7.68 (m, 2 H) HI (m, 2H) 7.83 (d, J = 7.72 Hz, 1H) 9.89 (s, 1 H) 11.49 (d, J = 2.21 Hz, 1 H). MS (ESI +)

15 m / z 496 (M + H) +.

Example 17, Preparation of (E) -N- (4- (5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -3- (furan-2-yl) -2- methoxystyryl) phenyl) methanesulfonamide (compound image 1 IB-L1-1.46).

The title compound was prepared according to the procedure of Example 16 by replacing furan-2-borboric acid with thiophene-2-ylboronic acid to give a white solid (22 mg, 56%). 1H NMR (300 MHz, DMSOd6) δ ppm 3.03 (s, 3H) 3.76 (s, 3H) 5.69 (d, J = 7.72 Hz, 1H) 6.69 (dd, J = 3 , 31, 1.84 Hz, 1H) 7.08 (d, J = 2.57 Hz, 1H) 7.25 (d, J = 8.46 Hz, 2H) 7.36 (m, 2H) 7, 63 (d, J = 8.82 Hz, 2H) 7.67 (d, J = 2.57 Hz, 1H) 7.77 (d, J = 2.57 Hz, 1H)

25 7.82 (m, J = 7.72 Hz, 2H) 9.88 (s, 1 H) 11.48 (s, 1 H). MS (ESI +) m / z 497 (M + NH4) +.

Example 18. Preparation of (E) -N- (4- (5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (pyridin-4-yl) styryl ) phenyl) methanesulfonamide (compound IB-L1-1.55).

image 1

The title compound was prepared according to the procedure of Example 16, substituting 4- (4,4,5,5

tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine by thiophene-2-ylboronic acid to give a white solid (15 mg, 38%). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.03 (s, 3H) 3.49 (s, 3H) 5.72 (dd, J = 7.72, 2.21 Hz, 1H) 7.25 (d, J = 8.46 Hz, 2H) 7.38 (d, J = 4.41 Hz, 2H) 7.51 (d, J = 2.57 Hz, 1H) 7.63 (d, J = 8.82 Hz, 2H) 7.80 (d, J = 5.88 Hz, 2H) 7.85 (d, J = 7.72 Hz, 1H) 7.97 (d, J = 2.57 Hz, 1H) 8.77 (d, J = 6.25 Hz, 2H) 9.90 (s, 1 H) 11.51 (d, J = 2.21 Hz, 1 H). MS (ESI +) m / z 491 (M + H) +.

Example 19. Preparation of (E) -N- (4- (5- (2,4-dioxo-3,4-dihydropyrimidin-1- (2H) -yl) -2-methoxy-3- (pyridin-3il) styryl) phenyl) methanesulfonamide (compound IB-L1-1.53).

image 1

The title compound was prepared according to the procedure of Example 16 by substituting 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine for thiophene-2-ylboronic acid to give a white solid (19 mg, 48%). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.02 (s, 3H) 3.45 (s, 3H) 5.71 (dd, J = 8.09, 2.211 Hz, 1 H) 7.24 ( d, J = 8.46 Hz, 2H) 7.37 (d, J = 2.94 Hz, 2H) 7.47 (d, J = 2.57 Hz, 1H) 7.63 (m, 3H) 7 , 85 (d, J = 7.72 Hz, 1H) 7.93 (d, J =

15 2.57 Hz, 1H) 8.15 (m, 1H) 8.68 (dd, J = 4.80 Hz, 1.47 Hz, IH) 8.86 (d, J = 1.84 Hz, 1H ) 9.89 (s, 1 H) 11.50 (d, J = 2.21 Hz, 1 H). MS (ESI +) m / z 491 (M + H) +.

Example 20. Preparation of (E) -N- (4- (5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (thiophene-3-yl) styryl ) phenyl) methanesulfonamide (compound image 1 IB-L1-1.47).

twenty

The title compound was prepared according to the procedure of Example 16, substituting thiophene-3-borboric acid with thiophene-2-ylboronic acid to give a white solid (19 mg, 38%). 1H NMR (300 MHz, DMSOd6) δ ppm 3.02 (s, 3H) 3.55 (s, 3H) 5.69 (d, J = 8.09 Hz, 1H) 7.24 (d, J = 8 , 46 Hz, 2H) 7.36 (s, 2H) 7.55 (m, 2H) 7.61

25 (d, J = 8.46 Hz, 2H) 7.67 (dd, J = 5.15, 2.94 Hz, 1H) 7.78 (d, J = 2.57 Hz, 1H) 7.83 (d, J = 7.72 Hz, 1H) 7.93 (dd, J = 2.57, 0.96 Hz, 1H) 9.88 (s, 1 H) 11.48 (s, 1 H). MS (ESI-) m / z 494 (M-H) +.

Example 21. Preparation of (E) -N- (4- (5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -3- (furan-3-yl) -2methoxystyryl) phenyl) methanesulfonamide (compound image 1 IB-L1-1.50).

30

The title compound was prepared according to the procedure of Example 16, substituting furan-3-borboric acid for thiophene-2-ylboronic acid to give a white solid (14 mg, 29%). 1H NMR (300 MHz, DMSOd6) δ ppm 3.02 (s, 3H) 3.69 (s, 3H) 5.69 (d, J = 8.09 Hz, 1H) 7.05 (dd, J = 2 , 57, 0.90 Hz, 1H) 7.24 (d, J = 8.82 Hz, 2H) 7.34 (s, 2H) 7.61 (m, 3H) 7.74 (d, J = 2 , 57 Hz, 1H) 7.80 (m, 2H) 8.25 (s, 1H) 9.88 (s, 1 H) 11.49 (s, 1 H). MS (ESI-) m / z 478 (M-H) +.

Example 22. Preparation of (E) -N- (4- (5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -3- (1-hydroxy-2-methylpropan-2 -yl) -2-methoxystyryl) phenyl) methanesulfonamide (compound IB-L1-1.45).

image 1

10 Part A. Preparation of 2- (2-hydroxy-3,5-diiodophenyl) acetic acid.

In a 250 ml round bottom flask, 2- (2-hydroxyphenyl) acetic acid (Aldrich, 3.04 g, 20 mmol) in acetonitrile (50 ml) was added to give a colorless solution. N-iodosuccimide (9.00 g, 40.0 mmol) was added portionwise

15 for 15 min to give a clear red / brown solution that was stirred for 16 h. The mixture was concentrated, the resulting solid was triturated in 75 ml of water and filtered to collect an orange solid which was dried under vacuum. The crude solid was recrystallized from toluene to give a light orange powder (6.0 g, 74%).

Part B. Preparation of methyl 2- (3,5-diiodo-2-methoxyphenyl) acetate.

In a 250 ml round bottom flask, the product of Part A (6 g, 14.85 mmol), potassium carbonate (6.16 g, 44.6 mmol) and dimethyl sulfate (4.12 g) were added , 32.7 mmol) in acetone (49.5 ml) to give a brown suspension. The suspension was heated at reflux for 16 h, cooled, concentrated and the residue was partitioned between EtOAc and water. The EtOAc layer was washed with brine, dried (Na2SO4) and concentrated to give a colored oil.

Brown which was chromatographed on a 40 g silica gel cartridge, eluting with 3: 1 hexane / EtOAc to give a yellow oil (6.0 g, 94%).

Part C. Preparation of methyl 2- (3,5-diiodo-2-methoxyphenyl) -2-methylpropanoate.

In a 100 ml round bottom flask in a nitrogen atmosphere, the product of Part B (1,728 g, 4 mmol) in anhydrous THF (20 ml) and HMPA (2 ml) was added to give a colorless solution. Methyl iodide (1,251 ml, 20.00 mmol) was added and the solution was cooled to -40 ° C. Potassium t-butoxide (12.00 ml, 12.00 mmol) was added dropwise and the mixture was stirred from -40 to -20 ° C for 30 min and quenched with 1M HCl at a pH of 1. The mixture was extracted 3 x 40 ml with EtOAc. The extracts were combined, washed with brine, dried (Na2SO4) and dried.

35 concentrated. The crude product was subjected to flash chromatography on a 40 g ISCO silica gel cartridge eluting with 9: 1 hexane / EtOAc to give the bis-methylated product as a yellow oil (1.63 g, 89%).

Part D. Preparation of 2- (3,5-diiodo-2-methoxyphenyl) -2-methylpropanoic acid.

A suspension of the product of Part C (2.63 g, 5.72 mmol) in MeOH (40 ml) and THF (40 ml) was treated with 4.0 M sodium hydroxide (28 ml, 112 mmol) and was heated at 80 ° C for 48 h. The organic solvent was evaporated and the remaining aqueous solution was acidified with 1M HCl to yield a solid that was collected by filtration, washed with water and dried to give the desired carboxylic acid (2.46 g, 96%).

45 Part E. Preparation of 2- (3,5-diiodo-2-methoxyphenyl) -2-methylpropan-1-ol.

A solution of the Part D product (1.00 g, 2.242 mmol) in THF (40 mL) was treated dropwise with 1.0 M borane-THF complex (20 mL, 20 mmol) and then heated to 50 ºC for 24 h. The mixture was treated with methanol (20

50 ml), heated at reflux for 30 min and concentrated. The resulting residue was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on silica gel eluting with hexane / EtOAc (4: 1) to give the desired product (810 mg, 84%).

Part F. Preparation of tert-butyl (2- (3,5-diiodo-2-methoxyphenyl) -2-methylpropoxy) -dimethylsilane. A solution of the product of Part E (432 mg, 1,000 mmol) in DMF (5 ml) was treated with tert-butyldimethylchlorosilane (301 mg, 2,000 mmol) and imidazole (204 mg, 3.00 mmol) and stirred for 2 h. The mixture was partitioned between 1M HCl and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on silica gel, eluting with

5 hexane / EtOAc (9: 1) to give the desired product (522 mg, 96%).

Part G. Preparation of 1- (3- (1- (tert-butyldimethylsilyloxy) -2-methylpropan-2-yl) -5-iodo-4-methoxyphenyl) pyrimidin2,4 (1H, 3H) -dione.

In a 50 ml round bottom flask, the product of Part F (520 mg, 0.952 mmol), pyrimidin-2.4 (1 H, 3H) -dione (117 mg, 1.047 mmol), N- ( 2-cyanophenyl) picolinamide (42.5 mg, 0.190 mmol), copper iodide (1) (18.13 mg, 0.095 mmol) and potassium phosphate (424 mg, 1,999 mmol) in DMSO (5 ml). The vessel was tightly sealed, sprayed with nitrogen and then heated at 60 ° C for 24 h. The mixture was partitioned between 1M HCl and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate and filtered. He

The filtrate was treated with 3-mercaptopropyl functionalized silica gel, filtered and evaporated. The residue was chromatographed on silica gel eluting with hexane / EtOAc (3: 2) to give the product as a solid (285 mg, 65%).

Part H. Preparation of (E) -N- (4- (3- (1- (tert-butyldimethylsilyloxy) -2-methylpropan-2-yl) -5- (2,4-dioxo-3,4-dihydropyrimidine20 1 (2H) -yl) -2-methoxystyryl) phenyl) methanesulfonamide.

In a 5 ml microwave tube the product of Part G (53 mg, 0.1 mmol), the product of Example 13B, Part B (24 mg, 0.1 mmol), potassium phosphate (44.0) were added mg, 0.2 mmol), PA-Ph (CAS 97739-46-3) (0.87 mg, 3.0 μmol) and tris (dibenzylideneacetone) palladium (0) (0.9 mg, 1 μmol) in THF (3.0 ml) and water (1.0 ml). The container is

25 sealed, the mixture was sprayed with nitrogen for 5 min and then heated at 50 ° C for 2 h. The mixture was partitioned between 1M HCl and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate and filtered. The filtrate was treated with 3mercaptopropyl functionalized silica gel, filtered and evaporated. The residue was chromatographed on silica gel eluting with hexane / EtOAc (1: 1) to give a solid (50 mg, 83%).

30 Part I. Preparation of (E) -N- (4- (5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -3- (1-hydroxy-2-methylpropan- 2-yl) -2methoxycyryl) phenyl) methanesulfonamide.

A solution of the product of Part H (120 mg, 0.20 mmol) in THF (5.0 ml) was treated with 1 M TBAF (0.800 ml,

0.800 mmol) in THF and stirred for 16 h. The mixture was partitioned with water and ethyl acetate. The organic layer was washed (3 x brine), dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on silica gel eluting with 4% methanol in CH2CI2 to give a solid (85 mg, 88%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.30 (s, 6H) 3.01 (s, 3H) 3.62 (d, J = 5.52 Hz, 2H) 3.77 (s, 3H ) 4.67 (t, J = 5.33 Hz, 1H) 5.66 (d, J = 8.09 Hz, 1H) 7.21 (m, 5H) 7.62 (m, 3H) 7.72 (d, J = 8.09 Hz, 1H) 9.85 (s, 1 H) 11.42 (s, 1 H). MS (ESI +) m / z 503 (M + NH4) +.

Example 23. Preparation of (E) -N- (4- (5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -3-iodo-2-methoxystyryl) phenyl) methanesulfonamide (compound IB-L1-1.51).

image 1

45 Part A. Preparation of 1,3,5-trio-2-methoxybenzene.

In a 250 ml pressure vessel, 2,4,6-triiodophenol (5 g, 10.60 mmol) in MTBE (60 ml) was added to give a yellow solution. The solution was cooled in an ice bath and 2.0M trimethylsilyldiazomethane (7.95 ml, 15.90 mmol) was added dropwise followed by dropwise addition of methanol (6 ml), resulting in a calm bubbling. . The vessel was tightly closed and stirred at room temperature for 4

h. The reaction solution was partitioned between EtOAc and water, and the organic layer was washed with 1M HCl, saturated NaHCO3 and saturated NaCl. The EtOAc was dried (MgSO4), filtered and concentrated to give a brown solid that was used without purification (4.8 g, 94%).

Part B. Preparation of 1- (3,5-diiodo-4-methoxyphenyl) pyrimidin-2,4 (1 H, 3H) -dione.

In a 100 ml round bottom flask under an N2 atmosphere, the product of Part A (3.5 g, 7.2 mmol), 1 H-pyrimidin-2,4-dione (0.97 g, 8.64 mmol) and tribasic potassium phosphate (3.2 g, 15.0 mmol) in DMSO (50 ml) 5 to give a colorless suspension. N- (2-cyanophenyl) picolinamide (320 mg, 1.44 mmol) was added, the mixture was sprayed with N2 for 5 min. Copper (I) iodide (137 mg, 0.72 mmol) was added and the mixture was sprayed again for 10 min, placed under an N2 atmosphere and heated at 60 ° C for 18 h. The mixture was cooled and partitioned between EtOAc and water, adjusting the pH to 1 with HCl. The aqueous layer was extracted 2x with EtOAc. The organic extracts were combined, washed with water, saturated NaHCO3 and saturated NaCl, dried (Na2SO4), treated with gel.

10 silica functionalized with 3-mercaptopropyl, filtered and concentrated. The resulting solid was triturated in 2: 1 hexane / EtOAc for an off-white powder (2.2 g, 62%).

Part C. Preparation of (E) -N- (4- (5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -3-iodo-2-methoxystyryl) phenyl) methanesulfonamide.

In a 5 ml microwave tube the product of Part B (141 mg, 0.30 mmol), the product of Example 13B, Part B (72.3 mg, 0.300 mmol), CH2CI2-bichloride complex were mixed. 1,1'-bis (diphenylphosphino) ferrocene-palladium (ll) (12.25 mg, 0.015 mmol) and potassium phosphate (70.0 mg, 0.330 mmol) in THF (3.0 ml) and water (1.0 ml) The mixture was sprayed with nitrogen for 5 min and heated at 50 ° C for 2 h. The mixture was partitioned with ethyl acetate and HCl.

20 1 M. The organic layer was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate and filtered. The filtrate was treated with 3-mercaptopropyl functionalized silica gel, filtered and evaporated. The residue was chromatographed on silica eluting with 5% methanol in CH2CI2 to give a solid (47 mg, 29%). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.02 (s, 3H) 3.77 (s, 3H) 5.67 (d, J = 7.72 Hz, 1H) 7.28 (m, 4H ) 7.60 (d, J = 8.82 Hz, 2H) 7.76 (d, J = 8.09 Hz, 1H) 7.81 (d, J = 2.57 Hz, 1H) 7.86 ( d, J = 2.21 Hz, 1H) 9.90 (s, 1 H) 11.48 (s, 1 H). MS (ESI-) m / z

25 538 (M-H) +.

Example 24. Preparation of (E) -N- (4- (5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3 (methylsulfonyl) styryl) phenyl) methanesulfonamide (compound IB-L1-1.49).

image 1

30 Part A. Preparation of 4-nitrobenzene-2-diazo-1-oxide.

In a 250 ml round bottom flask, 2-amino-4-nitrophenol (6.165 g, 40.0 mmol) in 48% tetrafluoroboric acid (15 ml) was added. Sodium nitrite (2.76 g, 40.0 mmol) in water (6 ml) was added dropwise at 0 ° C and the

The mixture was stirred at room temperature for 30 min. The solid was collected by filtration, washed with tetrafluoroboric acid and water. The solid was suspended in acetone (500 ml), filtered and dried to give a solid (3.31 g, 50%).

Part B. Preparation of 2- (methylthio) -4-nitrophenol.

In a base of precipitates of 1 l the product of Part A (2.70 g, 16.35 mmol) in ice-water (250 g) was added for a brown suspension. Copper (0.520 g, 8.18 mmol) was added, followed by the slow addition of sodium thiomethoxide (2.292 g, 32.7 mmol) in water (50 ml). The mixture was stirred at room temperature for 24 h. The mixture was filtered and the filtrate was acidified with 1M HCl, yielding a solid that was collected by filtration and dried.

45 (2.53 g, 84%).

Part C. Preparation of 2- (methylsulfonyl) -4-nitrophenol.

In a 250 ml round bottom flask, the product of Part B (1.11 g, 6.00 mmol) in MeOH (20 ml) was added

50 to give a brown suspension. Oxona (7.746 g, 12.60 mmol) in water (20 ml) was added slowly at 0 ° C. The mixture was heated to room temperature, stirred for 1 h and partitioned with ethyl acetate and 1 M HCl. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on silica gel eluting with 1% to 5% methanol in CH2CI2 to give a solid (0.472 g, 36%).

Part D. Preparation of 2-iodo-6- (methylsulfonyl) -4-nitrophenol.

In a 50 ml round bottom flask, the product of Part C (470 mg, 2,164 mmol) in MeOH (10 ml) and water (2.5 ml) was added. Iodine monochloride (0.130 ml, 2.60 mmol) in CH2CI2 (2.0 ml) was added dropwise and the mixture was stirred at room temperature, poured into water (200 ml) and stirred for 10 min. The resulting solid was collected by filtration and dried (636 mg, 86%).

Part E. Preparation of 1-iodo-2-methoxy-3- (methylsulfonyl) -5-nitrobenzene.

In a 50 ml pressure vessel the product of Part D (630 mg, 1,836 mmol) in MTBE (6 ml) was added to give a yellow solution. The mixture was cooled in an ice bath and 2M trimethylsilyldiazomethane (1.377 ml, 2.75 mmol) was added dropwise followed by dropwise addition of MeOH (0.4 ml), resulting in gentle bubbling. The vessel was tightly closed and stirred at room temperature for 1 h. The mixture was partitioned with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and evaporated to give an off-white solid (655 mg, 100%). .

Part F. Preparation of 3-iodo-4-methoxy-5- (methylsulfonyl) aniline.

In a 250 ml round bottom flask the product of Part E (0.650 g, 1.820 mmol), ammonium chloride (0.146 g, 2.73 mmol) and iron (0.508 g, 9.10 mmol) in THF were added / MeOH / water (50 ml, 2/2/1). The mixture was heated at reflux for 2 h, cooled and filtered. The filtrate was evaporated and the residue was partitioned with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to give a solid (590 mg, 99%).

Part G. Preparation of (E) -N- (3-iodo-4-methoxy-5- (methylsulfonyl) phenylcarbamoyl) -3-methoxyacrylamide.

In a 100 ml round bottom flask the product of Part F (500 mg, 1,528 mmol) in DMF (15.0 ml) was added. The solution was cooled under a nitrogen atmosphere at -20 ° C and (E) -3-methoxyacryloyl isocyanate (15.28 ml, 6.11 mmol) prepared as described by Santana, L; et al. J was added dropwise Heterocyclic Chem. 1999, 36, 293-295). The mixture was stirred at this temperature for 15 min, then heated to room temperature and stirred for 45 min. The mixture was diluted with ethyl acetate, washed with water (3 x 50 ml) and brine (3 x 50 ml), dried over sodium sulfate, filtered and evaporated. The residue was triturated with ethyl acetate / hexane to give a solid (425 mg, 61%).

Part H. Preparation of 1- (3-iodo-4-methoxy-5- (methylsulfonyl) phenyl) pyrimidin-2,4 (1H, 3H) -dione.

In a 100 ml round bottom flask, the product from Part G (420 mg, 0.925 mmol) in ethanol (10 ml) was added to give a suspension. Concentrated sulfuric acid (1 ml, 18.76 mmol) in water (10 ml) was added and the mixture was heated at 110 ° C for 2 h. The reaction mixture was cooled, diluted with water (50 ml) and stirred for 10 min. The solid material was collected by filtration, washed with water and dried to give a white solid (325 mg, 83%).

Part I. Preparation of (E) -N- (4- (5- (2,4-dioxo-3,4-dihydropyrimidin-1- (2H) -yl) -2-methoxy-3 (methylsulfonyl) styryl) phenyl ) methanesulfonamide.

In a 5 ml microwave tube the product of Part H (63.3 mg, 0.15 mmol), the product of Example 13B, Part B (36.2 mg, 0.155 mmol), potassium phosphate (66 , 9 mg, 0.315 mmol), PA-Ph (CAS 97739-46-3) (1,315 mg, 4.50 μmol) and tris (dibenzylideneacetone) dipaladium (0) (1,374 mg, 1,500 μmol) in THF (3.0 ml) and water (1.0 ml). The vessel was sealed, the mixture was sprayed with nitrogen for 5 min and heated at 50 ° C for 2 h. The mixture was partitioned with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate and filtered. The filtrate was treated with 3mercaptopropyl functionalized silica gel, filtered and evaporated. The residue was triturated with CH2CI2 methanol to give a solid (62 mg, 84%). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.03 (s, 3H) 3.37 (s, 3H) 3.94 (s, 3H) 5.72 (d, J = 7.72 Hz, 1H ) 7.26 (m, 3H) 7.45 (m, 1H) 7.65 (d, J = 8.46 Hz, 2H) 7.77 (d, J = 2.57 Hz, 1H) 7.81 (d, J = 8.09 Hz, 1H) 8.21 (d, J = 2.57 Hz, 1H) 9.93 (s, 1 H) 11.52 (s, 1 H). MS (ESI +) m / z 509 (M + NH4) +.

Example 25. Preparation of 2- (3-tert-Butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1- (2H) -yl) -2-methoxystyryl) -5 (methylsulfonamido) benzoate of ( E) -methyl (compound IB-L1-1.7).

image 1

5 Part A. Preparation of methyl 2- ((diethoxyphosphoryl) methyl) -5-nitrobenzoate

To a solution of methyl 2-methyl-5-nitrobenzoate (0.40 g, 2.05 mmol) in CCl4 (20 ml), Nbromosuccinimide (365 mg, 23.05 mmol) and 2.2'- azobisisobutyronitrile (34 mg, 0.21 mmol). The resulting mixture was stirred at reflux for 18 h over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by

10 silica gel chromatography using 1: 3 EtOAc: hexanes as eluent to give the bromide as an oil (345 mg, 61%). The oil was placed in triethyl phosphite (5 ml) and heated with stirring at 120 ° C for 3 h. The mixture was allowed to cool to room temperature and the crude product was purified by column chromatography on silica gel using 5% MeOH in CH2CI2 as eluent. The title compound was obtained as an oil (313 mg, 75%).

Part B. Preparation of 2- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) -5-nitrobenzoate of (E) -methyl.

To a solution of the product of Part A (360 mg, 1.09 mmol) and the product of Example 13A, Part D (329 mg,

1.09 mmol) in anhydrous CH2CI2 (10 ml) was added potassium tert-butoxide (305 mg, 2.72 mmol). The resulting dark red solution was stirred at room temperature for 1 h and then poured into aq HCl. 1 N (10 ml). The resulting mixture was extracted with CH2CI2 (10 ml), dried over Na2SO4, filtered and concentrated in vacuo to give a solid. A solution of the solid in thionyl chloride (2.3 ml) was heated at 85 ° C for 30 min and the thionyl chloride was removed in vacuo. The residue was stirred in a 2: 1 mixture of CH2CI2 and MeOH (3 ml) for 30 min and was

25 evaporated to dryness under vacuum. The crude product was purified by column chromatography on silica gel using 3% MeOH in CH2CI2 as eluent to give the title compound (350 mg, 69%).

Part C. Preparation of 2- (3-tert-Butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) -5 (methylsulfonamido) benzoate )-methyl.

To a solution of the product of Part B (465 mg, 0.97 mmol) in a 2: 2: 1 mixture of TBF: MeOH: H2O (10 ml) was added iron powder (271 mg, 4.85 mmol) and ammonium chloride (78 mg, 1.46 mmol). The mixture was heated at 80 ° C for 45 min, filtered through Celite and concentrated to dryness in vacuo. The residue was combined with methanesulfonyl chloride (0.16 ml, 2.0 mmol) and triethylamine (0.392 ml, 4.85 mmol) in anhydrous CH2CI2 (10 ml) and the mixture

The resulting was stirred at room temperature for 3 h. The mixture was partitioned between 1 N HCl (20 ml) and CH2CI2 (20 ml) and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 3% MeOH in CH2CI2 as eluent to give the title compound (270 mg, 53%). 1 H NMR (300 MHz, DMSO-d6) δ 11.42 (s, 1 H) 10.07 (s, 1 H) 7.90 (d, J = 8.82 Hz, 1 H) 7.66 7.79 ( m, 3H) 7.52 (d, J = 2.57 Hz, 1H) 7.44 (dd, J = 8.64, 2.39 Hz, 1H) 7.14-7.26 (m, 2H) 5.65 (dd, J = 7.72, 1.84

40 Hz, 1H) 3.86 (s, 3H) 3.79 (s, 3H) 3.04 (s, 3H) 1.38 (s, 9 H).

Example 26. Preparation of (E) -2- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) -5 (methylsulfonamido) ) benzoic (compound IB-L1-1.4).

image 1

A solution of the product of Example 25 (55 mg, 0.104 mmol) in THF (1 ml) and aq. NaOH. 1 N (1 ml) was stirred in the dark at room temperature for 1.5 h. 1 N aqueous HCl was added until pH 3 and the resulting mixture was extracted with EtOAc (2 x 2 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the title compound (53 mg, 99%). 1H NMR (300 MHz, DMSO-d6) δ 13.22 (sa, 1 H) 11.40 (d, J = 2.21 Hz, 1 H) 10.02 (s, 1H) 7.72-7, 91 (m, 3H) 7.68 (d, J = 2.57 Hz, 1H) 7.49 (d, J = 2.57 Hz, 1H) 7.42 (dd, J =

10 8.64, 2.39 Hz, 1H) 7.21 (d, J = 2.57 Hz, 1H) 7.16 (d, J = 16.18 Hz, 1H) 5.64 (dd, J = 7.72, 2.2 Hz, 1H) 3.79 (s, 3H) 3.04 (s, 3H) 1.38 (s, 9 H).

Example 27. Preparation of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) -3 (morpholin-4-carbonyl) phenyl) methanesulfonamide (compound image 1 IB-L1-1.23).

fifteen

Part A. Preparation of (E) -2- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) -5 ( methylsulfonamido) benzoyl.

A solution of the product of Example 26 (257 mg, 0.50 mmol) in thionyl chloride (1.5 ml) was heated at 85 ° C for 40 min and then concentrated and dried in vacuo to give the title compound. in the form of a solid (0.27 g).

Part B. Preparation of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) -3 - (morpholin-425 carbonyl) phenyl) methanesulfonamide.

To a solution of the product of Part A (24 mg, 0.045 mmol) in anhydrous CH2CI2 (1 ml) was added morpholine (0.02 ml, 0.226 mmol). The mixture was stirred at room temperature for 2 h and then partitioned between aq. HCl. 1 N (5 ml) and EtOAc (2 x 5 ml). The combined organic layers were dried over Na2SO4, filtered and

30 concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 4% MeOH in CH2CI2 as eluent to give the title compound (19 mg, 71%). 1 H NMR (300 MHz, DMSO-d6) δ ppm 11.41 (d, J = 1.84 Hz, 1 H) 10.04 (s, 1 H) 7.85 (d, J = 8.46 Hz, 1H) 7.75 (d, J = 8.09 Hz, 1H) 7.52 (d, J = 2.57 Hz, 1H) 6.99-7.34 (m, 5H) 5.65 (dd, J = 7.72, 1.84 Hz, 1H) 3.76 (s, 3H) 3.56-3.71 (m, 4H) 3.40 -3.51 (m, 2H) 3,113.22 (m , 2H) 3.06 (s, 3H) 1.38 (s, 9 H).

35

Example 28, Preparation of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) -3 (hydroxymethyl) phenyl) methanesulfonamide (compound IB-L1-1.10).

image 1

To a solution of the product of Example 27, Part A (375 mg, 0.705 mmol) in anhydrous THF (5 ml) at 0 ° C under an atmosphere of N2 gas was added dropwise a 1.0 M solution of hydride of lithium tert-butoxy aluminum (1.8 ml, 1.8 mmol). The resulting mixture was stirred at 0 ° C for 30 min and then allowed to warm to room temperature and stirred for 1 h. The mixture was partitioned between aq. HCl. 1 N (10 ml) and EtOAc (2 x 10 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by

10 column chromatography on silica gel using 3% MeOH in CH2CI2 as eluent to give the title compound (220 mg, 63%). 1 H NMR (300 MHz, DMSO-d6) δ ppm 11.41 (s, 1 H) 9.82 (s, 1 H) 7.73 (t, J = 8.27 Hz, 2 H) 7.66 (d , J = 2.57 Hz, 1 H) 7.31-7.39 (m, 2H) 7.20 (d, J = 2.57 Hz, 1 H) 7.12-7.19 (m, 2H ) 5.65 (d, J = 8.09 Hz, 1H) 5.28 (t, J = 5.52 Hz, 1H) 4.65 (d, J = 5.52 Hz, 2H) 3.79 ( s, 3H) 3.00 (s, 3H) 1.38 (s, 9H).

Example 29. Preparation of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1- (2H) -yl) -2-methoxystyryl) -3 (methoxymethyl) phenyl) methanesulfonamide (compound image 1 IB-L1-1.13).

To a solution of the product of Example 28 (32 mg, 0.064 mmol) in anhydrous CH2CI2 (1 ml) was added

Thionyl (23 µL, 0.32 mmol) and the resulting mixture was stirred at room temperature for 30 min. The mixture was partitioned between NaHCO3 aq. saturated (5 ml) and CH2CI2 (5 ml) and the organic layer was dried over Na2SO4, filtered and concentrated. The residue was dissolved in MeOH (1 ml) and a 25% NaOMe solution in MeOH (58 μl, 0.254 mmol) was added. The resulting mixture was stirred at 50 ° C for 2 h. The mixture was partitioned between aq. HCl. 1 N (10 ml) and EtOAc (2 x 10 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. He

The crude product was purified by column chromatography on silica gel using 3% MeOH in CH2CI2 as eluent to give the title compound (15 mg, 46%). 1 H NMR (300 MHz, DMSO-d6) δ 11.43 (s, 1 H) 9.86 (s, 1 H) 7.62-7.87 (m, 3 H) 7.12-7.39 ( m, 5 H) 5.66 (d, J = 7.72 Hz, 1 H) 4.58 (s, 2 H) 3.78 (s, 3 H) 3.35 (s, 3 H) 3, 00 (s, 3 H) 1.38 (s, 9 H).

30 Example 30. Preparation of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1- (2H) -yl) -2-methoxystyryl) -3 ((isopentylamino) methyl) phenyl) methanesulfonamide (compound IB-L1-1.31).

image 1

Part A. Preparation of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) -3

formylphenyl) methanesulfonamide.

To a solution of the product of Example 28 (0.60 g, 1.20 mmol) in anhydrous DMA (15 ml) was added acid 2

5 yodoxibenzoic (336 mg, 1.20 mmol). The mixture was stirred at room temperature for 1 h and then partitioned between EtOAc (20 ml) and H2O (2 x 20 ml). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 2% MeOH in CH2CI2 as eluent to give the title compound as a colorless solid (395 mg, 66%). 1 H NMR (300 MHz, DMSOd6 ) δ ppm 11.43 (d, J = 2.21 Hz, 1 H) 10.45 (s, 1 H) 10.15 (s, 1 H) 8.06 (d, JM 6.18 Hz, 1 H ) 7.97 (d, J = 8.82 Hz, 1 H)

10 7.73-7.78 (m, 2 H) 7.69 (d, J = 2.57 Hz, 1 H) 7.51 (dd, J = 8.64, 2.39 Hz, 1 H) 7.30 (d, J = 16.18 Hz, 1 H) 7.26 (d, J = 2.57 Hz, 1 H) 5.66 (dd, J = 7.72, 2.21 Hz, 1 H) 3.81 (s, 3H) 3.07 (s, 3 H) 1.39 (s, 9 H).

Part B. Preparation of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) -3 ((isopentylamino) methyl) phenyl) methanesulfonamide.

To a solution of the product of Part A (50 mg, 0.10 mmol) and 3-methylbutan-1-amine (12 μl, 0.10 mmol) in anhydrous THF (3 ml) was added sodium triacetoxyborohydride (32 mg, 0.15 mmol) and AcOH (9 µl, 0.15 mmol). The resulting mixture was stirred at room temperature for 4 h and then partitioned between H2O (10 ml) and EtOAc (2 x 10 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The product in

The crude was purified by column chromatography on silica gel using 3% MeOH in CH2CI2 as eluent to give the title compound (37 mg, 65%). 1 H NMR (300 MHz, DMSO-d6) δ 11.45 (d, J = 1.84 Hz, 1 H) 10.04 (s, 1 H) 8.80 -8.87 (m, 1 H) 7 , 88 (d, J = 8.46 Hz, 1 H) 7.71-7.77 (m, 2 H) 7.41-7.48 (m, 1 H) 7.37 (d, J = 2 , 21 Hz, 1 H) 7.21 -7.29 (m, 3 H) 5.67 (dd, J = 7.91, 2.02 Hz, 1 H) 4.30 -4.38 (m, 2 H) 3.80 (s, 3 H) 3.10 (s, 3 H) 2.95-3.04 (m, 2 H) 1.49-1.67 (m, 3 H) 1.38 (s, 9 H) 0.86 (d, J = 6.25 Hz, 6 H).

Example 31. Preparation of N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -5-methoxystyryl) -3 - (( E) (methoxyimino) methyl) phenyl) methanesulfonamide (compound IB-L1-1.19).

image 1

To a solution of the product of Example 30, Part A (35 mg, 0.070 mmol) in EtOH (2 ml) was added O-methoxylamine hydrochloride (29 mg, 0.35 mmol) and sodium bicarbonate (30 mg, 0 , 35 mmol). The resulting mixture was stirred at 70 ° C for 2 h. To the mixture was added aq HCl. 1 N (1 ml) to give a colorless precipitate that was filtered and dried to give the title compound as a colorless solid (24 mg, 64%). 1 H NMR (300 MHz, DMSO-d6) δ ppm 11.43 (d, J = 2.21 Hz, 1 H) 9.94 (s, 1 H) 8.74 (s, 1 H) 7.79- 7.85 (m, 2 H) 7.76 (d, J = 7.72 Hz, 1 H) 7.57-7.65 (m, 2 H)

35 7.32 (dd, J = 8.64, 2.39 Hz, 1 H) 7.23 (d, J = 2.57 Hz, 1 H) 7.18 (d, J = 16.18 Hz, 1 H) 5.66 (dd, J = 7.72, 2.21 Hz, 1 H) 3.93 (s, 3 H) 3.79 (s, 3 H) 3.03 (s, 3 H) 1.38 (s, 9 H).

Example 32. Preparation of (E) -N- (4- (3-tert-butyl-5- (2,4-d) oxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) -3- (oxazol2-yl) phenyl) methanesulfonamide (compound image 1 IB-L1-1.26).

40

To a solution of the product of Example 27, Part A (80 mg, 0.15 mmol) in tetramethylene sulfone (1.5 ml) was added 1H-1,2,3-triazole (10 μl, 0.17 mmol) and potassium carbonate (73 mg, 0.53 mmol). The mixture was heated for 35 min at 130 ° C in a microwave reactor. After cooling to room temperature, the mixture was partitioned between 1N aqueous HCl (10 ml) and EtOAc (2 x 10 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 3% MeOH in CH2CI2 as eluent to give the title compound (37 mg, 46%). 1 H NMR (300 MHz, DMSO-d6) δ 11, 41 (d, J = 1.84 Hz, 1 H) 10.10 (s, 1 H) 8.29 (d, J = 1.10 Hz, 1 H) 8.05 (d, J = l 6, 18 Hz, 1 H) 7.95 (d, J = 8.82 Hz,

5 1 H) 7.82 (d, J = 2.21 Hz, 1 H) 7.74 (d, J = 8.09 Hz, 1 H) 7.51 (d, J = 2.57 Hz, 1 H) 7.46 (d, J = 0.74 Hz, 1 H) 7.39 (dd, J = 8.64, 2.39 Hz, 1 H) 7.20-7.30 (m, 2 H ) 5.65 (dd, J = 7.91, 2.02 Hz, 1 H) 3.80 (s, 3 H) 3.07 (s, 3 H) 1.38 (s, 9 H).

Example 33. Preparation of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystrile) -3 - (1H10 imidazol-2-yl) phenyl) methanesulfonamide (compound IB-L1-1.16).

image 1

To a solution of the product of Example 30, Part A (50 mg, 0.10 mmol) in EtOH (2 ml) was added glyoxal (57 µl, 0.50 mmol) and concentrated aqueous NH4OH (70 µl, 0.50 mmol). The resulting mixture was stirred at room temperature for 16 h. To the mixture was added aq HCl. 1 N at pH = 7 and the mixture was partitioned between H2O (10 ml) and EtOAc (2 x 10 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 5% MeOH in CH2CI2 as eluent to give the title compound (27 mg, 50%). 1 H NMR (300 MHz, DMSO-d6) δ 12.39 (s, 1 H) 11.40 (d, J = 1.84 Hz, 1 H) 9.98 (s, 1 H) 7.89 (d , J = 8.82 Hz, 1 H) 7.66 -7.76 (m, 2 H) 7.38 (t, J = 2.21 Hz, 2 H) 7.23-7.31 (m, 2 H)

20 7.06-7.21 (m, 3 H) 5.63 (dd, J = 8.09, 1.84 Hz, 1 H) 3.78 (s, 3 H) 3.07 (s, 3 H) 1.37 (s, 9 H).

Example 34. Preparation of 2- (3-tert-Butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) -5 (methylsulfonamido) phenylcarbamate of (E ) -terc-butyl (compound IB-L1-1.32).

image 1

To a solution of the product of Example 26 (75 mg, 0.146 mmol) in tert-butanol (4 ml) was added diphenyl phosphoryl azide (47 μl, 0.219 mmol) and triethylamine (31 μl, 0.219 mmol). The resulting mixture was stirred at 80 ° C for 18 h. The cooled mixture was partitioned between H2O (10 ml) and EtOAc (2 x 10 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography.

30 on silica gel using 3% MeOH in CH2CI2 as eluent to give the title compound (16 mg, 19%). 1 H NMR (300 MHz, DMSO-d6) δ 11.45 (d, J = 1.84 Hz, 1 H) 9.86 (s, 1 H) 9.03 (s, 1 H) 7.75 (d , J = 7.72 Hz, 2 H) 7.55 (d, J = 2.57 Hz, 1 H) 7.10-7.33 (m, 4 H) 7.04 (dd, J = 8, 64, 2.39 Hz, 1 H) 5.66 (dd, J = 7.91, 2.02 Hz, 1H) 3.78 (s, 3 H) 3.02 (s, 3H) 1.45 ( s, 9 H) 1.38 (s, 9 H).

35

Example 35. Preparation of (E) -N- (3-amino-4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxistiryl) phenyl) methanesulfonamide (compound IB-L1-1.28).

image 1

The procedure described for the preparation of Example 34 provided the title compound, which was purified by column chromatography on silica gel using 5% methanol in CH2CI2 as eluent (6 mg, 9%). 1 H NMR (300 MHz, DMSO-d6) δ 11.44 (d, J = 2.21 Hz, 1 H) 9.55 (s, 1 H) 7.77 (d, J = 2.57 Hz, 1 H) 7.75 (d, J = 8.09 Hz, 1 H) 7.45 (d, J = 8.46 Hz, 1 H) 7.33 (d, J = 15.81 Hz, 1 H) 7.15 (d, J = 2.57 Hz, 1 H) 7.00 (d, J = 16.18 Hz, 1 H) 6.56 (d, J = 2.21 Hz, 1 H) 6, 44 (dd, J = 8.46, 2.21 Hz, 1 H) 5.66 (dd, J = 7.91, 2.02 Hz, 1 H) 5.56 (s, 2 H) 3.78 (s, 3 H) 2.97 (s, 3

10 H) 1.37 (s, 9 H).

Example 36. Preparation of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystrile) -2fluorophenyl ) methanesulfonamide (compound IB-L1-1.5).

image 1

15 Part A. Preparation of (3-fluoro-4-nitrophenyl) methanol.

To a solution of 3-fluoro-4-nitrobenzoic acid (2.0 g, 10.8 mmol) in THF (50 ml) at 0 ° C was added dropwise BH3-Me2S complex (2.215 ml, 22.15 mmol ). The mixture was stirred at 0 ° C for 3 h and then stirred 65 ° C for

20 18 h. Ice (50 g) was added to the cooled mixture, followed by ac HCl. 1 N (100 ml) and the resulting mixture was extracted with EtOAc (200 ml). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a white solid (1.79 g, 97%).

Part B. Preparation of 4- (bromomethyl) -2-fluoro-1-nitrobenzene.

A solution of the product of Part A (1.79 g, 10.46 mmol), N-bromosuccinimide (2.224 g, 12.55 mmol) and triphenylphosphine (3.29 g, 12.55 mmol) in CH2CI2 (100 ml) and THF (50 ml) was stirred at room temperature for 3 h. The mixture was partitioned between H2O (200 ml) and EtOAc (400 ml) and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 1: 1 of

EtOAc: hexanes as eluent to give the title compound (1.14 g, 47%).

Part C. Preparation of diethyl 3-fluoro-4-nitrobenzylphosphonate.

The product of Part B (1.25 g, 5.34 mmol) was subjected to the conditions described for Example 6, Part B 35 to provide the title product (0.75 g, 48%).

Part D. Preparation of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) -2fluorophenyl ) methanesulfonamide.

The product of Part C (0.193 g, 0.662 mmol) was subjected to the conditions described in Example 13A, Part E, Part F and Part G to provide the title product as a colorless solid (15 mg, 5 %). 1 H NMR (300 MHz, DMSO-d6) δ 11.43 (s, 1 H), 9.67 (s, 1 H), 7.76 (d, J = 8.1 Hz, 1 H), 7.62 (m , 2H), 7.41 (m, 2H), 7.38 (m, 1 H), 7.23 (m, 2H), 5.66 (dd, J = 8.0, 2.0 Hz, 1H ), 3.80 (s, 3H), 3.05 (s, 3H), 1.38 (s, 9H).

Four. Five

Example 37, Preparation of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1- (2H) -yl) -2-methoxystyryl) - 2-fluoro-5-methylphenyl) methanesulfonamide (compound IB-L1-1.15).

image 1

5 Part A. Preparation of N- (4-bromo-2-fluoro-5-methylphenyl) methanesulfonamide.

To a solution of 4-bromo-2-fluoro-5-methylaniline (2.04 g, 10.0 mmol) in anhydrous CH2CI2 (20 ml) and pyridine (3.23 ml, 40.0 mmol) was added chloride of methanesulfonyl (0.86 ml, 11.0 mmol) and the resulting mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc and aq. HCl. 1 M.

The organic layer was washed with saturated aqueous NaHCO3 and brine, and then dried over Na2SO4. The drying agent was filtered off and the filtrate was concentrated to give the title compound as a solid (2.80 g, 99%).

Part B. Preparation of N- (4-ethynyl-2-fluoro-5-methylphenyl) methanesulfonamide.

A mixture of the product from Part A (3.0 g, 10.63 mmol), triphenylphosphine (0.299 g, 1.06 mmol), trimethylsilyl acetate (6.0 ml, 42.5 mmol) and palladium acetate (ll) (0.12 g, 0.53 mmol) in triethylamine (30 ml) and toluene (15 ml) in an N2 atmosphere was heated at 80 ° C for 5 h. The mixture was allowed to cool to room temperature and partitioned between EtOAc and aq. HCl. 1 M. The organic layer was washed with saturated NaHCO3 and brine, dried over

20 Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 10% to 35% EtOAc in hexanes to give an oil (3.0 g, 94%). To a solution of the oil (3.0 g, 10.0 mmol) in MeOH (50 ml) was added aq NaOH. 1 M (21 ml, 21.0 mmol) and the resulting mixture was stirred at room temperature for 45 min. The mixture was partitioned between EtOAc and HCl aq. 1 M and the organic layer was washed with brine and dried over Na2SO4. The drying agent was filtered off and the filtrate

25 was concentrated in vacuo to give the title compound as a solid (2.3 g, quant.).

Part C. Preparation of (E) -5-fluoro-2-methyl-4- (methylsulfonamido) styrylboronic acid.

The product of Part B (0.20 g, 0.88 mmol) was subjected to the conditions described for the preparation of Example 30 13B, Part B to give the title compound (42 mg, 17%).

Part D. Preparation of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1- (2H) -yl) -2-methoxystyryl) - 2-fluoro-5-methylphenyl) methanesulfonamide.

The product of Part C (40 mg, 0.15 mmol) was subjected to the conditions described for the preparation of Example 13B, Part I to give the title compound (51 mg, 83%). 1 H NMR (300 MHz , DMSO-d6) δ 11.42 (d, J = 2.21 Hz, 1 H) 9.59 (s, 1 H) 7.70-7.78 (m, 2 H) 7.66 (d, J = 11.77 Hz, 1H) 7.20-7.32 (m, 3 H) 5.65 (dd, J = 7.72, 2.21 Hz, 1 H) 3.79 (s, 3 H ) 3.05 (s, 3 H) 2.38 (s, 3 H) 1.38 (s, 9 H).

Example 38, Preparation of methyl 2- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenethyl) -5 (methylsulfonamido) benzoate (compound IB-L5-2-1.1).

image 1

To a solution of the product of Example 25 (40 mg, 0.076 mmol) in MeOH (2 ml) and THF (2 ml) Pd was added to the

10% / C (20 mg) and the resulting mixture was stirred at room temperature under an atmosphere of H2 for 16 h. The mixture was filtered through Celite and concentrated in vacuo to give a solid (27.5 mg, 68%). 1 H NMR (300 MHz, DMSO-d6) δ 11.39 (s, 1 H) 9.88 (s, 1 H) 7.61 -7.71 (m, 2 H) 7.28 -7.36 ( m, 2 H) 7.20 (d, J = 2.57 Hz, 1 H) 7.13 (d, J = 2.94 Hz, 1 H) 5.64 (d, J = 7.72 Hz, 1 H) 3.83 (s, 3 H) 3.75 (s, 3 H) 3.14 (dd, J = 10.30, 5.88 Hz, 2 H) 2.96 (s, 3 H) 2.83 -2.92 (m, 2 H) 1.34 (s, 9 H).

Example 39, Preparation of N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl-2-methoxifentyl) phenyl) methanesulfonamide (compound IB-L5- 2-1.2).

image 1

The product of Example 13B, Part M (200 mg, 0.426 mmol) was dissolved in MeOH (10 ml) followed by the addition of 10% Palladium activated carbon (50 mg). The resulting mixture was evacuated and a hydrogen balloon was coupled, then stirred at room temperature for 48 h. Then, the mixture was filtered through Celite and the filtrate was concentrated in vacuo to an oil that was dissolved in ethanol (4 ml), then a 1 N solution of aqueous sodium hydroxide (3.8 ml, 3.8) was added. mmol) and the solution was stirred at room temperature for 18 h. Then, the ethanol was removed in vacuo and a 1 N solution of aqueous hydrochloric acid (4 ml) was added to acidify the mixture followed by extraction with EtOAc (2 x 10 ml). The organic extracts were combined, dried and purified by

Column chromatography on silica gel using 5% MeOH in CH2CI2 as eluent to provide the title compound as a colorless solid (82 mg, 41%). 1 H NMR (300 MHz, DMSO-d6) δ 11.39 (s, 1 H), 9.60 (s, 1 H), 7.65 (d, J = 8.1 Hz, 1 H), 7.23 (m , 3H), 7.17 (m, 3H), 5.64 (d, J = 7.7 Hz, 1 H), 3.77 (s, 3H), 2.93 (s, 3H), 2, 88 (sa, 4H), 1.35 (s, 9H).

Example 40. Preparation of (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1- (2H) -yl) -2-ethoxystyryl) phenyl) methanesulfonamide (compound IB-L1-1.30).

image 1

Part A. Preparation of 2-tert-butyl-4-iodophenol.

In a 250 ml round bottom flask, 2-tert-butylphenol (3.76 g, 25 mmol) in MeOH (50.0 ml) was added to give a colorless solution. Sodium hydroxide (1,200 g, 30.0 mmol) was added and the mixture was stirred until the hydroxide dissolved completely. The solution was cooled to 0 ° C and treated with sodium iodide (1.75 g, 11.6 mmol) followed by dropwise addition of 10% sodium hypochlorite solution (7.2 ml, 11.6 mmol) . The addition of sodium iodide

30 followed by sodium hypochlorite was repeated twice and the mixture was stirred at 0 ° C for 30 min. The mixture was treated with a 10% w / w solution of sodium thiosulfate, stirred for 30 min and treated dropwise with concentrated HCl at a constant pH of 1. The mixture was extracted 3 x with EtOAc. The extracts were combined, washed with brine, dried (MgSO4), filtered and concentrated. The crude oil was subjected to flash chromatography on an 80 g Isco silica cartridge eluting with hexane at> 4: 1 hexane / EtOAc to give a yellow oil (5.2

35 g, 75%).

Part B. Preparation of 2-bromo-6-tert-butyl-4-iodophenol.

The product of Part A (4.8 g, 17.38 mmol) and 1,3-dibromo was added to a 250 ml round bottom flask

5,5-dimethylhydantoin (2.61 g, 9.13 mmol) in chloroform (87 ml) to give an orange solution. The reaction mixture was stirred for 2 h, resulting in a black solution that was washed with water and brine, dried (Na2SO4) and concentrated. The black oil was subjected to flash chromatography on a 120 g Isco silica cartridge with hexane to give a pinkish solid (4.84 g, 78%).

Part C. Preparation of 1-bromo-3-tert-butyl-2-ethoxy-5-iodobenzene.

The product of Part B (888 mg, 2.5 mmol), ethyl iodide (409 mg, 2.63 mmol) and potassium carbonate (415 mg, 3.00 mmol) were added in a 50 ml round bottom flask ) in acetone (12 ml) to give a green suspension. The mixture was heated at reflux for 16 h, cooled and concentrated. The residue was partitioned between water and EtOAc. The organic layer was washed twice with brine, dried over Na2SO4, filtered and concentrated to give a red oil. The oil was subjected to flash chromatography on a 40 g Isco silica gel cartridge, eluting with hexane to give a clear oil (820 mg, 86%).

Part D. Preparation of 1 - (3-Bromo-5-tert-butyl-4-ethoxyphenyl) pyrimidin-2,4 (1 H, 3H) -dione.

The product of Part C (0.4 g, 1.044 mmol), 1H-pyrimidin-2,4-dione (0.134 g, 1,253 mmol) and potassium phosphate was added to a 20 ml microwave tube in abundant nitrogen washing tribasic (0.465 g, 2.193 mmol) in DMSO (5 ml) to give a colorless suspension. N- (2-cyanophenyl) picolinamide (0.047 g, 0.209 mmol) was added and the mixture was sprayed with nitrogen for 10 min. Copper (l) iodide (0.020 g, 0.104 mmol) was added and the mixture was sprayed once more for 10 min, placed under a nitrogen atmosphere and heated at 60 ° C for 18

h. The mixture was cooled and partitioned between EtOAc and water, adjusting the pH to 1 with HCl. The aqueous layer was extracted 2x with EtOAc. The organic extracts were combined, washed with water, saturated NaHCO3 and saturated NaCl. The organic layer was dried (Na2SO4), stirred with 3-mercaptopropyl-functional silica for 1 h, filtered and concentrated. The crude product was purified by chromatography on a 12 g Isco silica cartridge, eluting with 2% MeOH in CH2CI2 to give a white powder (266 mg, 69%).

Part E. Preparation of (E) -N- (4- (3-tert-Butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-ethoxystyryl) phenyl) methanesulfonamide.

A mixture of the product of Part D (55.1 mg, 0.15 mmol), the product of Example 13B, Part B (36.2 mg, 0.155 mmol), tribasic potassium phosphate (63.7 mg, 0.300 mmol) and 1,1'-bis (di-tert-butylphosphino) ferrocene palladium (4.89 mg, 7.50 μmol) bichloride in THF (3 ml) water (1 ml) was sprayed for 10 min with nitrogen, then sealed tightly and heated at 50 ° C for 4 h. The mixture was cooled to room temperature and diluted in EtOAc. The EtOAc layer was washed with 1M HCl, saturated NaHCO3, saturated NaCl, dried (Na2SO4) and treated simultaneously with mercaptopropyl-operated silica gel, concentrated. The crude product was purified by column chromatography on silica gel using 2% MeOH in CH2CI2 as eluent to give the title compound as a solid (40 mg, 55%) m.p. 265-266 ° C. 1 H NMR (300 MHz, DMSO-d6) δ 11.42 (s, 1 H) 9.87 (s, 1 H) 7.76 (d, J = 8.09 Hz, 1 H) 7.55 -7 , 66 (m, 3 H) 7.17 -7.27 (m, 5 H) 5.65 (dd, J = 7.72, 1.47 Hz, 1 H) 3.89 (c, J = 6 , 74 Hz, 2 H) 3.02 (s, 3 H) 1.45 (t, J = 6.99 Hz, 3 H) 1.39 (s, 9 H).

The following compounds were prepared using the above description:

(E) -N- (4- (1- (3-tert-Butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) prop-1-en-2-yl) phenyl) methanesulfonamide (compound IA-L1-1.6). 1 H NMR (300 MHz, DMSO-d6) δ 2.14 (s, 3 H) 2.70 (t, J = 6.62 Hz, 2 H) 3.01 (s, 3 H) 3.68 (s , 3 H) 3.78 (t, J = 6.62 Hz, 2 H) 6.82 (s, 1 H) 7.10 -7.17 (m, 2 H) 7.23 (d, J = 8.46 Hz, 2 H) 7.59 (d, J = 8 , 46 Hz, 2 H) 9.78 (s, 1 H) 10.32 (s, 1 H).

(Z) -N- (4- (3-tert-Butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxystyryl) phenyl) methanesulfonamide (compound IAL1-1,10). 1 H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1 H) 9.74 (s, 1 H) 7.23 (d, J = 8.46 Hz, 2H) 7.13 (d, J = 2.57 Hz, 1 H) 7.06 (d, J = 8.82 Hz, 2 H) 6.92 (d, J = 2.57 Hz, 1 H) 6.54 -6.67 ( m, 2 H) 3.78 (s, 3 H) 3.57 (t, J = 6.62 Hz, 2 H) 2.96 (s, 3 H) 2.60 (t, J = 6.80 Hz, 2 H) 1.34 (s, 9 H).

(E) -N- (4- (3-tert-Butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxystyryl) phenyl) -N- (methylsulfonyl) -acetamide (compound IA -L1-1.11). 1 H NMR (300 MHz, DMSO-d6) δ 10.36 (s, 1 H) 7.77 (d, J = 8.46 Hz, 2 H) 7.56 (d, J = 2.21 Hz, 1 H) 7.39-7.50 (m, 3 H) 7.25 (d, J = 16.55 Hz, 1 H) 7.19 (d, J = 2.57 Hz, 1 H) 3.74 -3.85 (m, 5 H) 3.54 (s, 3 H) 2.72 (t, J = 6.62 Hz, 2 H) 1.94 (s, 3 H) 1.38 (s, 9 H).

(E) -1- (3- (4-aminoestyryl) -5-tert-butyl-4-methoxyphenyl) dihydropyrimidin-2,4 (1 H, 3H) -dione (compound IA-L1-1,13). 1 H NMR (300 MHz, DMSO-d6) δ 1.36 (s, 9 H) 2.70 (t, J = 6.62 Hz, 2 H) 3.74 (s, 3 H) 3.77 (t , J = 6.62 Hz, 2 H) 5.34 (s, 1 H) 6.57 (d, J = 8.46 Hz, 2 H) 6.98 (s, 1 H) 7.07 (d , J = 2.21 Hz, 1 H) 7.17 (s, 2 H) 7.30 (d, J = 8.09 Hz, 2 H) 7.45 (d, J = 2.21 Hz, 1 H) 10.32 (s, 1 H).

(Z) -N- (4- (3-tert-Butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxystyryl) phenyl) methanesulfonamide (compound IAL1-1,20). 1H NMR (500 MHz, DMSO-d6): δ ppm 1.37 (s, 9H), 2.71 (t, J = 6.7 Hz, 2H), 3.01 (s, 3H), 3.75 (s, 3H), 3.79 (t, J = 6.6 Hz, 2H), 7.13 (d, J = 16.5 Hz, 1H), 7.15 (d, J = 2.4 Hz , 2H), 7.23 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 16.5 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H ), 7.61 (d, J = 8.6 Hz, 2H), 9.80 (sa, 1H), 10.30 (s, 1H).

N- (4- (2- (3-tert-Butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1-fluorovinyl) phenyl) methanesulfonamide (compound IA-L1- 1.21). (racemic mixture (1: 1) of compounds IA-L1-1.4 and IA-L1-1.5).

(E) -1- (3-tert-Butyl-4-methoxy-5- (4-nitrostyryl) phenyl) dihydropyrimidin-2,4 (1H, 3H) -dione (compound IA-L1-1,22).

1- {3-tert-butyl-5 - [(Z) -2-chloro-2- (4-nitro-phenyl) -vinyl] -4-methoxy-phenyl} -dihydropyrimidine-2,4-dione (compound IA -L1-1.23).

1- {3-tert-Butyl-4-methoxy-5 - [(E) -2- (4-nitro-phenyl) -propenyl] -phenyl} -dihydro-pyrimidin-2,4-dione (compound IA-L1 -1.24).

1- {3-tert-Butyl-5 - [(E) -2- (4-nitro-phenyl) -vinyl] -phenyl} -dihydro-pyrimidin-2,4-dione (compound IA-L1-1.25). 1 H NMR (300 MHz, DMSO-D6) δ ppm 1.33 (s, 9 H) 2.70-2.77 (m, 2 H) 3.84 (t, J = 6.80 Hz, 2 H) 7.33 (s, 1H) 7.49 (d, J = 4.04 Hz, 2 H) 7.56 (d, J = 5.88 Hz, 2 H) 7.89 (d, J = 8, 82 Hz, 2 H) 8.25 (d, J = 8.82 Hz, 2 H) 10.40 (s, 1H)

N- (4 - {(E) -2- [3-tert-butyl-5- (dioxo-tetrahydro-pyrimidin-1-yl) -2-methoxy-phenyl] -vinyl} -3-methoxy-phenyl) - methanesulfonamide (compound IA-L1-127). 1 H NMR (300 MHz, DMSO-D6) δ ppm 10.33 (s, 1 H) 9.86 (s, 1 H) 7.64 (d, J = 8.46 Hz, 1 H) 7.45 ( d, J = 2.21 Hz, 1 H) 7.26 (s, 2 H) 7.12 (d, J = 2.21 Hz, 1 H) 6.89 (s, 1 H) 6.85 ( dd, J = 8.46, 1.84 Hz, 1H) 3.84 (s, 3H) 3.78 (t, J = 6.80 Hz, 2H) 3.74 (s, 3H) 3.04 ( s, 3 H) 2.71 (t, J = 6.62 Hz, 2 H) 1.37 (s, 9 H)

N- (4 - {(E) -2- [3-tert-Butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxyphenyl] -vinyl} -3-formyl-phenyl) methanesulfonamide (compound IB-L1-1.6). 1 H NMR (300 MHz, DMSO-D6) δ ppm 1.39 (s, 9 H) 3.07 (s, 3 H) 3.81 (s, 3 H) 5.66 (dd, J = 7.72, 2.21 Hz, 1 H) 7.26 (d, J = 2.57 Hz, 1H) 7.30 (d, J = 16.18 Hz, 1H) 7.51 (dd, J = 8.64, 2.39 Hz, 1 H) 7.69 (d, J = 2.57 Hz, 1H) 7.73-7.78 (m, 2 H) 7.97 (d, J = 8.82 Hz, 1H ) 8.06 (d, J = 16.18 Hz, 1 H) 10.15 (s, 1H) 10.45 (s, 1H) 11.43 (d, J = 2.21 Hz, 1H)

N- [4 - {(E) 2- [3-tert-Butyl-5 (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxyphenyl] vinyl} -3- (hydroxyiminomethyl) -phenyl] methanesulfonamide (compound IB-L1-1.8). 1 H NMR (300 MHz, DMSO-d6) δ 1.38 (s, 9 H) 3.03 (s, 3 H) 3.79 (s, 3 H) 5.66 (dd, J = 7.91, 2.02 Hz, 1 H) 7.16 (d, J = 15.81 Hz, 1 H) 7.22 (d, J = 2.57 Hz, 1 H) 7.26 (dd, J = 8, 64, 2.39 Hz, 1 H) 7.59 (d, J = 16.18 Hz, 1 H) 7.63 (d, J = 2.21 Hz, 1H) 7.73-7.83 (m , 3 H) 8.64 (s, 1 H) 9.96 (s, 1 H) 11.42 (d, J = 2.21 Hz, 1H) 11.50 (s, 1H).

2 - {(E) -2- [3-tert-butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxyphenyl] -vinyl} -5- methanesulfonylamino-N- (2methoxyethyl) -benzamide (compound IB-L1-1.9). 1 H NMR (300 MHz, DMSO-D6) δ 1.38 (s, 9 H) 3.05 (s, 3 H) 3.20 (s, 3 H) 3.37-3.49 (m, 4H) 3.78 (s, 3H) 5.64 (d, J = 7.72 Hz, 1H) 7.15 (d, J = 2.57 Hz, 1H) 7.20 (d, J = 2.57 Hz , 1H) 7.24 (s, 2H) 7.28 (dd, J = 8.46, 2.21 Hz, 1H) 7.42 (d, J = 2.57 Hz, 1H) 7.73 (d , J = 7.72 Hz, 1H) 7.87 (d, J = 8.82 Hz, 1H) 8.49 (t, J = 5.15 Hz, 1H) 9.99 (s, 1H) 11, 42 (s, 1 H).

2 - {(E) 2- [3-tert-Butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxy-phenyl] - ethyl ester vinyl} -5methanesulfonylamino-benzoic acid (compound IB-L1-1.11). 1H NMR (300 MHz, DMSO-d6) δ 1.31 (t, J = 7.17 Hz, 3 H) 1.38 (s, 9H) 3.05 (s, 3H) 3.79 (s, 3H ) 4.33 (c, J = 7.23 Hz, 2H) 5.65 (dd, J = 7.72, 2.21 Hz, 1H) 7.15-7.25 (m, 2H) 7.46 (dd, J = 8.64, 2.39 Hz, 1H) 7.52 (d, J = 2.57 Hz, 1H) 7.68 (d, J = 2.57 Hz, 1H) 7.71- 7.81 (m, 2H) 7.90 (d, J = 8.46 Hz, 1H) 10.06 (s, 1H) 11.42 (d, J = 1.84 Hz, 1H).

N- (4 - {(E) -2- [3-tert-Butyl-2-chloro-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -phenyl] - vinyl} -phenyl) -methanesulfonamide (compound IB-L1-1.12). 1 H NMR (300 MHz, DMSO-d6) δ ppm 1.49 (s, 9 H) 3.02 (s, 3 H) 5.69 (d, J = 7.72 Hz, 1 H) 7.22 (m , 3H) 7.41 (d, J = 2.21 Hz, 1H) 7.51 (d, J = 16.18 Hz, 1H) 7.59 (d, J = 8.82 Hz, 2H) 7, 78 (d, J = 2.21 Hz, 1H) 7.80 (d, J = 8.09 Hz, 1 H) 9.90 (s, 1 H) 11.47 (s, 1H).

2 - {(E) -2- [3-tert-Butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxy-phenyl] -vinyl} - 5-methanesulfonylamino-N, N-dimethylbenzamide (compound IB-L1-1.14). 1 H NMR (300 MHz, DMSO-d6) δ 1.37 (s, 9 H) 2.76 (s, 3 H) 3.03 (s, 3H) 3.05 (s, 3H) 3.76 (s , 3H) 5.64 (dd, J = 7.91, 1.65 Hz, 1H) 6.95 (d, J = 16.55 Hz, 1H) 7.02 (d, J = 2.21 Hz, 1H) 7.17 7.25 (m, 2H) 7.27 (dd, J = 8.64, 2.39 Hz, 1H) 7.48 (d, J = 2.57 Hz, 1H) 7.74 (d, J = 8.09 Hz, 1H) 7.82 (d, J = 8.82 Hz, 1H) 10.03 (s, 1H) 11.39 -11.43 (m, 1 H).

2 - {(E) -2- [3-tert-Butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxy-phenyl] -vinyl} - 5-methanesulfonylamino-Nmethylbenzamide (compound IB-L1-1.17) .1 H NMR (300 MHz, DMSO-d6) δ 1.38 (s, 9 H) 2.77 (d, J = 4.41 Hz, 3 H) 3.06 (s, 3 H) 3.77 (s, 3 H) 5.64 (dd, J = 7.72, 1.84 Hz, 1 H) 7.16-7.33 (m, 5 H ) 7.43 (d, J = 2.21 Hz, 1H) 7.73 (d, J = 7.72 Hz, 1 H) 7.84 (d, J = 8.46 Hz, 1H) 8.37 (c, J = 4.41 Hz, 1H) 10.00 (s, 1 H) 11.40 (d, J = 1.84 Hz, 1H).

2 - {(E) -2- [3-tert-butyl-5 (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxy-phenyl] -vinyl} -N - (1,1-dioxotetrahydro-1lambda * 6 * thiophen-3-yl) -5-methanesulfonylamino-N-methyl-benzamide (compound IB-L1-1.18). 1 H NMR (300 MHz, DMSO-d6) δ 1.37 (s, 9 H) 2.17 -2.47 (m, 2 H) 2.70 (s, 3 H) 3.06 (s, 3 H) 3.15 -3.31 (m, 2 H) 3.36 -3.51 (m, 2 H) 3.77 (s, 3 H) 5.37 (dt, J = 17.74, 8.96 Hz, 1H) 5.65 (dd, J = 7.91, 2.02 Hz, 1 H) 6.93 (d, J = 16.18 Hz, IH) 7.05 (d, J = 2.2 Hz, 1 H) 7,197.35 (m, 3H) 7.50 (d, J = 2.57 Hz, 1H) 7.76 (d, J = 8.09 Hz, 1H) 7.87 (d, J = 8.82 Hz, 1 H) 10.04 (s, 1H) 11.38 (d, J = 2.21 Hz, 1H).

N- (4 - {(E) -2- [3-tert-butyl-5- (5-chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxyphenyl ] -vinyl} -phenyl) methanesulfonamide (compound IB-L1-1.20). 1 H NMR (300 MHz, DMSO-D6) δ ppm 11.31 (s, 1 H) 9.77 (s, 1 H) 7.53 (d, J = 8.09 Hz, 1H) 7.23 (d , J = 8.46 Hz, 2H) 7.17 (d, J = 2.57 Hz, 1H) 7.06 (d, J = 8.82 Hz, 2H) 7.01 (d, J = 2, 57 Hz, 1 H) 6.53-6.71 (m, 2 H) 5.56 (d, J = 7.72 Hz, 1 H) 3.81 (s, 3 H) 2.96 (s, 3 H) 1.35 (s, 9 H)

2 - {(E) -2- [3-tert-butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxy-phenyl] -vinyl} - 5-methanesulfonylamino-benzamide (compound IB-L1-1.21). 1 H NMR (300 MHz, DMSO-d6) δ 1.38 (s, 9 H) 3.07 (s, 3 H) 3.78 (s, 3 H) 5.64 (d, J = 7.72 Hz , 1H) 7.18-7.34 (m, 5H) 7.43 (d, J = 2.21 Hz, 1H) 7.54 (s, 1H) 7.73 (d, J = 7.72 Hz , 1H) 7.84 (d, J = 8.46 Hz, 1H) 7.93 (s, 1H).

N- (3- (azetidin-1-carbonyl) -4 - {(E) -2- [3-tert-butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1- il) -2-methoxyphenyl] -vinyl} -phenyl) methanesulfonamide (compound IB-L1-1.22) .1 H NMR (300 MHz, DMSO-d6) δ 1.38 (s, 9H) 3.07 (s, 3 H ) 3.78 (s, 3H) 5.64 (d, J = 7.72 Hz, 1H) 7.18-7.34 (m, 5H) 7.43 (d, J = 2.21 Hz, 1H ) 7.54 (s, 1 H) 7.73 (d, J = 7.72 Hz, 1H) 7.84 (d, J = 8.46 Hz, 1H) 7.93 (s, 1H).

2 - {(E) -2- [3-tert-Butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxy-phenyl] -vinyl} - 5-methanesulfonylamino-N- (2methoxyethyl) -N-methylbenzamide (compound IB-L1-1.24) .1 H NMR (300 MHz, DMSO-d6) 8 1.40 (s, 9H) 2.81 (s, 3H) 3 , 07 (s, 3H) 3.23 (s, 3H) 3.29 (t, J = 5.33 Hz, 1H) 3.39 (t, J = 4.96 Hz, 1H) 3.62 (t , J = 4.78 Hz, 2 H) 3.82 (s, 3H) 5.68 (d, J = 8.09 Hz, 1H) 6.96-7.07 (m, 1H) 7.09- 7.17 (m, 1H) 7.23-7.38 (m, 3H) 7.49 (dd, J = 16.55, 2.57 Hz, 1H) 7.71-7.76 (m, 1H ) 7.83-7.94 (m, 1H).

N- (4 - {(E) -2- [3-tert-butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxy-phenyl] - vinyl} -3-isopropoxymethylphenyl) methanesulfonamide (compound IB-L1-1.25) .1 H NMR (300 MHz, DMSO-d6) δ 1.16 (d, J = 5.88 Hz, 6H) 1.38 (s, 9H ) 3.01 (s, 3H) 3.69 (dt, J = 12.13, 6.07 Hz, 1H) 3.79 (s, 3H) 4.59 (s, 2H) 5.65 (dd, J = 7.91, 2.02 Hz, 1H) 7.13-7.29 (m, 4H) 7.32-7.40 (m, 1H) 7.59 (d, J = 2.57 Hz, 1H) 7.75 (d, J = 8.09 Hz, 2H) 9.86 (s, 1 H) 11.43 (d, J = 1.84 Hz, 1H).

N- [4 - {(E) -2- [3-tert-butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxy-phenyl] - vinyl} -3- (pyrrolidin-1-carbonyl) -phenyl] methanesulfonamide (compound IB-L1-1.27). 1 H NMR (300 MHz, DMSO-d6) δ 1.37 (s, 9 H) 1.73-1.89 (m, 4H) 3,033.12 (m, 5H) 3.51 (t, J = 6, 80 Hz, 2H) 3.76 (s, 3H) 5.64 (dd, J = 7.91, 2.02 Hz, 1H) 6.99-7.06 (m, 1H) 7.08 (d, J = 2.21 Hz, 1H) 7.19-7.31 (m, 3H) 7.46 (d, J = 2.57 Hz, 1H) 7.75 (d, J = 8.09 Hz, 1H ) 7.82 (d, J = 8.82 Hz, 1) 10.01 (s, 1H) 11.41 (d, J = 2.21 Hz, 1H).

N- [4 - {(E) -2- [3-tert-Butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxy-phenyl] - vinyl} -3- (3-hydroxyazetidin-1-ylmethyl) phenyl] -methanesulfonamide (compound IB-L1-1.29) .1 H NMR (300 MHz, DMSO-d6) 8 1.38 (s, 9H) 2.78- 2.85 (m, 2H) 2.99 (s, 3H) 3.50-3.58 (m, 2H) 3.71 (s, 2H) 3.79 (s, 3H) 4.19 (td, J = 12.41, 6.07 Hz, 1H) 5.29 (d, J = 6.25 Hz, 1H) 5.66 (d, J = 8.09 Hz, 1H) 7.10-7.18 (m, 2H) 7.20 (t, J = 2.21 Hz, 2H) 7.35-7.42 (m, 1 H) 7.63 (d, J = 2.57 Hz, 1H) 7, 69 (d, J = 8.46 Hz, 1H) 7.76 (d, J = 7.72 Hz, 1H) 9.78 (s, 1H) 11.42 (s, 1H).

N- (4 - {(E) -2- [3-tert-Butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxy-phenyl] - vinyl} -3-pyrrolidin-1-ylmethyl-phenyl) methanesulfonamide (compound IB-L1-133) .1 H NMR (500 MHz, DMSO-d6) δ 1.40 (s, 9 H) 1.72 -1.95 (m, 4 H) 2.84 (s, 2 H) 2.88 -2.98 (m, 2 H) 3.01 (s, 3H) 3.81 (s, 3H) 3.86 -4, 23 (m, 2 H) 5.63 (d, J = 7.81 Hz, 1H) 7.17 (d, J = 15.63 Hz, 1 H) 7.21-7.28 (m, 2 H ) 7.32 -7.38 (m, 1 H) 7.47 (d, J = 16.11 Hz, 1 H) 7.53 -7.59 (m, 1 H) 7.61 (d, J = 7.81 Hz, 1 H) 7.70 (d, J = 6.35 Hz, 1 H) 9.42 (s, 1 H) 10.88 (s, 1 H).

N- (4 - {(Z) -2- [3-tert-Butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxy-phenyl] - vinyl} -phenyl) -methanesulfonamide (compound IB-L1-1.34 1H NMR (300 MHz, DMSO-D6) δ ppm 11.31 (s, 1H) 9.77 (s, 1 H) 7.53 (d, J = 8.09 Hz, 1H) 7.23 (d, J = 8.46 Hz, 2 H) 7.17 (d, J = 2.57 Hz, 1H) 7.06 (d, J = 8.82 Hz, 2 H) 7.01 (d, J = 2.57 Hz, 1H) 6.53 -6.71 (m, 2 H) 5.56 (d, J = 7.72 Hz, 1 H) 3 , 81 (s, 3 H) 2.96 (s, 3 H) 1.35 (s, 9 H)

N- (4- (3-tert-Butyl-5- (2,4-dioxotetrahydropyrimidin-1- (2H) -yl) phenethyl) phenyl) methane sulfonamide (compound IA-L5-2-1,2). 1 H NMR (300 MHz, DMSO-d6) δ 1.25 (s, 9 H) 2.69 (t, J = 6.62 Hz, 2 H) 2.83 (s, 4 H) 2.91 (s , 3 H) 3.75 (t, J = 6.62 Hz, 2 H) 6.99-7.21 (m, 7 H) 9.60 (s, 1 H) 10.31 (s, 1 H ).

Methyl 2- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenethyl) -5- (methylsulfonamido) benzoate (compound IB-L5 -2-1.1). 1 H NMR (300 MHz, DMSO-d6) δ 1.34 (s, 9 H) 2.83 -2.92 (m, 2 H) 2.96 (s, 3 H) 3.14 (dd, J = 10.30, 5.88 Hz, 2 H) 3.75 (s, 3 H) 3.83 (s, 3H) 5.64 (d, J = 7.72 Hz, 1 H) 7.13 (d , J = 2.94 Hz, 1H) 7.20 (d, J = 2.57 Hz, 1 H) 7.28 -7.36 (m, 2 H) 7.61 -7.71 (m, 2 H) 9.88 (s, 1 H) 11.39 (s, 1 H)

N- (4- (3-tert-Butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenethyl) phenyl) methanesulfonamide (compound IBL5-2-1.2) . 1 H NMR (300 MHz, DMSO-d6): δ 11.39 (s, 1 H), 9.60 (s, 1 H), 7.65 (d, J = 8.1 Hz, 1 H), 7.23 ( m, 3H), 7.17 (m, 3H), 5.64 (d, J = 7.7 Hz, 1H), 3.77 (s, 3H), 2.93 (s, 3H), 2, 88 (sa, 4H), 1.35 (s, 9H)

The following compounds can be prepared using the above description:

image 1

HCV polymerase inhibition assay

Serial dilutions were incubated with dilution factor two (fractional inhibition assay) or a narrower dilution range spanning the IC50 of the inhibitor (tight binding assay) of the inhibitors with 20 mM Tris-Cl, pH 7.4, MnCl2 2 mM, 1 mM dithiothreitol, tetraacetic ethylenediamine acid (EDTA), 60 to 120 μM GTP and Δ21 NS5B (HCV strain 1B (BK, Genbank accession number M58335 or H77, Genbank accession number AF011751) from 20 to 50 nM for 15 min at room temperature The reaction began with the addition of 20 μM CTP, 20 μM ATP, 1 μM 3H-UTP (10 mCi / umol), 5 nM RNA template and 0.1 U RNase inhibitor / µl (RNasin, Promega) and allowed to continue for 2 to 4 h at room temperature The reaction volume was 50 µl The reaction was terminated with the addition of 1 volume of 4 mM spermine in 10 mM Tris-Cl, pH 8, 0, 1 mM EDTA After incubation for at least 15 min at room temperature, the precipitated RNA was captured by filtration through It is a GF / B filter (Millipore) in a 96-well format. Then, the filter plate was washed three times with 200 µl each of 2 mM spermine, 10 mM Tris-Cl, pH 8.0, 1 mM EDTA and 2 times with ethanol. After air drying, 30 µl of Microscint 20 scintillation cocktail (Packard) was added to each well and the retained rpm was determined by scintillation counting. IC50 values were calculated using a non-linear regression equation of two variables using an uninhibited control and a completely inhibited control sample to determine the minimum and maximum curve. Narrow-binding assays were performed on compounds that showed IC50 values less than 0.005 µM, in the fractional inhibition assay to more accurately measure IC50 values. The retained rpm was plotted against the concentration of the inhibitor and adjusted to an equation 1 using nonlinear regression (ref. 1) to obtain the IC60 values:

rpm retained = A [sqrt {(IC50 + It-Et) ^ 2 + 4 * IC50 * Et} - (IC50 + It-Et)] (equation 1)

in which A = Vmax [S] / 2 (Km + [S]); It = concentration of total inhibitor and Et = concentration of total active enzyme

Ref. Morrison, J. F. and S.R. Stone. 1985. Approaches to the study and analysis of the inhibition of enzymes by slowand tight-binding inhibitors. Comments Mol. Cell Biophys 2: 347-368.

The sequence of the template RNA used was: 5’-GGGCGAAUUG GGCCCUCUAG AUGCAUGCUC GAGCGGCCGC CAGUGUGAUG GAUAUCUGCA GAAUUCGCCC UUGGUGGCUC CAUCUUAGCC CUAGUCACGG CUAGCUGUGA AAGGUCCGUG AGCCGCUUU CUGCAGUGA CUGCAGUGA CUGCAGUGA CUGCAGUGA CUGUGA

When the compounds of this invention were tested by the above method they inhibited HCV 1A and / or 1B polymerase. The legend in the following table is as follows: A - IC50 ≤ 0.01 uM; B --0.1 uM ≥ IC50> 0.0 1 uM; C - 1 uM ≥ IC50> 0.1 uM; and D-IC50> 1 uM; ND - not determined.

IC50 table

compound

1st 1 B  compound 1st 1 B

IA-L1-13

TO TO IA-L1-1.4 TO TO

IA-L1-1.5

TO B IA-L1-1.6 TO B

IA-L1-1.9

TO B IA-L1-1.10 B B

IA-L1-1.11

B B IA-L1-1.12 C C

IA-L1-1.13

C C IA-L1-1.14 D D

IA-L1-1.16

TO TO IA-L1-1.17 B B

IA-L1-1.18

C C IA-L1-1.20 TO B

IA-L1-1.21

B B IA-L1-1.22 C C

IA-L1-1.23

C C IA-L1-1.24 D D

IA-L1-1.25

D D IA-L1-1.26 B B

IA-L1-1.27

TO B IB-L1-1.1 TO TO

IB-L1-1.2

B B IB-L1-1.4 TO TO

IB-L1-1.5

TO TO IB-L1-1.6 TO B

IB-L1-1.7

TO B IB-L1-1.8 TO B

IB-L1-1.9

TO B IB-L1-1.10 TO B

IB-L1-1.11

TO B IB-L1-1.12 TO B

IB-L1-1.13

TO B IB-L1-1.14 TO B

IB-L1-1.15

TO B IB-L1-1.16 TO B

IB-L1-1.17

TO B IB-L1-1.18 TO B

IB-L1-1.19

TO B IB-L1-1.20 TO B

IB-L1-1.21

TO B IB-L1-1.22 B B

IB-L1-1.23

B B IB-L1-1.24 B B

IB-L1-1.25

B B IB-L1-1.26 B B

IB-L1-1.27

B B IB-L1-1.28 B B

IB-L1-1.29

B B IB-L1-1.30 B B

IB-L1-1.31

B C IB-L1-1.32 C C

IB-L1-1.33

C C IB-L1-1.34 D D

IB-L1-1.45

TO B IB-L1-1.46 B B

IB-L1-1.47

B B IB-L1-1.48 B B

IB-L1-1.49

B C IB-L1-1.50 B B

IB-L1-1.51

B B IB-L1-1.52 C C

IB-L1-1.53

D D IB-L1-1.55 D D

IA-L5-2-1.1

B B IA-L5-2-1.2 B B

IB-L5-2-1.1

TO B IB-L5-2-1.2 B B

IA-L8-1.1

C C

HCV Polymerase Replicon Assay

10 Two stable subgenomic replicon cell lines were used for characterization of the compound in cell culture: one was obtained from genotype 1a-H77 and another was obtained from genotype 1b-Con1 (obtained from Apath, LLC, St. Louis, MO ). All of the replicon constructs were bicistronic subgenomic replicons similar to those described by Bartenschiager et al. (Lohmann et al., Replicon of Subgenomic Hepatitis C Virus RNAs in a Hepatoma Cell Line, SCIENCE 285: 110-3 (1999)). The genotype 1a replicon construct contained NS3-NS5B

15 encoding the region derived from HCV strain H77 (1a-H77) (Blight et al., Efficient Replication of Hepatitis C Virus Genotype Ia RNAs in Cell Culture, J. VIROL. 77: 3181-90 (2003)). The replicon also had a firefly luciferase indicator marker and a selectable neomycin phosphotransferase (Neo) marker. These two coding regions, separated by the FMDV 2a protease, comprise the first cistron of the bicistronic replicon construction, the second cistron containing the NS3-NS5B coding region with addition of mutations.

20 adaptive E1202G, K1691R, K2040R and S22041. The construction of replicon 1b-Con1 is identical to that of replicon 1a-H77, except that the NS3-NS5B coding region was obtained from strain 1b-Con1 and the adaptive mutations were E1202G, T12801 and S22041. Replicon cell lines were maintained in Dulbecco-modified Eagle's medium (DMEM) containing 10% fetal bovine serum / FBS), 100 IU / ml penicillin, 100 mg / ml streptomycin (Invitrogen) and G418 200 mg / ml (Invitrogen).

The inhibitory effects of the compounds on HCV replication were determined by measuring the activity of the luciferase reporter gene. Briefly, the cells containing the replicon were seeded in 96-well plates at a density of 5000 cells per well in 100 ul DMEM containing 5% FBS. 16-24 h later, the

Compounds were diluted in dimenti sulfoxide (DMSO) to generate a 200x reserve in a series of eight semi-logarithmic dilutions. Then, the dilution series were diluted 100 times more in the medium containing 5% FBS. The medium with the inhibitor was added to the overnight cell culture plates that already contained 100 µl of DMEM with 5% FBS. In the assays the measurement of inhibitory activity in the presence of human plasma, the medium of the overnight cell culture plates was replaced by DMEM containing 40% human plasma and 5% FBS. The cells were incubated for three days in tissue culture incubators and then lysed for RNA extraction. For the luciferase assay, Lisis Passive buffer (Promega) was added to each well and then the plates were incubated for 15 min with oscillating motion to perform cell lysis. To each well was added luciferin solution (50 to

10 100 μl, Promega) and luciferase activity was measured with a Victor II luminometer (Perkin-Elmer). The percent inhibition of HCV RNA replication was calculated for each compound concentration and the EC50 values were calculated using a non-linear regression curve fit for the 4-parameter logistic equation and GraphPad Prism 4 software.

When the compounds of this invention were tested by the above method they inhibited HCV 1A and / or 1B polymerase. The legend in the following table is as follows: A --CE50 ≤ 0.01 uM; B - 0.1 uM ≥ EC50> 0.01 uM; C - 1 uM ≥ EC50> 0.1 uM; and D -CE50> 1 uM; ND - not determined.

Table EC50

twenty

compound

1st 1 B  compound 1st 1 B

IA-L1-13

B TO IA-L1-1.4 TO TO

IA-L1-1.5

B TO IA-L1-1.6 B B

IA-L1-1.9

B TO IA-L1-1.10 B B

IA-L1-1.11

TO TO IA-L1-1.12 C C

IA-L1-1.13

D D IA-L1-1.14 D D

IA-L1-1.16

B B IA-L1-1.17 B B

IA-L1-1.18

C C IA-L1-1.20 B B

IA-L1-1.21

TO TO IA-L1-1.22 D C

IA-L1-1.23

D D IA-L1-1.24 D D

IA-L1-1.25

ND ND IA-L1-1.26 B B

IA-L1-1.27

B TO IB-L1-1.1 TO TO

IB-L1-1.2

ND B IB-L1-1.4 B TO

IB-L1-1.5

B TO IB-L1-1.6 TO TO

IB-L1-1.7

TO TO IB-L1-1.8 B TO

IB-L1-1.9

B TO IB-L1-1.10 TO TO

IB-L1-1.11

B TO IB-L1-1.12 B B

IB-L1-1.13

B TO IB-L1-1.14 B TO

IB-L1-1.15

TO TO IB-L1-1.16 C B

IB-L1-1.17

B TO IB-L1-1.18 B B

IB-L1-1.19

B TO IB-L1-1.20 B TO

IB-L1-1.21

B TO IB-L1-1.22 B TO

IB-L1-1.23

C TO IB-L1-1.24 B TO

IB-L1-1.25

B TO IB-L1-1.26 B TO

IB-L1-1.27

B TO IB-L1-1.28 TO TO

IB-L1-1.29

C C IB-L1-1.30 C B

IB-L1-1.31

D D IB-L1-1.32 C B

IB-L1-1.33

C B IB-L1-1.34 B TO

IB-L1-1.45

B TO IB-L1-1.46 C TO

IB-L1-1.47

C B IB-L1-1.48 C TO

IB-L1-1.49

D D IB-L1-1.50 C B

IB-L1-1.51

D D IB-L1-1.52 D C

IB-L1-1.53

ND ND IB-L1-1.55 ND ND

IA-L5-2-1.1

C B IA-L5-2-1.2 C C

IB-L5-2-1.1

B TO IB-L5-2-1.2 C B

IA-L6-1.1

C B IA-L8-1.1 C C

Claims (16)

1. A compound or salt thereof, in which: The compound corresponds in structure with the formula I: image 1 is selected from the group consisting of carbon-carbon single bond and carbon-carbon double bond; R1 is selected from the group consisting of hydrogen and methyl; R 2 is selected from the group consisting of hydrogen, halo, hydroxy, methyl, cyclopropyl and cyclobutyl; R3 is selected from the group consisting of hydrogen, halo, oxo and methyl; R4 is selected from the group consisting of halo, alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl and heterocyclyl, in which: 15 (a) the amino, aminocarbonyl and aminosulfonyl are optionally substituted with: (1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl and alkylsulfonyl, or (2) two substituents that, together with amino nitrogen, form a single ring heterocyclyl, and (b) alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy and alkylsulfonyl, are optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl and heterocyclyl, in which: the amino is optionally substituted with: 25 (1) one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, or (2) two substituents that, together with amino nitrogen, form a single ring heterocyclyl, and (c) the carbocyclyl and heterocyclyl are optionally substituted with up to three substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl and heterocyclyl, wherein: the amino is optionally substituted with: 35

(one)

one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, or

(2)

 two substituents that, together with amino nitrogen, form a single ring heterocyclyl;

R5 is selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylsulfunyloxy, carbocyclylsulfonyloxy, haloalkylsulfonyloxy and halo; L is selected from the group consisting of C (RA) = C (RB), ethylene and cyclopropyl-1,2-ene; RA and RB are independently selected from the group consisting of hydrogen, C1-C6 alkyl-alkyl, Alkyloxy-C1-C6, cycloalkyl-C3-C5 and halo, wherein: C1-C6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of carboxy, halo, hydroxy, nitro, oxo, amino, cyano, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl and heterocyclyl; fifty R6 is selected from the group consisting of carbocyclyl-C5-C6 and 5-6 membered heterocyclyl, in which each one of said substituents is optionally substituted with one or more selected substituents independently between the group consisting of RE, RF, RG, RH, R1, RJ and RK; each RE is independently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, cyano, amino, imino, azido and aldehyde, in which: the amino is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl; each RF is independently selected from the group consisting of alkyl, alkenyl and alkynyl, in which: each of said substituents is optionally substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyl , alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl, in which: the amino, imino, aminosulfonyl, aminocarbonyl, carbocyclyl and heterocyclyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl, alkylsulfonyl, alkylsulfonylamino, hydroxy and alkyloxy, in which: an alkylsulfonylamino portion is optionally substituted with a substituent selected from the group consisting of alkyl, alkenyl and alkynyl; each RG is independently selected from the group consisting of carbocyclyl and heterocyclyl, in which: each of said substituents is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkyloxycarbonyl, alkylcarbonyloxy , alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl, in which: the amino, aminosulfonyl and aminocarbonyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl and alkylsulfonyl; each RH is independently selected from the group consisting of alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, alkenylsulfunyloxy and alkynylsulfonyloxy, in which: each of said substituents is optionally substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy , alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl, in which: the amino, aminosulfonyl and aminocarbonyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl and alkylsulfonyl; each RI is independently selected from the group consisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aminocarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl and heterocyclylcarbonyl, in which:

(to)

 the alkylcarbonyl, alkenylcarbonyl and alkynylcarbonyl are optionally substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxycarbonyloxycarbonyloxycarbonylcarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonylcarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxy alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl, and

(b)

The aminocarbonyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxyalkyl, carbocyclyl, heterocyclyl, alkylsulfonyl and alkylsulfonylamino, wherein:

the carbocyclyl and heterocyclyl are optionally substituted with one or two substituents independently selected from the group consisting of halo, alkyl and oxo; each RJ is independently selected from the group consisting carbociclilsulfonilamino, heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, alquinilcarbonilamino, alkyloxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, alquinilsulfonilamino, aminocarbonylamino, alquiloxicarbonilaminoimino, alquilsulfonilaminoimino, alquenilsulfonilaminoimino and alquinilsulfonilaminoimino, wherein:

(to)

 the amino portion of said substituents is optionally substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkenyl, alkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxylalkyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl alkyloxycarbonyl that:

(one)

 the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl are optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido , oxo and amino, and

(2)

 the amino portion of the aminocarbonylalkyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl,

(b)

 the alkyl, alkenyl and alkyl portion of said substituents is optionally substituted with one or more substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl and cyano, in which: the amino is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy and alkynyloxy, in which:

the alkyl is optionally substituted with one or more hydroxy;

(C)

the carbocyclyl and heterocyclyl portions of said substituents are optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido and amino, in which:

the amino is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl; Y each RK is independently selected from the group consisting of aminosulfonyl, alkylsulfonyl, alkenylsulfonyl and alkylsulfonyl, in which:

(to)

 the alkylsulfonyl, alkenylsulfonyl and alkynylsulfonyl are optionally substituted with one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkyloxycarbonyl, alkylaryloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxy alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl, wherein: the amino, aminosulfonyl and aminocarbonyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl; Y

(b)

the aminosulfonyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl.

2. The compound or salt of claim 1, wherein: R2 is selected from the group consisting of hydrogen and halo; R3 is selected from the group consisting of hydrogen and halo; R4 is selected from the group consisting of C1-C4 alkyl, C3-C6 carbocyclyl and 5-6 membered heterocyclyl, in which:

(to)

C1-C4 alkyl is optionally substituted with up to three substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy and trimethylsilyl, and

(b)

 the 5-6 membered carbocyclyl-C3-C6 and heterocyclyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo and alkylsulfonylamino;

R5 is selected from the group consisting of hydrogen, hydroxy, alkyloxy and halo; one of RA and RB is hydrogen and the other is selected from the group consisting of hydrogen, methyl, methoxy, and halo; R6 is selected from the group consisting of carbocyclyl-C5-C6 and 5-6 membered heterocyclyl, in which each of said substituents is substituted with one, two or three substituents selected independently among the group consisting of RE, RF, RG, RH, RI, RJ and RK; each RE is independently selected from the group consisting of chlorine, fluorine, nitro, hydroxy, oxo, carboxy, amino, imino, aldehyde and alkylamino; each RF is an independently selected alkyl, optionally substituted with a substituent selected from the group consisting of carboxy, halo, amino, imino and aminusulfonyl, in which: the amino, imino and aminosulfonyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkylsulfonyl and alkylsulfonylamino; each R1 is independently selected from the group consisting of alkylcarbonyl and aminocarbonyl, in which: the aminocarbonyl is optionally substituted with a substituent selected from the group consisting of alkyl, alkyloxyalkyl, alkylsulfonyl and alkylsulfonylamino; each RJ is independently selected from the group consisting of alkylsulfonylamino, alkenylsulfonylamino, alkylsulfonylamino and alkylsulfonylaminoimino, in which:

(to)

 the amino portion of said substituents is optionally substituted with a substituent independently selected from the group consisting of carbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl and alkylsulfonyl:

(one)

 the carbocyclyl portion of the carbocyclylalkyl and the heterocyclyl portion of the heterocyclylalkyl are optionally substituted with one or two substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo and amino, and

(2)

 the amino portion of the aminocarbonylalkyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, alkenyl and alkynyl,

(b)

 the alkyl, alkenyl and alkyl portion of said substituents is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl and cyano, in the that:

the amino is optionally substituted with one or two substituents independently selected from the group consisting of alkyl and alkyloxy, in which: the alkyl is optionally substituted with one or more hydroxy; Y each RK is independently selected from the group consisting of aminosulfonyl and alkylsulfonyl, in which:

(to)

the alkylsulfonyl is optionally substituted with one or two substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, heterocyclyl, cyano and aminocarbonyl; Y

(b)

 the aminosulfonyl is optionally substituted with one or two independently selected alkyl substituents.

3.

The compound or salt of any one of claims 1 and 2, wherein R6 is selected from the group consisting of C5-C6 carbocyclyl and 5-6 membered heterocyclyl, wherein each of said substituents is substituted with one, two or three substituents independently selected from the group consisting of RE, RF, R1, RJ and RK.

Four.

The compound or salt of any one of claims 1-3, wherein:

R1 is hydrogen; R2 is selected from the group consisting of hydrogen and halo; R3 is hydrogen; R4 is tert-butyl; R5 is selected from the group consisting of hydroxy and methoxy; RA is hydrogen; Y RB is hydrogen.

5.

The compound or salt of any one of claims 1-4, wherein:

R6 is selected from the group consisting of C5-C6 carbocyclyl and 5-6 membered heterocyclyl, in which each of said substituents is substituted with one, two or three substituents independently selected from the group consisting of RE, RF and RJ.

6.

The compound or salt of any one of claims 1-5, wherein:

R6 is selected from the group consisting of C5-C6 carbocyclyl and 5-6 membered heterocyclyl, wherein each of said substituents is substituted with a substituent selected from the group consisting of RF and RJ; RF is alkylsulfonylaminoalkyl; and RJ is alkylsulfonylamino.

7.

The compound or salt of any one of claims 1-6, wherein:

R6 is phenyl substituted with a substituent selected from the group consisting of RF and RJ; RF is alkylsulfonylaminoalkyl; Y RJ is alkylsulfonylamino.

8.

The compound or salt of any one of claims 1-7, wherein L is C (RA) = C (RB).

9.

The compound or salt of any one of claims 1-8, wherein

image 1 It is a double carbon-carbon bond.

10.

The compound or salt of claim 1, wherein:

RA is hydrogen; Y RB is hydrogen. 11. The compound or salt of claim 1, wherein the compound is selected from the group consisting of: (E) -N- (4- (3-tert-Butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxystyryl) phenyl) methanesulfonamide; (Z) -N- (4- (2- (3-tert-Butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1-chlorovinyl) phenyl) methanesulfonamide; (E) -1- (3-tert-Butyl-5- (4-fluorostyryl) -4-methoxyphenyl) dihydropyrimidin-2,4 (1H, 3H) -dione; (Z) -N- (4- (2- (3-tert-Butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1-fluorovinyl) phenyl) methanesulfonamide; (E) -N- (4- (2- (3-tert-Butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1-fluorovinyl) phenyl) methanesulfonamide; (E) -N- (4- (3-tert-Butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxystyryl) -2-fluorophenyl) methanesulfonamide; N- (4- (2- (3-tert-Butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) cyclopropyl) phenyl) methanesulfonamide; N- (4- (3-tert-Butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenethyl) phenyl) methanesulfonamide; (E) -N- (4- (3-tert-Butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) styryl) phenyl) methanesulfonamide; (Z) -N- (4- (2- (3-tert-Butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1methoxyvinyl) phenyl) methanesulfonamide; (E) -1- (3-tert-Butyl-4-methoxy-5-styrylphenyl) dihydropyrimidin-2,4 (1H, 3H) -dione; (E) -1- (3-tert-Butyl-4-methoxy-5- (4-methoxystyryl) phenyl) dihydropyrimidin-2,4 (1H, 3H) -dione; (E) -N- (4- (3-tert-Butyl-5- (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) phenyl) methanesulfonamide ; (E) -N- (4- (3-Bromo-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) phenyl) methanesulfonamide; (E) -N- (4- (5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (thiophene-2-yl) styryl) phenyl) methanesulfonamide; (E) -N- (4- (5- (2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -3- (furan-2-yl) -2-methoxystyryl) phenyl) methanesulfonamide ; (E) -N- (4- (5- (2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (pyridin-4-yl) styryl) phenyl) methanesulfonamide; (E) -N- (4 (5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (pyridin-3-yl) styryl) phenyl) methanesulfonamide ; (E) -N- (4- (5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (thiophen-3-yl) styryl) phenyl) methanesulfonamide; (E) -N- (4- (5- (2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -3- (furan-3-yl) -2-methoxystyryl) phenyl) methanesulfonamide ; (E) -N- (4- (5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -3- (1-hydroxy-2-methylpropan-2-yl) -2-methoxycyryl ) phenyl) methanesulfonamide; (E) -N- (4- (5- (2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -3-iodo-2-methoxystyryl) phenyl) methanesulfonamide; (E) -N- (4- (5- (2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxy-3- (methylsulfonyl) styryl) phenyl) methanesulfonamide; (E) -methyl 2- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H-yl) -2-methoxystyryl) -5- (methylsulfonamido) benzoate; (E) -2- (3-tert-Butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) -5- (methylsulfonamido) benzoic; (E ) -N- (4- (3-tert-Butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) -3- (morpholin-4-carbonyl) phenyl ) methanesulfonamide; (E) -N- (4- (3-tert-Butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) -3 (hydroxymethyl ) phenyl) methanesulfonamide; (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) -3 (methoxymethyl) phenyl) methanesulfonamide; (E) -N- (4 (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) - 3 ((isopentylamino) methyl) phenyl) methanesulfonamide; N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) -3 - ((E) (methoxyimino) methyl) phenyl) methanesulfonamide; (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H ) -il) -2-methoxystyryl) -3- (oxazol-2 il) phenyl) methanesulfonamide; (E) -N- (4 (3-tert-Butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) -3- (1 H -imidazol- 2il) phenyl) methanesulfonamide; (E) tert-Butyl 2- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) -5- (methylsulfonamido) phenylcarbamate ; (E) -N- (3-amino-4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) phenyl) methanesulfonamide ; (E) -N- (4- (3-tert-Butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) -2-fluorophenyl) methanesulfonamide; (E) -N- (4 (3-tert-Butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxystyryl) -2-fluoro-5-methylphenyl ) methanesulfonamide; Methyl 2- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenethyl) -5- (methylsulfonamido) benzoate; N- (4- (3-tert-Butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -2-methoxyphenethyl) phenyl) methanesulfonamide; (E) -N- (4- (3-tert-Butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H-yl) -2-ethoxystyryl) phenyl) methanesulfonamide; (E) -N- (4- (1- (3-tert-Butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) prop-1-en-2yl) phenyl) methanesulfonamide; (Z) -N- (4- (3-tert-Butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxystyryl) phenyl) methanesulfonamide; (E) -N- (4- (3-tert-Butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxystyryl) phenyl) -N- (methylsulfonyl) acetamide; (E) -1- (3- (4-aminoestyryl) -5-tert-butyl-4-methoxyphenyl) dihydropyrimidin-2,4 (1H, 3H) -dione; (Z) -N- (4- (3-tert-Butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxystyryl) phenyl) methanesulfonamide; N- (4- (2- (3-tert-Butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methoxyphenyl) -1-fluorovinyl) phenyl) methanesulfonamide; (E) -1- (3-tert-Butyl-4-methoxy-5- (4-nitrostyryl) phenyl) dihydropyrimidin-2,4 (1H, 3H) -dione; 1- {3-tert-butyl-5 - [(Z) -2-chloro-2- (4-nitro-phenyl) -vinyl] -4-methoxy-phenyl-dihydropyrimidine-2,4-dione; 1- {3-tert-Butyl-4-methoxy-5 - [(E) -2- (4-nitro-phenyl) -propenyl] -phenyl} -dihydropyrimidin-2,4-dione; 1- {3-tert-Butyl-5 - [(E) -2- (4-nitro-phenyl) -vinyl] -phenyl} -dihydro-pyrimidin-2,4-dione; N- (4 - {(E) -2- [3-tert-Butyl-5- (dioxo-tetrahydro-pyrimidin-1-yl) -2-methoxyphenyl] -vinyl} -3-methoxyphenyl) -methanesulfonamide; N- (4 - {(E) -2- [3-tert-Butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxyphenyl] -vinyl} -3-formyl-phenyl) methanesulfonamide; N- [4 - {(E) -2- [3-tert-Butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxy-phenyl] - vinyl} -3- (hydroxyiminomethyl) -phenyl] methanesulfonamide; 2 - {(E) -2- [3-tert-Butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxy-phenyl] -vinyl} - 5-methanesulfonylamino-N- (2-methoxyethyl) -benzamide; 2 - {(E) -2- [3-tert-Butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxy-phenyl] ethyl ester -vinyl} -5methanesulfonylaminobenzoic acid; N- (4 - {(E) -2- [3-tert-Butyl-2-chloro-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -phenyl] - vinyl} -phenyl) -methanesulfonamide; 2 - {(E) -2- [3-tert-Butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxy-phenyl] -vinyl} - 5-methanesulfonylamino-N, N-dimethylbenzamide; 2 - {(E) -2- [3-tert-butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxy-phenyl] -vinyl} - 5-methanesulfonylamino-N-methylbenzamide; 2 - {(E) -2- [3-tert-butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxy-phenyl] -vinyl} - N- (1,1-dioxotetrahydro1lambda * 6 * -thiophene-3-yl) -5-methanesulfonylamino-N-methyl-benzamide; N- (4 - {(E) -2- [3-tert-butyl-5- (5-chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxyphenyl ] -vinyl} -phenyl) methanesulfonamide; 2 - {(E) -2- [3-tert-butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxy-phenyl] -vinyl} - 5-methanesulfonylaminobenzamide; N- (3- (azetidin-1-carbonyl) -4 - {(E) -2- [3-tert-butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1- il) -2-methoxy-phenyl] -vinyl} phenyl) -methanesulfonamide; 2 - {(E) -2- [3-tert-butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxy-phenyl] -vinyl} - 5-methanesulfonylamino-N- (2methoxyethyl) -N-methylbenzamide; N- (4 - {(E) -2- [3-tert-butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxy-phenyl] - vinyl} -3-isopropoxymethylphenyl) methanesulfonamide; N- [4 - {(E) -2- [3-tert-butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxy-phenyl] - vinyl} -3- (pyrrolidin-1-carbonyl) phenyl] -methanesulfonamide; N- [4-1 {(E) -2- [3-tert-butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxy-phenyl] -vinyl} -3- (3-hydroxy-azetidin-1-methylmethyl) -phenyl] -methanesulfonamide; N- (4 - {(E) -2- [3-tert-Butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxy-phenyl] - vinyl} -3-pyrrolidin-1-ylmethyl-phenyl) methanesulfonamide; N- (4 - {(Z) -2- [3-tert-Butyl-5- (2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl) -2-methoxy-phenyl] - vinyl} -phenyl) -methanesulfonamide; Y N- (4- (3-tert-Butyl-5- (2,4-dioxotetrahydropyrimidin-1 (2H) -yl) phenethyl) phenyl) methanesulfonamide.

12.

The compound or salt of claim 1, wherein the compound (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl)) -2-methoxystyryl) phenyl) methanesulfonamide.

13.

The salt of claim 1, wherein the salt is (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) ) -2-methoxystyryl) phenyl) methanesulfonamide, sodium salt.

14.

The salt of claim 1, wherein the salt is (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) ) -2-methoxystyryl) phenyl) methanesulfonamide, potassium salt.

15. The salt of claim 1, wherein the salt is (E) -N- (4- (3-tert-butyl-5- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) ) -25 methoxystyryl) phenyl) methanesulfonamide, monopotassium salt. 16. A composition comprising (a) one or more compounds and / or salts listed in any one of claims 1-15; (b) one or more excipients; and, optionally, (c) one or more additional therapeutic agents. 17. One or more compound and / or salts listed in any one of claims 1-15, and, optionally, one or more additional therapeutic agents, for use in the treatment of hepatitis C in a mammal in need of said treatment. .